Metabolic Acidosis in Inborn Errors of Metabolism and Hereditary Renal Tubular Acidoses: Approach

Applied acid–base physiology, high anion gap acidoses (lactic acidosis, ketoacidosis, organic acidurias, gluconeogenesis defects, ketone body transport defects, γ-glutamyl cycle defects, carbonic anhydrase VA deficiency, mitochondrial diseases), and normal anion gap acidoses (hereditary distal, proximal, and mixed renal tubular acidoses): diagnostic algorithm and emergency treatment.

Literature and regulatory information updated: 17 October 2026.

0. Reference Summary Table

0.1. Overview of the approach

0.2. Entities covered in depth

0.3. Related entities

1. Introduction

1.1. Metabolic acidosis as a gateway to inborn errors of metabolism

In metabolic paediatrics, metabolic acidosis is defined as a plasma bicarbonate below 18 mmol/L with a blood pH below 7.38, and it is one of the most common laboratory findings in the sick child [1]. In the great majority of cases the cause is acquired (infection, severe catabolic state, tissue anoxia, severe dehydration, intoxication), but these same conditions are also the usual triggers for decompensation of an as-yet unrecognised inborn error of metabolism, which is why a plausible acquired cause does not end the workup [1]. In IEMs, acidosis results from two mechanisms: accumulation of fixed anions (lactate, ketone bodies, organic acids, or combinations of these), with normal plasma chloride and an increased anion gap, or loss of bicarbonate, usually through renal tubular dysfunction, with elevated chloride and a normal anion gap [1]. The great majority of metabolic acidoses caused by IEMs have an increased anion gap, and the presence or absence of ketonuria is the main initial diagnostic clue [1]. Any patient with metabolic acidosis, and certainly one with an increased anion gap, should be regarded as possibly having a disorder of organic acid metabolism [9].

The clinical value of this approach rests on three facts. First, many of the diseases involved are treatable, and first-line therapeutic recommendations can be made within 2 to 4 hours using routine tests, without waiting for specialised investigations [1]. Second, the initial profile changes quickly: acidosis and ketosis may become moderate and transient under symptomatic treatment, and in advanced stages nonspecific changes appear (respiratory acidosis, severe hyperlactataemia, secondary hyperammonaemia) that obscure the original pattern [1]. Third, samples collected before treatment (plasma, urine, dried blood spots, cerebrospinal fluid) are often the only ones that allow a diagnosis, including after death [1, 37].

1.2. Historical milestones

The clinical description of acute neonatal and infantile metabolic acidosis as a manifestation of congenital lactic acidosis is credited to Hartmann and colleagues in 1962 [38]. The quantitative understanding of the respiratory response to metabolic acidosis is owed to Albert, Dell, and Winters, who in 1967 published the relationship between bicarbonate and PaCO2 known as Winter's formula [7, 8]. The oral ammonium chloride loading test to demonstrate the urinary acidification defect was described by Wrong and Davies in 1959 and remains the reference standard for incomplete distal RTA [2, 4].

Among the gluconeogenesis defects, fructose-1,6-bisphosphatase deficiency was described in 1970 by Baker and Winegrad in a girl with fasting hypoglycaemia and metabolic acidosis whose brother had died with a similar presentation; in 1971, Baerlocher and colleagues and Hülsmann and Fernandes described affected siblings from consanguineous unions [39, 40]. Pyruvate carboxylase deficiency was first described in 1968 by Hommes and colleagues in a patient with Leigh encephalopathy; the general association between PC deficiency and Leigh syndrome was later attributed to enzyme instability in autopsy material, since PC activity was preserved in six livers and five fibroblast cultures from patients with Leigh syndrome [14, 41]. Mitochondrial PEPCK deficiency, once described as an entity, is now considered a secondary phenomenon, and deficiency of the cytosolic isoform (PCK1) has been confirmed molecularly in recent series [32, 42].

Among the tubular acidoses, the autosomal recessive syndrome of osteopetrosis with RTA and cerebral calcification was recognised in 1972, and carbonic anhydrase II deficiency was identified as the primary defect by Sly and colleagues in 1983 in three sisters; in 1985 the same authors described 18 patients from 11 families of various origins, with virtual absence of the enzyme in haemolysates and intermediate levels in obligate heterozygotes [43, 44]. The association between sensorineural hearing loss and recessive distal RTA was described in 1971 [4]. The molecular basis of distal RTA was elucidated in sequence: heterozygous variants in the anion exchanger AE1 (band 3, SLC4A1) in the autosomal dominant form (Bruce and colleagues, 1997, four families); variants in the B1 subunit of the vacuolar H⁺-ATPase (ATP6V1B1) in the recessive form with hearing loss (Karet and colleagues, 1999), the first gene of this pump family to be linked to human disease; and variants in the a4 subunit (ATP6V0A4) in the recessive form initially described with preserved hearing (Smith and colleagues, 2000) [45–47]. Permanent isolated proximal RTA with ocular abnormalities was linked to SLC4A4 in 1999 [48]. In 2018, FOXI1, a transcription factor for the proton pump subunits, was added in a recessive form with hearing loss, and WDR72 in a recessive form with amelogenesis imperfecta [49, 50]. In 2025, a dominant-negative mechanism was demonstrated for specific variants at codon Arg394 of ATP6V1B1 [51].

Among the ketone body transporters, exome sequencing in a patient with severe recurrent ketoacidosis identified in 2014 a homozygous frameshift variant in SLC16A1, which encodes MCT1; among 96 patients with a suspected ketolysis defect, seven further inactivating variants, homozygous and heterozygous, were found, with severity proportional to mutational status [52].

1.3. Nomenclature and reclassification

The numerical classification of RTA remains in use: type 1 (distal, a defect of proton secretion in the collecting duct), type 2 (proximal, a defect of bicarbonate reabsorption), type 3 (mixed), and type 4 (hyperkalaemic, due to (pseudo)hypoaldosteronism) [4]. Type 3 was originally described in infants and probably referred to the transient proximal tubular dysfunction seen at presentation of recessive distal RTA; today it denotes the CA2-associated form, in which loss of carbonic anhydrase II, expressed in the proximal tubule and in type A intercalated cells, impairs both proximal bicarbonate reabsorption and distal proton secretion [4]. Type 4 RTA lies outside the scope of the ERKNet guideline and is treated as a differential [4, 53]. Hereditary distal RTA includes the "complete" form, with metabolic acidosis, and the "incomplete" form, with a urinary acidification defect without overt acidosis; the term "secretory-defect distal RTA" is also used [2].

PC deficiency is divided into three overlapping phenotypes: type A (infantile, North American), type B (severe neonatal, French, "complex"), and type C (intermittent, attenuated, "benign"), which form a continuum of decreasing severity from B to C [14, 54]. FBPase deficiency is also called Baker-Winegrad disease and, in older literature, fructose-1,6-diphosphatase deficiency [13, 40]. Pyroglutamic aciduria (5-oxoprolinuria) refers to urinary excretion of 5-oxoproline, which may be primary (glutathione synthetase deficiency) or secondary (paracetamol, amino acid infusion, urea cycle disorders) [35, 37]. The mnemonics for causes of high AG acidosis (DIMPLES, MUDPILES, GOLD MARK) remain useful for teaching but include IEMs as a single letter; the first explicitly includes "inborn error of metabolism," and the "mudpies" variant omits lactic acidaemia [8, 9].

1.4. Definition of the entities within scope

The hereditary high AG acidoses include primary lactic acidosis (defects of pyruvate oxidation, the Krebs cycle, the respiratory chain, and gluconeogenesis), the ketoacidoses (defects of ketolysis and ketone body transport), the organic acidurias, pyroglutamic aciduria due to glutathione synthetase deficiency, and the mixed acidosis of carbonic anhydrase VA deficiency, in which metabolic acidosis and respiratory alkalosis coexist [1, 15]. Hereditary distal RTA is defined as normal AG hyperchloraemic metabolic acidosis with an inappropriately high urine pH (>5.5) and a positive urine anion gap, without advanced chronic kidney disease or extrarenal bicarbonate loss, usually beginning in infancy or early childhood, and confirmed by biallelic variants in ATP6V0A4, ATP6V1B1, FOXI1, or WDR72, heterozygous or biallelic variants in SLC4A1, or heterozygous variants at codon Arg394 of ATP6V1B1 [2, 4, 55]. Proximal RTA is defined by renal bicarbonate wasting, with fractional excretion above 10–15% when plasma bicarbonate is normalised, and preserved urinary acidification below the reabsorption threshold; the isolated hereditary form is exceptional, and the usual form is part of renal Fanconi syndrome [2, 4, 56]. Osteopetrosis with RTA due to carbonic anhydrase II deficiency is the hereditary form of mixed RTA [4, 57].

2. Molecular Genetics and Pathophysiology

2.1. Principles of acid–base balance applied to inborn errors

Bicarbonate is a normal constituent of body fluids, with a plasma concentration of 24 to 31 mEq/L, and the ratio of carbonic acid to bicarbonate in extracellular fluid is normally 1:20; the kidney regulates this concentration by acidifying the urine when there is a deficit and alkalinising it when there is an excess, and in an adult with normal renal function less than 1% of filtered bicarbonate is excreted [58]. In clinical practice, bicarbonate measured as total CO2 in plasma and bicarbonate calculated from pH and PaCO2 on blood gas analysis are used interchangeably, because dissolved CO2 contributes only a small fraction of total CO2 [4].

The anion gap is the difference between the main plasma cation (Na⁺) and the main measured anions (Cl⁻ and HCO3⁻) and mainly reflects unmeasured anions, particularly anionic proteins such as albumin; it therefore varies with albumin concentration [4, 5]. When an organic acid is generated or administered, the proton is buffered by plasma bicarbonate and the accompanying anion remains in the circulation, with no concomitant change in Na⁺ or K⁺, which increases the anion gap [4]. In distal RTA, by contrast, failure of proton secretion in the collecting duct reduces the electrical gradient for Na⁺ reabsorption through the epithelial sodium channel (ENaC); the retained proton is buffered by bicarbonate, Na⁺ and HCO3⁻ are lost, and the resulting volume depletion stimulates Na⁺ and Cl⁻ reabsorption, so that the lost bicarbonate is replaced by retained chloride: the result is preserved sodium, increased chloride, and decreased bicarbonate, that is, normal AG hyperchloraemic acidosis [4].

Ammonia accumulation has the opposite effect to acid accumulation: hyperammonaemia by itself induces respiratory alkalosis by stimulating the respiratory centre, and this is the initial signature of urea cycle disorders, whereas the organic acidaemias combine hyperammonaemia with metabolic acidosis [1, 9]. In severe urea cycle defects, hyperammonaemia with initial respiratory alkalosis rapidly progresses to acidosis with nonspecific hyperlactataemia, which can mislead a late interpretation [1]. In CA-VA deficiency both mechanisms coexist, with respiratory alkalosis due to hyperammonaemia and metabolic acidosis due to accumulation of titratable organic acids, producing a complex acid–base picture [15].

2.2. Lactate, pyruvate, and redox state

Lactate dehydrogenase catalyses the reaction pyruvate + NADH + H⁺ ⇌ lactate + NAD⁺; lactate, pyruvate, and the lactate/pyruvate (L/P) ratio therefore reflect the cytoplasmic redox state (NADH/NAD⁺), and hyperlactataemia can result from increased pyruvate, an increased NADH/NAD⁺ ratio, increased H⁺ (acidosis), or combinations of these [1]. The 3-hydroxybutyrate/acetoacetate (3OHB/AcAc) ratio reflects the mitochondrial redox state [1]. The normal L/P ratio is about 10:1 and does not usually exceed 15; an elevated cytosolic ratio, often above 25, indicates an oxidative phosphorylation disorder, and an elevated L/P ratio without an elevated 3OHB/AcAc ratio indicates severe PC deficiency [37, 38].

Oxidative phosphorylation oxidises NADH and FADH2; in its absence the cell survives on anaerobic glycolysis, which is about 20 times less efficient and generates lactate, while accumulated pyruvate is transaminated to alanine [59]. Lactate and alanine act as "reservoirs" for accumulated pyruvate, which explains why large elevations of pyruvate are rare and why alanine, which does not rise as a sampling artefact, is a useful marker of true hyperlactataemia [37, 38]. Complete loss of OXPHOS is not seen in human systemic disease; there is always residual activity, which varies between tissues [59].

The pyruvate dehydrogenase complex (PDHc) comprises E1 (thiamine pyrophosphate dependent, with α and β subunits; the rate-limiting step, regulated by phosphorylation: the kinase inactivates it and the phosphatase activates it), E2 (lipoate dependent), E3 (shared by the three 2-ketoacid dehydrogenase complexes: PDHc, 2-ketoglutarate dehydrogenase, and branched-chain ketoacid dehydrogenase), and the E3-binding protein [42]. Dichloroacetate inhibits the E1 kinase and keeps the complex active, which is the rationale for its use to lower lactate [12, 42].

2.3. Ketone bodies and ketoacidosis

Serum ketone body concentrations reach 0.5–1 mmol/L in early neonatal life, but acetonuria in the newborn is always abnormal; ketonuria is physiologic during catabolism in late childhood and adolescence, and, as a general rule, hyperketosis above 6 mmol/L of total ketone bodies with bicarbonate <18 mmol/L is not physiologic [1]. Ketone bodies produced in the liver are taken up by peripheral tissues through MCT1; loss of function of this transporter impairs peripheral uptake and causes blood accumulation during catabolism, similar to the ketolysis defects [60]. MCT1 is also the most abundant lactate transporter in glia, which is related to the mild to moderate intellectual disability described in homozygotes and compound heterozygotes, and in some heterozygotes muscle lactate clearance is reduced to about 50% [60]. Ketosis of intercurrent illness raises acetoacetate, 3-hydroxybutyrate, 3-hydroxyisovalerate, 3-hydroxyisobutyrate, and dicarboxylic acids [9].

2.4. Organic acids

Many organic acidaemias are located in the catabolic pathways of the branched-chain amino acids downstream of the loss of the amino group, so the amino acids do not accumulate and the diseases are not detected by amino acid analysis; they are recognised by gas chromatography–mass spectrometry (GC-MS) of urine organic acids, and tandem mass spectrometry (MS/MS) of acylcarnitines has enabled newborn screening and shortened emergency diagnosis [9].

2.5. Gluconeogenesis and anaplerosis

Glucose sources vary with the duration of fasting: food in the postprandial period (up to about 2.5 h), glycogenolysis in short fasting (2.5–8 h), declining glycogenolysis and rising gluconeogenesis (8–15 h), and gluconeogenesis in prolonged fasting (more than 15 h), with variation according to age and nutritional status [1]. The enzymatic defects of gluconeogenesis (FBPase, PEPCK-C, glucose-6-phosphatase) are characterised by hypoglycaemia and hyperlactataemia that move in the opposite direction to blood glucose and peak during fasting, with lactate that can reach 15 mmol/L [1, 37].

Pyruvate carboxylase. PC is a biotinylated, homotetrameric mitochondrial enzyme, with highest expression in the liver and kidney, that converts pyruvate and CO2 into oxaloacetate; it takes part in gluconeogenesis, lipogenesis, and above all anaplerosis of the Krebs cycle, which is required for the synthesis of glutamate and γ-aminobutyric acid (GABA) [14, 54]. Lack of Krebs cycle intermediates reduces reducing equivalents in the mitochondrial matrix (low 3OHB/AcAc ratio); lack of aspartate impairs the malate–aspartate shuttle (high L/P ratio) and the urea cycle (elevated ammonia and citrulline); lack of 2-ketoglutarate lowers glutamate and glutamine; and deficient lipogenesis explains the demyelination and periventricular cavities [54]. Secondary PC deficiency occurs in biotin-responsive multiple carboxylase deficiency and in CA-VA deficiency [54].

Cytosolic phosphoenolpyruvate carboxykinase. PEPCK-C, encoded by PCK1, converts oxaloacetate into phosphoenolpyruvate; its deficiency causes fasting hypoglycaemia with hyperlactataemia, low ketones, and increased excretion of fumarate and succinate [32, 42]. Phenotype does not track genotype, and environmental factors (infection, fasting, strenuous exercise, alcohol, breastfeeding) determine clinical expression [32].

Fructose-1,6-bisphosphatase. Only the hepatic isoform (FBP1) has been characterised as a cause of disease; the muscle isoform, encoded by a different gene, is not affected [40, 61]. Without FBPase activity, normoglycaemia depends solely on glucose or galactose intake and on liver glycogen, and hypoglycaemia occurs when stores are limited (newborn) or exhausted (fasting) [61]. Lactate, pyruvate, alanine, and glycerol accumulate; the L/P ratio rises because of secondary impairment of the conversion of 1,3-bisphosphoglycerate to glyceraldehyde-3-phosphate, with NADH accumulation; and ketosis is absent in some patients because pyruvate converted to oxaloacetate and acetyl-CoA is diverted to citrate, whose increase raises malonyl-CoA and inhibits carnitine palmitoyltransferase I [61]. Activation of the pentose phosphate pathway generates ribose-5-phosphate, a precursor of uric acid, which explains the hyperuricaemia [13]. Metformin inhibits FBPase, reduces hepatic glucose output, and increases the propensity to lactic acidosis [61]. Patients tolerate up to 2 g of fructose/kg/day spread over the day, but a single dose above 1 g/kg is harmful [13, 61].

2.6. The γ-glutamyl cycle and 5-oxoproline

In glutathione synthetase deficiency, low glutathione (GSH) removes feedback inhibition of γ-glutamylcysteine synthetase; excess γ-glutamylcysteine is converted to 5-oxoproline by γ-glutamyl cyclotransferase in amounts that exceed the capacity of 5-oxoprolinase, resulting in metabolic acidosis and 5-oxoprolinuria [35]. In 5-oxoprolinase deficiency, urinary 5-oxoproline reaches 4–10 g/day, but GSH and acid–base balance are normal, and the biochemical condition appears benign [35].

2.7. Urinary acidification and the pathogenesis of the tubular acidoses

Between 80% and 90% of filtered bicarbonate is reabsorbed in the proximal tubule and the remainder mainly in the thick ascending limb of the loop of Henle; complete reabsorption lowers urine pH to about 6, and it is distal proton secretion that lowers it to 4.5–5.5 [4]. In the type A (α) intercalated cell of the connecting tubule and collecting duct, the proton, generated from CO2 and H2O by carbonic anhydrase II, is secreted into the lumen by the apical vacuolar H⁺-ATPase, which includes the B1 (ATP6V1B1) and a4 (ATP6V0A4) subunits, and bicarbonate returns to the blood through the basolateral AE1 exchanger (SLC4A1); FOXI1 is the transcription factor required for expression of the B1 and a4 subunits, and WDR72 probably takes part in membrane protein trafficking and binds proton pump subunits [2, 4]. The B1 and a4 subunits are also expressed in the inner ear (cochlea and endolymphatic sac), which explains the sensorineural hearing loss [2, 46]. FOXI1 is expressed mainly in acid-secreting epithelia (kidney, inner ear, epididymis) [4].

Hypokalaemia, often below 3.0 mmol/L before treatment, results from two mechanisms: acidosis reduces proximal Na⁺ reabsorption, with volume contraction and activation of the renin–angiotensin–aldosterone system, and Na⁺ uptake through ENaC without compensatory proton secretion creates an electrical gradient that favours K⁺ secretion [4]. Hypercalciuria results from bone buffering of the acidosis (with release of calcium, phosphate, and bicarbonate from hydroxyapatite), tubular resistance to parathyroid hormone, and reduced expression of the TRPV5 channel in animal models; acidosis increases proximal citrate reabsorption by the NaDC1 cotransporter (SLC13A2), causing hypocitraturia, and high urine pH favours calcium phosphate precipitation, which explains the nephrocalcinosis and nephrolithiasis [2, 4]. Patients with medullary nephrocalcinosis have a urinary concentrating defect (median maximal urine osmolality of 340 mOsm/kg in 12 patients), with increased risk of dehydration during vomiting or diarrhoea [4]. Nephrocalcinosis is absent on prenatal ultrasound because the placenta eliminates fetal acid [4]. Infants with severe untreated acidosis develop transient proximal tubular dysfunction (low-molecular-weight proteinuria, aminoaciduria and, less often, phosphaturia), which resolves with alkali and potassium treatment; glycosuria has never been described in this transient dysfunction [4].

Through alternative splicing, SLC4A1 produces two isoforms: the erythroid isoform (band 3) and the shorter renal isoform, which lacks part of the amino-terminal domain [4]. Most variants cause either distal RTA or an erythrocyte abnormality (Southeast Asian ovalocytosis, hereditary stomatocytosis, hereditary spherocytosis), and combined disease typically arises when one allele carries a haemolytic variant and the other a distal RTA–associated variant; the haemolytic anaemia worsens with systemic acidosis [4]. The autosomal dominant SLC4A1 form and the form linked to codon Arg394 of ATP6V1B1 act through a dominant-negative mechanism; in the latter, structural modelling places residue Arg394 in the nucleotide-binding site [2, 51]. The recessive forms result from loss of function [2].

In the proximal tubule, the basolateral sodium–bicarbonate cotransporter NBCe1 (SLC4A4) returns reabsorbed bicarbonate to the blood; its loss of function causes permanent isolated proximal RTA, with ocular abnormalities (band keratopathy, glaucoma, cataract) and enamel defects [4, 48]. Carbonic anhydrase II is expressed in the proximal tubule and in type A intercalated cells, so its deficiency impairs both proximal bicarbonate reabsorption and distal proton secretion (mixed RTA), and also affects bone resorption by osteoclasts (osteopetrosis) [4, 57].

2.8. Genes, transcripts, and inheritance

Transcripts, cytobands, and gene OMIM numbers are according to HGNC [2, 62]. Secondary sources differ for some cytobands: ATLAS places PC at 11q13.4–13.5 and FBP1 at 9q22.2–22.3, and the skeletal dysplasia atlas places CA2 at 8q22; current HGNC nomenclature takes precedence [40, 41, 57, 62].

2.9. Variant spectrum, historical nomenclature, and founder variants

The following variants were normalised in VariantValidator against the MANE Select transcript and the GRCh38 genome [63]. Nomenclature from older sources is not converted manually; where historical notation is incompatible with the reference sequence, the inconsistency is flagged.

More than 50 variants have been described in FBPase deficiency, and some patients have no identified coding variant, which has led to the hypothesis of promoter alterations or of alterations in the bifunctional fructose-2,6-bisphosphate enzyme [61]. ATLAS also lists other variants in older nomenclature (for example, "G620R" in a protein of 338 amino acids), which are not reproduced here because they are incompatible with the reference sequence [40]. More than 30 variants have been described in GSS deficiency, about 40% of them splicing variants, which justifies supplementing genomic analysis with RNA studies [35]. In CA-VA deficiency, a family with a homozygous 4-kb deletion of exon 6 and no hepatic protein did not have a more severe phenotype [15].

2.10. Genotype–phenotype correlations, penetrance, and modifiers

Distal RTA. RTA due to ATP6V0A4 is associated with more severe acidosis and later-onset hearing loss; the biallelic ATP6V1B1 form begins in infancy, with hearing loss also in infancy; FOXI1 is associated with early hearing loss; SLC4A1 causes the mildest form, often with compensated acidosis (low bicarbonate with normal pH), onset in childhood or later, and less impact on growth; WDR72 is associated with amelogenesis imperfecta [2]. Hearing loss occurs in about 90% of patients with ATP6V1B1 and about 40% with ATP6V0A4, and the need for hearing aids or a cochlear implant is greater and earlier with ATP6V1B1 (about 70% vs 25%) [4]. In the dominant ATP6V1B1 form (codon Arg394), hearing loss occurred in 8 of 22 patients with available data, a lower proportion than in the recessive form [51]. Beyond these trends, GeneReviews identifies no clinically relevant genotype–phenotype correlations [2]. Incomplete distal RTA has been described in some heterozygotes for variants in SLC4A1, ATP6V1B1 (outside codon Arg394), and ATP6V0A4 [2, 4]. The AD SLC4A1 form predominates in European patients and the AR form in Asian patients [4].

PC deficiency. At least one truncating variant tends to be associated with type B, whereas biallelic missense and intronic variants are more often associated with types A and C, with exceptions [14, 54]. There is no significant correlation between phenotype and residual activity, although undetectable activity or activity below 2% is more often associated with type B; activity in fibroblasts is below 5% in all phenotypes and does not distinguish them [14, 54]. The 125-kDa protein band is present in the mild forms and absent in the severe neonatal form, and messenger RNA was absent in 4 of 6 patients with the fatal form [41]. Mosaicism has been described in a few patients and was associated with prolonged survival [54].

PEPCK-C deficiency. In a systematic review of 32 patients from 25 families with 9 PCK1 variants, phenotype did not track genotype [32]; the asymptomatic 12-year-old sister of a patient with acute liver and kidney failure, carrying the same genotype, illustrates variable penetrance and expressivity [68].

MCT1 deficiency. The severity of ketoacidosis correlated with mutational status, protein level, and transport capacity, and heterozygotes can also have ketoacidosis [52]. Heterozygous relatives carrying the same variant as the index case are often asymptomatic, which points to additional factors; the myopathic form described is exclusively autosomal dominant [60].

GSS deficiency. Splicing, frameshift, and premature termination variants are associated with the moderate and severe forms, and the mild forms result from variants affecting enzyme stability; carriers have about 55% of normal activity and normal GSH [35].

CA-VA deficiency. Most patients are homozygous, in a context of consanguinity, and asymptomatic individuals with biallelic variants have been identified, so genotype does not reliably predict clinical expression [15].

2.11. Allelic disorders

No allelic disorders have been described for FBP1 or PC [13, 14]. Variants in SLC4A1 and ATP6V1B1 illustrate the distinction between a dominant-negative effect and loss of function: the same gene can show dominant or recessive inheritance depending on the variant, which has direct consequences for counselling (section 8) [2, 51].

3. Clinical Spectrum and Manifestations by System

3.1. Common manifestations of metabolic acidosis

The classic presentation of disorders of organic acid metabolism occurs in infancy, often in the neonatal period, followed by recurrent decompensations precipitated by infection: vomiting, anorexia, rapid deep (Kussmaul) breathing, ketotic odour, and lethargy progressing to coma or seizures; hypothermia may be the only manifestation besides feeding refusal and lethargy, and apnoea can lead to death without ventilation [9]. Recurrent dehydration in IEMs results from polyuria (organic acidurias), hyperventilation (severe acidosis or alkalosis), or sweating (cystic fibrosis), and ketoacidoses with polyuria, polypnoea, hyperglycaemia, and glycosuria mimic diabetic coma [1]. Propionic, methylmalonic, and isovaleric acidaemias can cause granulocytopenia and thrombocytopenia through bone marrow suppression, which may be mistaken for sepsis, and neutropenia, with or without thrombocytopenia, is characteristic of the organic acidaemias [1, 9]. Hypocalcaemia and high or low blood glucose are common in IEMs, but marked neurologic dysfunction should not be attributed to these findings alone [1].

A normal blood pH does not exclude hyperlactataemia: neutrality is generally maintained up to a lactate of about 6 mmol/L, while bicarbonate remains above 18 mmol/L [1]. Pulmonary hypertension can develop in chronic lactic acidosis and can be a cause of death [38]. In tubular acidosis the picture is chronic: growth failure, anorexia, polydipsia, and polyuria, with early-onset hyperchloraemic acidosis and alkaline urine pH [1].

3.2. High anion gap acidosis: clinical groups

Intoxication-type diseases with ketoacidosis. The branched-chain organic acidurias present with neurologic deterioration and ketoacidosis after a symptom-free interval of 1 to 3 days, rapid abnormal movements, dehydration, moderate to marked hyperammonaemia, and bone marrow suppression, and in the neonatal period they are almost always accompanied by hyperammonaemia; in maple syrup urine disease, by contrast, there is ketosis without significant metabolic acidosis, after a symptom-free interval of 4 to 8 days [1, 12]. The mild forms (pH >7.20, bicarbonate >15 mmol/L, dehydration <10% of birth weight, ammonia <400 µmol/L, and normal glucose, lactate, calcium, and blood count) comprise acidemias recognized early or through newborn screening; the severe forms with diagnosis delayed by a few days show severe ketoacidosis (pH <7.10, bicarbonate <10 mmol/L), dehydration >10%, hyperammonaemia >400 µmol/L, mild hyperlactataemia (<5 mmol/L), hypo- or hyperglycaemia, hypocalcaemia, leukopenia, and thrombocytopenia [12].

Energy deficiency with nonketotic acidosis. Fatty acid oxidation and ketogenesis defects cause acidosis with absent ketones, hypoketotic hypoglycaemia, hepatic or cardiac signs, and variable hyperammonaemia [1].

Primary hyperlactataemia. Defects of pyruvate oxidation, the Krebs cycle, the respiratory chain, and lipoylation present with polypnoea and hypotonia, sometimes with surprisingly well tolerated lactic acidosis, variable ketosis, and elevated lactate [1]. Congenital lactic acidosis manifests in the neonatal period with tachypnoea and a nonspecific sepsis-like picture and can be associated with Leigh syndrome and multisystem involvement (cardiomyopathy, renal tubulopathy) [59]. Mitochondrial forms with neonatal lactic acidosis include Pearson syndrome (lactic acidosis and transfusion-dependent sideroblastic anaemia soon after birth, with high mortality in the first 5 years from liver failure or fulminant acidosis, and renal tubulopathy in survivors), the hepatocerebral (DGUOK, POLG, TWNK, MPV17, SUCLG1) and myopathic (TK2) mitochondrial DNA depletion syndromes, the encephalomyopathic forms due to SUCLA2 and SUCLG1 with mild methylmalonic aciduria, "benign reversible" mitochondrial myopathy due to m.14674T>C/G in MT-TE (profound weakness and severe lactic acidosis in the first weeks, with recovery from 6 months of age), and the 3-methylglutaconic acidurias (TMEM70, Barth and Sengers syndromes) [59]. TMEM70 deficiency (48 patients) presents in the neonatal period or infancy with poor feeding, hypotonia, lethargy, respiratory and heart failure, cardiomyopathy, sometimes pulmonary hypertension, severe lactic acidosis, 3-methylglutaconic aciduria, and hyperammonaemia [12, 74]. Severe neonatal hepatic presentation of lactic acidosis, usually fatal, occurred in 9 of 22 patients in one series [38]. Severe acquired thiamine deficiency (Shoshin beriberi, preterm infants on parenteral nutrition without B-complex vitamins, oncology patients) causes acute heart failure and severe lactic acidosis with electrolyte disturbances similar to those of refeeding syndrome [12, 75].

3.3. Pyruvate carboxylase deficiency

Pyruvate carboxylase deficiency is a cause of primary hyperlactataemia with metabolic acidosis.

About 75 patients have been described, most with type A or B, and about 15 with type C [14]. GeneReviews summarises the natural history as follows: type A begins between birth and 10 months and usually leads to death in early childhood, although survival beyond 5 years has been described; type B begins on days 1 to 3 and leads to death in the neonatal period or by 8 months; type C begins between 3 months and 2 years, with unknown life expectancy and long survival described [14].

Type B (severe neonatal, French). Acute illness 3 to 48 hours after birth, with hypothermia, hypotonia, lethargy, vomiting, respiratory failure, and neurologic deterioration with rigidity, hypokinesia, and high-amplitude tremor (infantile parkinsonism), abnormal eye movements, hyporeflexia, pyramidal signs, dyskinesia, seizures, and hepatomegaly [14, 54]. Most die in the neonatal period with severe lactic acidosis, intractable tubulopathy, and multiorgan failure, mainly hepatic; survivors usually die before 5 months from respiratory infection [54]. The reported causes of death are RTA unresponsive to massive bicarbonate replacement and multiorgan failure, and liver histology shows ballooning degeneration of hepatocytes [14]. In the largest series (9 patients), all had axial hypotonia, hypokinesia, high-amplitude movements, white matter hyperintensity and periventricular cysts on magnetic resonance imaging (MRI), lactic acidaemia, tachypnoea, elevated transaminases, and hepatomegaly, with coagulopathy and liver failure in some and dysmorphic features (epicanthus, long philtrum, thin upper lip) [41]. The dominant abnormality is ketoacidosis with massive ketonuria [41]. The complex form has been observed in North American, Egyptian, and Saudi patients [41].

Type A (infantile, North American). Severe illness between 2 and 5 months of age, with progressive hypotonia, episodes of vomiting, dehydration, tachypnoea or Kussmaul breathing, pallor, cold cyanotic extremities, and lactic acidosis precipitated by stress; pyramidal signs, ataxia, nystagmus, epilepsy or epileptic encephalopathy, dysarthria, hepatomegaly or hepatosplenomegaly, and renal dysfunction with tubular acidosis; intellectual disability is severe in all [14, 54]. Episodes combine lactic acidosis with compensated metabolic acidosis, and gastrostomy is required in some patients [14]. Patients surviving into adolescence or early adulthood with varying degrees of cognitive impairment have been described, as has a patient with uncontrollable acidosis despite haemodialysis [14]. In ATLAS, the "simple" form common in Amerindians includes episodes of lactic acidosis in the first 6 months or developmental delay, macrocephaly, and subdural effusions, and it has also been described in Saudi Arabia, in White North Americans, and in Japan; one patient with this form had proximal RTA, mild acidosis not evaluated between 5 and 9 months, lactate of 6.5 mmol/L at 9 months, microcephaly, severe disability, sudden episodes of lactic acidosis with tachypnoea and patchy cyanosis of the extremities, and died at 46 months from pneumonia and severe acidosis [41].

Type C (intermittent, "benign"). Normal or mildly delayed motor development, with mild intellectual disability, autism with stereotypies, broad-based or toe walking, exertional dyspnoea, seizures, and acute episodes of lactic acidosis and ketoacidosis that respond rapidly to hydration and bicarbonate; dystonia, episodic ataxia, dysarthria, transient hemiparesis, and subcortical leukodystrophy may occur [14, 54]. Initial presentations mimicking diabetic ketoacidosis, transient acute flaccid paralysis with ketoacidosis in a healthy 11-month-old girl, and survival into adulthood have been described [14].

Neuroimaging. All three types may show T2 white matter hyperintensity, choroid plexus cysts, and cystic dilatation of the lateral ventricles; types A and B show periventricular or caudothalamic groove cysts, periventricular leukopathy, diffuse white matter oedema, atrophy or agenesis of the corpus callosum, brainstem hypoplasia, cortical atrophy, periventricular infarcts, subdural haematomas of different ages, subarachnoid haemorrhage, and abnormal myelination, and MR spectroscopy shows lactate peaks in the frontal white matter and basal ganglia [14]. The brain abnormalities are prenatal: they have been described in fetuses homozygous for p.(Ala610Thr) and, on day 10 of life, in Ojibwa/Cree patients; fetal ultrasound or MRI shows abnormal frontal horns with subependymal or paraventricular cysts [14, 54]. Cystic periventricular leukomalacia at birth together with lactic acidosis is highly suggestive [54].

Biochemistry by type. The table reproduces the blood findings described in GeneReviews (reference values vary between laboratories) [14].

The European reference textbook gives values from another series: in type B, lactate of 10–20 mmol/L (normal <2.2), L/P of 50–100 (normal <15), ammonia of 100–600 µmol/L (normal <50), and citrulline of 100–400 µmol/L (normal <40) consistently; in type A, lactate of 2–10 mmol/L with a normal or moderately increased L/P (<50) and alanine of 500–1400 µmol/L (normal <450) in all; in type C, lactate that may be normal and rises, usually above 10 mmol/L, during episodes; and a 3OHB/AcAc ratio below 2 (normal 2.5–3) [54]. The two sources use different reference intervals for the redox ratios, so each value must be interpreted against the interval of the laboratory that produced it [14, 54]. Overnight blood glucose is usually normal and hypoglycaemia appears during acute episodes; lactate rises with fasting and falls after carbohydrate; aspartate is very low during crises; cholesterol and mevalonate may rise in types A and B; and in cerebrospinal fluid (CSF), lactate, the L/P ratio, and alanine are high and glutamine is low [54].

3.4. Fructose-1,6-bisphosphatase deficiency

About half of patients present on days 1 to 4 of life with severe hyperventilation due to profound lactic acidosis and marked hypoglycaemia; most have their first episode before 6 months, with exceptions up to 4 years [40, 61]. The neonatal crisis progresses rapidly from irritability to somnolence, coma, apnoea, and cardiac arrest, with tachycardia, hepatomegaly, hypotonia, and an abnormal electroencephalogram; neonatal hyperbilirubinaemia requiring exchange transfusion in 3 infants and haematemesis have been described [40]. Subsequent crises are triggered by fever with feeding refusal and vomiting, fasting, or ingestion of a large amount of fructose (about 1 g/kg in a single dose), especially after fasting; most patients have several crises, often 4 to 5, before diagnosis [13, 61]. Patients are well between crises, although mild intermittent or chronic acidosis may persist; the frequency of crises decreases with age and most survivors have normal development [61]. Unlike hereditary fructose intolerance, there is no aversion to sweets, no growth failure, and no proximal tubular dysfunction after fructose, and chronic liver dysfunction is exceptional; transient liver dysfunction (elevated transaminases) and hepatomegaly resolve without specific treatment, and at least one patient has had elevated creatine kinase (possible rhabdomyolysis) [13, 40, 61].

During a crisis, lactate reaches 15–25 mmol/L, with low pH, an L/P ratio of up to 40, hyperalaninaemia, increased glycerol (which can mimic hypertriglyceridaemia), glucagon-resistant hypoglycaemia, a possible increase in free fatty acids and uric acid, and in urine lactate, alanine, glycerol and, in most cases, ketones and glycerol-3-phosphate [61]. GeneReviews defines the thresholds of a crisis: hypoglycaemia below 40 mg/dL in the newborn and below 60 mg/dL in older infants, children, and adults; lactate above 4 mmol/L; pH below 7.35; bicarbonate below 20 mmol/L; uric acid above 5.0 mg/dL [13]. Ketosis is a point of divergence between sources: the European reference textbook describes moderate or absent hyperketonaemia in several patients, ATLAS reports a frequently positive urine test during crises despite the historical classification among the hypoketotic causes, and GeneReviews describes episodes of lactic acidosis with ketotic hypoglycaemia as well as patients with normal to low ketones [13, 40, 61]. Without treatment, the disease progresses to multiorgan failure (liver, brain, and then heart), with sepsis, blindness, and Reye-like presentations [13]. Some patients are left with brain injury and intellectual disability from prolonged early hypoglycaemia, and obesity due to carbohydrate overtreatment is common [13]. Crises in adults are rare but have been described, and the UK adult protocol lists triggers such as infection, prolonged fasting, excess alcohol, diarrhoea, and vomiting, with liver or kidney injury described during crises [13, 76]. Recent series of patients from Egypt and Turkey confirm the pattern: in 14 Egyptian children (2022–2024), median onset was at 13 months (first week to 36 months), with lactic acidosis in all and hypoglycaemia in 13 of 14, two neonatal deaths, and normal neurodevelopment in the rest; in 6 Egyptian female patients, presentation occurred at a mean of 22.8 months and diagnosis at 62 months, a mean delay of about 3 years; and in a Turkish series of 10 patients with continuous glucose monitoring, asymptomatic hypoglycaemia was detected despite uncooked cornstarch [65, 77, 78]. In a series of 18 patients published in 2022, patients presented with fasting hypoglycaemia and lactic acidosis, with liver abnormalities and steatosis in adulthood [61].

3.5. Cytosolic PEPCK deficiency

In the Finnish national series of 24 patients (21 children and 3 adults) diagnosed between 2016 and 2019, all carrying the founder allele c.925G>A, the profile was consistent: fasting hypoglycaemia, hyperlactataemia, low ketones, and increased excretion of fumarate and succinate, with predominantly morning episodes [32, 42]. The first episode often occurred between 1 and 2 years of age but can appear or recur at school age or in adulthood; five patients had neonatal hypoglycaemia and 12 of 24 had hypoglycaemic seizures [32]. Liver involvement ranges from mildly elevated transaminases to acute liver failure, including a post-gastroenteritis case that mimicked a urea cycle disorder and a mitochondrial disease; a healthy 3-year-old boy died on day 5 of a respiratory infection with an apparent febrile seizure, hypoglycaemia, and cerebral oedema [32]. In 2026 an 8-year-old child was described with transient acute liver and kidney failure, very high glutamine, and reversal with continuous glucose [68]. In the six patients described in the reference textbook, neurodevelopment was normal [42].

3.6. Ketoacidosis due to MCT1 deficiency

MCT1 deficiency should be considered in recurrent episodes of ketoacidosis with hyperventilation or cyclic vomiting, typically from the first years of life, with severe acid–base imbalance induced by infection or fasting and normal or borderline blood glucose; some patients have cramps, stiffness, or exertional fatigue, with episodes of elevated creatine kinase and rhabdomyolysis, and normal electromyography and muscle histology between episodes [60]. Hypoglycaemia is not typical, although it can occur [60]. The 2026 systematic review gathered 8 patients from 6 countries, with onset between 2 months and 6 years; the index case of that publication, a 5-year-old Egyptian boy with a homozygous variant, had high AG acidosis with pH 6.8 and bicarbonate of 5.2 mmol/L, with normal glucose, lactate, and ammonia [79]. Prognosis is generally favourable with early diagnosis [60].

3.7. Glutathione synthetase deficiency and pyroglutamic aciduria

GSS deficiency is the most common inborn error of glutathione metabolism, with more than 80 patients described, and it has three forms: mild, with only mild haemolytic anaemia and no 5-oxoprolinuria; moderate, of neonatal onset, with severe chronic metabolic acidosis, mild to moderate haemolytic anaemia, jaundice, and 5-oxoprolinuria, with stabilisation but a risk of critical illness during infections (marked acidosis and electrolyte imbalances, with several deaths in such episodes); and severe, with progressive central nervous system symptoms (intellectual disability, seizures, spasticity, ataxia, intention tremor), recurrent bacterial infections due to granulocyte dysfunction, and ophthalmologic abnormalities [35]. Prenatal or perinatal cerebral haemorrhage has been described, and in 2026 a Turkish newborn with intrauterine periventricular cystic lesions, severe haemolytic anaemia, metabolic acidosis, and dilated cardiomyopathy required exchange transfusion and peritoneal dialysis for refractory hyperbilirubinaemia and acidosis [35, 80].

3.8. Carbonic anhydrase VA deficiency

CA-VA deficiency presents between day 2 of life and 20 months with hyperammonaemic encephalopathy (lethargy, feeding intolerance, weight loss, tachypnoea, seizures, coma), with markedly elevated ammonia, lactate, and ketones, possible hypoglycaemia, and a mixed acid–base disturbance; outside crises, parameters are usually normal apart from mildly elevated lactate or ketonuria, and transaminases, albumin, and coagulation are normal [15]. Almost all patients have normal development and no further crises; four had mild learning difficulties or motor delay [15]. The first two patients described, siblings homozygous for p.(Ser233Pro), were 16 and 14 years old in 2026, with normal growth, development, and neurologic examination; the sister had three further decompensations with intercurrent illnesses, the last at 8 years of age [69]. In a series of 9 patients from 5 centres, median onset was on day 3 (interquartile range 2.5–48.5), 77% had a single crisis, outcome was favourable in 55.5%, and there was moderate to severe neurologic impairment in 44.4%; all had MRI abnormalities, with a pattern similar to that of urea cycle disorders (insular and peri-insular, perisylvian, and perirolandic cortex) in the favourable group and extensive involvement of the thalamus, basal ganglia, and brainstem in the unfavourable group [81]. The first cases in Israel, in a Bedouin family with a novel missense variant, included one patient who required urgent haemodialysis and a sibling with a mild episode, both with normal development [82].

3.9. Hereditary distal renal tubular acidosis

Presentation by age. The table reproduces the presenting symptoms from the ERKNet/ESPN guideline [4].

Up to two-thirds of infants and children have additional proximal tubular dysfunction, which resolves with treatment, and almost all patients have metabolic acidosis and hypokalaemia at presentation, except for some adults with the secondary form and impaired acidification without acidosis (incomplete form) [4]. The recessive forms typically present in the first year with growth failure; in the dominant SLC4A1 form the median age at presentation is 2 to 12 years, and the youngest patients are often detected through family screening [4]. At presentation, blood pH ranges from 6.7 to 7.4 and bicarbonate from 5 to 20 mmol/L, with correspondingly elevated chloride, and acidosis is typically more pronounced in the recessive forms [4].

Kidney. Nephrocalcinosis or urolithiasis occurs in about 65% of patients with distal RTA of any cause and in 90–100% of patients with the primary form; in a mostly European cohort of 340 patients, more than 90% of those with molecular confirmation had nephrocalcinosis, which increased with age and with later initiation of alkali therapy [2, 4, 83]. Nephrocalcinosis is usually present at presentation but may be absent in the dominant form detected early through family screening [4]. Nephrolithiasis occurs in about 20% of patients with the primary form and in 42% of those with SLC4A1 variants, with calcium phosphate stones predominating [4]. Medullary cysts, probably related to hypokalaemia, can develop, including a picture resembling medullary sponge kidney [2]; renal cysts have been described in a child with a WDR72 variant [71]. Mild to moderate reduction in glomerular filtration rate (GFR) increases with age and may be present in childhood, and stage 2–3 chronic kidney disease (CKD) is more prevalent and occurs earlier than in the general population [2, 4]. In the European registry (214 patients, 2019–2024), the overall prevalence of CKD stage 2 or higher was 36%, patients older than 30 years had a significantly lower estimated GFR, and SLC4A1 variants were associated with a higher risk of CKD beyond stage 1 [23].

Potassium and muscle. Hypokalaemia is more severe in the ATP6V1B1 and ATP6V0A4 forms than in the dominant SLC4A1 form, and paralysis and respiratory depression can occur with severe hypokalaemia [2]. Hypokalaemic paralysis is more frequent in the form secondary to Sjögren syndrome [4].

Bone and growth. Acidosis releases bicarbonate and phosphate from bone and causes rickets in children and osteomalacia in adults (10–23% of adults in one series) [2]. In an Indian series of 72 patients aged 18 years or younger with non-nutritional rickets and normal renal function, 34 (47%) had distal RTA, with variants identified in 14 [2]. In a Thai study, 14 newly diagnosed adults all had osteopenia or osteoporosis with low bone turnover before alkali therapy, and the 10 who were reassessed improved significantly after 1 year of treatment [4]. Most patients have short stature before adequate alkali therapy, and with adequate treatment catch-up to normal height is common; acidosis interferes with growth hormone secretion and lowers IGF-1, without primary growth hormone deficiency [2, 4]. In the European registry, height (in standard deviations) was positively associated with serum bicarbonate and early diagnosis [23]. Asian cohorts with late diagnosis show a less favourable course: in a Mumbai cohort with a mean follow-up of 14.8 years, mean final height was −3.0 standard deviations and 33.9% still had bone deformities; in the Indian registry, short stature affected 75.8% (median −3.6 standard deviations), and rickets predominated in the SLC4A1 forms [25, 70].

Hearing. The sensorineural hearing loss associated with ATP6V0A4, ATP6V1B1, and FOXI1 can be profound and is not prevented by medical treatment [2]. It has not been described with WDR72, and with SLC4A1 its frequency (about 10% in two large studies) is similar to that in the general population [4]. Computed tomography of the inner ear shows an enlarged vestibular aqueduct in cases with hearing loss [2].

Blood and teeth. Haemolytic anaemia with biallelic SLC4A1 variants is most frequent in Southeast Asia and also occurs in the Middle East and India; in a series of 78 patients, haemoglobin ranged from 4.4 to 15.7 g/dL, and alkali therapy corrects the anaemia and reticulocytosis [2]. The Mumbai cohort associated biallelic SLC4A1 p.(Ala858Asp) with increased erythrocyte osmotic fragility and haemolytic anaemia [25]. The WDR72 form presents between 4 and 12 years of age, sometimes through the amelogenesis imperfecta, with RTA detected by reverse phenotyping; amelogenesis imperfecta can also accompany CLDN16, CLDN19, SLC4A4, and FAM20A, which can phenocopy distal RTA [4].

Incomplete form. Incomplete distal RTA is defined as an inability to acidify urine below 5.5 without overt acidosis, mainly in adults; its prevalence is 2–19% in patients with urolithiasis and 22% in adults with idiopathic low bone mineral density [4]. The form secondary to autoimmune disease affects 10–30% of patients with Sjögren syndrome, often in incomplete form, and is about ten times more prevalent than the primary form in an insured North American population [4].

3.10. Hereditary proximal RTA and mixed RTA

Isolated hereditary proximal RTA is extremely rare; only two families with an apparently isolated form and no identified genetic basis have been described, and the only genetically defined form is that associated with SLC4A4, with ocular abnormalities (band keratopathy, glaucoma, cataract) and few patients described [4]. A single case with an SLC4A4 variant, autoimmune thyroiditis, dental agenesis, enamel hypomaturation, and pulp stones is listed among the causes of distal RTA without an identified gene in GeneReviews, which illustrates the phenotypic overlap [2]. A transient, sporadic form of proximal RTA has been described in infants with growth failure, resolving after alkali therapy; it was more common in the United Kingdom in the early 1950s, especially in boys, and its rapid decline suggested environmental factors [4].

Osteopetrosis with RTA due to carbonic anhydrase II deficiency manifests between infancy and middle childhood, with RTA detectable in the neonatal period [57]. Most patients have intellectual disability or learning difficulties, abnormal dentition (conical teeth with caries, malocclusion, delayed eruption, retention of primary teeth), micrognathia, a narrow and prominent nose, a poorly formed philtrum, and short stature; some have cranial nerve involvement, repeated fractures, and episodic hypokalaemic paralysis [57]. Bone density and growth are normal in utero and in early infancy; infantile rickets responds to vitamin D; metaphyseal osteosclerosis appears from 10 months of age, fractures from 1–2 years (decreasing after adolescence), and basal ganglia calcifications (sometimes also cortical) on computed tomography at around 2 years, with attenuation of the radiologic changes by late childhood [57]. Radiologically there is a thick, sclerotic skull base, poor pneumatisation of the sinuses and mastoids, generalised osteosclerosis, wide metaphyses, metaphyseal and iliac striations, a "bone-within-bone" appearance, and sandwich vertebrae [57]. Reported adult height is 142–151 cm in women and 152–155 cm in men [57]. Most known cases come from Saudi Arabia, Kuwait, and North Africa, with distal or mixed RTA; intellectual disability appears more frequent or severe in the Middle East and North Africa, and fractures more frequent in patients from Europe and the United States [57].

4. Clinical Recognition and Red Flags

4.1. When to suspect: newborn and infant

A newborn who is normal at birth, feeds well, and then deteriorates is more likely to have an IEM than a secondary cause [84]. No single feature (age at onset, associated signs, course, or routine laboratory tests) can exclude an IEM at the outset in a comatose patient, and most metabolic comas result from intoxication-type or energy deficiency disorders, many of them treatable [1]. Unexplained metabolic acidosis, tachypnoea without lung disease, hypothermia, feeding refusal with lethargy, hyperammonaemia with acidosis, neutropenia or thrombocytopenia without proven sepsis, and elevated lactate without heart disease, shock, or hypoxaemia are the findings that should trigger collection of the emergency samples [1, 9]. Acetonuria in the newborn is always abnormal [1]. A sibling who died with acidosis often prompts early diagnosis of FBPase deficiency in the next sibling [40]. PC deficiency should be considered in any child with lactic acidosis and neurologic abnormalities, especially with hypoglycaemia, hyperammonaemia, or ketosis, and cystic periventricular leukomalacia at birth with lactic acidosis is highly suggestive [54].

4.2. When to suspect: child, adolescent, and adult

In children, recurrent episodes of vomiting, dehydration, and hyperventilation triggered by infection or fasting, with severe acidosis, call into question the label of "fasting ketoacidosis" or "idiopathic ketotic hypoglycaemia" [1]. Recurrent attacks of severe ketoacidosis with normal glucose and lactate are highly suggestive of ketolysis defects or MCT1 deficiency [1]. Hyperglycaemia with glycosuria during ketoacidosis does not confirm diabetes: propionic, methylmalonic, and isovaleric acidaemias and ketolysis defects can mimic it, and the hyperglycaemia resolves within a few hours with insulin [1]. Because not all children with diabetic ketoacidosis have polyuria and polydipsia, capillary blood glucose should be considered in any child with rapid breathing or with vomiting and abdominal pain without diarrhoea, according to the 2022 ISPAD guideline [20, 85].

Distal RTA should be suspected in an infant with growth failure, polyuria, vomiting, constipation, and recurrent dehydration; in a child with refractory rickets, nephrocalcinosis, sensorineural hearing loss, amelogenesis imperfecta, or haemolytic anaemia; and in an adult with nephrocalcinosis or calcium phosphate stones, osteomalacia, fractures, or hypokalaemic paralysis [2, 4]. Every patient with primary Sjögren syndrome and urolithiasis or hypokalaemia should be evaluated for distal RTA [4]. Urinary acidification should be assessed in patients with nephrocalcinosis or stones and low-normal bicarbonate or hypocitraturia, to identify the incomplete form [4].

In adults, unexplained encephalopathy or coma suggests an IEM when triggered by an external factor (surgery, fasting, exercise, high protein intake, a new drug) or when accompanied by specific lesions on MRI; intoxication-type disorders have normal or nonspecific MRI, and energy deficiency disorders often show bilateral basal ganglia lesions or stroke-like lesions [86]. In adults with known metabolic disease, symptoms may precede or predominate over the biochemical abnormalities [12].

4.3. Emergency signs and action thresholds

The BIMDG emergency cards stress not delaying treatment when in doubt and admitting, even if only for brief observation, any patient with a known disease about whom there is uncertainty [10, 11]. In FBPase deficiency, ketonuria is an early indicator of an impending crisis, and emergency treatment should begin in the presence of vomiting, abdominal pain, or feeding refusal, regardless of the other symptoms [13].

4.4. Newborn screening and screening of relatives

PC deficiency may be suspected from elevated citrulline on newborn screening in some newborns and in some US states, but the elevation is not specific and requires further testing according to the ACMG ACT algorithm; in p.(Ala610Thr) homozygotes from North American Indigenous peoples, citrulline may be elevated at presentation or during acute illness [14]. In CA-VA deficiency, MS/MS newborn screening (C3 and C5OH) was normal in some patients because of the mild profile and the lower sensitivity of acylcarnitines compared with organic acids, and newborns with elevated C3 and C5OH should be considered for CA-VA deficiency in addition to multiple carboxylase deficiency [15]. One symptomatic patient with GSS deficiency was detected by MS/MS newborn screening [35]. Distal RTA is not part of the newborn screening panels described in the sources consulted.

In newborns from families with distal RTA, blood gases and electrolytes (normal AG acidosis and hypokalaemia) should be monitored while molecular testing is pending, and identification of the familial variant allows presymptomatic diagnosis, including on umbilical cord blood [2, 4]. In newborns at risk of FBPase deficiency, fasting should be avoided, regular feeds given, and hypoglycaemia and acidosis monitored (capillary glucose; lethargy, poor intake, vomiting, hypothermia, tachypnoea) until results are available, with a low threshold for 5–10% IV glucose, especially in low-birth-weight or preterm newborns or infants of diabetic mothers [13]. In CA-VA deficiency, a newborn with an affected sibling needs close clinical monitoring in the first week, and one diagnosed prenatally should be born in hospital, with monitoring of ammonia, lactate, glucose, and blood gases for about 3 days [15].

5. Diagnosis: Criteria, Testing, and Algorithms

5.1. Confirming and characterising the acidosis: blood gases and compensation

Diagnosis begins with confirmation of metabolic acidosis (bicarbonate <18 mmol/L with pH <7.38) and assessment of the respiratory response [1]. The expected PaCO2 is calculated with Winter's formula, PaCO2 = 1.5 × HCO3⁻ + 8 ± 2 mmHg, and compensation is established within 12 to 24 hours [7, 8]. A PaCO2 above the predicted range indicates an associated respiratory acidosis (for example, from neurologic depression or respiratory fatigue), and a PaCO2 below it indicates an associated respiratory alkalosis, as occurs in hyperammonaemia or salicylate poisoning [1, 8]. The minimum PaCO2 attainable by hyperventilation is about 8 to 12 mmHg [8]. Venous bicarbonate is usually 2 to 4 mmol/L higher than arterial bicarbonate [8]. For example, in an infant girl with FBPase deficiency with pH 7.107, PaCO2 30 mmHg, and bicarbonate 15.9 mmol/L, the predicted PaCO2 is 31.9 ± 2 mmHg, indicating appropriate respiratory compensation [67].

5.2. Anion gap: calculation, reference interval, and limitations

The AG is calculated as Na⁺ − (Cl⁻ + HCO3⁻); K⁺ was part of the original formula and has been dropped from the major North American textbooks, but including it can be useful when it is markedly abnormal [5]. The reference interval depends on the analyser, as the values cited in the reference textbooks show [5].

In studies of patients and volunteers, the mean AG ranged from 6.4 ± 1.4 mmol/L (29 volunteers, ion-selective electrodes) to 15 ± 2.5 mmol/L (488 patients, continuous-flow analyser), and in a set of 18,987 patients (1997–2007) the interval was 10–18 mmol/L; the mean is lower with ion-selective electrodes, which measure higher chloride, and every clinician should know their own laboratory's interval [5]. The ERKNet guideline uses 8–16 mmol/L, and the reference textbook of metabolic diseases gives 10–15 mmol/L [1, 4]. With potassium in the formula, the usual interval is 12–16 mmol/L [8].

Albumin correction. In a study of 9 normal subjects and 152 critically ill patients (265 measurements; 49% with albumin <20 g/L), each 1 g/L fall in albumin caused the AG to underestimate unmeasured anions by 0.25 mmol/L (r² = 0.94): adjusted AG = observed AG + 0.25 × (normal albumin − observed albumin), with albumin in g/L, or with a factor of 2.5 if albumin is in g/dL [6]. The factor varies with pH, because the charge on albumin depends on it [5]. The normal albumin to use is the laboratory's; StatPearls uses 4.0 g/dL in one place and 4.5 g/dL in another [6, 8]. Example: an AG of 10 mmol/L with albumin of 2.0 g/dL corresponds to a corrected AG of 15 mmol/L [8].

Sensitivity for lactic acidosis. A normal AG does not exclude lactic acidosis [5]. In 272 emergency department patients, the sensitivity of the AG for hyperlactataemia was 58% without correction and 78% with albumin correction; in 438 patients, only 44% of those with lactate >2.5 mmol/L had an abnormal AG; in another series, 43% of patients with lactate of 2.5–4.9 mmol/L and 50% of patients with lactate of 5–9.9 mmol/L had a normal AG; in 143 intensive care patients, sensitivity rose from 63% to 94% with correction; and in a study of more than 18,000 intensive care patients, 35% of the 973 with lactate of 2–5 mmol/L and 17% of the 409 with lactate >5 mmol/L had no detectable rise in the AG [5]. The practical conclusion is to measure lactate directly, and the same presumably applies to the other high AG acidoses [5]. An AG above 18 mmol/L almost always indicates an organic acid, and in renal failure it rarely exceeds this value [8].

5.3. Delta ratio and mixed disorders

The classic relationship between the rise in AG and the fall in bicarbonate is 1:1; in 42 patients with lactic acidosis or ketoacidosis, the ΔHCO3⁻/ΔAG ratio was 0.98 ± 0.06 [5]. In humans, however, the ΔAG/ΔHCO3⁻ ratio is about 1:1 in ketoacidosis and 1.5 on average in lactic acidosis, because the fractional urinary excretion of ketoanions with sodium (45.8 ± 3.1%) is much higher than that of lactate (4.7 ± 0.3%); the measured organic anion accounts for at most about 76% of the increase in AG [5]. The delta ratio is calculated as (corrected AG − 12) / (24 − measured HCO3⁻): between 1 and 2, pure high AG acidosis; below 1, concomitant normal AG acidosis; above 2, concomitant metabolic alkalosis or a previously elevated bicarbonate [8]. In Kraut's terminology, a ΔAG greater than ΔHCO3⁻ suggests an associated metabolic alkalosis, and a ΔHCO3⁻ greater than ΔAG suggests an associated hyperchloraemic acidosis [5]. In ketoacidosis treated with large volumes of chloride-containing fluids, preferential renal excretion of ketoanions generates hyperchloraemia, and the base deficit may persist because of chloride rather than ketosis; direct measurement of ketones distinguishes the two situations, and the hyperchloraemic acidosis corrects spontaneously [19].

5.4. Osmolar gap

Calculated osmolality is 2 × (Na⁺ + K⁺) + glucose/18 + urea (BUN)/2.8 + ethanol/4.6, with the North American units in mg/dL; the osmolar gap is the difference between measured and calculated osmolality, normally less than 10 mOsm/kg [8]. A gap greater than 10 mOsm/kg suggests exogenous osmoles (methanol, ethylene glycol, isopropanol, and also mannitol, contrast media, sorbitol, maltose), and the combination of a high AG with a high osmolar gap strongly points to toxic alcohol poisoning; in the late phase, when the alcohol has already been metabolised to its acids, the osmolar gap may be normal [8]. In the metabolic setting, the osmolar gap serves mainly to exclude poisonings before attributing the acidosis to an IEM.

5.5. Emergency investigation protocol

First-line investigations allow initial therapeutic recommendations within 2 to 4 hours, and results for diseases with a specific emergency treatment should be available within 24 hours [1, 12].

Blood ketones can be measured at the bedside; 3-hydroxybutyrate and free fatty acids are rarely available in the emergency setting but help interpret the profile, and pyruvate and acetoacetate are not part of the emergency protocol [1]. The dinitrophenylhydrazine test for 2-ketoacids has been largely abandoned [1]. The UK protocol for undiagnosed recurrent hypoglycaemia, to be collected at the time of hypoglycaemia, includes laboratory glucose, lactate, free fatty acids, 3-hydroxybutyrate, insulin, cortisol, growth hormone, quantitative amino acids, a dried blood spot acylcarnitine profile, and ketones and organic acids in the next urine sample; the most important samples are glucose and insulin, followed by cortisol and lactate, and correction of hypoglycaemia should not be delayed if sampling is difficult [90]. In acidosis suggestive of an IEM, the investigations of choice are urine organic acids and the plasma acylcarnitine profile, and electrolytes and ammonia are the most important tests for early discrimination [9].

5.6. Initial classification of the newborn and infant

Classification adapted from the European reference textbook; normal values used: ammonia <80 µmol/L, lactate <1.5 mmol/L, glucose 3.5–5.5 mmol/L [1].

5.7. Algorithm for high anion gap acidosis

Step 1: ketonuria. The presence or absence of ketonuria is the main clinical clue [1]. The urine ketone test (Acetest) is highly sensitive: it becomes positive when plasma acetoacetate reaches 0.1 mmol/L (total ketone bodies >0.2 mmol/L) [1].

Step 2a: acidosis without ketosis (or with very mild ketosis), in the absence of a glucose infusion. Consider PDH deficiency (neurologic context), fatty acid oxidation defects, gluconeogenesis defects (glycogen storage disease I and FBPase), and HMG-CoA lyase deficiency (context of hypoglycaemia); in all of these lactate is elevated and the AG increased [1]. Absence of ketonuria during hypoglycaemia, fasting, or catabolism suggests a defect of fatty acid oxidation or ketogenesis, and also occurs in citrin deficiency, hyperinsulinism, and infantile growth hormone deficiency [1].

Step 2b: acidosis with ketosis; first parameter, blood glucose. The main groups are insulin-dependent diabetes, the branched-chain organic acidurias, the congenital lactic acidoses (multiple carboxylase deficiency, PC deficiency), glucose-6-phosphatase and FBPase deficiencies, and the ketolysis defects; heterozygous SLC16A1 variants can present as recurrent attacks of ketoacidosis [1].

The secondary literature diverges on glycogen storage disease III: the Oxford Desk Reference suggests considering it when ketonuria is associated with metabolic acidosis and mentions lactic acidosis in this disorder, whereas the European reference textbook states that glycogen storage disease III does not cause severe ketoacidosis and has normal fasting lactate, with mild hyperlactataemia only postprandially and never above 6 mmol/L [1, 84]. The interpretation most consistent with physiology is that of the European textbook, and severe ketoacidosis in a patient with suspected glycogen storage disease III should prompt a search for another diagnosis.

Step 3: ketosis without acidosis. Ketosis without acidosis, hyperlactataemia, or hypoglycaemia probably reflects a physiologic state (fasting, catabolism, vomiting, diets rich in medium-chain triglycerides, or ketogenic diets) [1]. Significant fasting ketonuria without acidosis suggests glycogen storage disease III (marked hepatomegaly) or glycogen synthase deficiency (normal liver), idiopathic ketotic hypoglycaemia, or adrenal insufficiency [1]. In severe forms of the ketolysis defects (SCOT and β-ketothiolase) there may be persistent moderate ketonuria, especially in the fed state at the end of the day, and paradoxical postprandial ketosis suggests deficient anaplerosis of the Krebs cycle (PC deficiency) [1]. In a sick newborn with significant ketonuria without acidosis, maple syrup urine disease should be excluded [84].

Step 4: associated hyperammonaemia. Severe neonatal hyperammonaemia (>500 µmol/L) points to a urea cycle disorder (respiratory alkalosis, no ketosis, no bone marrow suppression) or an organic aciduria (metabolic acidosis, ketosis, leukopenia and thrombocytopenia); plasma glutamine is usually above 1000 µmol/L in urea cycle disorders and lysinuric protein intolerance, and close to normal or low (<500 µmol/L) in the organic acidurias [1]. Neonatal hyperammonemia with lactic acidosis (>6 mmol/L) and hyperketosis suggests PC deficiency (low glutamine, high citrulline), GOT2 deficiency (high citrulline, low serine), multiple carboxylase deficiency, or CA-VA deficiency [1]. Mild ammonia elevations (<150 µmol/L) are an incidental finding in maple syrup urine disease, PDH deficiency, and valproate treatment [1]. Treatment of acidosis should not be delayed because a urea cycle disorder is suspected, and hyperammonaemia, whatever its cause, must be treated [9].

Step 5: normal AG acidosis. In the absence of hypoglycaemia or hyperlactataemia, the most frequent cause is RTA with bicarbonate loss and hyperchloraemia; severe early-onset forms of pyroglutamic aciduria can be mistaken for proximal RTA [1]. The detailed approach is in section 5.11.

5.8. Hyperlactataemia: confirmation, timing, and redox ratios

Confirm that the elevation is real. The most common cause of elevated lactate is poor sampling technique (tourniquet, difficult draw); blood should flow freely without a tourniquet, and an indwelling venous catheter for repeated sampling gives the best results [38]. Lactate may be appropriately elevated in a crying child or after a seizure, and exertion at the time of sampling should be taken into account [59]. Lactaturia with elevated blood alanine indicates true hyperlactataemia (the renal reabsorption threshold for lactate is about 4 mmol/L), and the alanine/lysine ratio is normally below 3:1 [37, 59]. The normal urine lactate/creatinine ratio is 0.028–0.22, and in congenital lactic acidosis blood and urine lactate are elevated but fluctuate, so several measurements at different times are recommended [38]. In primary mitochondrial disease, a truly elevated plasma lactate (>3 mmol/L in a properly collected sample) has a sensitivity of 34–62% and a specificity of 83–100%; postprandial lactate is more sensitive than fasting lactate, CSF lactate is useful when there are neurologic symptoms (it rises transiently in status epilepticus), and urine lactate correlates poorly [17]. CSF lactate may be elevated with normal or only intermittently elevated plasma lactate [38].

Exclude secondary causes. Lactate accumulates through an increased NADH/NAD⁺ ratio in circulatory collapse, hypoxia, failure of cellular respiration, and all severe acidotic states, and these causes must be excluded before looking for an IEM; acquired persistent hyperlactataemias include diarrhoea, persistent infections (especially urinary), hyperventilation, and liver failure [1]. Ketosis is absent in most hypoxic hyperlactataemias and almost always present in most of those caused by IEMs, except PDH deficiency, many cases of glycogen storage disease I, and fatty acid oxidation defects; the lactate level does not discriminate [1]. Hyperlactataemia is also secondary in the organic acidurias, HMG-CoA lyase deficiency, pyroglutamic aciduria, multiple carboxylase deficiency, and fatty acid oxidation defects, which are excluded by organic acids and acylcarnitines [38]. D-lactic aciduria occurs in malabsorption, short bowel syndrome, and necrotising enterocolitis; it can cause systemic acidosis and coma, is not distinguished from L-lactic acid by chromatography, and requires a specific enzymatic assay; factitious lactic acidaemia arises in the neonatal unit when infused glucose exceeds the infant's capacity to use it [38].

Timing in relation to meals. In gluconeogenesis defects (PEPCK-C, FBPase, glucose-6-phosphatase), lactate peaks during fasting (up to 15 mmol/L), with acidosis and hypoglycaemia; in glycogen storage diseases III and VI and in glycogen synthase deficiency, hyperlactataemia is mild, mainly or only postprandial, and never exceeds 6 mmol/L; in PC deficiency, hyperlactataemia is severe (>7 mmol/L) in both the fasting and fed states and tends to fall postprandially; in defects of the mitochondrial pyruvate carrier, PDH, 2-ketoglutarate dehydrogenase, and the respiratory chain, it peaks in the fed state, so a single early-morning fasting measurement may miss a moderate elevation; in disorders of thiamine metabolism, lactate rises mainly during acute episodes [1].

Redox ratios. The L/P and 3OHB/AcAc ratios, before and after meals, are useful in "mitochondrial" hyperlactataemias in a neurologic context and require careful sampling; three profiles are almost pathognomonic [1]. First, hyperpyruvicaemia (>0.3 mmol/L) with a normal or low L/P ratio (<12) without hyperketonemia indicates PDH or pyruvate carrier deficiency, whatever the lactate. Second, a very high L/P ratio (>30) with paradoxical postprandial hyperketonaemia and a normal or low 3OHB/AcAc ratio (<1.5) indicates deficiency of PC (isolated or secondary to biotinidase or holocarboxylase synthetase deficiency) or of 2-ketoglutarate dehydrogenase; in PC deficiency there is also hyperammonaemia, high citrulline, and low glutamine. Third, elevation of both L/P and 3OHB/AcAc with significant postprandial hyperketonaemia indicates a respiratory chain defect [1]. The normal 3OHB/AcAc ratio is above 1 after an overnight fast and below 1 in the fed state [37]. The L/P ratio distinguishes respiratory chain defects from pyruvate defects only when lactate is elevated (sensitivity 31%, specificity 100%) [17, 38].

Preanalytical handling. For lactate, pyruvate, and 3OHB/AcAc, immediately mix 1 mL of blood, drawn without forcing, with 0.5 mL of 18% perchloric acid on ice, centrifuge under refrigeration, and freeze the supernatant at −20 °C; without immediate deproteinisation pyruvate is falsely low, and this is the only way to interpret the redox ratios correctly [37, 59]. Ammonia is collected as 0.5 mL in a heparinised syringe on ice; blood gases as 0.5 mL in a heparinised syringe without air bubbles, capped immediately; glucose and free fatty acids in a fluoride–heparin tube; and insulin in EDTA on ice [37].

Adapted from the European reference textbook, whose column alignment was reconstructed from the digital text; all changes are highly variable, and many patients with respiratory chain defects do not have hyperlactataemia [37]. L/P cutoff values differ between sources: the GeneReviews chapter on FBP1 deficiency gives an L/P of 20–40 during crises, whereas the European table gives <15 for gluconeogenesis defects, and the European chapter devoted to FBPase reports an L/P of up to 40 during crises [13, 37, 61].

5.9. Organic acids, amino acids, and acylcarnitines

Urine for organic acids should be collected as early as possible after the onset of acute symptoms and analysed or frozen at −20 °C; amino acids are analysed simultaneously in blood and urine, and poorly stored plasma produces artefacts (falsely low cystine and homocystine through protein binding; falsely high aspartate and glutamate and low glutamine through hydrolysis) [37]. Quantification is essential: 3-hydroxyisovalerate, 3-hydroxypropionate, and methylcitrate suggest multiple carboxylase deficiency but are also present in propionic acidaemia (in multiple carboxylase deficiency 3-hydroxyisovalerate is very high and the others low; in propionic acidaemia the reverse is true), and confusing the two has had serious consequences in reported cases [9].

Among the amino acids, elevated lysine with low glutamine, high ammonia, high alanine, and high citrulline suggests PC deficiency; high glycine with high alanine (also in CSF) and high lactate suggests a lipoic acid synthesis defect, while high glycine and alanine with normal CSF suggest valproate; high branched-chain amino acids with alloisoleucine and high lactate suggest E3 deficiency; and isolated low glutamine with high lactate suggests ATP synthase deficiency [37]. Citrulline and arginine are low in maternally inherited Leigh syndrome, NARP, MELAS, and Pearson syndrome [59]. Among the acylcarnitines, C3 rises in propionic and methylmalonic acidaemias, C5 in isovaleric acidaemia, and C5OH in multiple carboxylase deficiency; respiratory chain defects can produce secondary patterns similar to SCAD (C4) or MCAD (C6, C8, C10) deficiency, and some MT-ATP6 variants raise C3 or C5OH, mimicking multiple carboxylase deficiency [9, 38, 59]. The ATLAS acylcarnitine reference table contains internal inconsistencies (for example, a control interval of "3.00–0.10" for C5DC) and should not be used as a cutoff without laboratory confirmation [9].

Several urine organic acids appear without hereditary disease: adipic (gelatin, fasting ketosis), benzoate (bacteria, treatment, additive), glutaric (gut bacteria), glycerol (suppositories), 5-hydroxyhexanoic and 3-hydroxyisovalerate (medium-chain triglycerides, ketosis, valproate), 2-ketoglutaric (urinary tract infection), 3-methylglutaconic (uraemia, pregnancy), methylmalonic (B12 deficiency, bacteria), oxalic (malabsorption, ethylene glycol, ascorbic acid), 5-oxoproline (vigabatrin, nonenzymatic conversion), pivalate (pivampicillin, pivmecillinam), and phenylacetate (treatment of urea cycle disorders) [9]. Gut bacteria produce D-lactate, propionate metabolites including methylmalonate, aromatic compounds, and glutaric acid, and urinary tract infection produces D-lactate, 2-oxoglutarate, succinate, and 3-hydroxypropionate; when D-lactate is found, treat with oral neomycin or metronidazole and repeat [9].

5.10. Functional tests

The diurnal metabolic profile, always performed before any provocation test, includes samples before and 1 hour after breakfast, lunch, and dinner and at 04:00 (glucose, lactate, pyruvate, free fatty acids, ketone bodies, ammonia, insulin, cortisol, growth hormone), acid–base status at 2 time points, amino acids, carnitine, and acylcarnitines once, and a 24-hour urine collection; continuous glucose monitoring for 2–3 days is useful [37]. In glycogen storage disease I and gluconeogenesis defects, glucose and lactate move in opposite directions; in glycogen storage diseases III, VI, and IX they move in parallel; in PDH deficiency, lactate and pyruvate are persistently elevated and fall during fasting [37].

The fasting test is dangerous and is reserved for unexplained hypoglycaemia after a baseline workup that has excluded fatty acid oxidation defects or adrenal insufficiency, or for assessing fasting tolerance during treatment; it is performed only in a specialised metabolic unit, after 3 days of good feeding and with no infection in the preceding week, lasting 12 h below 6 months of age, 20 h between 6 and 12 months, and 24 h from 1 year [37]. Glucose and bicarbonate are monitored; below a glucose of 3.2 mmol/L, both every 30 minutes, and the test ends with glucose <2.6 mmol/L, bicarbonate <15 mmol/L, or neurologic symptoms, when the full profile is collected [37]. At the end of the fast, a gluconeogenesis defect is defined by glucose <2.8 mmol/L with simultaneous lactate >3.0 mmol/L; a ketolysis defect by ketone bodies that are already high at baseline and rise sharply, with a glucose × total ketone bodies product >10; and a fatty acid oxidation or ketogenesis defect by glucose <2.8 mmol/L, high free fatty acids, low ketone bodies, a free fatty acid/ketone body ratio >2, and a glucose × ketone bodies product <4 [37]. The test is generally useless in PDH deficiency and uninformative in Krebs cycle and respiratory chain defects; it is contraindicated if ACTH deficiency is suspected [37].

Normal end-of-fast values, used to interpret the test, depend on age and duration [37].

In end-of-fast hypoglycaemia, the normal hormonal response is insulin <3 mU/L with glucose <2.8 mmol/L, cortisol >120 ng/mL, and growth hormone >10 ng/mL; adrenal insufficiency is defined by glucose <2.8 mmol/L with cortisol <250 nmol/L, and the possible complications of the test (hypoglycaemia, metabolic acidosis, dysrhythmia, cardiomyopathy, organ failure) require fluids and medication to be at the bedside [37].

The oral glucose loading test (2 g/kg, maximum 50 g, as a 10% solution) is performed after 3–8 h of fasting, with samples every 30 minutes for 3–4 h: lactate falls markedly in gluconeogenesis defects and glycogen storage disease I, rises excessively in other glycogen storage diseases, and stays the same or rises in PDH deficiency and respiratory chain defects; the L/P ratio increases in PC deficiency and mitochondrial diseases; and ketone bodies rise paradoxically in PC deficiency (with a low 3OHB/AcAc ratio) and in respiratory chain defects (with a high 3OHB/AcAc ratio) [37]. In PDH deficiency, a glucose load can precipitate lactic acidosis [37]. The metabolic muscle exercise test should be submaximal, to avoid rhabdomyolysis, myoglobinuric anuria, and metabolic acidosis; absence of a lactate rise indicates defective glycolysis, and an excessive rise occurs in mitochondrial disorders and AMP deaminase deficiency, although in mitochondrial myopathies the test is neither sensitive nor specific enough [37].

Sources diverge on provocation tests. ATLAS describes a fasting protocol with glucagon (0.5 mg IM at 6 h of fasting, extension to 18–24 h, and a second glucagon dose at the end) and fructose, alanine, or glycerol loading tests for the diagnosis of gluconeogenesis defects, including an IV fructose load of 200 mg/kg [38, 40]. The European reference textbook considers the glucagon test for glycogen storage diseases and the fructose and galactose loading tests obsolete, and states that loading and fasting tests should not be part of the initial workup for FBPase deficiency; GeneReviews considers the fructose tolerance test dangerous and advises against it [13, 37, 61]. With molecular diagnosis available as a first-line test, the current position is that of the more recent sources: loading tests are not used in the initial workup.

5.11. Normal anion gap acidosis and the diagnosis of RTA

Biochemical criterion for distal RTA. Normal AG hyperchloraemic metabolic acidosis, inappropriately high urine pH (>5.5), and a positive urine anion gap, in the absence of advanced CKD (stage below 4); hypokalaemia and hypercalciuria are typical, and imaging shows nephrocalcinosis or nephrolithiasis [4]. GeneReviews adds as suggestive findings bicarbonate <20 mmol/L in infants and <22 mmol/L in older children, normal fractional excretion of bicarbonate when bicarbonate normalizes with alkali, elevated urinary calcium, low urinary citrate, urine pH always >5.3, nearly universal nephrocalcinosis on ultrasound, rickets on radiographs, and an enlarged vestibular aqueduct in cases with hearing loss [2]. Extrarenal bicarbonate loss (diarrhoea, ostomy, laxatives) and systemic diseases and drugs must be excluded [2, 4].

Urine pH. A value of 5.3, measured by electrode, corresponds to maximal acidification; exposure of urine to air (CO2 diffusion) and the growth of urea-splitting bacteria raise the pH artificially, so urine should be fresh or collected under oil; in practice, 5.5 by dipstick is used at the bedside, and 5.3 by electrode in formal tests at a specialised centre [4]. Urine sodium should be above 10 mmol/L, because distal acidification depends on sodium and a transient defect may occur in dehydration, heart failure, or nephrotic syndrome [4].

Urine anion gap. The UAG (urinary Na⁺ + K⁺ − Cl⁻) indirectly reflects urinary ammonium and is negative in systemic acidosis with normal acidification; a positive value in the presence of acidosis indicates reduced ammonium excretion (distal RTA, CKD) [4, 8]. If urine pH is above 6.5, urinary bicarbonate must also be subtracted [8]. It is interpretable only in acidosis, should not be used in advanced CKD, is disturbed by other unmeasured anions or cations (ketoacids, salicylates, penicillin), and can be misleading in the incomplete form, in which ammonium excretion may be preserved [4]. The ERKNet guideline concludes that there is no evidence that the UAG adds information to urine pH, whereas StatPearls presents it as a routine tool and notes that urine pH can mislead in prolonged acidosis; the two positions are complementary, and the UAG is most useful when urine pH is difficult to interpret [4, 8].

Other parameters. Hypocitraturia is present at presentation and improves with treatment, but adds no information to bicarbonate and urinary calcium [4]. Urine PaCO2 and the urine-to-blood PaCO2 gradient after acute alkalinisation with sodium bicarbonate (normal >30 mmHg) were used before the molecular basis was known, but they are not specific (they are low in CKD), CO2 diffuses into the air, and bicarbonate infusion can acutely alter potassium, ionised calcium, and intracellular pH and cause hypernatraemia; they are reserved for experienced centres [4]. Normal 24-h urinary calcium is below 0.1 mmol/kg/day (4 mg/kg/day), regardless of age, and the spot calcium/creatinine ratio has age-dependent values [4].

Reference values from the supplementary material of the ERKNet/ESPN guideline [4].

Acidification tests for the incomplete form. The classic test uses oral ammonium chloride as a single dose of 100 mg/kg (or 4 g/m²); because it is unpalatable and causes nausea and vomiting, a prolonged test of 50 mg/kg/day for 3 days is also used; once systemic acidosis is reached (bicarbonate below normal), a urine pH above 5.3 indicates an acidification defect [2, 4]. The alternative, with better gastric tolerance, combines furosemide and fludrocortisone: in adults, 40 mg of furosemide and 1 mg of fludrocortisone orally; in children, furosemide 1 mg/kg and fludrocortisone 0.3 mg (<20 kg), 0.5 mg (20–50 kg), or 1 mg (>50 kg), with hourly urine collection and maximal acidification after 2–3 hours [4]. GeneReviews cites doses of 0.02 mg/kg of fludrocortisone and 0.5 mg/kg of furosemide [2]. In a cohort of 170 adults with stones, the furosemide–fludrocortisone test had a positive predictive value of only 30% and a negative predictive value of 98% compared with ammonium chloride [4]. A spontaneous urine with pH <5.3 makes the test unnecessary, and a serum potassium >3.8 mmol/L has a high negative predictive value for the incomplete form [4].

Distinguishing proximal RTA, distal RTA, and gastrointestinal loss. Proximal RTA preserves the ability to acidify urine below 5.5 when plasma bicarbonate is below the proximal wasting threshold, so urine pH should be measured before alkali therapy is started; with a bicarbonate load, fractional excretion is typically <5% in distal RTA and >10% (or 10–15%) in proximal RTA [2, 4]. Other proximal dysfunctions (low-molecular-weight proteinuria, generalised aminoaciduria, organic aciduria, phosphaturia, and above all glycosuria) suggest renal Fanconi syndrome, but transient proximal dysfunction without glycosuria is common at presentation of distal RTA [4]. In gastrointestinal loss, distal acidification is intact and urine pH is <5.5, although volume depletion can interfere [2, 4]. The ERKNet guideline organises the algorithm into four decisions: AG (acid gain or bicarbonate loss); gastrointestinal or renal loss; urine pH and UAG (proximal or distal); and plasma potassium (classic type 1 or hyperkalaemic type 4) [4].

The sources consulted do not describe urinary values for type 4 RTA; the column only summarises the position of the ERKNet guideline, which excludes it from its scope and distinguishes it by potassium [4].

Initial assessment of distal RTA. Venous blood gases or total CO2 (fasting and immediately before the alkali dose), creatinine, urea, sodium, potassium, chloride, calcium, phosphorus, alkaline phosphatase, magnesium, uric acid, and albumin; urinalysis; simultaneous spot urine for creatinine, sodium, potassium, calcium, and citrate; renal ultrasound; weight, length or height, and body mass index; audiometry (ATP6V0A4, ATP6V1B1, FOXI1); complete blood count with smear (SLC4A1); dental assessment (WDR72); genetic counselling [2]. Radiographs of the wrist, knee, or ankle are obtained if there are signs of rickets or markedly elevated alkaline phosphatase [4].

5.12. Genetic testing: strategy, sensitivity, and limitations

Distal RTA. The ERKNet guideline recommends offering genetic testing, in an accredited laboratory, to all patients with suspected primary distal RTA, using a next-generation sequencing (NGS) panel, which may be virtual on an exome or genome, including the distal RTA genes and those in the differential of nephrocalcinosis (for example, panel 149 of Genomics England PanelApp) [4]. If a single variant is found in a recessive gene, CNV analysis should be performed; even so, 6–12% of patients are left with a single heterozygous variant, including ATP6V1B1 p.(Arg394Gln), which is recurrent and typically de novo and is now recognised as causal through a dominant mechanism [4, 51]. A negative test requires review of the clinical diagnosis and analysis of the differential genes, and variant classifications can change [4]. The analytical sensitivity of current tests for distal RTA is 90–100% and the specificity 100%; clinical sensitivity is about 80% in children with a typical phenotype and falls to about 20% in adults, reflecting the higher prevalence of the acquired form [4]. CNVs detected by NGS should be confirmed by a second method (MLPA, microarray, or quantitative PCR), and they have been described in ATP6V0A4 [4]. GeneReviews gives, by gene, the proportion of variants detected by sequencing and by deletion/duplication analysis: ATP6V0A4, about 98% and 2%; ATP6V1B1, 100%, with no deletions or duplications described; SLC4A1, more than 95%, with intraexonic deletions of 27–170 bp; FOXI1 and WDR72, 100% by sequencing [2]. In recent Indian cohorts, the diagnostic yield of the panel was 58.7% in 63 probands and 61.5% in 91 patients, with VUS in 9.6% in one series and reclassification of 5 of 96 suspected cases by NGS in the other [25, 70]. Genetic testing has practical benefits: diagnosis in overlapping phenotypes (infantile hypercalcaemia, familial hypomagnesaemia with hypercalciuria and nephrocalcinosis, secondary proximal tubulopathy mistaken for Fanconi syndrome or Dent disease), early audiologic surveillance, prognostic information, cascade testing, and prenatal diagnosis [4].

PC deficiency. Diagnosis rests on enzyme activity (in fibroblasts or lymphocytes, usually <10% of controls) and biallelic PC variants, often studied in parallel [14]. Sequencing detects about 100% of known variants; no deletions or duplications have been described by targeted methods, but genome sequencing has detected splicing variants outside the canonical junction, deep intronic and structural variants, including a t(1;11)(p36.32;q13.2) translocation, and a 12-bp deletion in exon 8 [14]. Rapid exome or genome sequencing is the option in critically ill newborns or infants [14]. Activity in fibroblasts (incorporation of ¹⁴C-labelled bicarbonate) is below 5% in all types and is useful for assessing a variant of unknown significance [54].

FBPase deficiency. Diagnosis rests on biallelic FBP1 variants or deficient activity in liver or mononuclear leucocytes, and molecular testing is preferred [13]. Sequencing detects about 90% of variants and deletion/duplication analysis about 10% [13]. Leucocyte activity is measured spectrophotometrically in few laboratories: the NADPH assay is nonspecific, and specificity is obtained by comparison with and without AMP (a specific inhibitor); the enzyme is stable in untreated blood at +4 °C for 24 hours, which allows long-distance transport [13]. Activity is not diagnostic in mixed leucocytes but is reliable in stimulated isolated monocytes, and the enzyme is not expressed in fibroblasts, amniocytes, or chorionic villi; on liver biopsy, residual activity is 0–30% [61]. In Lebanon, first-line exome sequencing diagnosed two cases in one month, with a good prognosis at 6 years, whereas a third patient who went undiagnosed for 10 years was left with neurologic sequelae [66].

CA-VA deficiency. Sequencing detects about 50% and deletion/duplication analysis about 50% of the variants described, so CNV analysis is essential [15].

GSS deficiency. Diagnosis rests on urinary 5-oxoproline (up to 1 g/kg/day), low GSH in erythrocytes or fibroblasts, GSS activity of 1–30%, and molecular confirmation; because about 40% of variants are splicing variants, genomic analysis should be supplemented with RNA studies [35].

PEPCK-C and MCT1 deficiencies. Diagnosis is genetic, and in MCT1 deficiency the key finding is severe recurrent high AG metabolic acidosis due to accumulation of ketones in blood and urine [32, 60].

General genomic approach. Some centres use NGS as a first-line test and others perform metabolic investigations before panels; NGS does not replace metabolic investigation, requires functional tools to validate variants, and is complicated for genes with both dominant and recessive inheritance, and inexpensive, sensitive biochemical tests remain first line, especially in adults [37]. Exome sequencing has a higher yield with consanguinity, affected siblings, or trio analysis [37]. Untargeted metabolomics identifies thousands of signals and generates "features of unknown significance," analogous to VUS [37]. A VUS neither establishes nor excludes the diagnosis in any of these entities, and segregation analysis in the parents is part of the interpretation [2, 14]. Apparent homozygosity should prompt consideration of an undetected deletion or uniparental isodisomy [2].

Report content. The report should state the gene, the transcript with version (MANE Select), HGVS nomenclature at the complementary DNA and protein levels, zygosity, the ACMG/AMP class, and the criteria used, as in the case of PC deficiency type B described in section 10, in which the novel paternal variant was classified as likely pathogenic under criteria PM2_Supporting, PM3, PP3_Moderate, and PP4 [64]. A negative result does not exclude the diseases described, because panels may not cover noncoding regions, deep introns, structural variants, or mosaicism [4, 14].

5.13. Postmortem investigation

After death, plasma, urine (about 10 mL; if no urine is available, instill 20 mL of normal saline into the bladder), and CSF (about 4 mL) should be frozen at −20/−80 °C; vitreous humour is comparable to plasma for organic acids, and bile is useful for acylcarnitines [37]. Lactate, ammonia, carnitine, and amino acids cannot be interpreted after death because of tissue lysis, whereas the acylcarnitine profile in a dried blood spot or bile can be diagnostic of fatty acid oxidation defects and organic acidurias; autopsy should be performed as early as possible, with consent, freezing liver, spleen, muscle, heart, kidney, and brain [37]. FBPase is rapidly inactivated by autolysis, so activity in postmortem tissue is unreliable [40]. EDTA whole blood for molecular studies is the sample that secures the family diagnosis [1].

5.14. Prenatal diagnosis

Prenatal diagnosis and preimplantation genetic testing are possible with known familial variants in all the entities in the article; biochemical methods are unreliable in FBPase deficiency (low activity in the placenta) and have often been wrong in respiratory chain diseases [13, 38]. In PC deficiency, fetal MRI and ultrasound can show subependymal cysts and ventriculomegaly from the second trimester [54, 64]. In GSS deficiency, prenatal diagnosis can be made by molecular analysis of chorionic villi, activity in amniocytes or chorionic villi, or 5-oxoproline in amniotic fluid [35]. In CA-VA deficiency, prenatal diagnosis does not reliably predict the phenotype [15]. The corresponding counselling is in section 8.

5.15. Integrated algorithm

6. Differential Diagnosis

6.1. Differential diagnosis table of hereditary causes

6.2. Biochemical differential of crises with hypoglycaemia and acidosis

Transcription of table 2b of the GeneReviews chapter on FBP1 deficiency [13]. This table differs from other sources in some respects: the European textbook describes hypoketosis and only moderate hyperlactataemia in fatty acid oxidation defects, and an L/P <15 in glycogen storage disease I; for the fatty acid oxidation defects column, the original source gives "C16–C22" as the organic acid finding, replaced here by the class of metabolites described in the European textbook (dicarboxylic acids) [1, 37].

6.3. Acquired causes of high anion gap acidosis

Acquired causes should be excluded in parallel with the metabolic workup, without delaying collection of the emergency samples [1]. The DIMPLES mnemonic (diabetic ketoacidosis; inborn error, iron, isoniazid; methanol, metformin; paraldehyde, phenformin; lactic acidaemia; ethanol, ethylene glycol; salicylates, solvents, strychnine) and the GOLD MARK mnemonic (glycols; 5-oxoproline; L-lactate; D-lactate; methanol; aspirin; renal failure and rhabdomyolysis; ketones; toluene) cover the main situations [8, 9]. Acquired 5-oxoprolinuria occurs with chronic paracetamol use or with some antibiotics that disrupt the γ-glutamyl cycle, especially in malnourished or chronically ill patients, and is the acquired differential of GSS deficiency [8, 37]. D-lactic acidosis results from bacterial fermentation in short bowel syndrome [8, 38]. Acquired L-lactic acidosis includes shock, sepsis, liver or renal failure, metformin, linezolid, and cocaine; metformin is contraindicated with an estimated GFR <30 mL/min/1.73 m², and the risk increases with SGLT2 inhibitors [8]. Toluene mainly causes normal AG acidosis resembling distal RTA and, through hippurate excretion, can cause a high AG [8]. Salicylate poisoning combines uncoupling of oxidative phosphorylation with initial respiratory alkalosis; methanol generates formic acid (visual disturbances), ethylene glycol glycolic and oxalic acids (calcium oxalate crystals), propylene glycol lactic acid, diethylene glycol diglycolic acid, and isopropanol acetone with a normal or slightly increased AG [8]. The supplementary material of the ERKNet guideline also lists carbon monoxide, cyanide, isoniazid, iron, and propofol among the toxic causes of secondary lactic acidosis, and thiamine deficiency and seizures among the nonhypoxic causes [4].

In the 2021 British paediatric guideline, diabetic ketoacidosis is defined by acidosis (venous pH <7.3 or bicarbonate <15 mmol/L) and ketonemia (3-hydroxybutyrate >3 mmol/L), with severity graded as mild (pH 7.2–7.29 or bicarbonate <15 mmol/L), moderate (pH 7.1–7.19 or bicarbonate <10 mmol/L), and severe (pH <7.1 or bicarbonate <5 mmol/L) [19]. According to the 2022 ISPAD guideline, the criteria are glucose >11 mmol/L, venous pH <7.3 or bicarbonate <18 mmol/L, and 3-hydroxybutyrate ≥3 mmol/L or moderate to marked ketonuria [20, 85]. Organic acidurias and ketolysis defects presenting with hyperglycaemia and glycosuria meet these biochemical criteria; hyperammonaemia, neutropenia, resolution of hyperglycaemia within a few hours, and the organic acid and acylcarnitine profile allow the distinction [1]. Adrenal insufficiency, including undiagnosed X-linked adrenoleukodystrophy, should systematically be in the differential of a ketoacidotic crisis with hypoglycaemia, especially with hypotension, dehydration, and hyponatraemia [1].

6.4. Causes of normal anion gap acidosis

Normal AG acidosis with hypokalaemia results from proximal or gastrointestinal bicarbonate loss or from a distal acidification defect [2, 4]. Nonrenal causes include congenital sodium diarrhoea, enteric infections, laxative abuse, pancreatic fistula, high-output jejunostomy or ileostomy, and ureterointestinal diversions, all distinguishable by the history and a urine pH <5.5 [4]. Other causes are Addison disease, carbonic anhydrase inhibitors (acetazolamide, topiramate, which cause acquired proximal or mixed RTA), parenteral nutrition, cholestyramine, and large volumes of 0.9% saline, which contains 154 mmol/L of chloride [2, 4, 8]. Acquired distal RTA is typical of adults, mainly due to autoimmune tubulopathy with antibodies against the collecting duct (Sjögren syndrome, primary biliary cirrhosis, rheumatoid arthritis, systemic lupus erythematosus, autoimmune hepatitis and thyroiditis), and also due to medullary sponge kidney, nephrocalcinosis from other causes (including familial hypomagnesaemia with hypercalciuria and nephrocalcinosis), and drugs such as amphotericin B [2, 4]. Autoimmune distal RTA responds to immunosuppression in addition to alkali [4].

IEMs that cause tubulopathy with type I or II RTA include PC deficiency, SURF1 deficiency with Leigh syndrome, methylmalonic acidaemia, glycogen storage disease I, CPT I deficiency, Dent disease, carbonic anhydrase II deficiency (proximal), and the FOXI1 and vacuolar H⁺-ATPase forms, both with early hearing loss; tubulointerstitial nephropathy occurs in glycogen storage disease I, methylmalonic acidaemia, and respiratory chain defects (pseudo-Senior-Løken presentation) [1]. Fanconi-Bickel syndrome combines hypoglycaemia, hepatic glycogenosis, and Fanconi syndrome, and cystinosis presents at 3–6 months with Fanconi syndrome and photophobia [1]. RTA unresponsive to massive bicarbonate replacement is one of the causes of death in PC deficiency type B, and proximal RTA has been described in both the simple and complex forms [14, 41]. Mitochondrial diseases can show Fanconi-type proximal tubulopathy, RTA, or a Bartter-like syndrome [18].

6.5. Specific differentials

FBPase deficiency and glycogen storage disease I. Both share fasting hypoglycaemia with hyperlactataemia and acidosis, but glycogen storage disease I has constant hepatonephromegaly, hyperlipidaemia, and hyperuricaemia and no urinary glycerol; glyceroluria in FBPase deficiency strongly indicates a gluconeogenesis defect [12, 13, 61]. Recovery from acidosis with glucose alone is a good diagnostic indicator of FBPase deficiency [61]. Hepatic presentations of respiratory chain diseases (for example, complex III, UQCRB) with hypoketotic fasting hypoglycaemia, liver failure, and hyperlactataemia can mimic FBPase deficiency [1, 61]. The presentation of FBPase deficiency can also be mistaken for mitochondrial disease, as in the alternative case in section 10 [67].

FBPase deficiency and hereditary fructose intolerance. FBPase deficiency does not cause aversion to sweets, growth failure, or proximal tubular dysfunction after fructose [40, 61]. Late-onset hereditary fructose intolerance rarely presents with post-fructose hypoglycaemia alone [1].

PC deficiency and PDH deficiency. In PDH deficiency, ketone bodies are usually undetectable and the L/P ratio is normal, unlike in PC deficiency [14]. PC deficiency shares with FBPase deficiency episodes of high L/P, hyperalaninaemia, hypoglycaemia, and acidosis, but has neurologic involvement, severe intellectual disability, and seizures in types A and B [13].

CA-VA deficiency versus urea cycle disorders or organic acidurias. CA-VA deficiency combines hyperammonaemia with lactic acidosis and ketonuria, low to normal citrulline, and elevated glutamine and alanine, and the organic acids suggest multiple carboxylase deficiency; hypoglycaemia is possible [1, 15].

MCT1 deficiency and ketolysis defects. Both cause recurrent ketoacidosis with normal glucose and lactate; the distinction is genetic [1, 60].

GSS deficiency and proximal RTA. Severe early-onset forms of pyroglutamic aciduria can be mistaken for proximal RTA; urinary 5-oxoproline and the high AG make the distinction [1, 35].

Osteopetrosis with RTA and other osteopetroses. Early- and late-onset osteopetroses have no RTA and have normal erythrocyte carbonic anhydrase II; isolated RTA has no skeletal changes or cerebral calcifications and more frequent nephrocalcinosis and stones; physiologic sclerosis of the newborn is distinguished by testing for RTA [57].

Distal RTA and other causes of early nephrocalcinosis. Infantile hypercalcaemia and familial hypomagnesaemia with hypercalciuria and nephrocalcinosis are part of the differential, and severe hypokalaemic acidosis with secondary proximal tubulopathy can be misdiagnosed as Fanconi syndrome or Dent disease; absence of glycosuria favours distal RTA [4]. Primary hyperoxalurias, with nephrocalcinosis and calcium oxalate stones from infancy, also belong in this differential.

7. Treatment and Risk Management Strategies

7.1. Principles of emergency treatment

The emergency plan begins as soon as metabolic disease is suspected, simultaneously with the workup, and is modified as results arrive [12]. Supportive measures (ventilation, circulation, rehydration, correction of electrolytes, calcium, and phosphorus) should not delay specific therapies, and sepsis, which is common during crises and a cause of persistent catabolism, should be actively investigated and treated [12]. The four goals are to suppress catabolism with adequate energy supply (glucose and, when allowed, lipids), to remove toxic metabolites (alternative pathway drugs, carnitine, extracorporeal clearance), to give cofactors in potentially vitamin-dependent diseases, and to correct fluid, electrolyte, and acid–base balance without causing cerebral oedema [12]. Nutrition may be normal, low-protein, carbohydrate-restricted, or glucose-rich, with or without lipid restriction, and the enteral route is preferable when tolerated [12]. In newborns with organic acidurias and urea cycle disorders, the three main risks are overhydration, cerebral oedema, and acute protein malnutrition [12].

Emergency regimen in known disease (BIMDG cards). In propionic, methylmalonic, and isovaleric acidaemias, HMG-CoA lyase deficiency, ketolysis defects, FBPase deficiency, and glycogen storage disease I, the first measure is glucose 200 mg/kg IV over a few minutes (2 mL/kg of 10% glucose or 1 mL/kg of 20% glucose), or glucose gel on the buccal mucosa if venous access fails, with a nasogastric tube to continue glucose if rapid IV access is not available [10, 11, 87, 88]. In the organic acidurias and ketolysis defects, this is followed by 0.9% NaCl 10 mL/kg (20 mL/kg if there is poor peripheral perfusion or shock; 20 mL/kg routinely in methylmalonic acidaemia), repeated if poor perfusion persists; then 10% glucose with 0.45% NaCl at 5 mL/kg/h only until the definitive solution at the calculated rate is ready, without maintaining high rates for long [10, 88]. In FBPase deficiency and glycogen storage disease I, if the child deteriorates, rebound hypoglycaemia should be sought [11, 87].

Fluids in decompensated organic acidurias. In the mild form, hydration is given over 24 hours with 5–10% glucose containing Na⁺ 75 mmol/L (NaCl 4.5 g/L) and K⁺ 20 mmol/L (KCl 1.5 g/L), with protein-free hypercaloric nutrition of 100–120 kcal/kg/day, and the protein-free diet should not exceed 2 days [12]. In the severe form, intracellular dehydration is often underestimated, and aggressive rehydration with hypotonic solutions and alkalinisation can cause or worsen cerebral oedema; after an initial 10–20 mL/kg bolus of normal saline to restore perfusion, rehydration is planned over 48 hours, at a rate below 70–150 mL/kg/24 h (depending on age), with a mean Na⁺ of 75–150 mmol/L (NaCl 4.5–9 g/L), K⁺ of 30–40 mmol/L (KCl 2–3 g/L), and 5% glucose [12]. Insulin, 0.05–0.2 IU/kg/h, with large amounts of glucose, suppresses catabolism but is effective only if dehydration and acidosis are also corrected, and it is adjusted to blood glucose [12]. Ondansetron 0.15 mg/kg IV over 15 minutes, up to 3 times a day, can be used for persistent vomiting [12].

Adult with methylmalonic or propionic acidaemia (BIMDG, 2026). High-priority triage, early contact with the metabolic team and intensive care, and early haemofiltration in the presence of shock, critical illness, or persistently elevated ammonia or acidosis [93]. Immediate IV 10% glucose at 2 mL/kg/h (200 mg/kg/h), continued until the specialist advises otherwise, withdrawal of protein, and correction of hypovolaemia with 0.9% NaCl; carnitine 100 mg/kg/day orally in divided doses (or IV if not tolerated); metronidazole 400 mg 3 times a day and treatment of constipation; for hyperammonaemia, carglumic acid 100 mg/kg/day and sodium benzoate 10 g/day (in adults over 50 kg, 10 g in 500 mL of 10% glucose over 24 hours, without abrupt discontinuation because of the risk of rebound hyperammonaemia; higher doses only under the guidance of the metabolic specialist; no maximum dose defined in the source; the label limits for carglumic acid are given in the table in section 7) [93, 94]. Glucose should be kept between 4 and 10 mmol/L, with a variable-rate insulin infusion if it remains above 10 mmol/L, without reducing the glucose infusion rate; venous blood gases, ammonia, and lactate are repeated every 4 hours; sodium phenylbutyrate, sodium valproate, and nitrous oxide should be avoided; and severe or progressive acidosis is treated "according to local guidelines," with no bicarbonate dose given [93].

7.2. Intravenous sodium bicarbonate

Position of the sources. The use of IV sodium bicarbonate in organic metabolic acidosis is controversial. The European reference textbook accepts partial correction of acidosis with IV bicarbonate in the organic acidurias, especially if it does not improve with the first toxin-removal measures, and proposes that sodium bicarbonate replace ¼ to ½ of the sodium requirement in the first 6–12 hours of rehydration, given through a Y-connector to avoid precipitation with calcium; it warns that repeated boluses can induce hypernatraemia, cerebral oedema, and cerebral haemorrhage [12]. The UK organic aciduria protocols give no bicarbonate dose [93]. In FBPase deficiency, acidosis usually corrects with glucose, and bicarbonate is considered only if, after the initial glucose bolus, pH remains <7.1 or deteriorates rapidly, or if the base deficit remains above 15 mmol/L; GeneReviews advises, if pH remains <7.1 or worsens, half the calculated dose over 30 minutes [13, 76]. In PC deficiency, the European textbook accepts bicarbonate if acidosis is severe (pH <7.0), and GeneReviews notes that acidosis may require IV sodium bicarbonate; massive bicarbonate requirements have been described in type B, which after liver transplantation proved to depend on the ketoacidosis rather than the lactic acidaemia [14, 41, 54]. In primary lactic acidosis, ATLAS states that acute acidosis may require large amounts of sodium bicarbonate and that sodium citrate may be ineffective in an oxidative defect, because the Krebs cycle is compromised [38]. In paediatric diabetic ketoacidosis, the 2021 British guideline prohibits IV bicarbonate except for life-threatening hyperkalaemia or severe acidosis with impaired myocardial contractility, and always after discussion with the intensivist; the ADA reserves it for pH <6.9 [8, 19]. In adult intensive care, the BICAR-ICU trial (severe metabolic acidosis, pH <7.2) showed no mortality benefit, except in the subgroup with acute kidney injury [8].

The risks of IV bicarbonate include hypernatraemia, hyperosmolality, ionised hypocalcaemia, hypokalaemia, paradoxical intracellular acidification (diffusion of CO2 into the cell), increased lactate production, reduced contractility and, in newborns, reduced CSF pressure and intracranial haemorrhage [4, 8, 58]. In MCT1 deficiency, a child with pH 6.8 and bicarbonate of 5.2 mmol/L developed severe rebound hypokalaemia (K⁺ 1.7 mmol/L) during bicarbonate treatment [79]. In distal RTA, patients have a urinary concentrating defect, and the osmotic load of a bicarbonate infusion can cause hypernatraemia [4].

Dosing in the product labels. The label doses were not designed for IEMs and apply as a ceiling and as rules of administration.

Sources: labels and SmPCs accessed 17 October 2026 [58, 95]. 1 mEq of bicarbonate corresponds to 1 mmol, and the difference between the US limit of 8 mEq/kg/day and the UK limit of 5 mmol/kg/day in children under 2 years is a genuine regulatory divergence [58, 95]. The Portuguese SmPC for Sodium Bicarbonate 8.4% B. Braun matches the UK one: the base deficit × weight × 0.2 formula starting with half the calculated dose, a maximum rate of 1.5 mmol/kg/h, a first paediatric dose of up to 1 mmol/kg, and a limit of 5 mmol/kg/day in infants, newborns, and young children, preferring the 4.2% solution [96]. The UK contraindications include hypokalaemia, which means potassium must be corrected beforehand or simultaneously in patients with distal RTA, MCT1 deficiency, or methylmalonic aciduria [79, 95]. The European reference textbook also mentions urinary alkalinisation with sodium bicarbonate in methylmalonic acidaemia, combined with forced diuresis, given the high urinary clearance of methylmalonic acid [12].

7.3. Trometamol (THAM)

Trometamol 0.3 M (THAM®, Hospira, USA) is indicated for the prevention and correction of metabolic acidosis, and the estimated dose in mL is weight (kg) × base deficit (mEq/L) × 1.1; each individual dose should not exceed 500 mg/kg over at least 1 hour, with a target pH of 7.35–7.45 [97]. In newborns and infants with respiratory distress syndrome, the label gives an initial dose of about 1 mL/kg for each pH unit below 7.4, then adjusted according to PaO2, pH, and PaCO2 [97]. Paediatric use is based on more than 30 years of experience; trometamol does not increase PaCO2 and has been used in metabolic acidosis with concomitant respiratory acidosis and in acidosis with hypernatraemia [97]. It is contraindicated in uraemia and anuria and, in newborns, in chronic respiratory acidosis and salicylate poisoning; risks include ventilatory depression, prolonged hypoglycaemia (especially in preterm infants and newborns), hyperkalaemia in renal failure, and tissue injury from extravasation [97]. In GSS deficiency, the reference textbook lists THAM among the agents for correcting acidosis [35]. The sources consulted identify no trometamol SmPC on the EMC and no centralised authorisation in the EU.

7.4. Hyperammonaemia associated with acidosis

Hyperammonaemia of any cause should be treated without waiting for the diagnosis [9]. The 2020 paediatric consensus (28 studies, 172 patients aged 1 day to 7 years, no randomised trials) defines hyperammonaemia as ammonia >100 µmol/L in newborns and ≥50 µmol/L in term infants, children, and adolescents, associates values >200 µmol/L with a poor neurologic prognosis, and identifies hyperammonaemic coma lasting more than 3 days, intracranial hypertension, and ammonia >1000 µmol/L as adverse prognostic factors [16].

Ammonia is measured every 3 hours [16]. The dialysis indications in the paediatric consensus are guides rather than rigid rules: ammonia >500 µmol/L, or a lower level without response after 4 hours of medical treatment; with 301–499 µmol/L and moderate to severe encephalopathy, nitrogen scavengers while dialysis is being prepared; with 100–300 µmol/L and severe encephalopathy or seizures, scavengers and reassessment at 2 hours [16]. Continuous kidney replacement therapy, especially high-dose continuous venovenous haemodialysis, is first line when available (recommendation 9, level 3B) and should be started with neurologic deterioration, coma, or cerebral oedema with ammonia >150 µmol/L, moderate or severe encephalopathy, refractory ammonia >400 µmol/L, or a rise >300 µmol/L within a few hours; above 1000 µmol/L, high-dose therapy (blood flow of 30–50 mL/min and dialysate-to-blood flow ratio >1.5) or intermittent haemodialysis is recommended as initial therapy; peritoneal dialysis is used only when other modalities are unavailable [16]. Intermittent haemodialysis reduces ammonia by 75% in 3–4 hours, with a risk of rebound and hypotension [16]. The European textbook considers extracorporeal clearance with ammonia >300–400 µmol/L in newborns, infants, and young children, when ammonia does not fall adequately within 4–6 hours of conservative treatment at any age, or with neurologic symptoms in adolescents and adults; in adults, ammonia >100 µmol/L with neurologic symptoms justifies immediate haemodialysis, in short sessions because of the risk of central pontine myelinolysis [12]. Early initiation is the main determinant of outcome [12].

7.5. Cofactors, carnitine, and vitamins

Vitamin megadoses should be tried systematically in potentially vitamin-dependent diseases, with a higher likelihood of response in late-onset forms, and the trial should be repeated in a stable phase and compared with in vitro studies [12]. Biotin applies to holocarboxylase synthetase and biotinidase deficiencies, hydroxocobalamin to all methylmalonic acidaemias, riboflavin to multiple acyl-CoA dehydrogenase deficiency, and thiamine to any severe decompensation with insufficient nutritional intake and severe lactic acidaemia; in adults, a short trial of high-dose B-complex vitamins (thiamine, riboflavin, pyridoxine, biotin, folate, cobalamin) is given [12]. In severe thiamine deficiency (Shoshin beriberi, parenteral nutrition without vitamins, leukaemia), IV thiamine 100–200 mg can be lifesaving [12, 75]. L-carnitine compensates for secondary deficiency due to urinary excretion of conjugates and is never contraindicated in the organic acidurias, but boluses should be limited when a long-chain fatty acid oxidation defect is suspected, because of the risk of arrhythmia from accumulation of long-chain acylcarnitines [12]. Vitamin doses in undifferentiated hyperammonaemia are given in table 7.4 [16]. The Mitochondrial Medicine Society guidelines give no doses for bicarbonate or dichloroacetate [17, 18].

7.6. Primary hyperlactataemia

Most newborns with primary hyperlactataemia present with acute high AG metabolic acidosis, with or without ketosis, and dehydration, and support similar to that for the organic acidurias usually lowers lactate to a level without severe acidosis; none requires toxin removal, except TMEM70 deficiency [12]. Hyperlactataemia sustained by a high glucose infusion can be corrected by lowering the glucose to 5% or even 2.5% [12]. The Mitochondrial Medicine Society recommends limited or no glucose in suspected or confirmed defects of pyruvate metabolism, in patients on a ketogenic diet, and after an adverse response to high-dose glucose; lipids can be used even with secondary β-oxidation dysfunction, and in other patients prolonged fasting should be avoided and glucose added to fluids before, during, and after procedures [17, 18]. This recommendation conflicts with the use of high-dose glucose in gluconeogenesis defects and organic acidurias, which makes the differential diagnosis between hyperlactataemia due to a pyruvate defect and that due to a gluconeogenesis defect an immediate therapeutic decision: in PDH deficiency, a glucose load can precipitate lactic acidosis [37].

Strategies of proven efficacy are few: trials of thiamine (PDH cofactor), riboflavin (complex II), and biotin (PC), and L-carnitine for secondary deficiency [12]. Sodium dichloroacetate, a PDH kinase inhibitor, can lower lactate and correct acidosis in PDH and respiratory chain deficiencies at a dose of 50 mg/kg/day in 1–2 doses (no maximum dose defined in the source), but it has little clinical effect beyond reducing tachypnoea, and reversible sensorimotor peripheral neuropathy limits chronic use [12, 102, 103]. Dichloroacetate is not recommended in gluconeogenesis defects, because it can cause hypoglycaemia [38]. Use of dichloroacetate is off-label and investigational, and its regulatory status is given in section 7.12. In glucose-sensitive oxidative defects, a high-fat diet (≥50% of calories, not necessarily ketogenic) lowers lactate [38].

7.7. Specific treatment of gluconeogenesis, ketone body transport, and γ-glutamyl cycle defects

Acute hypoglycaemia. Samples (acylcarnitines, glucose, insulin, free fatty acids, ammonia, ketone bodies) should be collected before correction; this is followed by a glucose bolus of 0.2–0.5 g/kg and a continuous infusion of 10% glucose with electrolytes at about 10 mg/kg/min [12]. A supply equal to hepatic glucose output (8 mg/kg/min in the newborn) is usually sufficient in glycogen storage disease I and gluconeogenesis defects, whereas hyperinsulinism requires 10–20 mg/kg/min and responds to glucagon [12]. A requirement above 8 mg/kg/min is virtually diagnostic of congenital hyperinsulinism [84]. The UK protocol for undiagnosed hypoglycaemia gives 10% glucose 2 mL/kg (200 mg/kg) followed by an infusion of 4–6 mg/kg/min to maintain normoglycaemia [90].

FBPase deficiency. During a crisis, the glucose bolus is 2 mL/kg of 10% glucose in GeneReviews and 1 mL/kg of 20% glucose in the European textbook (both about 0.2 g/kg), followed by a continuous high-rate infusion (for example, 10–12 mg/kg/min in the newborn) and transition to the oral or enteral route as tolerated; recovery occurs within hours, usually without sequelae [13, 61]. Acidosis generally corrects without bicarbonate, and bicarbonate is indicated only at the thresholds in section 7.2 [13, 76]. In adults, the UK protocol (2024) specifies correction of dehydration with 0.9% NaCl, correction of hypoglycaemia with 50 mL of 50% glucose over 30 minutes, and 10% glucose at 2 mL/kg/h (for example, 140 mL/h in a 70-kg adult), with a target blood glucose of 6–10 mmol/L, insulin per local protocol if glucose exceeds 10 mmol/L (rather than reducing the glucose), potassium monitoring (risk of hypokalaemia), and secure venous access, because hypoglycaemia develops rapidly if the line fails; a mildly unwell patient can use the oral emergency regimen (generally 200 mL of 25% glucose polymer solution every 2 hours) [76]. Fructose, sucrose, sorbitol, and glycerol are prohibited during a crisis, and only sugar-free medications should be given; IV fructose can be fatal, and glycerol infusions (a Japanese practice for cerebral oedema with hypoglycaemia) and repeated sorbitol infusions for "cerebral oedema" have been lethal in undiagnosed patients [40, 61, 76]. Antipyretics and syrups must be free of fructose, sucrose, glycerol, and sorbitol [13, 40].

For maintenance, infants are fed every 2–3 hours and fasting is avoided, especially during fever; from 6–12 months of age, 1–2 g/kg of uncooked cornstarch in milk or water at bedtime prevents nocturnal hypoglycaemia; fructose, sucrose, sorbitol, and glycerol are restricted, with individual tolerance of small amounts (up to 2 g of fructose/kg/day spread over the day), and in young children fat is limited to 20–25% and protein to 10% of energy [13, 61, 104]. In an international survey of 36 centres (126 patients), fructose and sucrose restriction practices varied widely, and there is no consensus on dietary restriction [13, 104]. Prolonged or strenuous exercise requires carbohydrate and hydration, routine vaccination (including annual influenza vaccination) is recommended with carbohydrate-rich meals after the vaccine, and travel is planned with the centre nearest the destination [13]. The frequent obesity due to overfeeding can be treated with a fructose-free hypocaloric diet (800–900 kcal/m²/day) without lactic acidosis [61]. In a Turkish pilot study of 10 patients, a higher cornstarch dose was associated with fewer annual crises (ρ = −0.854), and a percentage of time below target ≥2% was associated with more crises, less frequent cornstarch dosing, and more steatosis, suggesting that continuous glucose monitoring is useful for fine-tuning the regimen [78]. Written protocols for parents, school, and physicians, the emergency letter, and a medical alert bracelet are part of treatment [13].

PC deficiency. There are no published guidelines; the following recommendations reflect the experience of the GeneReviews authors and the reference textbooks [14]. In acute decompensation, IV dextrose reverses catabolism, acidosis may require IV sodium bicarbonate, triggers should be treated, and anaplerotic therapy should be started [14]. Maintenance includes a high-carbohydrate, high-protein diet with frequent meals, avoidance of fasting, and nasogastric tube or gastrostomy feeding, which is almost universal in types A and B [14]. The doses described, all off-label, are citrate "2.5–7.5 mmol/kg/day" as sodium citrate with citric acid, aspartate "2.5–10 mmol/kg/day" (lowers ammonia, with little cerebral effect), and biotin "5–30 mg/day" (generally of little benefit) [14]. In one type B patient, high-dose citrate and aspartate lowered lactate and ketones and normalised plasma amino acids except arginine, without changing the CSF; in another, large amounts of aspartate, citrate, and sodium succinate did not alter the ketoacidosis; glutamine 400–800 mg every 4 hours appeared to reduce episodes in one patient [41, 54]. Biotin, thiamine, dichloroacetate, and high-fat or high-carbohydrate diets have no demonstrated clinical benefit, and the ketogenic diet is contraindicated because it worsens the paradoxical ketosis [14, 54]. Exogenous lipoic acid is not used [14].

Triheptanoin (Dojolvi®), an odd-chain triglyceride that generates acetyl-CoA and anaplerotic propionyl-CoA (converted to succinyl-CoA) and supplies five-carbon ketone bodies that cross the blood–brain barrier, has had variable results in PC deficiency [14]. In type B, a girl treated from the neonatal period had reversal of liver failure within 48 hours, complete biochemical correction, and increased CSF glutamine and free GABA, but died of severe infection after about 6 months of treatment; two patients treated continuously from 11 and 21 days of age, also with citrate, aspartate, and dichloroacetate, had no clinical or biochemical improvement and died at 7 and 8 months [105, 106]. In type C, the first of two patients described started triheptanoin at 3 years of age, titrated to 35 mL/day (25% of energy) over 6 months, with transient diarrhoea, and had fewer hospital admissions, resolution of post-exercise hyperlactataemia, better exercise tolerance, and improved myelination on MRI at 18 months, with 2 years of follow-up; the authors described the results in types A and B as disappointing [107]. GeneReviews cites doses of 1.5–2.0 g/kg/day (up to 35% of energy) in type C; in the European textbook, one type B patient received 4 g/kg (35% of energy) [14, 54]. For comparison, the FDA label for Dojolvi® (indication: long-chain fatty acid oxidation disorders) specifies starting at about 10% of the prescribed daily caloric intake, in at least 4 doses mixed with food, with increases of about 5% every 2–3 days up to a target of up to 35% [108]; this titration scheme can guide gradual introduction, and the published doses in PC deficiency fall outside the terms of the label. Triheptanoin is not FDA-approved for PC deficiency; the US compassionate use programme for energy metabolism defects has been unavailable since 2021, and monitoring includes gastrointestinal effects, feeding tube integrity, and the acylcarnitine profile at each visit [14, 108, 109].

Orthotopic liver transplantation, performed between 6.5 months and 2.5 years of age in type A and B patients, improves lactic acidosis, ketoacidosis, and RTA but does not reverse neurologic involvement; one patient transplanted at 6.5 months was alive at 20 years [14]. In one severely affected patient, transplantation abolished the ketoacidosis, systemic acidosis, abnormal redox state, and RTA, showing that the massive bicarbonate requirement was due to ketoacidosis and not to lactic acidaemia; blood, CSF, and urine lactate persisted, CSF glutamine remained low, and there was functional improvement in the first year [41, 54]. ACTH worsened lactic acidosis in a type B patient with infantile spasms, and valproate and barbiturates have adverse effects in energy defects [54]. Palliative care should be discussed early in types A and B [14].

PEPCK-C deficiency. IV dextrose should be given as soon as the condition is suspected; fasting is avoided; an emergency regimen with glucose polymers was sufficient to prevent recurrent episodes of liver failure; the emergency plan is maintained into adulthood, and blood glucose should be measured with any seizure or altered consciousness [32]. There is no GeneReviews chapter or guideline [32].

MCT1 deficiency. Treatment consists of a high-rate glucose infusion to interrupt catabolism, correction of acidosis during episodes, and early preventive measures (avoidance of prolonged fasting, emergency regimen), identifying triggers even in heterozygotes [60, 72]. The ketogenic diet is dangerous: a child treated with a ketogenic diet for early-onset absence epilepsy developed severe metabolic acidosis [72]. Diazoxide has no role [72]. Correction of acidosis with bicarbonate requires close potassium monitoring (section 7.2) [79].

GSS deficiency. Acidosis is corrected with bicarbonate, citrate, or THAM, and the reference textbook notes that doses of up to 10 mmol/kg/day or more may be needed during episodes of acute infection [35]. Vitamin E (10 mg/kg/day) and vitamin C (100 mg/kg/day), started early and continued for life, appear to prevent central nervous system injury: in the follow-up of 28 patients, none of the severely affected had received vitamins C and E from the neonatal period [35, 110]. Transfusions are indicated for massive haemolysis; erythropoietin has been used in one patient and selenium in another [35, 110]. N-acetylcysteine is not recommended (accumulation of neurotoxic cysteine in fibroblasts), oral GSH has no lasting benefit, and GSH esters are toxic [35]. Drugs and foods that precipitate haemolysis in glucose-6-phosphate dehydrogenase deficiency, such as phenobarbital, aspirin, and sulfonamides, should be avoided [35, 110]. Early diagnosis, correction of acidosis, and vitamins E and C determine survival [35]. In a newborn with the severe form in 2026, refractory acidosis required exchange transfusion and peritoneal dialysis despite sodium bicarbonate and vitamins [80]. All these doses are off-label.

CA-VA deficiency. There are no guidelines [15]. A patient with insufficient oral intake or signs of decompensation should be admitted for IV fluids (maintenance glucose with supplementary calories as IV lipids), with monitoring of ammonia, lactate, glucose, blood gases, electrolytes, and liver function [15]. If an ammonia-lowering drug is needed, carglumic acid should be considered, as it shortened hyperammonaemia in isolated cases (off-label in the USA and the EU), and sodium benzoate is a reasonable alternative without conclusive evidence [15, 100, 101]. In the Vancouver patients, decompensations were treated with IV glucose, a single enteral dose of carglumic acid and, at times, IV lipids, and in Australia two siblings with a prenatal diagnosis were breastfed every 3–4 hours with supplements and received carglumic acid 100 mg/kg/day for 5 days, without neonatal decompensation [69, 111]. Prevention during catabolism uses a sick-day formula with supplementary calories and lipids and limited protein [15]. Acetazolamide (a carbonic anhydrase inhibitor) and topiramate should be avoided [15]. The authors of recent series call for a management consensus [69].

Carbonic anhydrase II deficiency. There is no standard pharmacologic therapy; acidosis is treated with alkali, often started when growth is complete, rickets with vitamin D, hypokalaemia with oral potassium, and the teeth with dental treatment [57, 112]. The skeletal dysplasia atlas states that growth improved in some patients with correction of the RTA with oral sodium bicarbonate, but that prolonged correction of acidosis is generally not attempted because of its probable adverse effect on the bone disease [57]. This statement diverges from the practice of alkali therapy in distal RTA and is not supported by data in the sources consulted; the 2023 review cited by GeneGuidance describes alkali therapy as the treatment for the acidosis [112]. Haematopoietic cell transplantation improves the skeletal disease, but the RTA and neurologic difficulties persist, because the kidney and brain are not repopulated [57, 112].

7.8. Treatment of distal renal tubular acidosis

Goals. The ERKNet/ESPN guideline recommends alkali therapy aimed at maintaining plasma bicarbonate, chloride, and potassium and urinary calcium within the normal range for age [4]. Adequate treatment resolves rickets, osteomalacia, growth failure, and muscle weakness, and slows or halts CKD and nephrocalcinosis; compensated acidosis (normal pH with low bicarbonate) is not enough for growth; alkali and citrate prevent progression of nephrocalcinosis but do not reverse it, and they reduce the risk of stones [2, 4]. In an international study of 340 patients from 29 countries, the median prescribed dose was 1.9 mEq/kg/day, and adequate metabolic control (normal bicarbonate and normocalciuria) was achieved in about half of patients and was associated with better growth and renal function [83, 113]. In the 2019–2024 European registry, mean bicarbonate was below 22 mmol/L in 42% and there was hypercalciuria in 25%, regardless of age, and the authors advocate a bicarbonate target of 24 mmol/L to improve growth [23]. This target derives from observational data and does not formally replace the 2021 recommendation, which had not been updated as of the date of access [4, 23].

Doses. The usual starting dose is 2–3 mEq/kg/day, and infants and young children need more because of metabolism, protein intake, and bone mineralisation; doses above 10 mEq/kg/day have been described, which generally fall to 2–3 mEq/kg/day in older children and adults [4]. In infants with bicarbonate <15 mmol/L, the starting dose is about 5 mEq/kg/day, with trough bicarbonate (before the next dose) every 24–48 hours until stable; in infants detected through family screening with normal bicarbonate, 1–2 mEq/kg/day; in children after the first year, 2–3 mEq/kg/day; in adults, 60 mEq/day, increasing by 15–20 mEq every 1–2 weeks until normalisation [4]. GeneReviews summarises requirements as highest in infants (above 8 mEq/kg/day in some) and about 1 mEq/kg/day in adults [2]. Dosing should be as frequent as possible, because large, widely spaced doses cause post-dose alkalosis with bicarbonaturia and a risk of calcium phosphate precipitation, followed by acidosis: in infants, a small amount with each feed; in older children and adults, 3–4 doses a day (ideally every 6 hours, adapted to sleep, work, and school); with the prolonged-release formulation, 2 doses a day [2, 4]. Additional potassium should be given if hypokalaemia persists with the acidosis controlled; potassium chloride causes dyspepsia and should be split into 3–4 doses, and liquid potassium aspartate may be better tolerated and also provides alkali [4]. These ERKNet guideline doses are the reference for all alkalinising preparations. For comparison, the SmPC of Sibnayal®, the only European medicinal product indicated for distal RTA and described below, starts at 4 mEq/kg/day from 1 to 3 years, 2 mEq/kg/day from 4 to 11 years, and 1 mEq/kg/day from 12 years and in adults, with a maximum of 10 mEq/kg/day or 336 mEq/day; the ERKNet doses that differ from these (2–3 mEq/kg/day after the first year; a fixed 60 mEq/day in adults) lie outside the terms of the label [4, 114]. There is no labelled dose below 1 year of age, and the ERKNet doses for infants likewise lie outside the terms of the label [4, 114].

In a European survey, patients were using more than 30 different preparations, and in practice the choice depends on availability, cost, and palatability [4, 83].

Sibnayal® (potassium citrate and potassium hydrogen carbonate). It is indicated in the EU for the treatment of distal RTA in adults, adolescents, and children aged 1 year or older, with no extension of indication since the initial authorisation; safety and efficacy below 1 year have not been established [114]. It is supplied in sachets of prolonged-release granules of 8 mEq (282 mg of potassium citrate and 527 mg of potassium hydrogen carbonate; 7.9 mEq of alkali and 7.9 mEq, or 308 mg, of potassium) and 24 mEq (847 mg and 1582 mg; 23.6 mEq of alkali and 23.6 mEq, or 924 mg, of potassium) [114]. The SmPC dosing is as follows: adults, starting at 1 mEq/kg/day with a maximum adjustment of 0.5 mEq/kg/day per step until the optimal dose; adolescents from 12 years, starting at 1 mEq/kg/day with a maximum adjustment of 1.0 mEq/kg/day; children aged 4 to 11 years, starting at 2 mEq/kg/day with a maximum adjustment of 1.5 mEq/kg/day; children aged 1 to 3 years, starting at 4 mEq/kg/day with a maximum adjustment of 1.5 mEq/kg/day; when switching from another alkalinising agent, start at the same dose in mEq/kg/day; the maximum dose, in any age group, is 10 mEq/kg/day or 336 mEq/day, whichever is lower, in 2 daily doses (usually 12 hours apart) combining whole sachets [114]. If vomiting occurs within 2 hours of a dose, the dose is repeated; a missed dose is taken at once unless the next dose is due in less than 6 hours; the granules are swallowed with a large glass of water, preferably with meals, or mixed without crushing into soft food, never with hot food or liquid or with alcohol, and never chewed [114]. It is used only with GFR >44 mL/min/1.73 m²; between 45 and 59 only if the benefit outweighs the risk, with monitoring of renal function and potassium at initiation, after each increase, and at least twice a year; it is contraindicated in hypersensitivity, with GFR ≤44, and in hyperkalaemia [114]. Caution is required in conditions predisposing to hyperkalaemia and in gastrointestinal disorders (malabsorption, delayed gastric emptying, diarrhoea, vomiting), and the granule matrix may be visible in the stool [114]. Interactions include angiotensin-converting enzyme inhibitors, potassium-sparing diuretics, potassium supplements and potassium-containing salt substitutes, ciclosporin, heparin, and nonsteroidal anti-inflammatory drugs (monitor potassium), digitalis glycosides, corticosteroids, and antiarrhythmics (periodic potassium and electrocardiogram), and urinary alkalinisation increases the elimination of salicylates, tetracyclines, and barbiturates and reduces that of quinidine [114]. Adverse reactions are abdominal pain (14%), upper abdominal pain (8%), gastrointestinal pain and nausea (2% each), diarrhoea, dyspepsia, and vomiting, which were mild or moderate and resolved within 24 hours to 3 days without a change in treatment; overdose causes hyperkalaemia [114]. Mean maintenance doses in a 2-year European study were 2.3 (standard deviation 1.3) mEq/kg/day in adults, 2.6 (1.7) in adolescents, 3.4 (1.3) in children, and 4.8 (2.0) in young children [2, 116, 117]. The formulation avoids a dose at school and had a positive impact on quality of life compared with standard treatment [2].

Urocit-K® (extended-release potassium citrate, USA). The labelled indication is "renal tubular acidosis with calcium stones," in addition to hypocitraturia with calcium oxalate stones and uric acid stones, in adults; the dose is 60 mEq/day (30 mEq twice daily or 20 mEq three times daily, with meals) for severe hypocitraturia and 30 mEq/day for mild to moderate hypocitraturia, and doses above 100 mEq/day have not been studied and should be avoided [115]. The label recommends electrolytes, creatinine, and blood count every 4 months and a periodic electrocardiogram, and contraindicates the drug in hyperkalaemia or predisposition to it, delayed gastrointestinal transit, peptic ulcer, active urinary tract infection, and renal failure [115]. Paediatric use in distal RTA is not a labelled indication. In Portugal, the SmPC for Acalka® (potassium citrate 1080 mg, 10 mEq, modified-release tablet) includes distal RTA with calcium nephrolithiasis and specifies starting with 20 mEq three times daily with meals (60 mEq/day), adjusting according to response with citrate and pH in 24-hour urine every 4 months, and avoiding doses above 100 mEq/day; it is contraindicated, among other situations, in renal failure, hyperkalaemia, active peptic ulcer, and delayed gastric emptying [118].

Adjunctive measures. The ERKNet guideline recommends advising patients on the effect of diet: the acid load comes almost entirely from sulfur-containing amino acids (cysteine, methionine), which are more abundant in animal proteins, and fruits and vegetables supply alkali, so a vegan diet can reduce the need for alkali, provided the recommended protein intake is ensured in children [4]. Thiazides are not recommended routinely, because there are no efficacy data, hypercalciuria normalises with alkali (and is a marker of adequacy), and they worsen hypokalaemia [4]. Growth hormone is not recommended, except for persistent growth failure despite good metabolic control [4]. Hearing loss is treated with hearing aids or a cochlear implant, because it does not respond to correction of the acidosis; haemolytic anaemia with alkali, transfusion, and iron; and amelogenesis imperfecta by the dentist [2]. In the incomplete form, alkali is indicated: small studies with citrate showed fewer stone recurrences, better bone, lower urinary calcium, and higher urinary citrate in adults and better growth in children [4]. In the autoimmune form, immunosuppression is added to alkali therapy (corticosteroids, antimetabolites, calcineurin inhibitors, rituximab, or alkylating agents, mostly in isolated reports; mycophenolate mofetil in one study) [4]. Follow-up should involve an experienced tertiary centre, shared with the local nephrologist or urologist [4].

7.9. Proximal RTA with ocular abnormalities

Proximal RTA requires large amounts of alkali, because administered bicarbonate is lost whenever plasma levels exceed the reabsorption threshold [2]. The sources consulted give no specific doses for the SLC4A4 form, and the ocular abnormalities (band keratopathy, glaucoma, cataract) require ophthalmologic follow-up [4].

7.10. Comparative regulatory status

The sources consulted do not cover reimbursement or access status in Portugal (INFARMED) or Brazil (ANVISA) for these medicinal products.

7.11. Trials and interventional studies

None of these studies allows an indirect comparison between drugs: the pivotal ADV7103 trial was not randomised and compared the formulation with each patient's previous treatment, with a short-term biochemical endpoint; the only randomised, placebo-controlled trial of alkali in distal RTA was terminated with 3 participants, and the authors of the extension and of the pivotal trial are affiliated with the sponsor, which also funded the ERKNet guideline through an unrestricted grant to ESPN [4, 116, 119]. A placebo-controlled trial of alkali in distal RTA is considered unethical [129]. For dichloroacetate, the primary endpoint of the phase 3 trial was not met, and the positive results cited come from secondary analyses or comparisons with historical controls, disclosed by press release [123]. Searches of ClinicalTrials.gov on 17 October 2026 found no active interventional trials for FBPase, GSS, CA-VA, or PC deficiencies (only the unavailable compassionate use programme), which does not prove an absence of research [130].

7.12. Developments in the past 12 months

Most of the clinical developments were read only in the published abstract, and none by itself changes the recommendations of current guidelines.

7.13. Agents and practices to avoid

7.14. Pregnancy and lactation

In distal RTA, pregnant women can develop severe metabolic acidosis and hypokalaemia, especially with hyperemesis gravidarum, and need close monitoring [2, 133]. The Sibnayal® SmPC has limited data (fewer than 300 pregnancies) and recommends avoiding it unless the benefit outweighs the risk, but acknowledges that in pregnancy, and especially during delivery, the risk of severe acidosis and hypokalaemia is greater than that of alkali treatment; it warns of the risk of hyperkalaemia with high potassium intake in complicated pregnancies and allows use during breastfeeding [114].

Successful pregnancies have been described in FBPase deficiency; GeneReviews recommends preconception counselling (frequent meals, glucose monitoring), follow-up by high-risk obstetrics and a metabolic physician, home glucose monitoring, uncooked cornstarch at night if needed, increased intake in the third trimester, and a continuous glucose infusion during labour [13]. In a Saudi series of 3 patients, all with obesity, pregnancies and vaginal deliveries were successful with a multidisciplinary team; the patient with morbid obesity and poor adherence had severe hypoglycaemia with lactic acidosis and required intensive care, with full recovery and no fetal effects, and the two with gestational diabetes developed lactic acidosis immediately after delivery despite stable blood glucose; management of gestational diabetes is difficult because the disease predisposes to hypoglycaemia [131].

Pregnancy has not been described in PC deficiency and would be high risk in type C (dehydration, acidosis) [14]. In GSS deficiency, the first pregnancy described in a woman with the moderate form was uneventful [35]. The sources consulted do not describe pregnancy in PEPCK-C, MCT1, CA-VA, or carbonic anhydrase II deficiencies.

7.15. Surgery, anaesthesia, and procedures

In the organic acidurias, elective surgery should take place in a hospital with a regional metabolic unit, preferably in the afternoon, and is cancelled if ammonia is >100 µmol/L, if there is overt acidosis (pH <7.30 or base deficit >10 mmol/L), or if the child is unwell [89]. On the day of surgery, the child should be receiving 10% glucose with 0.45% NaCl at the start of the operation, at a rate of 100 mL/kg/24 h for the first 10 kg, 50 mL/kg/24 h for the next 10 kg, and 20 mL/kg/24 h thereafter, with 10 mmol of potassium per 500 mL (in methylmalonic acidaemia only once electrolytes are known) [89]. If no infusion is running, a glucose polymer drink is given 3 hours before anaesthesia, and an IV infusion is mandatory if anaesthesia starts more than 4 hours after that drink [89].

Source: BIMDG protocol for surgery in the organic acidurias [89]. After surgery, the infusion is stopped only when the child tolerates food, and discharge occurs only after full recovery is confirmed and discussed with the metabolic team [89]. In FBPase deficiency, surgery involving several hours of fasting requires IV glucose, with perioperative planning by the metabolic centre [13]. In mitochondrial disease, anaesthetic risk is increased: preoperative fasting should be minimised and glucose added to fluids (unless the patient is on a ketogenic diet), volatile agents used with caution, and propofol avoided or limited to short procedures; local anaesthetics are well tolerated [17, 18].

7.16. After discharge, emergency letters, and transition

Parents should be taught to recognise early signs and to start emergency treatment at home, with an emergency letter containing the individual plan for home and for the first-line hospital; in patients with recurrent decompensations, a gastrostomy or a totally implanted catheter may be justified [12]. The MetabERN tool generates personalised emergency letters for urea cycle disorders (pilot in Dutch), hepatic glycogen storage diseases, and β-oxidation defects, recommends renewing them every 6 months and, as of October 2026, had no letters for organic acidurias, gluconeogenesis defects, CA-VA deficiency, or primary lactic acidoses [134]. The BIMDG maintains paediatric emergency cards and protocols for adults over 40 kg, and the emergency regimen for infants up to 1 year uses a glucose polymer solution of about 10% (about 40 kcal/100 mL), at 150 mL/kg/day below 6 months and 120–150 mL/kg/day between 7 and 12 months (maximum 1200 mL), divided every 1–3 hours [132, 135]. In FBPase deficiency, planned transition to adult care and a medical alert bracelet are recommended [13]. In mitochondrial disease, the centre provides an emergency summary document updated at each visit [18].

7.17. Guideline recommendations and divergences

8. Reproductive Options and Family Counselling

8.1. Recurrence risks by mode of inheritance

Autosomal recessive forms. All the entities in the article have autosomal recessive loss-of-function forms: distal RTA due to ATP6V0A4, ATP6V1B1, FOXI1, WDR72, and biallelic SLC4A1; proximal RTA due to SLC4A4; carbonic anhydrase II deficiency; PC, FBPase, PEPCK-C, GSS, 5-oxoprolinase, and CA-VA deficiencies; and the recessive form of MCT1 deficiency [2, 13–15, 35, 60]. When both parents are heterozygous, each sibling has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither variant [2, 13]. Heterozygotes are generally asymptomatic, with exceptions: some ATP6V1B1 heterozygotes outside codon Arg394 have a mild acidification defect without a change in blood pH (incomplete distal RTA), with frequent hypercalciuria and stones, which can be diagnosed with the ammonium chloride or furosemide–fludrocortisone test; heterozygous parents of children with biallelic SLC4A1 p.(Ala858Asp) have mild acanthocytosis; and incomplete forms have been described in SLC4A1 and ATP6V0A4 heterozygotes [2, 4]. Apparent homozygosity requires consideration of an undetected deletion on one allele or uniparental isodisomy [2].

Autosomal dominant forms. In dominant distal RTA due to SLC4A1, the dominant-negative variant arises de novo in most cases, and very few patients have an affected parent [2]. In the dominant ATP6V1B1 form (codon Arg394), about 40% (8 of 20) of cases were de novo and about 50% had an affected parent; in one family, the unaffected mother of two affected children was mosaic [2, 51]. The risk to siblings is 50% if a parent carries the variant and about 1% if the variant is not detected in parental leucocytes, because of the possibility of gonadal mosaicism; a mosaic parent may be mildly affected, and each child of an affected individual has a 50% risk [2]. In MCT1 deficiency, heterozygous index patients can have ketoacidosis, but heterozygous relatives carrying the same variant are often asymptomatic, which makes penetrance incomplete and individual risk difficult to quantify [52, 60].

Mitochondrial diseases. Diseases due to mitochondrial DNA variants are maternally inherited, and prenatal diagnosis is accurate only with the familial molecular variant, because biochemical methods have often been wrong [38].

8.2. Carriers and cascade testing

In the Algonquian Ojibwa, Cree, and Mi'kmaq peoples, the carrier frequency of PC p.(Ala610Thr) reaches 1 in 10 [14]. Carrier detection for PC deficiency by enzyme activity is unreliable, and carrier detection for FBPase deficiency is reliable only by molecular testing (parents have intermediate hepatic activity, but heterozygosity in leucocytes is unreliable) [13, 40, 41]. GSS carriers have about 55% of normal activity with normal GSH [35].

The genetic status of asymptomatic at-risk relatives should be clarified in distal RTA, because presymptomatic identification of siblings allows alkali therapy that prevents rickets, growth failure, and progression of nephrocalcinosis [2, 129]. In FBPase deficiency, at-risk siblings should be evaluated, and at-risk newborns protected from fasting until the result is available [13]. In PC deficiency type C, the status of at-risk siblings should be clarified [14]. In PEPCK-C deficiency, the identification of an asymptomatic sister with the same genotype shows that cascade testing can identify individuals who benefit from an emergency plan even without symptoms [32, 68]. Identification of the causal variant allows presymptomatic diagnosis, including on umbilical cord blood in a newborn at risk of distal RTA [4].

Testing asymptomatic children at risk of these diseases is justified by the immediate therapeutic benefit (alkali therapy, avoidance of fasting, emergency plan). The sources consulted do not address carrier testing in minors for these diseases.

8.3. Prenatal diagnosis and preimplantation genetic testing

Prenatal diagnosis and preimplantation genetic testing (PGT-M) are technically possible in all the entities once the familial variants have been identified, after genetic counselling and in accordance with national ethical and legal standards [2, 4, 13, 14]. Preconception counselling and DNA banking from the affected individual are indicated when the molecular diagnosis has not been confirmed [2]. In FBPase deficiency, biochemical prenatal diagnosis is unreliable, because placental activity is low and the enzyme is not expressed in amniocytes or chorionic villi [13, 61]. In PC deficiency, prenatal diagnosis was historically made by the absence of biotin-labelled protein in amniocytes and is now molecular; fetal brain abnormalities (subependymal cysts, ventriculomegaly) may appear in the second trimester, and the authors of the case in section 10 emphasise the usefulness of PGT-M in subsequent pregnancies [14, 41, 64]. In GSS deficiency, prenatal diagnosis can be molecular, enzymatic, or based on 5-oxoproline in amniotic fluid [35]. In CA-VA deficiency, prenatal diagnosis does not reliably predict the phenotype, because there are asymptomatic biallelic individuals, but it allows delivery to be planned at a tertiary centre with monitoring [15, 111].

8.4. Content of counselling

Counselling should explain the mode of inheritance specific to the gene and the variant (the same gene can be recessive or dominant), the risk to siblings and offspring, the meaning of VUS, the possibility of variant reclassification, and the importance of testing the parents to establish phase and de novo origin [2, 4]. In distal RTA, counselling should be offered to all patients and to the parents of an affected child [4]. In diseases with a risk of acute decompensation (FBPase, PC, PEPCK-C, MCT1, CA-VA, GSS), counselling includes the emergency plan for the at-risk newborn, management of pregnancy in an affected woman (section 7.14), and patient resources (section 9.4) [13–15].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

Differences between estimates reflect different methods (registries, case series, prevalence classes) and should not be compared directly; in diseases with very few cases, the count of published patients measures publication activity rather than true frequency [14, 15]. PC deficiency type C and CA-VA deficiency are probably underdiagnosed [14, 15].

9.2. Geography, ancestry, and founder effects

North America. PC deficiency type A shows a founder effect in the Algonquian peoples of Canada (Ojibwa, Cree, Mi'kmaq), with PC p.(Ala610Thr) and a carrier frequency of up to 1 in 10; the "simple" form has also been described in White North Americans [14, 41]. In the United States, some newborn screening programmes detect PC deficiency through elevated citrulline [14].

Europe. Prevalence estimates for FBPase deficiency come from the Netherlands, France, and Italy, and the FBP1 c.959dup variant accounts for 14% of alleles in Central Europe according to the reference textbook [13, 61, 140]. Distal RTA has the most complete European population data: the mostly European cohort of 340 patients from 29 countries, the UK primary care registry, and the ERKNet European registry (214 patients, 69% with a documented genetic diagnosis and only 22% older than 18 years at the last visit) [23, 83, 136]. The dominant SLC4A1 form predominates in European patients [4]. Finland has the PCK1 founder allele c.925G>A, which should not be generalised to other populations [32]. In Turkey and Armenia, deletion of exon 2 of FBP1 is common, and in one European series most patients with FBPase deficiency were Turkish [40, 61].

Middle East, North Africa, and Asia. FBPase deficiency is common in Saudi Arabia (14 patients in one series) and has been described in Israel (9 patients from 6 Jewish, Arab, and Druze families), Lebanon, and Egypt, with c.960delinsGG in 9 of 14 Egyptian children [40, 65, 66]. The c.841G>A p.(Glu281Lys) variant is recurrent in Pakistan and India, and c.959dup accounts for 46% of alleles in Japan [61]. Osteopetrosis with RTA is concentrated in Saudi Arabia, Kuwait, and North Africa [57]. CA-VA deficiency is concentrated in consanguineous families from the Indian subcontinent (India, Pakistan, Sri Lanka) with p.(Glu241Lys) and has been described in a Bedouin family in Israel [15, 82]. Haemolytic anaemia with distal RTA due to biallelic SLC4A1 variants is concentrated in Southeast Asia, the Middle East, and India, where SLC4A1 p.(Ala858Asp) is the predominant variant (79.3% of SLC4A1 variants in the Indian registry) and the WDR72 form is relatively frequent (12.5–13.5% of diagnoses) [2, 25, 70]. The recessive SLC4A1 form is more frequent in Asian patients [4]. Bone mass studies in distal RTA include Thai patients [4].

Portugal and Brazil. The sources consulted contain no epidemiologic data from Portugal or Brazil for any of the entities in the article; the only Portuguese participation identified is the coauthorship of a Lisbon centre (Hospital de Dona Estefânia) in the European study that described the dominant ATP6V1B1 form [51]. Absence from the sources consulted does not demonstrate an absence of published data.

9.3. Special populations

Newborns and preterm infants. Neonatal hypoglycaemia is defined, after 72 hours in the term newborn and after the first week in the preterm infant, as glucose <2.6 mmol/L (some use <2.5 mmol/L), and most cases are secondary (prematurity, low birth weight, sepsis, diabetic mother) [84]. Newborns are the group at highest risk of toxicity from hypertonic bicarbonate and from trometamol (hypoglycaemia) [58, 97]. In FBPase deficiency, at-risk newborns who are of low birth weight, preterm, or infants of diabetic mothers warrant a low threshold for IV glucose [13].

Adults. The clinical sensitivity of genetic testing in distal RTA is about 20% in adults, reflecting the predominance of acquired forms, mainly autoimmune [4]. Late-onset forms of IEMs can present with isolated encephalopathy, and decompensations of FBPase deficiency in adults, although rare, do occur [13, 86].

Consanguinity. Almost all the recessive entities in this article are more frequent with consanguinity, and exome sequencing has a higher yield in these families [13, 15, 37].

9.4. Reference networks, registries, and patient organisations

10. Illustrative Clinical Case

10.1. Pyruvate carboxylase deficiency type B with prenatal neurologic injury

Xue (2023) described a Chinese newborn girl, the first child of a nonconsanguineous couple, born by caesarean section at 38 weeks and 6 days, weighing 2.79 kg, with Apgar scores of 9/10 [64]. Nuchal translucency at 12 weeks was 0.7 mm; at 22 weeks and 5 days, ultrasound showed small cysts in the anterior horns and enlargement of the posterior horns, with biparietal diameter and head circumference persistently above the 90th–95th percentiles, and fetal MRI showed subependymal cysts and posterior ventriculomegaly, which became more marked as gestation advanced [64]. At 5 hours of life she developed tachypnoea and agitation and was admitted to intensive care, with seizures and irritability [64].

Initial evaluation showed lactate of 24.8 mmol/L (reference 0.5–2.5), with an approximately 10-fold increase within a few hours, ammonia of 294.4 µmol/L (reference 18–72), glucose of 4.2 mmol/L, 3-hydroxybutyrate of 0.37 mmol/L, 2+ ketonuria, albumin of 31.7 g/L, AST of 74, alkaline phosphatase of 187, total bilirubin of 54.6 µmol/L (peak 269.8), creatine kinase of 973 U/L, and blood gases with pH 7.24 and bicarbonate of 5.2 mmol/L [64]. Amino acids showed citrulline of 109.4 µmol/L, tyrosine of 223.4 µmol/L, and alanine of 408.5 µmol/L, and urine organic acids showed lactate (7262), pyruvate (1416.8), 3-hydroxybutyrate (1725.3), 2-hydroxybutyrate (310.9), and 4-hydroxyphenyllactate (979.6 nmol/mg creatinine) [64]. MRI at 3 days showed multiple subependymal cysts, the largest more than 4 cm, and a left posterior horn of more than 2 cm; the echocardiogram showed a small patent ductus arteriosus and foramen ovale, and the karyotype was 46,XX, with a probably benign 0.64-Mb 10q microdeletion [64]. Figure 2 of the article, with the fetal and neonatal MRI images, was opened on the journal's page and its legend confirmed (https://pmc.ncbi.nlm.nih.gov/articles/PMC10360024/figure/f2/) [64].

Trio exome sequencing, with results in 2–3 weeks, identified compound heterozygosity in PC (NM_001040716.2): c.1154_1155del p.(Arg385GlnfsTer10), maternally inherited and classified as likely pathogenic in ClinVar (PVS1, PM2_Supporting, PP4), and c.152G>A p.(Arg51His), paternally inherited, novel, absent from gnomAD, with a REVEL score of 0.928, and classified as likely pathogenic (PM2_Supporting, PM3, PP3_Moderate, PP4), establishing the diagnosis of PC deficiency type B [64]. The family opted for palliative care, and the infant was discharged on oral L-carnitine, coenzyme Q10, and thiamine; 9 days after discharge, lactate was 16 mmol/L, ammonia 87.46 µmol/L, pH 7.2, and bicarbonate 3.7 mmol/L, and she died at home on day 26 [64]. The authors emphasise that the neuroradiologic changes were detected at the earliest gestational age described to date (22 weeks and 5 days) and recommend PGT-M in subsequent pregnancies [64].

The case brings together the features of type B described in sections 3.3 and 5.8: severe lactic acidosis in the first hours, hyperammonaemia, elevated citrulline and alanine, ketosis with elevated urinary ketone bodies, and prenatal periventricular cystic lesions [14, 54]. The discharge therapy (L-carnitine, coenzyme Q10, thiamine) reflected a palliative care decision and corresponds neither to the measures described in GeneReviews for decompensation (IV dextrose, bicarbonate, anaplerotic therapy) nor to a treatment of demonstrated benefit in PC deficiency [14]. Early discussion of palliative care in types A and B is, however, a GeneReviews recommendation [14].

10.2. Alternative case: FBPase deficiency mimicking mitochondrial disease

Chandrasekhar and colleagues (2024) described an 18-month-old girl, the daughter of third-degree consanguineous parents, asymptomatic until 12 months of age, who developed recurrent sudden vomiting with hypoglycaemia and dehydration, with weight, height, and weight-for-height below −3 standard deviations and no hepatomegaly on ultrasound [67]. Arterial blood gases showed pH 7.107, PaCO2 30 mmHg, bicarbonate of 15.9 mmol/L, AG of 19.2, and lactate of 7.1 mmol/L; alanine was 2322.47 µmol/L, glycine 1486.82 µmol/L, and the free fatty acid/3-hydroxybutyrate ratio 6.83 (reference 0.5–5.0); organic acids showed elevated lactate, pyruvate, 3-hydroxyisovalerate, fumarate, and 4-hydroxyphenylacetate, which led to an initial suspicion of mitochondrial disease and the start of coenzyme Q10 and riboflavin [67]. Clinical exome sequencing identified homozygous FBP1 c.611_614del p.(Lys204ArgfsTer72), described in families from India and Pakistan; with frequent meals, uncooked cornstarch, and avoidance of simple sugars, growth and development approached normal [67]. The article has no figures, only tables. The case illustrates the differential in section 6.5 and the need to consider FBPase deficiency in any fasting hypoglycaemia with lactic acidosis, even without hepatomegaly [13, 61].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis by entity

Distal RTA. With early diagnosis and adequate metabolic control, most patients grow within the normal range, although below the mean, and early diagnosis and good control improve final height and estimated GFR [2, 4, 83]. The disease is permanent, and alkali therapy does not prevent hearing loss or reverse established nephrocalcinosis [2]. In the European registry, CKD stage 2 or higher affected 36% of patients, GFR was significantly lower after 30 years of age, and the risk was higher with SLC4A1 variants [23]. In Asian cohorts with late diagnosis (median 17 months in the Mumbai cohort), prognosis was worse: mean final height of −3.0 standard deviations, persistent bone deformities in 33.9%, mean estimated GFR of 89.4 (standard deviation 26.1) mL/min/1.73 m² after a mean follow-up of 14.8 years, and CKD progression in 16.5% of patients in the Indian registry, none in stage 5 [25, 70]. These figures come from treated cohorts with heterogeneous diagnosis and control and do not describe the untreated natural history.

PC deficiency. The prognosis of types A and B is very poor: type B leads to death in the neonatal period or within the first 8 months, and type A usually leads to death in early childhood, with survivors into adolescence or young adulthood with variable cognitive impairment [14, 54]. Liver transplantation has allowed long survival in type A and B patients (one patient alive at 20 years after transplantation at 6.5 months), without reversing neurologic involvement [14]. Life expectancy in type C is unknown, with survival into adulthood described [14].

FBPase deficiency. After diagnosis, the prognosis is usually benign, with normal growth and development, improving fasting tolerance with age, and successful pregnancies; obesity due to overfeeding is common, and one patient with gout at 32 years of age treated with allopurinol has been described [13, 40, 61]. Late diagnosis is associated with sequelae: some patients are left with brain injury from prolonged early hypoglycaemia, and in the Lebanese series the patient who went undiagnosed for 10 years had neurologic sequelae [13, 66]. In the Egyptian series of 14 children there were two neonatal deaths [65].

PEPCK-C deficiency. Neurodevelopment is usually normal, but the disease can be fatal in a decompensation with hypoglycaemia and cerebral oedema, and crises can recur in adulthood [32, 42].

MCT1 deficiency. The prognosis is generally favourable with early diagnosis and preventive measures [60].

GSS deficiency. Early diagnosis, correction of acidosis, and vitamins C and E determine survival; in the moderate forms, infections can cause critical illness and death, and one patient has been followed for 19 years [35, 110].

CA-VA deficiency. GeneReviews describes normal development and no further crises in almost all patients, with 4 patients having mild learning difficulties or motor delay [15]. In an MRI series of 9 patients, 44.4% had moderate to severe neurologic impairment, with extensive involvement of the thalamus, basal ganglia, and brainstem [81]. The difference between the two estimates may reflect selection of patients with neuroimaging in a series from tertiary centres, and the sources do not allow individual risk to be estimated.

Carbonic anhydrase II deficiency. Fractures decrease after adolescence, and radiologic changes attenuate by late childhood; adult height is reduced (142–151 cm in women, 152–155 cm in men) [57]. RTA and neurologic difficulties persist after haematopoietic cell transplantation [112].

Organic acidurias, PDH deficiency, and mitochondrial diseases. In Pearson syndrome, mortality is high in the first 5 years [59].

11.2. Surveillance

The sources consulted establish no formal surveillance intervals for GSS, MCT1, PEPCK-C, and carbonic anhydrase II deficiencies; in severe GSS deficiency, the authors of a 2026 case propose cardiac surveillance [80]. None of the metabolic diseases in this article has a formal follow-up guideline, and the intervals in the GeneReviews chapters on FBP1 deficiency and PC deficiency reflect the authors' experience [13, 14].

12. Summary and Concluding Remarks

Metabolic acidosis is one of the most common findings in the sick child and one of the main gateways to the diagnosis of inborn errors of metabolism. The approach rests on a sequence of simple questions: confirm the acidosis and the respiratory compensation using Winter's formula; calculate the anion gap against the laboratory's interval and correct it for albumin, remembering that a normal gap does not exclude lactic acidosis; exclude toxic causes using the osmolar gap and the clinical context; and, in high-gap acidoses, classify by ketonuria, blood glucose, ammonia, and lactate, with emergency samples collected and stored before treatment.

In the hereditary high-gap acidoses, biochemical profiles guide the diagnosis: fasting hyperlactataemia with hypoglycaemia and urinary glycerol points to FBPase deficiency; a high lactate/pyruvate ratio with a low 3-hydroxybutyrate/acetoacetate ratio, paradoxical postprandial ketosis, high citrulline, and low glutamine point to PC deficiency; fasting hypoglycaemia with low ketones and urinary fumarate to PEPCK-C deficiency; recurrent ketoacidosis with normal glucose and lactate to the ketolysis defects and MCT1 deficiency; chronic acidosis with 5-oxoprolinuria and haemolysis to GSS deficiency; and hyperammonaemia with lactic acidosis, ketonuria, and respiratory alkalosis to CA-VA deficiency. Molecular diagnosis, by panel or rapid exome, has replaced loading and fasting tests in the initial workup, and historical variant nomenclature should be normalised before it is used in counselling.

Among the normal-gap acidoses, hereditary distal RTA is defined by hypokalaemic hyperchloraemic acidosis with an inappropriately high urine pH, nephrocalcinosis and, depending on the gene, hearing loss, amelogenesis imperfecta, or haemolytic anaemia. Genetic testing has a clinical sensitivity of about 80% in children and about 20% in adults, and the same gene can show recessive or dominant inheritance. Alkali therapy with potassium salts, at doses ranging from about 5 mEq/kg/day in infants to about 1 mEq/kg/day in adults (with doses above 10 mEq/kg/day described in infants and young children) and divided through the day, prevents rickets, growth failure, and progression of nephrocalcinosis, but not hearing loss; the European registry shows that about half of patients do not achieve the recommended control and that chronic kidney disease is common in adulthood.

Emergency treatment is common to almost all the entities: glucose at a dose sufficient to suppress catabolism, correction of dehydration without aggressive hypotonic solutions, treatment of the trigger, immediate treatment of hyperammonaemia, and extracorporeal clearance when indicated. IV sodium bicarbonate has restricted indications, with explicit thresholds in FBPase deficiency (pH <7.1 or base deficit >15 mmol/L after glucose) and risks of hypernatraemia, hypokalaemia, and cerebral oedema; the exceptions requiring particular caution are the defects of pyruvate metabolism, in which glucose should be limited, and MCT1 deficiency, in which correction of the acidosis can cause severe hypokalaemia. On the regulatory front, the prolonged-release formulation for distal RTA is authorised in the EU but not in the USA, triheptanoin is approved only for long-chain fatty acid oxidation disorders, and dichloroacetate for PDH deficiency awaits an FDA decision, having not met its primary endpoint in the phase 3 trial.

13. References

1. Saudubray JM, García-Cazorla Á. Clinical approach to inborn errors of metabolism in paediatrics. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 1. https://doi.org/10.1007/978-3-662-63123-2_1
2. Alexander RT, Gil-Peña H, Greenbaum LA, Santos F. Hereditary distal renal tubular acidosis. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Initial posting 10 Oct 2019; last update 3 Apr 2025. PMID:31600044. https://www.ncbi.nlm.nih.gov/books/NBK547595/
3. Orphanet. Primary renal tubular acidosis. ORPHA:314822. https://www.orpha.net/en/disease/detail/314822
4. Trepiccione F, Walsh SB, Ariceta G, Boyer O, Emma F, Camilla R, et al. Distal renal tubular acidosis: ERKNet/ESPN clinical practice points. Nephrol Dial Transplant. 2021;36(9):1585–96 (including supplementary material). https://doi.org/10.1093/ndt/gfab171. PMID:33914889.
5. Kraut JA, Nagami GT. The serum anion gap in the evaluation of acid-base disorders: what are its limitations and can its effectiveness be improved? Clin J Am Soc Nephrol. 2013;8(11):2018–24. https://doi.org/10.2215/CJN.04040413
6. Figge J, Jabor A, Kazda A, Fencl V. Anion gap and hypoalbuminemia. Crit Care Med. 1998;26(11):1807–10. https://doi.org/10.1097/00003246-199811000-00019. PMID:9824071.
7. Albert MS, Dell RB, Winters RW. Quantitative displacement of acid-base equilibrium in metabolic acidosis. Ann Intern Med. 1967;66(2):312–22. https://doi.org/10.7326/0003-4819-66-2-312. PMID:6016545.
8. Kharsa A, Vashisht R, Rout P, Meseeha M. Anion gap and non-anion gap metabolic acidosis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 [updated 6 Aug 2025]. https://www.ncbi.nlm.nih.gov/books/NBK448090/
9. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Introduction to the organic acidemias. In: Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 3–8.
10. British Inherited Metabolic Diseases Group. A&E emergency management cards (paediatric): propionic acidaemia, methylmalonic acidaemia, isovaleric acidaemia, HMG-CoA lyase deficiency. Last revised September 2016 [cited 17 Oct 2026]. https://bimdg.org.uk/wp-content/uploads/2024/11/ER-AandE_PA_2016_141662_09092016.pdf
11. British Inherited Metabolic Diseases Group. Fructose-1,6-bisphosphatase deficiency: A&E emergency management (paediatric). Last revised September 2016 [cited 17 Oct 2026]. https://bimdg.org.uk/wp-content/uploads/2024/11/ER-AandE_F16diPase_2016_147924_09092016.pdf
12. Schiff M, Mochel F, Dionisi-Vici C. Emergency treatments. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 4. https://doi.org/10.1007/978-3-662-63123-2_4
13. Bijarnia-Mahay S, Bhatia S, Arora V. Fructose-1,6-bisphosphatase 1 deficiency. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Initial posting 5 Dec 2019; last update 7 Jul 2026. PMID:31804789. https://www.ncbi.nlm.nih.gov/books/NBK550349/
14. Duque Lasio ML, Lehman AN, Ahmad A, Bedoyan JK. Pyruvate carboxylase deficiency. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Initial posting 2 Jun 2009; last update 30 May 2024. PMID:20301764. https://www.ncbi.nlm.nih.gov/books/NBK6852/
15. van Karnebeek C, Häberle J. Carbonic anhydrase VA deficiency. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. Initial posting 2 Apr 2015; last update 26 Aug 2021. PMID:25834911. https://www.ncbi.nlm.nih.gov/books/NBK284774/
16. Raina R, Bedoyan JK, Lichter-Konecki U, Jouvet P, Picca S, Mew NA, et al. Consensus guidelines for management of hyperammonaemia in paediatric patients receiving continuous kidney replacement therapy. Nat Rev Nephrol. 2020;16(8):471–82. https://doi.org/10.1038/s41581-020-0267-8
17. Parikh S, Goldstein A, Koenig MK, Scaglia F, Enns GM, Saneto R, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015;17(9):689–701. https://doi.org/10.1038/gim.2014.177
18. Parikh S, Goldstein A, Karaa A, Koenig MK, Anselm I, Brunel-Guitton C, et al. Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2017;19(12). https://doi.org/10.1038/gim.2017.107
19. British Society for Paediatric Endocrinology and Diabetes. BSPED guideline for the management of children and young people under the age of 18 years with diabetic ketoacidosis – 2021 (v3) [Internet]. BSPED; 2021 [cited 17 Oct 2026]. https://bsped.org.uk/media/v2ydcuv0/bsped-dka-guideline-v3.pdf
20. Glaser N, Fritsch M, Priyambada L, Rewers A, Cherubini V, Estrada S, et al. ISPAD clinical practice consensus guidelines 2022: diabetic ketoacidosis and hyperglycemic hyperosmolar state. Pediatr Diabetes. 2022;23(7):835–56. https://doi.org/10.1111/pedi.13406. PMID:36250645.
21. MetabERN — European Reference Network for Hereditary Metabolic Disorders [Internet]. [cited 17 Oct 2026]. https://metab.ern-net.eu/
22. ERKNet — European Rare Kidney Disease Reference Network [Internet]. [cited 17 Oct 2026]. https://www.erknet.org/
23. Giaccari M, Veligratli F, Hayes W, Topaloglu R, Ozdemir G, Ruggiero B, et al. The European distal renal tubular acidosis registry: a 5-year analysis. Nephrol Dial Transplant. 2026;41(10):1839–48. https://doi.org/10.1093/ndt/gfag051. PMID:41790493.
24. Orphanet. Autosomal recessive distal renal tubular acidosis. ORPHA:402041. https://www.orpha.net/en/disease/detail/402041
25. Thakare S, Lila A, Keskar V, Geetha T, Kumar Bs K, Rao N, et al. Molecular genetics and long-term outcomes of primary distal renal tubular acidosis in Asia. Nephrol Dial Transplant. 2026;41(5):942–55. https://doi.org/10.1093/ndt/gfaf222. PMID:41134021.
26. Orphanet. Autosomal dominant distal renal tubular acidosis. ORPHA:93608. https://www.orpha.net/en/disease/detail/93608
27. Orphanet. Distal renal tubular acidosis with anemia. ORPHA:93610. https://www.orpha.net/en/disease/detail/93610
28. Orphanet. Autosomal recessive proximal renal tubular acidosis. ORPHA:93607. https://www.orpha.net/en/disease/detail/93607
29. Orphanet. Osteopetrosis with renal tubular acidosis. ORPHA:2785. https://www.orpha.net/en/disease/detail/2785
30. Orphanet. Pyruvate carboxylase deficiency. ORPHA:3008. https://www.orpha.net/en/disease/detail/3008
31. Orphanet. Phosphoenolpyruvate carboxykinase deficiency. ORPHA:2880. https://www.orpha.net/en/disease/detail/2880
32. GeneGuidance. PCK1: clinical gene curation (clinical aspects, treatment). Local database geneguidance.db, version of 26 Sep 2026.
33. Orphanet. Ketoacidosis due to monocarboxylate transporter-1 deficiency. ORPHA:438075. https://www.orpha.net/en/disease/detail/438075
34. Orphanet. Glutathione synthetase deficiency. ORPHA:32. https://www.orpha.net/en/disease/detail/32
35. Wevers RA, Mayatepek E, Walker V. Disorders of peptide and amine metabolism: disorders of glutathione metabolism. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 31, section 31.3. https://doi.org/10.1007/978-3-662-63123-2_31
36. Orphanet. 5-oxoprolinase deficiency. ORPHA:33572. https://www.orpha.net/en/disease/detail/33572
37. Touati G, Mochel F, Artuch R. Diagnostic procedures. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 3. https://doi.org/10.1007/978-3-662-63123-2_3
38. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Introduction to lactic acidemias. In: Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 353–363.
39. Baker L, Winegrad AI. Fasting hypoglycaemia and metabolic acidosis associated with deficiency of hepatic fructose-1,6-diphosphatase activity. Lancet. 1970;2(7662):13–6. https://doi.org/10.1016/s0140-6736(70)92474-8. PMID:4193749.
40. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Fructose-1,6-diphosphatase deficiency. In: Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 371–375.
41. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Pyruvate carboxylase deficiency. In: Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 364–370.
42. Brivet M, Gaignard P, Schiff M. Disorders of pyruvate metabolism and the tricarboxylic acid cycle: phosphoenolpyruvate carboxykinase deficiency and pyruvate dehydrogenase complex. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 11, section 11.2. https://doi.org/10.1007/978-3-662-63123-2_11
43. Sly WS, Hewett-Emmett D, Whyte MP, Yu YS, Tashian RE. Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. Proc Natl Acad Sci U S A. 1983;80(9):2752–6. https://doi.org/10.1073/pnas.80.9.2752. PMID:6405388.
44. Sly WS, Whyte MP, Sundaram V, Tashian RE, Hewett-Emmett D, Guibaud P, et al. Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. N Engl J Med. 1985;313(3):139–45. https://doi.org/10.1056/NEJM198507183130302. PMID:3925334.
45. Bruce LJ, Cope DL, Jones GK, Schofield AE, Burley M, Povey S, et al. Familial distal renal tubular acidosis is associated with mutations in the red cell anion exchanger (Band 3, AE1) gene. J Clin Invest. 1997;100(7):1693–707. https://doi.org/10.1172/JCI119694. PMID:9312167.
46. Karet FE, Finberg KE, Nelson RD, Nayir A, Mocan H, Sanjad SA, et al. Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness. Nat Genet. 1999;21(1):84–90. https://doi.org/10.1038/5022. PMID:9916796.
47. Smith AN, Skaug J, Choate KA, Nayir A, Bakkaloglu A, Ozen S, et al. Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing. Nat Genet. 2000;26(1):71–5. https://doi.org/10.1038/79208. PMID:10973252.
48. Igarashi T, Inatomi J, Sekine T, Cha SH, Kanai Y, Kunimi M, et al. Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities. Nat Genet. 1999;23(3):264–6. https://doi.org/10.1038/15440. PMID:10545938.
49. Enerbäck S, Nilsson D, Edwards N, Heglind M, Alkanderi S, Ashton E, et al. Acidosis and deafness in patients with recessive mutations in FOXI1. J Am Soc Nephrol. 2018;29(3):1041–8. https://doi.org/10.1681/ASN.2017080840. PMID:29242249.
50. Rungroj N, Nettuwakul C, Sawasdee N, Sangnual S, Deejai N, Misgar RA, et al. Distal renal tubular acidosis caused by tryptophan-aspartate repeat domain 72 (WDR72) mutations. Clin Genet. 2018;94(5):409–18. https://doi.org/10.1111/cge.13418. PMID:30028003.
51. Daenen M, Hureaux M, Ashton E, Becherucci F, Berry I, Benz M, et al. A novel, dominant disease mechanism of distal renal tubular acidosis with specific variants in ATP6V1B1. Nephrol Dial Transplant. 2025;40(8):1531–7. https://doi.org/10.1093/ndt/gfaf016. PMID:39837581.
52. van Hasselt PM, Ferdinandusse S, Monroe GR, Ruiter JP, Turkenburg M, Geerlings MJ, et al. Monocarboxylate transporter 1 deficiency and ketone utilization. N Engl J Med. 2014;371(20):1900–7. https://doi.org/10.1056/NEJMoa1407778. PMID:25390740.
53. Orphanet. Hyperkalemic renal tubular acidosis. ORPHA:89939. https://www.orpha.net/en/disease/detail/89939
54. Brivet M, Gaignard P, Schiff M. Disorders of pyruvate metabolism and the tricarboxylic acid cycle: pyruvate carboxylase deficiency. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 11, section 11.1. https://doi.org/10.1007/978-3-662-63123-2_11
55. Orphanet. Distal renal tubular acidosis. ORPHA:18. https://www.orpha.net/en/disease/detail/18
56. Orphanet. Proximal renal tubular acidosis. ORPHA:47159. https://www.orpha.net/en/disease/detail/47159
57. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Osteopetrosis with renal tubular acidosis. In: Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford: Oxford University Press; 2018. p. 591–595.
58. Hospira Inc. Sodium Bicarbonate Injection USP 8.4% (revised 05/2025) and 4.2% Sodium Bicarbonate Injection USP (Infant) (revised 01/2018): prescribing information. DailyMed [cited 17 Oct 2026]. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=8664c7ce-707b-4c6c-9ce4-7160b5f877f8
59. Rahman S, Mayr JA. Disorders of oxidative phosphorylation. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 10. https://doi.org/10.1007/978-3-662-63123-2_10
60. Santer R, Klepper J. Disorders of glucose and monocarboxylate transporters. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 8, section 8.7 (MCT1 deficiency). https://doi.org/10.1007/978-3-662-63123-2_8
61. Steinmann B, Santer R. Disorders of fructose metabolism: fructose-1,6-bisphosphatase deficiency. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 15, section 15.3. https://doi.org/10.1007/978-3-662-63123-2_15
62. HUGO Gene Nomenclature Committee. HGNC database [Internet]. [cited 17 Oct 2026]. https://www.genenames.org/
63. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61–8. https://doi.org/10.1002/humu.23348. https://variantvalidator.org/ [cited 17 Oct 2026]
64. Xue M. Case report: prenatal neurological injury in a neonate with pyruvate carboxylase deficiency type B. Front Endocrinol (Lausanne). 2023;14:1199590. https://doi.org/10.3389/fendo.2023.1199590. PMCID:PMC10360024.
65. Magdy RM, Sadek AA, Hemdan SB, Mahmoud AS, Abdel Fattah NH, Abdelkreem E, et al. Clinical and molecular characterization of 14 Egyptian children with fructose-1,6-bisphosphatase deficiency. Ital J Pediatr. 2025;51(1):314. https://doi.org/10.1186/s13052-025-02146-w
66. Yazbeck N, Barhoumi A, Karam PE. Towards next-generation sequencing as a first-tier diagnostic test for fructose-1,6-bisphosphatase deficiency. Metabolites. 2026;16(1):56. https://doi.org/10.3390/metabo16010056
67. Chandrasekhar V, Yelkur P, K V. Infantile fructose-1,6-bisphosphatase deficiency masquerading as mitochondriopathy. Cureus. 2024;16(8):e67291. https://doi.org/10.7759/cureus.67291. PMCID:PMC11412278.
68. Vasiļevska L, Puķīte I, Auzenbaha M, Rots D, Grīnfelde I, Lazdāne A, et al. A novel PCK1 gene variant associated with cytosolic phosphoenolpyruvate carboxykinase deficiency: two siblings with different clinical presentations. JIMD Rep. 2026;67(1):e70065. https://doi.org/10.1002/jmd2.70065
69. Shurrab S, Mobarak A, Horvath G, Stocker-Ipsiroglu S, van Karnebeek C, Salvarinova-Zivkovic R. Long-term follow-up of patients with mitochondrial carbonic anhydrase VA deficiency: a case report and literature review. JIMD Rep. 2026;67(4):e70102. https://doi.org/10.1002/jmd2.70102
70. Bhatt GC, Krishnamurthy S, Sinha A, Mittal A, Kumar M, Vijay N, et al. Clinical and genetic spectrum of distal renal tubular acidosis in children: findings from Indian tubular disorders registry. Pediatr Nephrol. 2026. https://doi.org/10.1007/s00467-026-07505-1. PMID:42622870.
71. Vallabhaneni P, Dawman L, Bhatia A, Kumar V, Bala A, Tiewsoh K. Renal cysts in WDR72-associated distal renal tubular acidosis: expanding the phenotypic spectrum. CEN Case Rep. 2026;15(5):129. https://doi.org/10.1007/s13730-026-01168-5. PMID:42545441.
72. GeneGuidance. SLC16A1: clinical gene curation (treatment, frequency). Local database geneguidance.db, version of 26 Sep 2026.
73. GeneGuidance. FOXI1: clinical gene curation (clinical aspects, ClinGen). Local database geneguidance.db, version of 26 Sep 2026.
74. Magner M, Dvorakova V, Tesarova M, Mazurova S, Hansikova H, Zahorec M, et al. TMEM70 deficiency: long-term outcome of 48 patients. J Inherit Metab Dis. 2015;38(3):417–26. https://doi.org/10.1007/s10545-014-9774-8
75. Maiorana A, Vergine G, Coletti V, Luciani M, Rizzo C, Emma F, et al. Acute thiamine deficiency and refeeding syndrome: similar findings but different pathogenesis. Nutrition. 2014;30(7–8):948–52. https://doi.org/10.1016/j.nut.2014.02.019
76. British Inherited Metabolic Diseases Group. Adult emergency management: fructose 1,6-bisphosphatase deficiency (intravenous). 2024 [cited 17 Oct 2026]. https://bimdg.org.uk/wp-content/uploads/2024/10/Fructose1-6-Adult-IV.pdf
77. Elsayed SM, Mahmoud RG, Fereig YA. Clinical and molecular characteristics of fructose 1,6 bisphosphatase deficiency in 6 Egyptian patients and two common variants. Orphanet J Rare Dis. 2025;20(1):595. https://doi.org/10.1186/s13023-025-04100-9
78. Goksoy E, Kumru Akin B. Utility of continuous glucose monitoring for identifying silent hypoglycemia in fructose-1,6-bisphosphatase deficiency: a pilot prospective evaluation. Front Endocrinol (Lausanne). 2025;16:1664863. https://doi.org/10.3389/fendo.2025.1664863
79. Khalifa YM, Assem MY, Ahmed ZF, Hasan LT, Qutob IA. Monocarboxylate transporter 1 deficiency: a rare case report and systematic review of genetically confirmed cases. Ann Med Surg (Lond). 2026;88(9):6024–32. https://doi.org/10.1097/MS9.0000000000005477
80. Demirsu A, Aliyev F, Yucel E, Çıkı K, Yıldız Y, Ürel-Demir G, et al. Glutathione synthetase deficiency: severe hemolysis and metabolic acidosis with symptoms in the intrauterine period. J Pediatr Endocrinol Metab. 2026;39(2):188–92. https://doi.org/10.1515/jpem-2025-0459
81. Fragoso DC, Al-Ajmi E, Cardenas AM, Quijada-Fraile P, Biswas A, Sudhakar S, et al. Neuroimaging findings in carbonic anhydrase VA deficiency: a case series highlighting diagnostic and prognostic patterns in a potentially reversible mitochondrial dysfunction. AJNR Am J Neuroradiol. 2026;47(1):200–7. https://doi.org/10.3174/ajnr.A8948
82. Abelson N, Kristal E, Hershkovitz E, Wormser O, Dolgin V, Amar S, et al. A novel variant in an Israeli Bedouin family: the first reported cases of carbonic anhydrase VA (CA5A) deficiency in Israel. Genes (Basel). 2026;17(5):537. https://doi.org/10.3390/genes17050537
83. Lopez-Garcia SC, Emma F, Walsh SB, Fila M, Hooman N, Zaniew M, et al. Treatment and long-term outcome in primary distal renal tubular acidosis. Nephrol Dial Transplant. 2019;34(6):981–91. https://doi.org/10.1093/ndt/gfy409. PMID:30773598.
84. Firth HV, Hurst JA. Hypoglycaemia in the neonate and infant. In: Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 182–183.
85. UC Davis Health. International Society for Pediatric and Adolescent Diabetes releases new DKA guidelines [Internet]. 31 Oct 2022 [cited 17 Oct 2026]. https://providervideos.ucdavis.edu/news/international-society-for-pediatric-and-adolescent-diabetes-releases-new-dka-guidelines
86. Mochel F, Sedel F. Inborn errors of metabolism in adults: a diagnostic approach to neurological and psychiatric presentations. In: Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 2. https://doi.org/10.1007/978-3-662-63123-2_2
87. British Inherited Metabolic Diseases Group. Glycogen storage disease type 1a/1b: A&E emergency management (paediatric). Last revised September 2016 [cited 17 Oct 2026]. https://bimdg.org.uk/wp-content/uploads/2024/11/ER-AandE_GSD1-1b_2016_465539_09092016.pdf
88. British Inherited Metabolic Diseases Group. Defects of ketone metabolism: A&E emergency management (paediatric). Last revised September 2016 [cited 17 Oct 2026]. https://bimdg.org.uk/wp-content/uploads/2024/11/ER-AandE_ketone_2016_653680_09092016.pdf
89. British Inherited Metabolic Diseases Group. Management of surgery in children with an organic acidaemia and MSUD. Reviewed April 2017 [cited 17 Oct 2026]. https://bimdg.org.uk/wp-content/uploads/2024/10/Management_of_surgery_in_children_with_organic_acidaemia_201_911749_09092016.pdf
90. British Inherited Metabolic Diseases Group. Recurrent hypoglycaemia (undiagnosed). Last reviewed September 2016 [cited 17 Oct 2026]. https://bimdg.org.uk/wp-content/uploads/2024/11/Hypoglycaemia_2016_189288_09092016.pdf
91. Moey LH, Abdul Azize NA, Yakob Y, Leong HY, Keng WT, Chen BC, et al. Fructose-1,6-bisphosphatase deficiency as a cause of recurrent hypoglycemia and metabolic acidosis: clinical and molecular findings in Malaysian patients. Pediatr Neonatol. 2018;59(4):397–403. https://doi.org/10.1016/j.pedneo.2017.11.006
92. Orphanet. Hereditary fructose intolerance. ORPHA:469. https://www.orpha.net/en/disease/detail/469
93. British Inherited Metabolic Diseases Group. Adult emergency management advice for methylmalonic aciduria (MMA), with flowchart. June 2026 [cited 17 Oct 2026]. https://bimdg.org.uk/wp-content/uploads/2026/06/ADULT_MMA.docx
94. British Inherited Metabolic Diseases Group. Adult emergency management advice for propionic aciduria (PA). June 2026 [cited 17 Oct 2026]. https://bimdg.org.uk/wp-content/uploads/2026/06/ADULT_PA.docx
95. B. Braun Melsungen AG. Sodium Bicarbonate 8.4% w/v solution for infusion: summary of product characteristics (revised 8 May 2024); Torbay Pharmaceuticals, Sodium Bicarbonate 8.4% w/v Solution for Injection (revised 27 Nov 2025); Martindale Pharma, Sodium Bicarbonate Injection BP 8.4% (revised 19 Sep 2018). Electronic Medicines Compendium [cited 17 Oct 2026]. https://www.medicines.org.uk/emc/product/15216/smpc
96. B. Braun Medical. Bicarbonato de Sódio 8,4% Braun, solução para perfusão: resumo das características do medicamento [Sodium Bicarbonate 8.4% Braun, solution for infusion: summary of product characteristics]. INFARMED, Infomed; text revised Dec 2025 [cited 26 Oct 2026]. https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=1033&tipo_doc=rcm
97. Hospira Inc. THAM Solution (tromethamine injection) 0.3 M: prescribing information. Revised 2/2020. DailyMed [cited 17 Oct 2026]. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=4af52118-c12b-4ad5-30bb-959848357e8a
98. Sodium phenylacetate and sodium benzoate injection 10%/10%: prescribing information. ANDA 217526; label of 30 Oct 2023 (reference product Ammonul®, NDA 020645, approved 17 Feb 2005) [cited 17 Oct 2026]. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=217526
99. Leadiant Biosciences. Carnitor (levocarnitine) injection: prescribing information. Label of 20 Nov 2023 [cited 26 Oct 2026]. https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=carnitor
100. European Medicines Agency. Carbaglu (carglumic acid): EPAR — product information (Annex I, summary of product characteristics). EMEA/H/C/000461. Authorized 24 Jan 2003 [cited 17 Oct 2026; SmPC accessed 26 Oct 2026]. https://www.ema.europa.eu/en/medicines/human/EPAR/carbaglu
101. Recordati Rare Diseases. Carbaglu (carglumic acid) tablets for oral suspension: prescribing information. NDA 022562 (approved 18 Mar 2010; extension to propionic and methylmalonic acidemias 22 Jan 2021); label of 25 Jan 2024 [cited 17 Oct 2026]. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=022562
102. Stacpoole PW, Barnes CL, Hurbanis MD, Cannon SL, Kerr DS. Treatment of congenital lactic acidosis with dichloroacetate. Arch Dis Child. 1997;77(6):535–41. https://doi.org/10.1136/adc.77.6.535
103. Abdelmalak M, Lew A, Ramezani R, Shroads AL, Coats BS, Langaee T, et al. Long-term safety of dichloroacetate in congenital lactic acidosis. Mol Genet Metab. 2013;109(2):139–43. https://doi.org/10.1016/j.ymgme.2013.03.019
104. Pinto A, Alfadhel M, Akroyd R, Atik Altınok Y, Bernabei SM, Bernstein L, et al. International practices in the dietary management of fructose 1-6 biphosphatase deficiency. Orphanet J Rare Dis. 2018;13(1):21. https://doi.org/10.1186/s13023-018-0760-3
105. Mochel F, DeLonlay P, Touati G, Brunengraber H, Kinman RP, Rabier D, et al. Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy. Mol Genet Metab. 2005;84(4):305–12. https://doi.org/10.1016/j.ymgme.2004.09.007. PMID:15781190.
106. Breen C, White FJ, Scott CA, Heptinstall L, Walter JH, Jones SA, et al. Unsuccessful treatment of severe pyruvate carboxylase deficiency with triheptanoin. Eur J Pediatr. 2014;173(3):361–6. https://doi.org/10.1007/s00431-013-2166-5. PMID:24114256.
107. Bernhardt I, Van Dorp L, Dixon M, McSweeney M, Gan C, Baruteau J, et al. Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin. JIMD Rep. 2024;65(1):10–6. https://doi.org/10.1002/jmd2.12405. PMID:38186850.
108. Ultragenyx Pharmaceutical. Dojolvi (triheptanoin) oral liquid: prescribing information. NDA 213687 (approved 30 Jun 2020); label of 10 Jun 2025 [cited 17 Oct 2026]. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=213687
109. ClinicalTrials.gov. NCT01461304: Compassionate use of triheptanoin (C7) for inherited disorders of energy metabolism [cited 17 Oct 2026]. https://clinicaltrials.gov/study/NCT01461304
110. GeneGuidance. GSS: clinical gene curation (treatment, evidence). Local database geneguidance.db, version of 26 Sep 2026.
111. Manoy S, Minto T, Demetriou K, Lynch M, Selvanathan A, Jardine L, et al. Antenatal and neonatal management of siblings with carbonic anhydrase VA deficiency. JIMD Rep. 2026;67(2):e70076. https://doi.org/10.1002/jmd2.70076
112. GeneGuidance. CA2: clinical gene curation (treatment, evidence, frequency). Local database geneguidance.db, version of 26 Sep 2026.
113. GeneGuidance. SLC4A1: clinical gene curation (treatment, evidence, regulation). Local database geneguidance.db, version of 26 Sep 2026.
114. European Medicines Agency. Sibnayal (potassium citrate/potassium hydrogen carbonate): EPAR — product information. EMEA/H/C/005407. Authorized 30 Apr 2021; renewed 8 Jan 2026; page updated 1 Oct 2026 [cited 17 Oct 2026]. https://www.ema.europa.eu/en/medicines/human/EPAR/sibnayal
115. Mission Pharmacal. Urocit-K (potassium citrate) extended-release tablets: prescribing information. NDA 019071 (approved 30 Aug 1985); label of 2 Dec 2021 [cited 17 Oct 2026]. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=019071
116. Bertholet-Thomas A, Guittet C, Manso-Silván MA, Joukoff S, Navas-Serrano V, Baudouin V, et al. Safety, efficacy, and acceptability of ADV7103 during 24 months of treatment: an open-label study in pediatric and adult patients with distal renal tubular acidosis. Pediatr Nephrol. 2021;36(7):1765–74. https://doi.org/10.1007/s00467-020-04873-0. PMID:33635379.
117. Bertholet-Thomas A, Manso-Silván MA, Navas-Serrano V, Guittet C, Joukoff S, Bacchetta J, et al. Bone mineral density and growth changes in patients with distal renal tubular acidosis after two-years treatment with a new alkalizing drug (ADV7103). Nefrologia (Engl Ed). 2023;43(4):458–66. https://doi.org/10.1016/j.nefroe.2022.02.012
118. Ferrer Portugal. Acalka 1080 mg comprimido de libertação modificada (citrato de potássio): resumo das características do medicamento [Acalka 1080 mg modified-release tablet (potassium citrate): summary of product characteristics]. INFARMED, Infomed [cited 26 Oct 2026]. https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=8921&tipo_doc=rcm
119. ClinicalTrials.gov. NCT03644706: A phase 3 multicenter, randomized, double-blinded, placebo-controlled withdrawal study evaluating ADV7103 in pediatric and adult subjects with distal renal tubular acidosis. Advicenne [cited 17 Oct 2026]. https://clinicaltrials.gov/study/NCT03644706
120. ClinicalTrials.gov. NCT03831152: Extension study in primary distal renal tubular acidosis. Advicenne [cited 17 Oct 2026]. https://clinicaltrials.gov/study/NCT03831152
121. European Medicines Agency. Medicines for human use — data download (medicines output) [Internet]. 2026 [cited 17 Oct 2026]. https://www.ema.europa.eu/en/medicines/download-medicine-data
122. Horizon Therapeutics. Buphenyl (sodium phenylbutyrate): prescribing information. NDA 020572 (approved 13 May 1996); label of 30 Oct 2024 [cited 17 Oct 2026]. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020572
123. Saol Therapeutics. Saol Therapeutics announces the acceptance of resubmission of SL1009 (DCA) by the FDA with PDUFA date of Dec. 30, 2026 [press release]. 28 Jul 2026 [cited 17 Oct 2026]. https://www.biospace.com/press-releases/saol-therapeutics-announces-the-acceptance-of-resubmission-of-sl1009-dca-by-the-fda-with-pdufa-date-of-dec-30-2026
124. NeurologyLive. FDA accepts SL1009 resubmission for PDCD, sets December PDUFA date. 4 Aug 2026 [cited 17 Oct 2026]. https://www.neurologylive.com/view/fda-accepts-sl1009-resubmission-pdcd-sets-december-pdufa-date
125. ClinicalTrials.gov. NCT02616484: Phase 3 trial of dichloroacetate in pyruvate dehydrogenase complex deficiency. Saol Therapeutics [cited 17 Oct 2026]. https://clinicaltrials.gov/study/NCT02616484
126. Bertholet-Thomas A, Guittet C, Manso-Silván MA, Castang A, Baudouin V, Cailliez M, et al. Efficacy and safety of an innovative prolonged-release combination drug in patients with distal renal tubular acidosis: an open-label comparative trial versus standard of care treatments. Pediatr Nephrol. 2021;36(1):83–91. https://doi.org/10.1007/s00467-020-04693-2. PMID:32712761.
127. ClinicalTrials.gov. NCT06340685: Triheptanoin for children with primary-specific pyruvate dehydrogenase complex deficiency [cited 17 Oct 2026]. https://clinicaltrials.gov/study/NCT06340685
128. ClinicalTrials.gov. NCT03734263: Use of phenylbutyrate therapy for patients with pyruvate dehydrogenase complex deficiency [cited 17 Oct 2026]. https://clinicaltrials.gov/study/NCT03734263
129. GeneGuidance. ATP6V1B1: clinical gene curation (actionability, frequency). Local database geneguidance.db, version of 26 Sep 2026.
130. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine; searches by condition (distal RTA, PC, PDH, FBPase, GSS, and CA-VA deficiencies, congenital lactic acidosis, dichloroacetate) [cited 17 Oct 2026]. https://clinicaltrials.gov/
131. Sulaiman RA, Alqasir I, Alqasabi D, AlTassan R, Tulbah M, Alnemer M, et al. Challenges in managing pregnancy in patients with fructose 1,6-bisphosphatase deficiency: a single-centre experience. JIMD Rep. 2026;67(5):e70116. https://doi.org/10.1002/jmd2.70116
132. British Inherited Metabolic Diseases Group. Emergency regimen (ER) for infants age ≤1 year. Version 2026 [cited 17 Oct 2026]. https://bimdg.org.uk/wp-content/uploads/2026/06/PAEDS_ER_under1_2026.pdf
133. Seeger H, Salfeld P, Eisel R, Wagner CA, Mohebbi N. Complicated pregnancies in inherited distal renal tubular acidosis: importance of acid-base balance. J Nephrol. 2017;30(3):455–60. https://doi.org/10.1007/s40620-016-0370-x
134. MetabERN. Metabolic Emergency Letter — Metabolic Emergency Protocol [Internet]. 2026 [cited 17 Oct 2026]. https://www.emergencyprotocol.net/
135. British Inherited Metabolic Diseases Group. Emergency management advice — undiagnosed problems [Internet]. BIMDG; 2026 [cited 17 Oct 2026]. https://bimdg.org.uk/emergency-guides/undiagnosed-problems/
136. Bianic F, Guelfucci F, Robin L, Martre C, Game D, Bockenhauer D. Epidemiology of distal renal tubular acidosis: a study using linked UK primary care and hospital data. Nephron. 2021;145(5):486–95. https://doi.org/10.1159/000516876. PMID:34198293.
137. GeneGuidance. PC: clinical gene curation (frequency). Local database geneguidance.db, version of 26 Sep 2026.
138. GeneGuidance. FBP1: clinical gene curation (frequency). Local database geneguidance.db, version of 26 Sep 2026.
139. Lebigot E, Brassier A, Zater M, Imanci D, Feillet F, Thérond P, et al. Fructose 1,6-bisphosphatase deficiency: clinical, biochemical and genetic features in French patients. J Inherit Metab Dis. 2015;38(5):881–7. https://doi.org/10.1007/s10545-014-9804-6
140. Orphanet. Fructose-1,6-bisphosphatase deficiency. ORPHA:348. https://www.orpha.net/en/disease/detail/348
141. Orphanet. Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency. ORPHA:401948. https://www.orpha.net/en/disease/detail/401948
142. Mejía N, Santos F, Claverie-Martín F, García-Nieto V, Ariceta G, Castaño L; RenalTube group. RenalTube: a network tool for clinical and genetic diagnosis of primary tubulopathies. Eur J Pediatr. 2013;172(6):775–80. https://doi.org/10.1007/s00431-013-1934-6