Hereditary Fructose Intolerance and Gluconeogenesis Defects

Inborn errors of the hepatic fructose pathway — hereditary fructose intolerance (ALDOB) and essential fructosuria (KHK) — and enzyme deficiencies of gluconeogenesis — fructose-1,6-bisphosphatase (FBP1) and cytosolic and mitochondrial phosphoenolpyruvate carboxykinase (PCK1, PCK2) —, with hypoglycaemia, lactic acidosis and hepatic and renal injury that are preventable through diet, avoidance of excipients and emergency regimens.

Literature and regulatory information update: 26 October 2026.

0. Initial Reference Table

The class brings together the entities that Orphanet groups as «Disorder of fructose metabolism» (ORPHA:308463) and «Gluconeogenesis disorder» (ORPHA:79177) [1, 2]. Fructose-1,6-bisphosphatase (FBPase) deficiency is covered in textbooks of metabolic disease among the errors of fructose metabolism, although it is, strictly speaking, a gluconeogenesis defect [3]. Sorbitol dehydrogenase deficiency (SORD), which belongs to the polyol pathway and to the same reference chapter, and pyruvate carboxylase deficiency (PC), the first step of gluconeogenesis from pyruvate, appear in the table only as a related entity and as a differential diagnosis, respectively. In the table, AR stands for autosomal recessive, HFI for hereditary fructose intolerance, PEPCK for phosphoenolpyruvate carboxykinase, CNV for copy-number variation, IV for intravenous, CMT2 for axonal Charcot-Marie-Tooth disease and ERN for European Reference Network.

Gene identity, cytoband and gene OMIM number were confirmed in NCBI Gene and in the OMIM entries for each gene, and the phenotype OMIM numbers, inheritance and cytobands agree with the OMIM entries for each phenotype, all with mapping key 3 (molecular basis known), except PEPCK-M deficiency, with key 1 [4, 8, 12, 16–28]. OMIM lists essential fructosuria in square brackets and with a question mark, which classifies it as a biochemical variation without disease and with a gene-phenotype association that is still provisional, and identifies SORD deficiency as autosomal recessive distal hereditary motor neuronopathy 8 (HMNR8, 618912) [21, 28]. ClinGen classified the FBP1–FBPase deficiency relationship as definitive (AR, 14 November 2025) and the actionability of HFI as strong in the paediatric context and limited in adults [29, 30]. The relevant ERN is MetabERN, C-FAO subnetwork (carbohydrate, fatty acid oxidation and ketone bodies disorders), which lists «Disorders of galactose and fructose metabolism» (1.03.a) and «Disorders of gluconeogenesis» (1.03.b) [31].

1. Introduction

1.1. Historical overview

Essential fructosuria is one of the oldest known inborn errors of metabolism and for decades was detected by chance, when screening for reducing sugars in urine was routine laboratory practice [3, 32]. Czapek and Zimmer described it independently in 1876, in a man who also had diabetes mellitus; Lasker demonstrated autosomal recessive transmission in 1941; in 1961 Laron counted 50 published cases, 18 of them in Jews, and Schapira and colleagues demonstrated the enzyme deficiency in the liver in the same year [21]. Hereditary fructose intolerance was recognised as an entity in the 1950s. Chambers and Pratt published a letter entitled «Idiosyncrasy to fructose» in the Lancet in 1956, and Froesch, Prader, Labhart, Stuber and Wolf described «hereditäre Fructoseintoleranz» in the Schweizerische Medizinische Wochenschrift in 1957 as a hitherto unknown congenital disorder of metabolism [3, 33, 34]. Shortly afterwards, in 1962, Perheentupa and Pitkänen described two Finnish siblings with very different expression: the infant had vomiting and recurrent hypoglycaemia after weaning, with marked undernutrition, whereas the 3-year-old brother, healthy and with an aversion to sweets and fruit, only had hepatomegaly and hypoglycaemic shock after an oral test dose; in 1963, Froesch and colleagues described two adults aged 33 and 39 years with an aversion to fructose-containing foods and absence of dental caries [19]. Several hundred patients have since been identified [3]. The term «fructosaemia», proposed by Levin and colleagues in 1963 to designate the abnormal presence of fructose in plasma, is now considered obsolete, because the finding is not specific to HFI and also occurs in fructokinase deficiency and in other situations [4].

Fructose-1,6-bisphosphatase deficiency (then «fructose-1,6-diphosphatase») was described in 1970 by Baker and Winegrad in a girl with fasting hypoglycaemia and metabolic acidosis, whose brother had died of a similar illness [35, 36]. This patient's first episode was triggered by fever with food refusal and vomiting [3]. In 1971, Baerlocher, Gitzelmann, Nüssli and Dumermuth published infantile lactic acidosis due to hereditary fructose-1,6-diphosphatase deficiency, and Hülsmann and Fernandez described further patients, with several affected siblings from consanguineous marriages [36, 37]. The eponym «Baker-Winegrad disease» has persisted in the literature [8]. In 1972, Pagliara and colleagues described an 8-month-old girl with episodes of hyperventilation since the introduction of cereals at 6 months, admitted with severe lactic acidosis and hypoglycaemia, with no hepatic FBPase activity, in whom an adequate intake of carbohydrate without sucrose or fructose prevented further episodes; in the same year, Greene and colleagues reported treatment with folic acid in two patients, an approach that is not part of current protocols (section 7) [23].

Cytosolic PEPCK deficiency was first described by Søvik and colleagues (1975) and by Vidnes and Søvik (1976), in a boy with seizures and severe hypoglycaemia on the second day of life who did not respond to subtotal pancreatectomy or diazoxide; in the liver, total PEPCK activity was normal but practically absent in the cytosolic fraction, and the child died at 2 years and 10 months (section 3.5) [25, 26]. PEPCK deficiency was proposed as a cause of infantile hypoglycaemia by Fiser, Melsher and Fisher in 1974, in an abstract, and by Hommes and colleagues in 1976, in two unrelated children with hypoglycaemia and liver injury, in whom PEPCK activity was reduced in liver obtained immediately after death and autopsy showed massive fatty infiltration of the liver and kidneys [12]. In 1980, Robinson and colleagues studied fibroblasts from 40 children with lactic acidosis and found one with mitochondrial PEPCK activity of 6% of normal [12]. These reports predate molecular study, and the reduced mitochondrial activity described in these patients is now interpreted as a secondary phenomenon [12, 13].

Molecular biology reached the class in three stages. In 1994, Bonthron, Brady, Donaldson and Steinmann cloned the complementary DNA of human ketohexokinase (KHK, fructokinase), described the isoforms generated by alternative polyadenylation and splicing and identified, in a family with three of eight fructosuric siblings, compound heterozygosity p.Gly40Arg/p.Ala43Thr [32]. In 1997, Kikawa and colleagues made the first molecular diagnosis of FBPase deficiency in 13 Japanese patients from 11 families, from messenger RNA of cultured monocytes, and showed that a G insertion in exon 7 accounted for 46% of mutant alleles [38]. The first biallelic PCK1 genotype was published in 2014 by Adams and colleagues, who found by exome sequencing the p.Ile45Thr variant in homozygosity in two Ashkenazi sisters with fasting and illness-induced hypoglycaemia; each sister also had a de novo variant in another gene (RAI1, Smith-Magenis syndrome, and GRIN2B), which made the phenotype composite [25, 26]. In 2016, Santra and colleagues identified by exome sequencing a homozygous 12 bp deletion in PCK1 in a consanguineous family, with enzymatic confirmation, in the first patient with an isolated PEPCK-C deficiency phenotype [17, 39]. In 2022, Vieira and colleagues brought together 24 Finnish patients and Goetz and colleagues 32 patients from 25 families in a systematic review [10, 11].

The history of HFI has also been marked by iatrogenic harm. By 1993, 23 cases of parenteral administration of fructose or sorbitol to patients with HFI had been published, 17 of them fatal (73%); three adults died after receiving about 25 to 50 g of sorbitol [40]. The death of an 18-month-old child treated with an intravenous solution containing fructose led to a European benefit-risk assessment in 2001 and, later, to the excipient labelling rules adopted in 2016–2017 [40, 41].

1.2. Definition of the entities within scope

Hereditary fructose intolerance is the autosomal recessive deficiency of aldolase B, the fructaldolase of the liver, renal cortex and small intestine, which cleaves fructose-1-phosphate; patients are healthy as long as they do not ingest fructose, sucrose or sorbitol and develop hypoglycaemia, vomiting and hepatic and tubular injury when they do [3, 4]. Essential fructosuria is the autosomal recessive deficiency of the hepatic C isoform of ketohexokinase, without clinical manifestations, defined by the intermittent presence of fructose in urine [3, 18]. Fructose-1,6-bisphosphatase deficiency is the autosomal recessive deficiency of the hepatic enzyme that hydrolyses fructose-1,6-bisphosphate to fructose-6-phosphate; it blocks gluconeogenesis from all precursors and presents with episodes of fasting hypoglycaemia and lactic acidosis [3, 8]. Cytosolic PEPCK deficiency is the autosomal recessive deficiency of the GTP (guanosine triphosphate)-dependent enzyme that converts oxaloacetate into phosphoenolpyruvate, with hypoglycaemia triggered by catabolism, inadequate ketogenesis and urinary excretion of Krebs cycle intermediates [11, 17]. Mitochondrial PEPCK deficiency (OMIM 261650) remains an entity without an established molecular basis; the reduced mitochondrial activity described in patients is now interpreted as a secondary phenomenon [13, 14].

1.3. Current classifications

The reference chapter on fructose metabolism groups four inborn errors of the pathway: essential fructosuria, HFI, sorbitol dehydrogenase deficiency and FBPase deficiency [3]. Orphanet distinguishes two categories — «Disorder of fructose metabolism» (ORPHA:308463), with HFI (ORPHA:469) and essential fructosuria (ORPHA:2056), and «Gluconeogenesis disorder» (ORPHA:79177), with FBPase deficiency (ORPHA:348) and PEPCK deficiency (ORPHA:2880, which groups the cytosolic and mitochondrial forms; the former subtypes ORPHA:79316 and ORPHA:79317 are flagged as obsolete) [1, 2, 42–45]. MetabERN places these diseases in the C-FAO subnetwork, with groups 1.03.a (galactose and fructose) and 1.03.b (gluconeogenesis) [31]. In the pathophysiological classification of inherited metabolic diseases, HFI belongs to the «small-molecule intoxication» group, with galactosaemia, the aminoacidopathies, the organic acidurias and the urea cycle defects, because symptoms depend on exposure to the substrate [46]. FBPase deficiency and PEPCK-C deficiency belong to the «enzymatic» defects of gluconeogenesis, with hypoglycaemia after moderate to prolonged fasting [46].

1.4. Scope and related entities

The article covers the class uniformly and examines HFI and FBPase deficiency in depth, the two entities with the largest case series, while treating with equal detail the little that is known about PEPCK-C deficiency and essential fructosuria. The differential diagnosis includes the other genetic causes of hypoglycaemia, monogenic neonatal and recurrent acute liver failure, the glycogen storage diseases, galactosaemia, tyrosinaemia type 1, the congenital disorders of glycosylation (CDG), pyruvate dehydrogenase complex deficiency and neuropathy due to sorbitol dehydrogenase deficiency.

2. Molecular Genetics and Pathophysiology

2.1. The hepatic fructose pathway and gluconeogenesis

Fructose is the main sweetener in the diet: it occurs free in honey, fruit and many vegetables, is bound to glucose in sucrose and also derives from the sorbitol of fruit and vegetables, which sorbitol dehydrogenase converts into fructose in the liver [3]. Increasing consumption, particularly of high-fructose corn syrup, has been associated with obesity, metabolic syndrome, hepatic steatosis, type 2 diabetes and gout [3]. Fructose is absorbed in the intestine by the apical membrane transporter GLUT5, passes into the portal circulation via basolateral GLUT2 and is taken up by GLUT2 in the liver and renal cortex. There it is metabolised in three steps: fructokinase (KHK) phosphorylates it to fructose-1-phosphate (F-1-P), aldolase B cleaves F-1-P into dihydroxyacetone phosphate (DHA-P) and glyceraldehyde, and triokinase phosphorylates glyceraldehyde [3, 4]. Isotope tracer studies in rodents have shown that low doses of fructose are almost entirely converted into glucose in the intestine, whereas high doses are only partly metabolised, with fructose and organic acids produced by colonic bacteria appearing in the portal vein [3].

Hepatic and renal gluconeogenesis produces glucose from lactate, pyruvate, alanine, glycerol and Krebs cycle intermediates. Two irreversible steps of glycolysis are bypassed by dedicated enzymes: PEPCK converts oxaloacetate into phosphoenolpyruvate, and FBPase hydrolyses fructose-1,6-bisphosphate to fructose-6-phosphate; the reverse reaction of the latter requires phosphofructokinase and ATP (adenosine triphosphate) [17, 36]. FBPase is the point of convergence of all gluconeogenic precursors, including dietary fructose and glycerol, which enter the pathway at the level of the triose phosphates [3, 8]. During fasting, normoglycaemia depends first on hepatic glycogen and then on gluconeogenesis; this is why FBPase and PEPCK deficiencies become manifest when glycogen is scarce (newborn) or depleted (fasting, fever, vomiting) [3, 36].

2.2. Hereditary fructose intolerance: aldolase B and fructose-1-phosphate toxicity

There are three aldolase genes: isoenzyme A predominates in muscle, C in brain, and B is the main fructaldolase of the liver, renal cortex and small intestine [3]. ALDOB maps to 9q31.1 and encodes fructose-bisphosphate aldolase B, which has two functions: the reversible cleavage of fructose-1,6-bisphosphate into DHA-P and glyceraldehyde-3-phosphate, shared by glycolysis and gluconeogenesis, and, in fructolysis, the cleavage of the F-1-P formed by fructokinase [4, 50]. The disease mechanism is loss of function [4]. The gene has nine exons, the first untranslated, and the active enzyme is a tetramer of identical subunits of about 40 kDa; aldolase A predominates in the embryo, and in the adult liver, kidney and intestine expression of A is repressed and replaced by that of B, which reverts to the A form in transformed hepatic cells [20]. Hepatic ALDOB expression is induced by fructose ingestion and modulated by cortisol, thyroid hormones, insulin and glucagon, whereas in the kidney and intestine it responds little to these stimuli; there is an aldolase pseudogene on 10q [20]. Recombinant expression of patient variants separated two groups: catalytic mutants, which retain the tetramer but have altered kinetics (W147R, R303W, A337V, in historical numbering, = NM_000035.4:c.442T>C p.(Trp148Arg), c.910C>T p.(Arg304Trp) and c.1013C>T p.(Ala338Val)), and structural mutants, whose tetramers dissociate with severe loss of activity (A174D, N334K, = c.524C>A p.(Ala175Asp) and c.1005C>G p.(Asn335Lys)); the A149P protein (= c.448G>C p.(Ala150Pro)) is inactive, and the A174D proteins and the 6 bp exon 6 deletion cannot be recovered in soluble form [20].

Because fructokinase activity is high, fructose ingestion by a patient with HFI causes F-1-P to accumulate in the hepatocyte and sequesters inorganic phosphate. Two main effects follow. The first is inhibition of glucose production: F-1-P blocks gluconeogenesis (by inhibiting aldolase A) and glycogenolysis (by inhibiting glycogen phosphorylase a), which causes blood glucose to fall rapidly. The second is overutilisation and reduced regeneration of ATP, with increased uric acid production, magnesium release, impaired protein synthesis and ultrastructural lesions that explain hepatic and renal dysfunction [3]. Acute post-fructose hypoglycaemia is refractory to glucagon [4]. F-1-P is also a potent competitive inhibitor of phosphomannose isomerase (Ki about 40 µM), which produces a secondary N-glycosylation defect with a CDG type I sialotransferrin profile and serum lysosomal enzyme abnormalities identical to those of CDG type I [51]. The cause of serious events with infusions is not hypoglycaemia but intracellular accumulation of F-1-P [40].

The residual activity measured with fructose-1,6-bisphosphate as substrate is due mainly to aldolase A. Therefore, in HFI, glycolysis and gluconeogenesis are not impaired during fasting and patients tolerate long fasts — the feature that separates HFI from gluconeogenesis defects [3]. Intravenous fructose causes the same changes in healthy individuals (fall in ATP and phosphate, rise in urate and magnesium) to an equivalent but transient degree, documented by phosphorus-31 magnetic resonance spectroscopy (31P-MRS); in people without HFI it raises blood glucose, but rapid conversion to lactate can cause metabolic acidosis, which is why fructose, sorbitol and invert sugar were withdrawn from parenteral nutrition in general [3].

Steatosis in treated patients has explanations that have accumulated in recent years. The Aldob knockout mouse reproduces HFI, with growth retardation and hepatic dysfunction aggravated by fructose and rapid-onset steatosis that reverses when fructose is removed from the diet [19, 20]. In animal models, F-1-P increases intrahepatic triglycerides and endogenous fructose synthesis via the polyol pathway contributes to this accumulation [3, 52]. In 14 patients and 14 controls, serum fructose rose at 30 and 60 minutes of a 75 g oral glucose tolerance test, demonstrating endogenous fructose production from glucose; in Aldob−/− mice, 13C-labelled glucose was incorporated into F-1-P, and an aldose reductase inhibitor reduced hepatic fructose without reducing intrahepatic lipid [53]. In rats with CRISPR-inactivated Aldob, steatosis appeared during fasting even on fructose-free chow, owing to deficient β-oxidation and increased de novo lipogenesis, attributed to activation of ChREBP (carbohydrate response element-binding protein) by the accumulation of glycolytic metabolites resulting from impaired gluconeogenesis [54].

2.3. Essential fructosuria: ketohexokinase

KHK (2p23.3) gives rise, by tissue-specific alternative splicing, to two isoforms: KHK-C, with high affinity for fructose, expressed in adult liver, kidney and small intestine, and KHK-A, widely distributed in fetal and adult organs, with much lower affinity but greater thermostability [3, 55]. Only two causal variants have been described in affected individuals, in a single family. p.Gly40Arg is null — it inactivates both isoforms and renders the protein insoluble —, whereas p.Ala43Thr reduces thermostability and, at 37 °C, abolishes KHK-C activity but not KHK-A activity; the compound heterozygotes would thus have a selective hepatic deficiency with preserved peripheral KHK-A [32, 55]. The structure of the variants has been characterised by crystallography [3]. Without fructokinase, 10–20% of ingested fructose is excreted unchanged in urine and the remainder is slowly metabolised by hexokinase in adipose tissue and muscle to fructose-6-phosphate [3]. The common variant p.Val49Ile (rs2304681), present on 36.8% of chromosomes in the UK Biobank and in the same region as the p.Ala43Thr allele of the original family, is benign [56, 57]. In the original Swiss family, the offspring of third cousins, homozygosity was expected, but the affected individuals were compound heterozygotes, and the p.Val49Ile change was on the same allele as p.Ala43Thr (the father was homozygous for Ile49 and the mother for Val49) [22]. KHK lies less than 500 kb from GCKR, the gene for glucokinase regulatory protein, another gene of hepatic carbohydrate metabolism [22].

2.4. Fructose-1,6-bisphosphatase deficiency

FBP1 maps to 9q22.32 (9q22.2–q22.3 in early publications), spans about 31 kb and has a non-coding exon 1 and seven coding exons [8, 36, 58]; the original description of the structure, summarised in OMIM, counted seven exons in total, with the six introns in the same positions as in the rat gene [24]. Linkage analysis excluded FBP1 as a candidate gene for maturity-onset diabetes of the young (MODY) and type 2 diabetes in European and African American families [24]. FBPase (EC 3.1.3.11) is most active in the liver and kidney, is tightly regulated and has fructose-2,6-bisphosphate as its main physiological regulator [3, 36]. There is more than one isoenzyme with FBPase activity in humans: the muscle isoform, encoded by FBP2, has different kinetics and is not affected [3, 36]. The mechanism is loss of function [8].

The deficiency impairs glucose formation from all gluconeogenic precursors. Normoglycaemia then depends on glucose and galactose intake, hepatic glycogenolysis and, to a lesser extent, muscle glucose production [3]. When glycogen is depleted, lactate, pyruvate, alanine and glycerol accumulate [3, 8]. The lactate/pyruvate (L/P) ratio may increase owing to secondary impairment of the conversion of 1,3-bisphosphoglycerate to glyceraldehyde-3-phosphate, which accumulates NADH (reduced nicotinamide adenine dinucleotide) and shifts the pyruvate/lactate equilibrium [3]. Ketosis may be absent: accumulated pyruvate increases oxaloacetate, diverts acetyl-CoA to citrate synthesis, increases cytosolic malonyl-CoA and inhibits carnitine palmitoyltransferase I (CPT I), reducing the entry of fatty acids into the mitochondrion and ketogenesis; the same mechanism favours the accumulation of fatty acids in the liver and plasma [3]. Hyperuricaemia results from activation of the pentose phosphate pathway, with increased purine synthesis and degradation [8], and, after fructose, from degradation of adenine nucleotides [36].

Fructose intake is tolerated in moderate amounts, because F-1-P can still be converted into lactate; children generally tolerate up to 2 g of fructose/kg/day spread throughout the day and grow well [3]. Intravenous fructose loads nevertheless induce hypoglycaemia through inhibition of glycogen phosphorylase a by F-1-P, although at higher doses than in HFI; on hepatic 31P-MRS after 200 mg/kg of intravenous fructose, F-1-P falls more slowly and recovery from phosphate and ATP depletion is delayed [3]. Glycerol and sorbitol produce similar responses, and galactose tolerance is normal [36]. Metformin inhibits AMP (adenosine monophosphate)-sensitive FBP1, which explains part of its reduction of hepatic glucose production and its propensity to cause lactic acidosis [3, 59].

Interpretation of FBP1 variants has been organised along three dimensions: protein abundance and stability, catalytic activity and a non-canonical function of restraining AKT signalling. Many missense variants preserve the protein but abolish catalysis, others reduce both through misfolding, and some C-terminal variants disturb the AKT regulatory function [60]. In patients without a variant in the coding region, variants in the promoter or in the gene for the bifunctional enzyme that controls fructose-2,6-bisphosphate have been hypothesised [3].

Steatosis in FBPase deficiency has no established mechanism. In the Fbp1-disrupted mouse, activation of endoplasmic reticulum stress and de novo lipogenesis is accompanied by hepatomegaly, triglyceride accumulation and stellate cell senescence, and the authors of the Franco-Belgian series consider that the same may occur in patients during decompensations; unlike HFI, F-1-P accumulates only after a fructose load, so it does not explain chronic steatosis [61]. The nuclear function of FBPase as a transcriptional regulator, which in renal cancer cells reduces the expression of glycolytic genes induced by hypoxia-inducible factors (HIF), may contribute to the chronic phenotype, with no data in patients [61]. FBP1 is uniformly depleted in more than 600 clear cell renal carcinomas analysed, where it restrains glycolysis and, independently of catalytic activity, inhibits the nuclear function of HIF through direct interaction; loss of 9q22 is associated with a worse prognosis in this tumour [24]. These oncology data do not demonstrate tumour risk in patients with the hereditary deficiency.

2.5. Cytosolic and mitochondrial PEPCK deficiency

PCK1 (20q13.31) encodes PEPCK-C, the rate-limiting enzyme of gluconeogenesis, the main control point of hepatic and renal glucose production from lactate, glycerol, amino acids and Krebs cycle precursors during fasting; its expression is regulated by insulin, glucagon, glucocorticoids, cAMP (cyclic AMP) and diet, and the enzyme governs cataplerosis and anaplerosis of the Krebs cycle [17]. The block prevents the conversion of oxaloacetate into phosphoenolpyruvate, so the liver does not produce glucose from lactate and Krebs cycle precursors once glycogen is depleted. Cycle intermediates accumulate and pass into the urine, with characteristic fumarate; ketogenesis during hypoglycaemia is inadequate, and the patient is left without glucose and without alternative fuel [11, 17]. Protein modelling suggests that the variants alter manganese and substrate binding [10]. PEPCK-C has 622 amino acids, and the PCK1 promoter contains thyroid hormone and glucocorticoid response elements [26]. Functional studies of the first three variants show loss-of-function mechanisms: p.Ile45Thr is expressed mainly as insoluble protein, with normal kinetics but thermostability of 59% of normal at 37 °C and a half-life in HEK293 cells of about 2 hours, against more than 24 hours for the normal protein, in agreement with hepatic immunoreactive PEPCK-C of 10% or less; the 12 bp deletion removes four conserved amino acids from the N-terminal domain, next to the GTP-binding site, and abolishes activity in COS-1 cells; p.Gly309Arg reduces protein quantity and activity to values similar to those of the empty vector [26]. An association between the −232C>G promoter polymorphism and type 2 diabetes (odds ratio of 1.9 in a Canadian Aboriginal sample and 2.8 in a European sample) is classified by OMIM as an association pending confirmation [26]. PCK2 (14q11.2-q12) encodes mitochondrial PEPCK, a 640-amino-acid protein with 70% identity with the cytosolic form, encoded by ten exons and expressed mainly in the liver and kidney, but also in the intestine, pancreas and fibroblasts; in human liver, PEPCK activity is distributed in similar proportions between cytosol and mitochondria [27]. In the rat, Pck2 silencing by antisense oligonucleotides reduced gluconeogenesis from lactate and alanine and lowered blood glucose and insulin in the fed state, differences that disappeared after prolonged fasting, suggesting compensation by PEPCK-C; in rodent β cells, PEPCK-M participates in glucose-stimulated insulin secretion [27]. In Shetland sheepdogs, a heterozygous Pck2 variant was associated with exercise-induced paroxysmal dyskinesia with borderline hypoglycaemia and mild lactic acidosis; the same change is present in 27 human heterozygotes in gnomAD, with no human phenotype described [27]. There are no established human pathogenic variants and the reduced mitochondrial activity described in patients is considered secondary [13, 14]. OMIM maintains entry 261650 as a Mendelian phenotype of unknown molecular basis, records autosomal recessive inheritance and links it to PCK2 only with mapping key 1, which indicates association with a gene without a known underlying defect [12]. According to Clayton and colleagues (1986), fibroblasts contain only the mitochondrial isoform, which made it possible to measure it in this tissue; they described the deficiency in a girl who died of liver failure at 6 months and, probably, in her brother, who died suddenly at 4 weeks. In a third sibling with similar liver failure, PEPCK activity was normal in leucocytes and fibroblasts (Leonard and colleagues, 1991), and study of a fourth sibling showed mitochondrial DNA depletion corrected by nuclear complementation (Bodnar and colleagues, 1993), so the familial picture was attributed to a nuclear-controlled mitochondrial DNA depletion syndrome and not to a primary deficiency of the enzyme [12].

2.6. Variant spectrum and nomenclature

The variants in the table were normalised in VariantValidator (GRCh38, MANE Select transcript, Matched Annotation from NCBI and EMBL-EBI) and checked against ClinVar in October 2026 [57, 62]. Historical ALDOB nomenclature omitted the initiator methionine, so A149P corresponds to p.(Ala150Pro) [4]. For KHK, the MANE Select transcript returned by VariantValidator is NM_006488.3.

The insertion was also the most frequent variant in a non-Japanese population studied by Herzog and colleagues [36, 71]. Two nomenclature issues require attention when reading the FBP1 literature. The Japanese insertion described by Kikawa as «960/961insG» was renamed c.959dup by Santer and colleagues (who write it «c.959dupG … originally named c.960_1insG»), but the literal notation c.960_961insG and the Egyptian variant c.960delinsGG in ClinVar produce, according to VariantValidator, p.(Ser321ValfsTer13), whereas c.959dup produces p.(Ser321IlefsTer13); they are therefore descriptions of distinct variants, which should not be merged without checking the genomic DNA of each series [38, 58, 62, 66]. In addition, the historical nomenclature of the reference atlas (807delG, 704-705insC, A177D, N213K, G294V, F194S, P284R) predates HGVS (Human Genome Variation Society) and can only be converted with verification in the databases; at the protein level, the numbering of these FBP1 changes coincides with that of the MANE transcript (N213K = p.(Asn213Lys), with c.639C>G and c.639C>A both recorded in ClinVar; G294V = NM_000507.4:c.881G>T p.(Gly294Val)) [36]. OMIM also records the Japanese variants F194S and P284R (= NM_000507.4:c.581T>C p.(Phe194Ser) and c.851C>G p.(Pro284Arg); ClinVar VCV000000871 and VCV000000872), in compound heterozygosity in a 2-month-old girl, and counts 11 pathogenic FBP1 variants published up to 2002 [23, 24]. The OMIM nucleotide numbering for the two KHK variants (121G>A and 135G>A) also follows the complementary DNA of the original publication and does not coincide with the HGVS of the MANE transcript; the table uses the description returned by VariantValidator [22, 62].

About 70 causal variants have been described in ALDOB [3]. The three most common missense variants (p.Ala150Pro, p.Ala175Asp, p.Asn335Lys) account for more than 90% of alleles in some European regions and for more than 50% in the more heterogeneous population of North America [3]; in the USA, seven tested alleles covered 65% of alleles, against 82% worldwide [64]. France added eight new variants, Central Europe another eight and Poland c.250delC and c.522C>G p.(Tyr174Ter) [5, 6, 63]. An intragenic 6.5 kb deletion (g.7840_14288del6448) had an allele frequency of 11% in a small Italian cohort, in which a deletion of the promoter and exon 1 and c.940_941dupT were also described [65]. Earlier, in 2010, Esposito and colleagues had described a 6.5 kb deletion of exons 2 to 6, mediated by repetitive sequences, in compound heterozygosity in six unrelated Italian patients, without excluding a founder effect [19, 20]. The 1995 review counted 21 ALDOB variants: 15 single-base substitutions (nine amino acid changes, four stop codons and two presumed splicing defects) and six deletions, with recurrence in exons 5 and 9 [20]. Other variants in OMIM, known only by historical nomenclature, include R3X («R3op») in homozygosity in a consanguineous family from eastern Turkey, R59X (= NM_000035.4:c.178C>T p.(Arg60Ter)) on an Austrian allele, the change of the last base of intron 6 in a French patient, C240X (recorded in ClinVar as NM_000035.4:c.720C>A p.(Cys240Ter), VCV000000468, without numbering shift) in homozygosity in a Japanese patient, the single-base deletion at codon 288 in Sicilian patients, a 7 bp deletion with 1 bp insertion at the intron 8 acceptor site, W147R and the in-frame 6 bp deletion of exon 6 that removes Leu182 and Val183 [20]. In 1990, Cross and colleagues estimated that a small number of allele-specific probes would detect more than 95% of patients, a prediction that later series, with proportions of 65–75% for common-variant panels, did not confirm (section 5.5) [20, 63, 64]. In FBP1, Santer and colleagues counted 35 published variants in 2016, and the most recent reference chapter mentions more than 50, distributed across all regions of the gene; these include deletions encompassing FBP2 and part of ONPEP (about 0.28 Mb) or FBP2 (about 0.13 Mb) [3, 58]. In PCK1, the 2022 review brought together eight genotypes with nine distinct variants; ClinVar records 17 pathogenic, 7 likely pathogenic and 165 variants of uncertain significance, numbers that measure submissions and not frequency [10, 17].

2.7. Inheritance, penetrance, genotype-phenotype correlation and modifiers

All entities of the class with an established molecular basis are autosomal recessive, and the sources consulted do not document a second inheritance pattern for any of these genes [4, 8, 17, 18]. OMIM also assigns autosomal recessive inheritance to PEPCK-M deficiency, an entity without an established molecular basis [12]. In HFI there is no clinically useful genotype-phenotype correlation: severity and organ injury depend on the nutritional environment, patients with the same variant have different sensitivities to fructose and residual activity has never correlated with tolerance [3, 4]. Homozygous null genotypes have the classical picture, which shows that aldolase B is not required for development [64]. In an Italian cohort, p.Ala150Pro homozygotes had lower transaminases at diagnosis than p.Ala175Asp homozygotes (alanine aminotransferase, ALT, 58 ± 55 versus 143 ± 90 IU/L; p = 0.01) [72]. In FBPase deficiency there is also no clinically relevant correlation, and residual activity of 0–30% reflects genetic heterogeneity [3, 8]. In PEPCK-C deficiency the phenotype depends mainly on environmental factors, and a 12-year-old sister with the same genotype as a Latvian patient was asymptomatic [10, 48].

ALDOB heterozygotes are not at risk of HFI and are generally asymptomatic [4, 30]. In controlled studies, eight heterozygotes had normal postprandial fructose metabolism, but an increase in plasma uric acid of 7.2% after a test meal with 0.35 g/kg of labelled fructose, against −1.1% in controls [73]; in a randomised crossover comparison, seven days of a high-fructose diet (1.4 g/kg/day) increased postprandial uric acid, insulin and the hepatic insulin resistance index only in heterozygotes [74]. Older publications described hyperuricaemia in presumed carriers, suggesting a predisposition to gout [4]. On hepatic 31P-MRS, fructose caused sugar phosphates to accumulate and inorganic phosphate to fall in heterozygotes as well, with a greater rise in plasma urate than in controls; the authors proposed the method for diagnosis and for monitoring dietary adherence [19]. Esposito and colleagues (2010) described two symptomatic patients with only one detected ALDOB variant, after a second variant and a deletion had been excluded by targeted study: with p.Arg46Trp (R46W), mild hypoglycaemia and ketosis after fructose and marked aversion to sweets and fruit, with catalytic efficiency for F-1-P 14 times lower in vitro; with p.Tyr343His (Y343H), febrile episodes with severe hepatic dysfunction at 8 months and death one month later, of unknown cause, with activity towards F-1-P reduced at high temperature [19, 20]. A 21-year-old Belgian man developed, during a fructose infusion for viral meningitis, jaundice, gastrointestinal bleeding, hypoglycaemia, proximal tubular acidosis and disseminated intravascular coagulation; hepatic F-1-P cleavage activity was 30% of normal, with normal activity towards fructose-1,6-bisphosphate, against 0–6% and 10–50% in the classical form, and the authors considered a mild form or heterozygosity unmasked by the massive load [19]. These data have no established clinical implication and do not demonstrate a causal relationship between heterozygosity and symptoms [30]. No allelic disorders of ALDOB or FBP1 are known [4, 8]. Coexistence of HFI with phenylketonuria, coeliac disease or Duchenne muscular dystrophy delayed diagnosis in some patients [4].

3. Clinical Spectrum and Manifestations by Organ System

3.1. Hereditary fructose intolerance: natural history by age

Patients with HFI are healthy as long as they do not ingest fructose, sucrose or sorbitol, and there is no metabolic disturbance during breastfeeding. The severity of the reaction increases the younger the child and the greater the fructose load [3]. The most severe form is that of the newborn fed a formula sweetened or enriched with fructose or sucrose, which can progress to hepatic and renal failure and death [3]. HFI typically presented at weaning, but now presents earlier, before 5–6 months, owing to the addition of fructose-containing nutrients to infant formulas [4]. Four previously undiagnosed North American newborns homozygous for p.(Ala150Pro) had life-threatening acute liver failure from widely available infant formulas containing fructose or sucrose [75]. European Delegated Regulation (EU) 2016/127 allows sucrose to make up to 20% of the total carbohydrate of infant formulas [3]. Newborns given 24% sucrose solution for analgesia during minor procedures may have fatal hypoglycaemia [4].

At weaning from breast milk or from a fructose-free formula, the first symptoms appear with the introduction of fruit and vegetables: gastrointestinal discomfort, nausea, vomiting, restlessness, pallor, sweating, tremor and lethargy and, eventually, apathy, coma, myoclonus and seizures; laboratory tests show acute liver failure and generalised proximal tubular dysfunction [3]. HFI is one of the few inborn errors with hypoglycaemia in the immediate postprandial period [4]. In Odièvre's classical series (55 French paediatric patients), the manifestations were nausea, abdominal distension and ascites, vomiting, sweating, abdominal pain, hepatomegaly and growth restriction [4, 76]; in a series of 50 symptomatic children cited by ClinGen, postprandial pallor, shock or seizures were present in 8 (16%) at presentation [30]. Post-fructose hypoglycaemia is brief and may go unnoticed or be masked by simultaneous glucose intake [3].

Without diagnosis or exclusion of fructose, the course becomes chronic and fluctuating, with growth faltering, liver disease (hepatomegaly, jaundice, bleeding tendency, oedema, ascites) and proximal tubular dysfunction [3]. Older children develop a protective aversion to fructose-containing foods, sometimes interpreted as disordered eating behaviour; at school age the disease is occasionally recognised through hepatomegaly or growth faltering [3]. Two boys (5.3 and 3.8 years) with isolated growth faltering (−2.71 and −2.40 standard deviations), without acute intoxication, showed catch-up growth with stricter restriction (about 40 mg/kg/day): growth velocity rose from the 25th to the 97th centile in one and from below the 3rd to above the 75th in the other [77]; an experimental fructose challenge in these boys caused sustained hyperuricaemia and hyperuricosuria and a rise in plasma and urinary magnesium, without symptoms, hypoglycaemia or hepatic or renal dysfunction [19]. About half of adults with HFI have no dental caries, which allows dentists to raise suspicion [3]. Adults were diagnosed after potentially fatal reactions to infusions of fructose, sorbitol or invert sugar while these solutions were in use, and affected individuals who self-restrict fructose may remain undiagnosed and have a normal life expectancy [3].

3.2. Hereditary fructose intolerance: manifestations by organ system

Metabolism. After exposure, hypoglycaemia, lactic acidaemia, hypophosphataemia, hyperuricaemia, hypermagnesaemia and hyperalaninaemia appear [4]. In an 18-year-old man, oral fructose produced fructosaemia, hypoglycaemia, hypophosphataemia, hyperuricaemia and mainly lactic metabolic acidosis [19]. Plasma methionine and tyrosine are often raised during decompensation [40].

Liver. Hepatomegaly with steatosis and lipid vacuolation may persist despite restriction, even in patients identified through family history and treated from birth: in Odièvre's 55 patients, hepatomegaly and fatty vacuolation often persisted, including in five homozygotes on diet from birth [4, 76]. On a fructose-free diet most abnormalities disappear rapidly, except hepatomegaly, which may persist for months or years [3]. In a Naples cohort of 48 young patients followed for a mean of 10.3 ± 5.6 years, with a mean fructose intake of 169 ± 145.4 mg/day, ALT was persistently raised in 18 and ultrasound steatosis present in 45 (94%); fructose intake did not correlate with ALT or with the severity of steatosis [72]. In 15 treated adults compared with 15 matched controls, intrahepatic triglycerides on proton spectroscopy were 2.5% versus 0.6% (P = 0.001), with greater glycaemic excursion on the oral glucose test and lower β-hydroxybutyrate [78]. In a Spanish national cohort (32 treated patients and 28 controls), steatosis by magnetic resonance fat fraction was present in 75% of patients versus 7% of controls, associated with low-grade systemic inflammation and markers of intestinal permeability [79]. Hepatic adenomatosis and a potential risk of fibrosis have been described [4, 80], and in electronic health records the diagnosis of metabolic dysfunction-associated steatohepatitis (MASH) is more frequent in people with HFI [54].

Kidney. Proximal tubular dysfunction (glycosuria, aminoaciduria, phosphaturia, acidosis) generally resolves shortly after restriction is started, in about three days [30, 76]; rare historical cases retained renal dysfunction despite the diet; chronic kidney disease may result from early or chronic exposure (inadequate self-restriction) or, in part, from a persistent primary defect of aldolase and its interaction with the proximal tubular ATPase, with dysfunctional acidification, tubular insufficiency (glycosuria, aminoaciduria, phosphaturia) and nephrocalcinosis despite a strict diet [4]. The GeneReviews authors report a patient untreated until 5 years of age who progressed to stage IV chronic kidney disease [4]. In the 15 treated adults from Maastricht, estimated glomerular filtration rate was 119 versus 104 mL/min/1.73 m² (P = 0.001) and median systolic blood pressure 127 versus 122 mmHg (P = 0.045), with no difference in proximal tubular function [81].

Growth, eyes, coagulation and other. Growth faltering may be the only manifestation of insufficient restriction [77]. Lenticular cataracts with hepatic fibrosis have been described in untreated adolescents and adults, and coagulopathy is part of decompensation [4]. An infant with growth faltering, hepatomegaly and hepatic dysfunction before solids, exposed to a fructose-containing formula, had raised levels of several plasma lysosomal enzymes that mimicked mucolipidosis II/III [82]. A girl with neonatal hypertonia, trismus and absent swallowing reflexes, microcephaly and hepatomegaly at 14 months had a CDG I-type transferrin profile that led to a wrong diagnosis; aversion to fruit led to the diagnosis (p.Ala150Pro/p.Asn335Lys), but cirrhosis required liver transplantation [83]. HFI with haematochezia has been described [84].

Treated and untreated disease. With fructose restriction, vomiting disappears almost immediately, the bleeding tendency in about 24 hours, tubular dysfunction in about three days and the remaining findings, except hepatomegaly, within a few weeks; growth normalises within 2–3 years [30]. The data on steatosis, blood pressure and glomerular filtration refer to treated patients [78, 79, 81]. In a Turkish series of nine patients from eight families, all had aversion to fructose and one had syncopal hypoglycaemia; 87.5% were homozygous [85].

3.3. Essential fructosuria

Essential fructosuria is a rare «non-disease», detected through screening for reducing sugars in urine and asymptomatic [3]. In the UK Biobank, no participant had the compound genotype p.Gly40Arg/p.Ala43Thr, and carriers of other KHK variants showed no relevant cardiometabolic differences after correction for multiple comparisons [56]. Based on Khk knockout mice, the condition could be protective against metabolic syndrome [3]. After ingestion of fructose, sucrose or sorbitol, blood fructose rises higher and for longer than in a normal individual, and 10–20% of the load appears in the urine; in fructosuric adults, hepatic 31P-MRS showed no change in F-1-P, ATP or inorganic phosphate after fructose, confirming the inactivity of fructokinase in vivo [21].

3.4. Fructose-1,6-bisphosphatase deficiency

Neonatal presentation and crises. In about half of cases, the disease presents on days 1–4 of life with hyperventilation due to profound lactic acidosis and marked hypoglycaemia; most patients present before 6 months, with exceptions up to 4 years [3, 36]. The first neonatal symptom is generally hyperventilation, sometimes with irritability, and progression may be rapid to drowsiness, coma, apnoea and cardiac arrest [36]. A history of a sibling who died in acidosis was often the alert that allowed early diagnosis and survival of the next sibling [36]. After the neonatal period, episodes of irritability, drowsiness or coma, apnoea, dyspnoea and tachycardia, hypotonia and moderate hepatomegaly appear; most have several crises before diagnosis [3], often four to five [8]. Triggers are fever with food refusal and vomiting, fasting, reduced oral intake, infections and ingestion of large amounts of fructose (about 1 g/kg in a single dose), especially after fasting [3, 8]. During a provoked fast, hypoglycaemia appears when glycogen is depleted, within a few hours in the infant or after 14–20 hours in an older patient; glucagon in the fed state may give a normal response, but has no glycaemic effect once hypoglycaemia is established, and hypoglycaemia may also appear on a diet low in carbohydrate and rich in protein and fat [36]. During a crisis, lactate may reach 15–25 mM, the L/P ratio up to 40, with hyperalaninaemia, raised glycerol that mimics hypertriglyceridaemia and glucagon-resistant hypoglycaemia [3].

Between crises. Patients are generally well, although mild intermittent or chronic acidosis may be present; unlike HFI, chronic fructose intake does not cause gastrointestinal symptoms, aversion to sweets or growth faltering, and there is no proximal tubular dysfunction after fructose [3, 36]. The frequency of crises decreases with age, and most survivors have normal somatic and psychomotor development [3]. The electroencephalogram is abnormal during a crisis and normal afterwards [36]. Some children are left with brain injury or intellectual disability, probably owing to early and prolonged hypoglycaemia [8]. Many patients become obese because parents overfeed them and these habits persist [3].

Liver and other organs. Hepatomegaly is regularly present in the infant, generally without signs of liver disease; three infants required exchange transfusion for neonatal hyperbilirubinaemia [36]. These three patients belonged to a German series of four unrelated infants (Bührdel and colleagues, 1990), all with residual hepatic activity below 25% [23]. In a Franco-Belgian series of 18 patients, all had hepatic abnormalities at some point: during follow-up, hepatomegaly in 8 of 18, raised transaminases in 6 of 15 and hyperechoic liver in 7 of 11; during crises, hepatomegaly in 10 of 17 (massive, mimicking glycogen storage disease type I, in 3), raised transaminases in 13 of 16 (more than 10 times the upper limit of normal in 5, mimicking acute hepatitis), acute liver failure in 6 of 14 (prothrombin time between 57% and 27%, with rapid recovery after correction of hypoglycaemia and acidosis; Reye syndrome in 2) and hyperechoic liver in 6 of 14, with normal bilirubin in all [61]. The hepatomegaly of crises regressed with dietary treatment; over a mean follow-up of 7.8 years (7 months to 19 years), 11 of the 17 patients with ultrasound had a hyperechoic liver at some point, the only biopsy showed clarified hepatocytes and rare fibrous septa, and 4 of the 18 became overweight [61]. Liver biopsies from the time of enzymatic diagnosis already described steatosis, mild to severe, and three cases of fibrosis have been published, two moderate periportal and one extensive [61]. CK (creatine kinase) rose in at least one patient during a crisis [8]. Without treatment, continued catabolism leads to multi-organ failure (liver, brain and, later, heart), and sepsis, blindness and Reye-like presentations have been described [8]. One patient developed gout at 32 years [36].

Cohorts. In Israel, nine patients from six families (two Jewish, three Muslim Arab and one Druze) all had neonatal hypoglycaemia and lactic acidosis and, later, hypoglycaemia with or without intercurrent illness, accompanied by severe hyperuricaemia and metabolic acidosis [23]. In Japan, the 13 patients from 11 families (three consanguineous) of the first molecular series had recurrent crises of metabolic acidosis and hypoglycaemia with vomiting, drowsiness or tachypnoea, with onset between the first day of life and 4 years; in a Japanese girl presenting at 2 months with fever and hyperventilation, a high-carbohydrate diet with reduced fructose prevented all subsequent crises [23, 38]. In France (2001–2013), the first decompensation occurred before 2 years in most of the 12 patients, triggered by fever, fasting or reduced intake, and diagnosis was made at a mean of 3 years, after initial suspicion of mitochondrial disease or glycogen storage disease [86]. In the Franco-Belgian series of 18 patients with molecular confirmation (8 of them already included in the 2015 series), the first crisis occurred in the first days of life in 8 and between 6 months and 2.5 years in 10; presentation was hypoglycaemia with lactic acidosis in 14, a Reye-like picture with lactic acidosis in 2 and lactic acidosis without hypoglycaemia in 2, and genetic diagnosis came a mean of 19 months after the first crisis [61]. In Malaysia, the 7 patients had their first decompensation before 2 years; there was one neonatal death from sepsis and multi-organ failure, and among the 6 survivors (4 to 27 years) 4 had normal growth and cognition, 1 short stature and 1 a neurological deficit after hypoglycaemic status [87]. In Egypt, 14 children from 11 families had a median onset at 13 months (first week to 36 months), lactic acidosis in all and hypoglycaemia in 13; there were two neonatal deaths and the others had normal neurodevelopment [66]. Six Egyptian girls presented at 22.8 ± 16.16 months and were diagnosed at 62 ± 45.16 months, a mean delay of three years [88]. In Lebanon, two patients diagnosed by exome sequencing in the first month had a favourable course at 6 years, and a third, undiagnosed for 10 years, was left with neurological sequelae [9]. In a Swedish family, one patient died at 6 months and two siblings followed for more than 30 years had a favourable course [70]. In a Turkish study of ten patients with blinded continuous glucose monitoring, there was asymptomatic hypoglycaemia despite uncooked cornstarch, with a mean time below target of 11.2 ± 31.2% [89].

Adults. Reports of crises in adults are scarce [8]. A 30-year-old man, with mild episodes in childhood, had a severe decompensation shortly after the diagnosis of hepatitis C, with a novel homozygous variant [90]. A 29-year-old woman with a known diagnosis, after vomiting and about 20 hours of fasting, arrived confused, with a Glasgow coma scale of 8, capillary glucose of 2.2 mmol/L, pH 7.185, bicarbonate 6.3 mmol/L and lactate 6.49 mmol/L, and recovered fully after 48 hours of intensive care [91]. In a Saudi centre following 39 adults, the three pregnant women described were all obese and two had gestational diabetes [92].

3.5. Cytosolic PEPCK deficiency

The first patient described, Norwegian, had generalised seizures and severe hypoglycaemia on the second day of life, with frequent episodes of cyanosis and apnoea; at 8 weeks he had global delay and optic atrophy, and the lack of response to subtotal pancreatectomy and diazoxide, at 3.5 months, led to a search for a gluconeogenesis defect; he died at 2 years and 10 months, and autopsy showed severe cerebral atrophy, optic atrophy, fatty infiltration of the liver, kidney and heart and hyperplasia of the islets of Langerhans [25]. In the two Ashkenazi sisters of the first molecular report, the elder had her first episode at 20 months (fasting hypoglycaemia with fever, lethargy and ketonuria, with appropriately raised growth hormone and cortisol, undetectable insulin and normal C-peptide) and at least 12 episodes over the following five years, sometimes with lactic acidaemia; liver biopsy at 4 years showed mild to moderate portal inflammation, mild portal fibrosis and moderate patchy macrovesicular steatosis; the younger presented at 8 months; the intellectual and motor delay of both is attributable, at least in part, to the de novo RAI1 and GRIN2B variants [25]. A previously healthy Norwegian girl had severe gastrointestinal bleeding after gastroenteritis at 16 months, with markedly raised transaminases, and then two episodes of ketotic hypoglycaemia with metabolic acidosis and raised lactate during infections; on a controlled fasting test, hypoglycaemia appeared at 17 hours [25]. In the first three Finnish patients (two siblings and an unrelated boy), hypoglycaemia appeared in the first 24 hours of life and at 14 months after about 12 hours of fasting, at 15 months after 13 hours of fasting and at 4.5 years with a morning seizure after a night of intense activity; on a low-fat, high-carbohydrate diet with frequent meals, all had normal growth and development at 5, 2.5 and 6.8 years, with a single later episode in the context of illness [25]. In the systematic review of 32 individuals from 25 families, onset was generally in infancy, but ranged from the neonatal period to adulthood, without correlation with genotype [10]. According to the OMIM synopsis, seven patients had neonatal hypoglycaemia and the mean age at presentation after the neonatal period was 2.6 years; triggers were fasting, illness and physical activity in children and alcohol, lactation and exercise in adults; 15 patients had hypoglycaemic seizures, 28 had normal cognition and neurodevelopment, transaminases rose during episodes, the liver was enlarged in one patient and hyperechoic in two, and one patient died at 3.5 years from fasting hypoglycaemia with seizures and cerebral oedema [25]. In the Finnish national series (21 children and 3 adults), triggers were infection, fasting or poor intake, intense exercise, alcohol consumption and, in an affected mother, breastfeeding; episodes occurred mainly in the morning; the first episode was often at 1–2 years, but could appear or recur at school age or in adulthood; five patients had neonatal hypoglycaemia and half (12 of 24) hypoglycaemic seizures [11]. Hepatic involvement ranges from mildly raised transaminases to acute liver failure: one child had transient acute liver failure after gastroenteritis, with a biochemical picture that mimicked a proximal urea cycle defect and mitochondrial dysfunction [39]. An 8-year-old Latvian girl, with no history other than prolonged neonatal jaundice, had severe acute hepatic and renal failure (ALT 6759 U/L, aspartate aminotransferase, AST, 9165 U/L, creatinine 250 µmol/L, prothrombin 30.6%, international normalised ratio 2.40), with plasma glutamine of 3217.1 µmol/L and normal ammonia, reversible with continuous glucose infusion, after infection, fasting and high sucrose intake [48]. A previously healthy 3-year-old boy, admitted for an apparent febrile seizure during an upper respiratory infection, had hypoglycaemia and cerebral oedema and died on the fifth day; the diagnosis was only made by post-mortem trio exome sequencing [17]. Morbidity results from the hypoglycaemic episodes; with appropriate treatment, the biochemical abnormalities normalise after each episode [10, 17]. In one patient, the inaugural episode of liver failure with hyperammonaemia and encephalopathy resolved with dextrose, without impairment of neurological development [13].

3.6. Sorbitol dehydrogenase deficiency

SORD deficiency causes a slowly progressive neuropathy, classified as CMT2 or distal hereditary motor neuropathy, with mild to moderate distal weakness, mainly of the lower limbs, often with foot deformities, without cataracts, with onset in late childhood or early adulthood; the SORD protein is absent in fibroblasts, and intracellular sorbitol and fasting serum sorbitol are markedly increased [3, 47]. Conduction studies invariably show axonal motor neuropathy; screening for raised serum sorbitol in patients with undiagnosed CMT2 or distal motor neuropathy has a detection rate of about 10%, and genetic study by Sanger or neuropathy panel must take account of the pseudogene, which caused the variant to be missed on exome sequencing [3]. In the series that defined the disease, 45 patients from 38 families were identified in three cohorts of about 1000 people with peripheral neuropathy studied by exome or genome sequencing; the c.757del variant, present in 623 of 142,588 gnomAD genomes (0.4%), also exists in the pseudogene SORD2 on more than 95% of control chromosomes, which requires Sanger confirmation that it is in the functional gene; serum sorbitol was more than 100 times higher than in controls in ten homozygotes, and intracellular sorbitol in fibroblasts ten times higher [28]. Aldose reductase inhibitors (epalrestat, ranirestat) lowered sorbitol in patient fibroblasts and, in Drosophila, normalised sorbitol and corrected locomotor and synaptic defects; the Sord−/− rat has motor deficits, reduced nerve conduction and histological changes of the peripheral nerve [28]. In a Chinese cohort of 485 patients with hereditary neuropathy, SORD deficiency accounted for about 1% of the total and 6.4% of undiagnosed patients [28]. Old reports of low SORD activity in families with cataracts did not establish a causal relationship [28]. There is no liver disease or hypoglycaemia; treatment and follow-up are those of the hereditary neuropathies.

4. Clinical Recognition and Red Flags

4.1. When to suspect hereditary fructose intolerance

Suspicion of HFI rests on the temporal relationship between symptoms and exposure. It should be considered in the presence of nausea, vomiting, abdominal discomfort or pain, distension, ascites and hepatomegaly or chronic growth restriction after exposure to fructose, sucrose, sorbitol or sucralose, in the presence of the characteristic metabolic abnormalities and in the presence of a family history compatible with recessive inheritance (affected siblings, consanguinity), although the absence of a family history does not exclude the diagnosis [4]. The presentation is multifaceted and non-specific, and fructose sources should be withdrawn as soon as suspicion arises [4]. The index of suspicion should be high in any infant with recurrent or profound hypoglycaemia, metabolic acidosis, recurrent vomiting, hepatic dysfunction or renal failure [4]. HFI features in the algorithm for the «sick» newborn for the investigation of treatable inborn errors and, together with galactosaemia and tyrosinaemia type 1, among the causes of liver failure with tubulopathy in the infant [46].

By age and context, the red flags are as follows. In the newborn and young infant: liver failure or hypoglycaemia after a formula containing fructose or sucrose, or after 24% sucrose solution for analgesia [4, 75]. Any child with a severe adverse reaction (vomiting, hypoglycaemia, lethargy, hepatic or renal failure) immediately after one of the sucrose-containing oral rotavirus vaccines (Rotarix® pre-filled oral suspension and RotaTeq®) should be investigated for HFI [4]. At weaning: symptoms with the introduction of fruit, vegetables, juices or sweetened cereals; in an asymptomatic infant, suspicion may arise because the parents have on their own initiative excluded foods that were not tolerated [3]. In the older child: aversion to sweets and fruit, hepatomegaly or growth faltering at school age [3]. In the adolescent and adult: absence of dental caries noticed by the dentist, «lean» steatosis with non-specific digestive symptoms, unexplained raised transaminases, or a severe reaction to an infusion or medicine containing fructose, sorbitol, invert sugar or polysorbate [3, 93–95]. HFI should be included in the investigation of isolated raised transaminases, together with Wilson disease, alpha-1 antitrypsin deficiency, cystic fibrosis and the glycogen storage diseases [46].

4.2. When to suspect fructose-1,6-bisphosphatase deficiency

FBPase deficiency should be suspected in the presence of hyperventilation due to lactic acidosis with hypoglycaemia in the first days of life, a sibling who died in acidosis, crises triggered by fever, vomiting, fasting or a large fructose load after fasting, and hepatomegaly with hypoglycaemic seizures [3, 36, 46]. Together with glycogen storage disease type I, it is the main cause of hepatomegaly with fasting hypoglycaemia and lactic acidosis [46]. The laboratory red flags are glycerol and glycerol-3-phosphate in urinary organic acids and transient pseudohypertriglyceridaemia during decompensation [87, 96]. Recovery from acidosis with glucose alone is a positive indicator of the diagnosis [3]. In adults, a decompensation with lactic acidosis and hypoglycaemia after vomiting, prolonged fasting, infection or alcohol excess should suggest the diagnosis [90, 97]. Hypoglycaemia appears late in the crisis, so a normal blood glucose does not exclude decompensation [98]. Because childhood signs may be subtle and go unnoticed, FBPase deficiency belongs in the aetiological diagnosis of hepatic steatosis, and anicteric acute hepatitis with markedly raised transaminases or massive hepatomegaly during a crisis with lactic acidosis should suggest it [61].

4.3. When to suspect cytosolic PEPCK deficiency

PEPCK-C deficiency should be considered in the presence of fasting or illness-induced hypoglycaemia with inappropriately low ketones, especially in the morning, acute liver failure after gastroenteritis with a biochemical pattern mimicking a urea cycle defect or mitochondrial disease, and urinary organic acids with prominent fumarate [11, 17, 39]. Blood glucose should be measured in any patient with a seizure, altered consciousness or apparent febrile seizure, because fatal hypoglycaemic seizure has been described [17]. The combination of hypoglycaemia, raised glutamine and normal ammonia has been proposed as suggestive [48]. In the Finnish population, the frequency of the founder allele justifies a low threshold for testing [11].

4.4. Timing of hypoglycaemia and emergency signs

The interval between the last meal and hypoglycaemia guides the diagnosis [46]:

Emergency signs are hyperventilation or tachypnoea (acidosis), drowsiness, vomiting with food refusal, seizures, hypothermia, jaundice with coagulopathy and oliguria. In the British emergency protocols for FBPase deficiency, treatment is started if the child is unwell, drowsy or vomiting, hypoglycaemic (glucose below 2.6 mmol/L), acidotic or hyperventilating (base deficit above 10 mmol/L) [98]. In HFI, a severe reaction during an infusion containing fructose or sorbitol requires the infusion to be stopped immediately [40].

4.5. Newborn screening

None of the entities of the class is part of newborn screening panels. HFI cannot be screened for biochemically because there is no marker without fructose exposure [99]. Raised glutamine in dried blood spots has been proposed as a possible marker for a subgroup of patients with PEPCK-C deficiency, as an unvalidated hypothesis [10, 17]. The strong paediatric actionability assigned by ClinGen to HFI underpins the reporting of biallelic ALDOB variants found as secondary findings in children, because identification before a large exposure prevents encephalopathy and hepatic or renal failure [30, 50].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

No published consensus clinical diagnostic criteria exist for HFI or FBPase deficiency [4, 8]. For HFI, the diagnosis is established in a proband with suggestive metabolic and clinical abnormalities after exposure and with biallelic pathogenic or likely pathogenic variants in ALDOB or, now rarely, with deficient aldolase B activity in a liver biopsy [4]. For FBPase deficiency, suggestive findings are required together with biallelic pathogenic variants in FBP1 and/or deficient activity in liver or mononuclear leucocytes [8]. PEPCK-C deficiency is diagnosed by identifying biallelic variants in PCK1; the enzyme assay is not first line [17]. In all of them, two variants of uncertain significance (VUS) or one pathogenic variant with one VUS neither establish nor exclude the diagnosis [4, 8].

5.2. Biochemistry of hereditary fructose intolerance

The first diagnostic element is the response to fructose exclusion: within days, transaminases and bilirubin fall, coagulation factors improve and proximal tubular dysfunction regresses (proteinuria, glycosuria, generalised hyperaminoaciduria, hyperphosphaturia, hypophosphataemia, hyperuricosuria, metabolic acidosis) [3]. The mainstay of diagnosis is a detailed nutritional history, with emphasis on weaning and the introduction of fruit and vegetables [3]. The characteristic plasma abnormalities after exposure are as follows [4]:

Hypermagnesaemia, hyperuricaemia, hypophosphataemia and metabolic acidosis are the key biochemical features [4]. Supporting findings include the urinary abnormalities of a proximal tubular defect, abnormal transferrin isoelectric focusing (IEF) and raised levels of several plasma lysosomal enzymes, especially aspartylglucosaminidase [4]. Carbohydrate-deficient transferrin (CDT) fell from 27.3 ± 11.5% to 9.3 ± 5.1% after diagnosis in 10 patients with HFI, and in 25 patients on diet it was raised in 104 of 134 tests [100]. In a laboratory in Southern Brazil (2008–2017), 51 of 1546 individuals (3%) had abnormal transferrin IEF; among the 14 with a final diagnosis, 4 had HFI and 4 classical galactosaemia [101]. The transferrin pattern in HFI is not characteristic of a specific glycosylation defect, corrects with restriction and may resolve spontaneously in those who self-restrict fructose, so it is a supporting and monitoring test and not a confirmatory one [4, 50]. Fructosuria, when present, may be secondary to liver injury of any cause [3]. Serum glucoselysine, a fructose-specific glycation product, was lower in 15 patients on diet than in controls (35.1 versus 45.8 nmol/L), a biomarker that is still experimental [102].

5.3. Biochemistry of fructose-1,6-bisphosphatase deficiency

The suggestive findings during a crisis are hypoglycaemia (plasma glucose below 40 mg/dL in the newborn and below 60 mg/dL in older infants, children and adults), metabolic acidosis with a raised anion gap, lactic acidaemia (lactate above 4 mmol/L), pH below 7.35, bicarbonate below 20 mmol/L, hyperalaninaemia, ketosis (with patients described with normal to low ketones), hyperuricaemia and, in some, increased free fatty acids [8]. Urinary organic acids show raised glycerol and glycerol-3-phosphate during a crisis, which normalise after resolution [8, 87]. In Malaysia, this finding prompted genetic study in 4 of the 7 patients [87]. Glycerol and glycerol-3-phosphate, which are strongly hydrophilic, are better detected with urease pretreatment without extraction, hydrophilic interaction chromatography or ion-pair reversed-phase chromatography; solvent extraction in gas chromatography-mass spectrometry may fail to detect them [3]. Pseudohypertriglyceridaemia results from the usual methods not distinguishing free glycerol from triglycerides; methods with a «glycerol blank» measure true triglycerides [8, 96]. In four Pakistani patients, pseudohypertriglyceridaemia was transient, normalising in the stable phase [96].

The L/P ratio is described inconsistently. A reference table of lactic acidosis gives an L/P below 15 for gluconeogenesis defects in general; the specific text mentions L/P up to 40 during a crisis; GeneReviews gives 20–40; and Santer's review lists an increased ratio among the findings [3, 8, 49, 58]. The sources consulted contain no primary series with measured values; the ratio should be read as normal to moderately raised (up to about 40 during a crisis), distinct from the ratios above 30 with very low 3-hydroxybutyrate/acetoacetate, raised ammonia and citrulline and low glutamine of pyruvate carboxylase deficiency [49]. Ketosis is equally variable: GeneReviews describes ketotic hypoglycaemia with cases of normal or low ketones, the reference chapter describes moderate or absent ketosis in several patients, and the atlas states that the usual crisis is ketotic, although the disease has been classified among the hypoketotic causes [3, 8, 36]. Ketonuria is an early indicator of an impending crisis and correlates with crisis frequency [8, 89].

5.4. Biochemistry of cytosolic PEPCK deficiency and essential fructosuria

In PEPCK-C deficiency, urinary organic acids show increased Krebs cycle intermediates, with prominent fumarate (and succinate), a pattern reproducible across cohorts; during hypoglycaemia, ketone bodies are inappropriately low; lactate is raised, ALT and AST mildly raised and plasma glutamine raised in some patients [10, 17, 49]. In the synopsis of the 2022 review, urinary organic acids showed increased fumarate, malate and α-ketoglutarate and plasma amino acids raised glutamine with low ornithine, citrulline and arginine, and most of these abnormalities normalised outside episodes; during a crisis, ketonuria, dicarboxylic aciduria and urea cycle dysfunction may also appear [25]. In one patient, the controlled fasting test caused hypoglycaemia at 17 hours, and urine after 12 hours of fasting had increased 3-hydroxybutyrate, fumarate and glutarate [25]. Blood glucose must be measured during the episode [17]. The pattern is not specific: in the fatal case it was interpreted as an energy deficit and, in acute liver failure, the amino acids and hyperammonaemia mimicked a proximal urea cycle defect [17, 39]. In essential fructosuria, fructose gives a positive test for reducing substances and a negative one with glucose oxidase, is identified by thin-layer chromatography and quantified enzymatically; fructosuria is inconstant and depends on the timing and quantity of fructose, sorbitol and sucrose ingested [3]. Laboratories are abandoning reducing-substance tests in favour of glucose-specific tests, which reduces detection [3].

5.5. Molecular tests and their limits

Molecular testing is the preferred confirmatory test for HFI and FBPase deficiency, because it is non-invasive and avoids the secondarily low aldolase B activity of an injured liver [3, 4, 8]. There are two strategies: gene sequencing (or a multigene panel for carbohydrate metabolism, hypoglycaemia or hepatic dysfunction), followed by targeted deletion/duplication analysis if only one or no variant is found; or exome or genome sequencing when the phenotype does not suggest the disease [4, 8]. Exome and genome sequencing can detect CNVs, but with lower sensitivity than targeted analysis [8].

These percentages are proportions of variants detectable by each method and not clinical sensitivity. The European document on excipients states that three variants account for 95% of patients of European origin, a value higher than the proportions measured in the French, North American and Italian series [40, 63–65]. Common-variant panels have known limits: in France, restriction enzyme digestion diagnosed 75% of patients with HFI and the addition of sequencing 97% [63]; in the USA, seven alleles covered 65% of alleles [64]; a North American five-variant panel may have underestimated prevalence in people of non-European ancestry [4]. Sanger sequencing diagnosed 9 of 14 patients with FBPase deficiency in Hamburg, and MLPA, SNP (single-nucleotide polymorphism) arrays and junction-fragment PCR (polymerase chain reaction) detected the exon 2 deletion [58]. Apparent homozygosity may correspond to an undetected deletion on the other allele (false homozygosity) or to uniparental isodisomy [8]. A negative test does not exclude the diagnosis when the history is suggestive; in that case, HFI can be confirmed by enzyme study in a liver biopsy or by functional assessment after weeks of fructose exclusion [3, 4]. In populations with founder variants, a targeted first-line test is possible: c.472C>T and c.841G>A in Pakistan, p.(Glu281Lys) and p.(Arg158Trp) in India, ALDOB c.324+1G>A in the Agarwal community, c.960delinsGG in Egypt, c.958G>A and c.986T>C in Southern Brazil, PCK1 c.925G>A in Finland [11, 66–69, 103]. In Lebanon, first-line exome sequencing allowed the diagnosis of two patients with FBPase deficiency within one month [9].

The molecular report should state the gene, the versioned transcript (NM_000035.4, NM_000507.4, NM_002591.4, NM_006488.3), the variant in HGVS and, when useful, the historical designation, the zygosity, the ACMG/AMP class (American College of Medical Genetics and Genomics/Association for Molecular Pathology) and the method used for CNVs [4, 62]. Variant phase is confirmed by parental testing, which also allows a de novo variant or isodisomy to be detected [4, 8]. ClinVar classifications diverge from the literature in three cases: PCK1 c.925G>A has conflicting classifications despite 22 Finnish homozygotes, PCK1 c.134T>C p.(Ile45Thr) is classified as of uncertain significance by a single submitter despite functional data on protein instability, and KHK p.(Gly40Arg) is classified as of uncertain significance despite functional data showing it is null [11, 26, 55, 57].

5.6. Enzyme studies

In HFI, liver biopsy shows F-1-P cleavage capacity reduced to a few per cent of normal (mean 5%, range 0–15%), although residual activities up to 30% have been described; the reduction in activity towards fructose-1,6-bisphosphate is smaller (mean 17%, range 5–30%), and the ratio between the maximal activities with the two substrates, close to 1 in normal liver, increases to 2 or more in HFI [3, 99]. Aldolase activity is normal in blood cells, muscle and fibroblasts, which express isoenzyme A; assay in small intestinal mucosa is not recommended [3]. Post mortem, molecular study and activity in liver and renal cortex are possible [3]. The biopsy assay is more invasive, but GeneReviews considers it more sensitive than molecular testing and useful when the latter does not identify biallelic variants [4, 99].

In FBPase deficiency, the enzyme can be measured in liver (residual activity of 0–30%; heterozygotes with intermediate activity), kidney and jejunum, but not in fibroblasts, amniocytes or chorionic villi, which do not express it [3, 36]. In blood, FBPase is expressed only in monocytes: the assay in mixed leucocytes is not suitable, because it may give normal activity, but the assay in isolated calcitriol-stimulated monocytes is reliable [3, 70]. In France, measurement in mononuclear leucocytes from a single blood sample, combined with molecular study, diagnosed 12 patients with activity below 10% [86]. The usual assay measures the NADPH (reduced nicotinamide adenine dinucleotide phosphate) formed and is non-specific; specificity is obtained by testing in the presence and absence of AMP, a specific inhibitor. FBP1 is stable for 24 hours in untreated blood at +4 °C, which allows long-distance transport; there are severely affected patients with normal leucocyte activity [8]. Female patients with demonstrated hepatic deficiency and normal leucocyte activity have been described, and the first Japanese series considered the leucocyte assay unreliable [23]. Autopsy tissue should be interpreted with caution because of rapid enzyme inactivation [36]. In PEPCK-C deficiency, the enzyme assay in specialised laboratories confirmed the pathogenicity of the 12 bp deletion [39].

5.7. Functional tests: current position and divergence

The intravenous fructose tolerance test was used historically in HFI (200 mg/kg of 20% solution over 2 minutes, with samples at 0, 5, 10, 15, 30, 45, 60 and 90 minutes for glucose and phosphate; in patients, glucose and phosphate fall within 10–20 minutes, with an earlier and faster fall in phosphate) [3]. The European document on excipients mentions doses of 0.25 g/kg and 0.5 g/kg of 30% solution and considers the test dangerous [40]. GeneReviews, ClinGen, Maiorana and colleagues and the review by Úbeda and colleagues consider that the test should be avoided, because it caused deaths in the past, has been replaced by molecular analysis or is used only exceptionally; the 1 g/kg oral test is also no longer recommended because of the risk to life [4, 30, 99, 104]. The reference chapter by Steinmann and Santer retains the intravenous test as an option in an experienced metabolic centre, with a cannula and glucose ready, when the history is suggestive and no variants are found, and advises against oral tests; in another section of the same work, fructose loading tests are described as having fallen completely into disuse [3, 49]. An oral variant, used historically in the vomiting infant, showed a fall in serum glucose and phosphorus in the first hour [19]. The fructose breath hydrogen test, used in the diagnosis of fructose malabsorption, caused life-threatening adverse effects in a 13-year-old boy with undiagnosed HFI; HFI should be excluded by the dietary history before this test [3, 105]. In current practice, genotyping is the test of choice and the fructose test is not part of first-line investigation.

In FBPase deficiency, loading tests (fructose, glycerol, alanine) and fasting tests should not be part of the initial investigation; they may have a place, in a specialised unit, when molecular analysis and enzyme activity are normal despite strong suspicion [3, 8]. The atlas describes the response to 200 mg/kg of intravenous fructose (hypoglycaemia within 15 minutes, lactic acidaemia and an increase in alanine and uric acid) and coma in one patient after 500 mg/kg [36]. The fasting test, potentially very dangerous, is only indicated for unexplained hypoglycaemia after baseline investigation has excluded fatty acid oxidation defects and adrenal insufficiency, or to assess fasting tolerance during treatment; it is performed in a metabolic unit, with an adequate diet in the three preceding days and no infection in the previous week, for 12 hours before 6 months, 20 hours between 6 and 12 months and 24 hours from 1 year; glucose and bicarbonate are monitored (every 30 minutes if glucose is below 3.2 mmol/L) and the test is stopped if glucose falls below 2.6 mmol/L, if bicarbonate falls below 15 mmol/L or if neurological symptoms appear, collecting the full profile; glucose below 2.8 mmol/L with simultaneous lactate above 3.0 mmol/L suggests a gluconeogenesis defect [49]. An oral glucose load lowers lactate from a raised fasting value in gluconeogenesis defects and in glycogen storage disease type I [49].

5.8. Diagnostic algorithm

The review by Úbeda and colleagues proposes, for HFI, that the combination of postprandial symptoms, aversion to sweets and absence of caries should lead to molecular study and that, if this is negative, other causes should be sought with a mixed-meal tolerance test [99].

5.9. Prenatal and preimplantation diagnosis

Once the familial variants have been identified, prenatal diagnosis and preimplantation genetic testing (PGT) are possible for HFI and FBPase deficiency [4, 8]. Prenatal biochemical testing for FBPase deficiency is not reliable, because enzyme activity is low in the placenta and absent in amniocytes and villi [3, 8]. DNA banking is recommended when the molecular diagnosis has not been confirmed in an affected individual [4, 8].

6. Differential Diagnosis

6.1. Comparative table

6.2. Differential diagnosis of hereditary fructose intolerance

HFI has been confused with pyloric stenosis, gastro-oesophageal reflux, galactosaemia, tyrosinaemia, non-IgE (immunoglobulin E)-mediated gastrointestinal food hypersensitivity, intrauterine infection, glycogen storage diseases and other storage disorders, ornithine transcarbamylase deficiency and, later, Wilson disease, leukaemia and growth faltering [3]. Fructose sensitivity has also been described in food protein-induced enterocolitis syndrome (FPIES) [4]. In one infant, haemophagocytosis in the bone marrow delayed the diagnosis of HFI [19]. In the presence of liver failure, unexplained jaundice, hypoglycaemia or a Reye-like illness in an infant, GeneReviews lists, in addition to acquired causes (infectious hepatitis, sepsis or disseminated intravascular coagulation, autoimmune disease, neonatal haemochromatosis, toxic ingestion, haemophagocytic lymphohistiocytosis), fatty acid oxidation defects, hepatic glycogen storage diseases, CDG, urea cycle defects, Wilson disease, maple syrup urine disease, hepatocerebral mitochondrial DNA depletion syndromes, tyrosinaemia type 1, propionic and methylmalonic acidaemias, FBPase deficiency, galactosaemia, alpha-1 antitrypsin deficiency and transaldolase deficiency [4]. In the presence of hyperlactataemia with hypoglycaemia in an infant, pyruvate dehydrogenase complex deficiency, glycogen storage disease 0 and HMG-CoA lyase deficiency are added; in the presence of renal Fanconi syndrome with growth faltering, CDG, cystic fibrosis, cystinosis and Fanconi-Bickel syndrome [4]. In advanced liver disease of any cause, secondary melliturias (galactosuria, glycosuria, fructosuria), hyperammonaemia, hyperlactataemia, hypoglycaemia after a short fast, hypertyrosinaemia and hypermethioninaemia appear, findings that do not discriminate the aetiology [46]. Unexplained early cataracts lead to consideration of cerebrotendinous xanthomatosis or galactokinase deficiency, and unexplained vomiting to urea cycle defects and galactose epimerase deficiency [4].

Two biochemical mimics deserve attention. HFI causes a secondary glycosylation defect by inhibiting phosphomannose isomerase, with a type 1 transferrin IEF that may lead to a wrong diagnosis of CDG; the profile corrects with restriction and regression of the liver disease [4, 51, 83]. Raised levels of several plasma lysosomal enzymes may mimic mucolipidosis II/III; a normal plasma α-mannosidase in the context of multiple elevations should suggest HFI [82]. In an adult or adolescent, HFI belongs in the differential diagnosis of «lean» steatosis and of chronic abdominal pain attributed to irritable bowel syndrome [93, 99].

The most frequent distinction in practice is from fructose malabsorption, also called dietary fructose intolerance: a benign intestinal transport defect, due to osmotic load, with diarrhoea, distension and flatulence and, in severe cases, vomiting and abdominal pain; fructose appears in the stools and not in the urine [3, 4, 40]. Diets for fructose malabsorption are less restrictive and may aggravate HFI [4]. Sucrase-isomaltase deficiency causes distension, colic and diarrhoea with sucrose, but free fructose is well tolerated [3].

6.3. Differential diagnosis of gluconeogenesis defects

FBPase deficiency shares with glycogen storage disease types Ia and Ib the profile of fasting hypoglycaemia and lactic acidosis, but the latter adds hepatonephromegaly, hyperlipidaemia and hyperuricaemia, and has no glycerol in urinary organic acids [3, 8]. In both, unlike glycogen storage diseases III, VI and IX, glucose and lactate vary in opposite directions through the day, and maximal hyperlactataemia (up to 15 mmol/L) occurs during fasting [46, 49]. All three improve with intravenous glucose at a physiological rate (below 6–8 mg/kg/min) [46]. Pyruvate carboxylase deficiency should be considered when there are neurological symptoms; fatty acid oxidation defects and the hepatic presentations of respiratory chain diseases, with hypoketotic fasting hypoglycaemia and hyperlactataemia, complete the differential diagnosis [3]. Metformin, by inhibiting FBP1, produces a pharmacological picture of reduced glucose production and lactic acidosis [3, 59]. Compared with HFI, in FBPase deficiency vomiting is not a usual response to fructose, there is no aversion to fruit and there is no proximal tubular dysfunction after fructose [36]. In the French series, diagnosis was made at a mean of 3 years, after initial suspicion of mitochondrial disease or glycogen storage disease [86]. Between β-oxidation defects and FBPase deficiency, urinary organic acids during a crisis (glycerol, glycerol-3-phosphate) and plasma acylcarnitines discriminate, and next-generation sequencing hypoglycaemia panels are increasingly used [60].

GeneReviews compares FBPase deficiency with six groups of diseases [8]:

In the HFI column, the table in the FBPase chapter indicates fasting hyperlactataemia and normal uric acid, whereas the HFI chapter of the same collection describes lactic acidaemia and hyperuricaemia after fructose ingestion and normal fasting tolerance; the description in the HFI chapter is the one that corresponds to the pathophysiology [3, 4, 8].

PEPCK-C deficiency may mimic a proximal urea cycle defect, a mitochondrial disease (because of the urinary Krebs cycle profile) and acute liver failure of another cause, and should be considered in the presence of an apparent febrile seizure with hypoglycaemia [17, 39]. Raised urinary fumarate, with or without succinate and malate, also occurs in fumarase deficiency and in MDH2 (mitochondrial malate dehydrogenase) deficiency [46, 49]. Severe fasting hypoglycaemia without ketosis brings PEPCK-C deficiency close to the fatty acid oxidation and ketogenesis defects (HMG-CoA lyase and synthase), which acylcarnitines and organic acids distinguish [46].

6.4. Secondary fructosuria

Fructosuria may be secondary to acute liver disease, such as tyrosinaemia or galactosaemia, and to any liver injury [3, 46]. In essential fructosuria, the historical tolerance test showed no rise in blood glucose, hypoglycaemia or other abnormalities, and hepatic 31P-MRS was normal [3]. Small amounts of fructose appear in the urine of healthy people on a usual diet, but a positive reaction for reducing sugars on routine examination occurs only in essential fructosuria, HFI and advanced liver disease [21]. In 1963, Khachadurian described non-alimentary fructosuria in an 18-month-old Arab boy, the son of first cousins, with sickle cell-thalassaemia and hepatosplenomegaly: the fructosuria persisted after all fructose was excluded from the diet, the fructose tolerance test was normal and the fructosuria decreased two years later; three siblings had intermittent fructosuria [21].

7. Treatment and Risk Management Strategies

7.1. Sources of recommendations and general principles

There are no clinical practice guidelines from scientific societies for HFI, FBPase deficiency or PEPCK-C deficiency [4, 8, 17]. The available recommendations are those of the GeneReviews chapters (HFI, 2021; FBPase, 2026), the emergency protocols of the British Inherited Metabolic Diseases Group (BIMDG) for FBPase deficiency (paediatric, revised in 2016; adult intravenous, 2018; adult oral regimen, 2023), the ClinGen actionability report for HFI, the reference chapters of textbooks of metabolic disease, the systematic review by Úbeda and colleagues (which, despite its title, has no society sponsorship) and the practice surveys of the Society for the Study of Inborn Errors of Metabolism (SSIEM) and of the Italian society SIMMESN [3, 4, 8, 30, 97–99, 107, 108]. The BIMDG protocol lists consulted in October 2026 do not include a protocol for HFI or PEPCK deficiency [98]. No medicine is authorised for any of these diseases, and treatment is dietary, preventive and supportive [17, 29, 50]. The doses of glucose, bicarbonate and glucose polymers follow the BIMDG protocol as reference; glucose and sodium bicarbonate solutions are for general use and have no labelled dose for these diseases, so there is no label dose for comparison [98].

Essential fructosuria requires no dietary or pharmacological treatment [3, 18]. Sorbitol dehydrogenase deficiency is a hereditary neuropathy; aldose reductase inhibitors normalised intracellular sorbitol in fibroblasts and improved the motor phenotype in an animal model, and one of them, ranirestat, had a good safety profile and improved nerve conduction in trials in diabetic neuropathy [3, 47].

7.2. Hereditary fructose intolerance: acute treatment

On suspicion, all sources of fructose, sucrose and sorbitol are withdrawn immediately [3, 4]. Acute intoxication may require intensive care. Treatment is symptomatic in hospital: intravenous glucose (dextrose) for hypoglycaemia; support for liver failure, including fresh frozen plasma or exchange transfusion; correction of metabolic acidosis, if present; and replacement of fructose by glucose, maltose and cornstarch, to reverse the symptoms and normalise the abnormalities [3, 4, 30]. In infant liver failure in which galactosaemia, HFI or tyrosinaemia type 1 are being considered, galactose, fructose and protein are excluded from the diet, with normal intake of the other nutrients, until confirmation; once galactosaemia or HFI is confirmed, protein is reintroduced [106]. In neonatal hypoglycaemia of any cause, it is corrected immediately with a glucose bolus of 0.2–0.5 g/kg, followed by continuous infusion of 10% glucose with electrolytes by peripheral line (about 10 mg/kg/min), after the critical samples have been collected [106]. If intolerance is suspected during an infusion containing fructose or sorbitol, the infusion is stopped immediately, normoglycaemia restored and organ function stabilised in intensive care [40]. Renal dysfunction is monitored until it normalises, with renal replacement therapy if needed [4].

7.3. Hereditary fructose intolerance: diet

Restriction of fructose, sucrose, sorbitol and sucralose is the basis of treatment, led by a dietitian experienced in metabolic disease and reassessed as the child grows [4, 30]. Ingredients to avoid include fructose, high-fructose corn syrup, honey, agave syrup, invert sugar, maple-flavoured syrup, molasses, palm or coconut sugar, sorghum, inulin and fructo-oligosaccharides (FOS); on labels, «sugar», «table sugar», «natural flavourings» and even «sugar-free» or «no added sugar», when they do not specify the carbohydrate, should raise suspicion [4, 30]. Sucrose is replaced by glucose, maltose or starch, so that the diet does not end up with excess fat [3]. Infant formulas containing fructose, high-fructose corn syrup, sucrose, inulin or FOS are contraindicated [30]. The fructose content of foods varies, and storage temperature, preparation and cooking alter its bioavailability [3]. GeneReviews, based on the HFI laboratory of Boston University, organises foods as follows [4, 109]:

The fructose threshold that causes symptoms varies, in the literature, between 40 and 250 mg/kg/day, against an average intake of 1–2 g/kg/day in Western societies; maximum doses have not been validated for different genotypes, and patients with the same variants have different sensitivities [3]. Parents should keep intake as low as possible and, at least in childhood, not guide it by subjective tolerance [3]. GeneReviews sets no limit for any age and recommends strict restriction, especially in the infant [4]. The European document on excipients cites an international recommendation of less than 40 mg/kg/day and a stricter restriction of 10 mg/kg/day [40]. In two boys, reduction to about 40 mg/kg/day restored growth, and an experimental increase from 10 to 250 mg/kg/day, without symptoms or hepatic or renal dysfunction, produced sustained hyperuricaemia and hyperuricosuria and an increase in plasma and urinary magnesium [77]. Gitzelmann advocated strict restriction in early childhood (exclusive breastfeeding or sucrose-free formula), avoidance of fructose-containing foods until 2–3 years of age and later liberalisation [99]. The GeneReviews authors advise against following diets for fructose malabsorption, which are less restrictive [4]. Complete adherence may be unrealistic because of unreliable labelling [4].

Actual practice varies between centres. In the 2026 Italian survey, 27 dietitians from 15 centres (75% of the country's centres) responded; all provide written material, 14 of 15 use lists of vegetables (one excludes all), 64.3% accept foods with less than 1 g of fructose/100 g of raw product and 35.7% require less than 0.5 g/100 g, and 57.1% allow controlled portions of low-fructose vegetables in the stable phase; 8 centres individualise the diet and 7 use a standardised protocol [108]. In a Spanish national cohort of 36 patients, the median total fructose intake was 9.79 mg/kg/day, with no difference between children and adults, and protein intake was higher than in controls (92.43 versus 70.39 g/day) [110]. The classification of sweeteners also diverges between Italian centres [108]:

Maltitol (about 40%) and isomalt (about 10%) are hydrolysed in the intestine and release sorbitol, and about 25% of oral mannitol is absorbed and converted in the liver [108]. The survey describes practice and does not define recommendations. Sucralose is among the compounds to avoid in GeneReviews and ClinGen [4, 30].

A diet without fruit and with few vegetables exposes patients to deficiencies of water-soluble vitamins. A daily sugar-free multivitamin supplement is recommended, especially for ascorbic acid and folate [3, 4]. In the Italian survey, all centres supplement vitamin C, 86.6% folic acid and 5 of 15 docosahexaenoic acid (DHA) and a multivitamin; one third use fibre or osmotic laxatives for constipation [108]. The sources consulted do not give vitamin C or folic acid doses specific to HFI; the formulations chosen should respect the excipient thresholds of section 7.4.

7.4. Hereditary fructose intolerance: medicines, excipients and hospitalisation

Fructose, sorbitol and sucrose are present in medicines (syrups, oral suspensions and paediatric chewable tablets, immunoglobulin and antibody solutions, vaccines, iron supplements, enema and irrigation solutions) and in infant formulas without adequate declaration of composition [3, 4]. A search of the British medicines compendium for «fructose OR sorbitol OR sucrose OR sucralose» returned 1574 results in 2020 [4]. The annex to the European Commission guideline on excipients (revision 5, published by the European Medicines Agency, EMA, in December 2025; fructose and sorbitol entries from 2017) sets the mandatory warnings in the package leaflet and in the summary of product characteristics (SmPC) [111]:

The 5 mg/kg/day threshold derives from the strictest oral restriction (10 mg/kg/day) divided by two for the subcutaneous and intramuscular routes; it is not a «safe daily dose», but the limit above which the leaflet must contain a detailed warning, and it corresponds to one eighth of 40 mg/kg/day [40]. For the intravenous route the threshold is zero, and in children under 2 years of age, who may not yet be diagnosed, intravenous medicines containing fructose or sorbitol should be contraindicated unless there is a compelling need without an alternative, with a prior history taken for symptoms of HFI [40, 111]. The examples in the European document include the intravenous normal human immunoglobulin Flebogamma DIF® (50 mg/mL of sorbitol; at 0.2–2 g/kg per dose, a 10 kg child with Kawasaki disease would receive about 20 g of sorbitol), whose SmPC withdrew the indications below 2 years of age; intravenous anidulafungin (Ecalta®), with 204 mg of fructose per dose; monoclonal antibodies and growth factors such as filgrastim (2–80 mg per dose); oral sorbitol-containing formulations of desloratadine, ondansetron, antibiotics and orodispersible tablets; and fructose in lopinavir/ritonavir oral solution (Kaletra®) and raltegravir chewable tablets (Isentress®) [40]. Sorbitol reduces the bioavailability of orally administered lamivudine and risperidone [40].

Hospital is a high-risk environment, because the patient loses control of the diet and receives medicines containing fructose, sucrose and sorbitol [95]. Iatrogenic deaths persist when the restrictions are not communicated [4, 41]. It is recommended that the whole team know the diagnosis, that the patient wear an alert bracelet or necklace and carry an emergency card, that the clinical record have alerts for foods and medicines containing fructose, sucrose, sorbitol or sucralose, and that the hospital pharmacist approve parenteral medication case by case [3, 4, 30]. Patients and parents should know that infusions containing fructose, sorbitol or invert sugar are potentially fatal [3].

7.5. Hereditary fructose intolerance: vaccines

Vaccines are generally safe in HFI. According to Maiorana and colleagues, based on the Istituto Superiore di Sanità, an oral or parenteral vaccine can be given safely with a fructose (or equivalent) content of up to 2.4 mg/kg per dose, which includes most vaccines in the North American and European schedules [4, 104]. Oral rotavirus vaccines with more than 1000 mg of sucrose per dose are the exception.

The 2017 European document recorded, for reconstituted Rotarix®, 13.5 mg of sorbitol per dose (4.5–6.8 mg/kg in a newborn of 2–3 kg), with no known events [40]. The parenteral vaccines for measles, varicella, measles-mumps-rubella (MMR), measles-mumps-rubella-varicella and yellow fever (Stamaril®) contain 8–16 mg of sorbitol per dose, less than 2.4 mg/kg from 9 months [40]. In 2020, the product information for M-M-RvaxPro® and ProQuad® stated «do not administer to individuals with HFI», and Maiorana considered them administrable despite this warning; the current European SmPCs contain only the statement on the additive effect [104, 116, 117]. In the USA, the only approved rotavirus vaccines are the two high-sucrose formulations, given at 2, 4 and 6 months, usually before any diagnosis [4]. In Portugal, these vaccines are centrally authorised and the EMA SmPC applies. In Brazil, the open database of the National Health Surveillance Agency (ANVISA) shows active registrations of Rotarix®, RotaTeq®, the human rotavirus G1P[8] (attenuated) vaccine of the Oswaldo Cruz Foundation, M-M-R II®, Priorix®, Priorix Tetra®, ProQuad®, Varilrix®, Varivax® and the Fiocruz triple and tetravalent viral vaccines [120]; the sucrose and sorbitol content of the Brazilian presentations was not documented in the sources consulted. The siblings of a patient should be tested in time to avoid the high-sucrose rotavirus vaccines [4].

7.6. Fructose-1,6-bisphosphatase deficiency: treatment of decompensation in children

Most of the time patients are healthy and need no special diet, but infections, fasting, diarrhoea or vomiting can lead to serious illness with drowsiness, tachypnoea, marked acidosis and hypoglycaemia; because hypoglycaemia appears late, intervention should take place while blood glucose is still normal, and tachypnoea is the early sign to look for [8, 98]. During illness no fructose or sucrose is given, and only sugar-free medicines are used, always checking the constituents [98]. Emergency treatment is indicated if the child vomits, has abdominal pain or refuses to eat or drink, regardless of other symptoms [8]. Assessment includes pH and blood gases, glucose (laboratory and strip), urea and electrolytes, full blood count, lactate and blood culture, and the Glasgow coma scale and blood pressure even without apparent encephalopathy [98]; ketonuria is an early indicator of an impending crisis [8].

If the child is relatively well, without vomiting or respiratory difficulty, the oral emergency regimen with glucose polymer is used, given every two hours (daily volume divided by 12) or, if there is nausea, in smaller and more frequent amounts or by continuous nasogastric infusion; one level 5 mL measuring scoop holds about 7 g of glucose polymer; if there is vomiting or diarrhoea, rehydration solutions are prepared with the polymer solution instead of water [98]:

If the child is unwell, the intravenous route is followed [98]:

In neonatal hypoglycaemia, once blood glucose has normalised, the infusion may be replaced by continuous enteral feeding, initially with a lactose-free milk formula with maltodextrin, normal energy for age and 50–60% carbohydrate, equivalent to 10–12 mg/kg/min of glucose, later adjusted to the final diagnosis [106]. Concentrations differ between sources, but the bolus load is the same (200 mg/kg) [3, 8, 98]. Acidosis generally corrects rapidly without bicarbonate, and symptoms subside shortly after intravenous dextrose, with recovery within hours, generally without sequelae [8, 98]. The hepatomegaly and raised transaminases of the crisis are transient and require no specific treatment [8]. A prompt response to parenteral fluids with glucose and sodium bicarbonate has been described since the first series [36]. Fever is treated with antipyretics free of fructose, sucrose, glycerol or sorbitol [8]. In home management of mild catabolism (fever, cough or cold, loose stools, a child who continues to eat and is not lethargic), the frequency of carbohydrate meals and glucose polymers is increased, restricting fructose, sucrose, glycerol and sorbitol, with frequent reassessment and good communication between the family and the team [8].

7.7. Fructose-1,6-bisphosphatase deficiency: treatment of decompensation in adults

The adult BIMDG protocol applies to patients weighing more than 40 kg and targets a blood glucose of 6–10 mmol/L [97]. In adults, triggers also include alcohol excess, and because hypoglycaemia appears late, capillary blood glucose should not be used to delay treatment [97]. Investigations include blood gases, glucose, urea and electrolytes, full blood count, liver tests, lactate, C-reactive protein and cultures [97].

The trade names of glucose polymers in the oral regimen are those available in the United Kingdom [97]; the sources consulted do not identify equivalents marketed in Portugal or Brazil. In a 29-year-old patient, intravenous 30% dextrose followed by continuous infusion allowed complete recovery within 48 hours [91].

7.8. Fructose-1,6-bisphosphatase deficiency: maintenance treatment

Prevention of crises rests on avoiding fasting, especially during fever, with frequent meals, slowly absorbed carbohydrates and, if needed, continuous gastric feeding [3, 8]. Infants feed every two or three hours [8]. Uncooked cornstarch (UCCS) at bedtime, at a dose of 1–2 g/kg mixed in milk or water, is used in children aged 6–12 months or older who have nocturnal hypoglycaemia [8, 107]. In a Saudi centre, adults use UCCS at night and when needed (15–60 g per dose), with meals every 4 to 6 hours [92]. In the Turkish study with continuous glucose monitoring, higher doses of UCCS or modified starch were associated with fewer annual crises (ρ = −0.854), more time in range and less time below range, and a time below range of at least 2% was associated with more crises and more steatosis [89]. Surgery requiring several hours of fasting is performed with intravenous glucose [8]. Prolonged or intense exercise should be covered by carbohydrate and hydration [8].

Fructose restriction is the point on which the sources diverge most. GeneReviews considers that small amounts (up to 2 g/kg/day) are well tolerated, that a single high dose (above 1 g/kg) is harmful, especially in young children, and that there is no consensus on restriction in the usual diet; it recommends restricting foods and medicines containing fructose, sucrose, glycerol and sorbitol especially during crises [8]. The reference chapter recommends, in young children, restricting fructose, sucrose and sorbitol and limiting fat (20–25%) and protein (10% of energy requirements), and considers that, without triggers, patients do not need carbohydrate supplements [3]. The atlas advises avoiding fructose and sucrose without eliminating them entirely, cautiously exploring individual tolerance and avoiding soft drinks with a sucrose or fructose load [36]. In the 2018 SSIEM survey (126 patients from 36 centres), 75% of centres imposed restrictions — only foods rich in sucrose in 19%, fruit and sugars in 11%, fruit, vegetables and sugars in 36% —, 25% did not restrict when the patient was well, restrictions were more frequent above 16 years of age, 56% of centres prescribed nocturnal UCCS (to 37% of patients) regardless of fasting tolerance, and all used an emergency regimen with glucose polymer; the authors called for international guidelines [107]. In a pregnant woman, fruit was limited to one portion per day (10–20 g of fructose at a time), below the limit of less than 1 g/kg at a time [121].

Obesity is frequent because of overfeeding; under supervised conditions, a fructose-free hypocaloric diet (800–900 kcal/m²/day) allowed considerable weight loss without lactic acidosis or hypoglycaemia, according to the personal observation of one of the authors of the reference chapter [3]. GeneReviews attributes obesity, in treated patients, to probable overtreatment with a high-carbohydrate diet and recommends monitoring weight gain [8]. Gout, described in a 32-year-old patient, was treated with allopurinol [36]. The Franco-Belgian series recommends preventing excess weight through dietary management, as it is an additional factor for steatosis, and proposes lifelong hepatic surveillance, at the intervals of the FBPase deficiency surveillance table [61].

The maintenance plan includes written maintenance and emergency protocols for parents, the attending physician, teachers and school staff, provided before they are needed; an emergency letter with the principles of treatment and the contact details of the metabolic centre; an alert bracelet; prior contact with a centre near the travel destination; routine vaccination, including the annual influenza vaccine, without restrictions (there is no immunodeficiency), followed by frequent carbohydrate-rich meals; advance notification of the metabolic centre before surgery and dental procedures; and the usual management of intellectual disability, when present [8]. At diagnosis, referral to a specialised centre is strongly recommended and a brief admission for carer education may be considered [8].

7.9. Fructose-1,6-bisphosphatase deficiency: agents to avoid

The atlas list of sugar-containing medicines (old North American brands) is historical and not usable as a current list [36]. Intravenous glycerol should only be used after FBPase deficiency has been excluded, for example by measuring lactate [122]. The recommendation to avoid metformin is a mechanistic inference, without clinical study in patients [59].

7.10. Cytosolic PEPCK deficiency

There is no approved medicine. In the acute phase, intravenous dextrose is started as soon as the diagnosis is suspected in a child with unexplained hypoglycaemia or liver failure; continuous glucose infusion reversed acute liver failure in the cases described [13, 17, 39, 48]. The sources consulted do not describe a specific dosing protocol; in the absence of a dedicated protocol, the glucose rates of gluconeogenesis defects (200 mg/kg bolus and infusion at about 8–12 mg/kg/min in the newborn and infant) are the closest extrapolation, by analogy with FBPase deficiency [98, 106]. In the long term, management consists of avoiding fasting and maintaining a written emergency regimen with glucose polymers for intercurrent illness, which in published experience was sufficient to prevent recurrence of liver failure [17, 39]. Counselling addresses the triggers (infection, missed meals, intense exercise, alcohol and breastfeeding in an affected mother), and the risk persists into adulthood, so the emergency plan is maintained in adults [11, 17]. Early diagnosis prevents decompensations [10]. There is no therapy under clinical investigation; hepatic re-expression of PEPCK-C corrected neonatal hypoglycaemia only in mice [17].

7.11. Dosing table

The doses in the BIMDG protocols are outside any disease-specific label, because glucose and bicarbonate solutions are for general use. The use of glucose, bicarbonate and glucose polymers in these diseases is based on expert protocols and clinical experience, not on trials [17, 29, 50].

7.12. Regulatory status

7.13. Trials and intervention studies

The only study in patients with HFI has three participants, has no placebo arm, lasts nine days and measures acute tolerance, without clinical outcomes; the authors consider that studies with longer follow-up and clinically relevant outcomes are needed [126]. The NAFLD trials measure liver fat in a different population and do not allow efficacy in HFI to be inferred; the percentages are relative reductions in fat fraction and cannot be compared between trials of different design [127, 128]. Pfizer removed PF-06835919 from its steatohepatitis programme in 2021, and Lilly abandoned two KHK inhibition programmes in 2021 and 2023, according to the trade press; no primary sponsor document with the date of discontinuation was found [123, 129]. A ClinicalTrials.gov search in October 2026 found no recruiting interventional trials for HFI, FBPase deficiency, PEPCK deficiency or essential fructosuria, which does not prove that no studies exist outside the registry [130]. In a discrete choice experiment with 90 adults with HFI, the majority on average preferred to keep their current diet, but 86% chose pharmacological therapy in at least one task, especially a daily tablet on special occasions, without adverse effects or costs [131].

Fructokinase inhibition has a preclinical rationale: absence or pharmacological inhibition of Khk prevents hypoglycaemia and hepatic and intestinal injury in aldolase B-deficient mice, and protection results from inhibition of isoform C and not A [52]. Osthole, a coumarin derivative, prevented hepatic triglyceride accumulation in Aldob−/− mice [3]. Inhibitors of ACC (acetyl-CoA carboxylase) and DGAT2 (diacylglycerol acyltransferase 2) reduced hepatic lipids and triglycerides in Aldob-inactivated rats [54], and an aldose reductase inhibitor reduced hepatic fructose without reducing steatosis in mice [53]. All these data are preclinical.

7.14. Developments in the last twelve months

The result of the only trial of a KHK inhibitor in patients with HFI was published in February 2025, outside the twelve-month window, and remains the most recent pharmacological intervention data in the disease [126]. No application for authorisation, opinion or regulatory decision was identified for any medicine in this class.

7.15. Pregnancy and lactation

HFI. Reports are scarce; in general, maternal HFI does not appear to harm the mother or child if strict avoidance is maintained during pregnancy [4]. In one family, a woman with enzymatically documented HFI had three children with HFI; the first two died (at 6 months from sepsis with cirrhosis and growth faltering, and at 5 years from HIV (human immunodeficiency virus) infection acquired through transfusion), complications attributed to the poorly controlled HFI of the children or to comorbidities, and the third pregnancy, with a strict maternal diet, was normal [4, 133]. In one case, fetal exposure to high maternal fructose (heterozygous mother) was proposed to explain neonatal abnormalities [83].

FBPase deficiency. Successful pregnancies have been described [8]. An African American woman with about 30 previous admissions and an initial wrong diagnosis of glycogen storage disease had three successful pregnancies with a strict diet and nocturnal UCCS, with mild gestational diabetes and an increasing need for starch [134]. A 24-year-old Japanese primipara, with preconception education, glucose self-monitoring and intravenous glucose prepared, had no hypoglycaemia with altered consciousness and had a caesarean section at 38 weeks [135]. A 31-year-old North American primipara had vomiting at 14 weeks with lactate of 3.8 mmol/L and ketonuria, followed a diet rich in complex carbohydrates, was induced at 37 weeks for gestational hypertension and received during delivery 10% dextrose in 0.45% NaCl with 20 mEq/L of potassium chloride at twice the maintenance rate; at 4 months post partum she had hypoglycaemia and lactic acidosis attributed to the demands of breastfeeding [121]. In a Saudi centre, of the three pregnant women, the one with morbid obesity and poor adherence had severe hypoglycaemia with lactic acidosis in intensive care, and the two with gestational diabetes developed lactic acidosis immediately after delivery with stable blood glucose, corrected with bicarbonate in the infusion [92]. GeneReviews recommends preconception counselling, frequent glucose self-monitoring, consideration of a high-risk obstetric centre, uncooked cornstarch at night as needed, increased intake and surveillance in the third trimester and continuous glucose infusion during delivery [8]. The Saudi plan details: antenatally, regular meals with complex carbohydrates, avoidance of fasting and of fructose, sorbitol and sucrose, UCCS if needed and continuous glucose monitoring preferably; during labour, glucose, lactate and renal profile at the start and every 6 hours, 10% dextrose in 0.45% NaCl at maintenance rate, blood glucose every 4 hours with a target of 6–10 mmol/L and insulin if persistently above 10 mmol/L, avoidance of Ringer's lactate, bicarbonate in the infusion if there is acidosis and epidural analgesia; post partum, blood glucose every 4 hours and electrolytes and lactate every 6 to 8 hours [92].

PEPCK-C deficiency. Breastfeeding triggered hypoglycaemia in an affected mother, and the emergency plan is maintained in adulthood [11, 17].

7.16. Perioperative care, hospitalisation and transition

In HFI, infusions and parenteral medicines are checked by the hospital pharmacist, solutions containing fructose, sorbitol or invert sugar are excluded and 24% sucrose is not used in newborns [4, 30]. In FBPase deficiency, the metabolic centre is notified before any surgery or dental procedure, to plan perioperative fluids and nutrition with surgeons and anaesthetists; preoperative fasts are covered with intravenous glucose, and high-risk patients have a specialised anaesthetic consultation [8]. Transition from paediatric to adult care should be planned, because the disease is lifelong [8]; in adults with FBPase deficiency, patients often cease to be followed in hepatology, despite steatosis [61].

7.17. Source recommendations and divergences

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

All entities with an established molecular basis are autosomal recessive [4, 8, 17, 18]. The parents of an affected individual are obligate (or presumed) heterozygotes, and their molecular testing is recommended to confirm the phase of the variants [4, 8]. If only one parent is a carrier, with confirmed maternity and paternity, a de novo variant in the proband, a post-zygotic de novo variant in a mosaic parent or uniparental isodisomy should be considered; apparent homozygosity may correspond to a deletion of one or more exons not detected by sequencing [4, 8].

The carrier frequency of ALDOB makes pseudodominance possible: Wolf and colleagues described HFI in a father and son in 1959, with the mother probably heterozygous, and Cox and colleagues showed in 1982, in a Jewish family, that apparently dominant transmission resulted from the union of a homozygote with a heterozygote, identifying carriers by intestinal biopsy, a method now replaced by molecular study [19]. In the general population, the carrier frequency of ALDOB variants in the USA was 1:122 (about 0.8%) in a multi-disease screening of 23,453 people, 1:97 in people from the Middle East and 1:226 in African Americans, with European frequencies of 0.8–1.3% [30, 136]. In the context of consanguinity (FBPase deficiency in Turkey, Pakistan, India, Egypt and Saudi Arabia; HFI in the Agarwal community), the recurrence risk and the probability that the partner is a carrier increase, and founder variant panels allow rapid testing [58, 66–68, 92, 103].

8.2. Cascade testing and evaluation of relatives at risk

In HFI, once the familial variants are known, apparently asymptomatic older and younger siblings are tested, in order to restrict fructose as early as possible and avoid the high-sucrose rotavirus vaccines [4]. In FBPase deficiency, asymptomatic siblings are evaluated to start prevention (frequent meals, avoidance of fasting) and prompt treatment of infections and fever; the newborn at risk should avoid fasting and be fed regularly, with bedside blood glucose monitoring and observation for signs of hypoglycaemia and acidosis (lethargy, poor feeding, vomiting, hypothermia, tachypnoea) while awaiting results, and with a low threshold for infusion of 5–10% dextrose, especially if of low birth weight, preterm or the infant of a diabetic mother [8]. In PEPCK-C deficiency, the asymptomatic sister of a Latvian patient had the same genotype, which justifies screening of siblings and a preventive emergency plan [48]. The history of a sibling who died in acidosis was often what allowed the next one to be saved [36]. In essential fructosuria, testing of relatives has no clinical consequence.

8.3. Carriers

Carrier detection requires prior identification of the familial variants [4, 8]. In FBPase deficiency, the leucocyte enzyme test is not reliable for carriers; molecular detection was possible in 73% of the Japanese families of the first series [8, 36, 38]. It is recommended that FBP1 testing be offered to the reproductive partners of affected individuals or heterozygotes [8]. ALDOB heterozygotes are not at risk of HFI; the studies showing a greater rise in uric acid and insulin after fructose have no established clinical implication [30, 73, 74]. Isolated cases of symptoms in heterozygotes (hypoglycaemia, ketosis, recurrent fever, hepatic dysfunction) have been described, without a demonstrated causal relationship; the two Italian patients with p.Arg46Trp and p.Tyr343His are summarised in section 2.7 [19, 30].

8.4. Prenatal diagnosis and preimplantation genetic testing

Once the familial pathogenic variants have been identified, prenatal diagnosis and PGT are possible for HFI and FBPase deficiency [4, 8]. In FBPase deficiency, prenatal diagnosis must be molecular, because activity is low in the placenta and absent in amniocytes and chorionic villi [3, 8]. There are differences in perspective among professionals and among families regarding the use of prenatal diagnosis in these diseases [4]. The ideal time for these discussions is before pregnancy, with counselling of young adults who are affected, carriers or at risk [4, 8]. DNA banking from an affected individual is recommended when the molecular diagnosis has not yet been confirmed [4, 8].

8.5. Pregnancy in affected women and counselling of minors

Pregnancy in a woman with HFI generally proceeds without complications if avoidance is strict; the child of a woman with HFI and a carrier partner has a 50% risk of being affected, as in the family described by Marks and colleagues [4, 133]. Pregnancy in a woman with FBPase deficiency requires a joint metabolic and obstetric plan, with intravenous glucose during delivery (section 7.15) [8, 92]. Testing of the minor siblings of a patient with HFI or FBPase deficiency is justified by the direct benefit (prevention of fructose exposure or fasting), and ClinGen assigns strong paediatric actionability to HFI [4, 8, 30]. Among support resources, GeneReviews lists Metabolic Support UK and parent networks [4, 8].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Hereditary fructose intolerance: prevalence and what each figure measures

Almost all prevalence estimates for HFI derive from the carrier frequency of the common variants, converted by the Hardy-Weinberg law and corrected for the detection rate; they measure an expected genotypic prevalence at birth and not diagnosed cases [4]. They range from 1:18,000 to 1:31,000 in Europe [4].

The reference chapter attributes to Santer 2005 the value of 1:29,600 for Germany; the abstract of the original article gives 1:26,100, the value used here [3, 5]. The Orphanet prevalence class for HFI (1–9 per million, with geographical data from China) is much lower than the European genetic estimates and measures something else (registered cases by region) [50]. The five-variant panel of the North American study may have underestimated prevalence in people of non-European ancestry [4]. Inclusion of predicted rare alleles increases the estimate and is more informative in populations with few published patients [138].

The variant spectrum reflects the history of populations: p.(Ala150Pro) is the most frequent in all studies and has a worldwide distribution with its own pattern in Europe; p.(Ala175Asp) and p.(Asn335Lys) are concentrated in Europe [5, 63, 138]. In the USA, null alleles are more prevalent than in Europe and seven alleles cover only 65% [64]. In the 1990 European and North American study, p.(Ala150Pro) (A149P) accounted for 67% of alleles and was significantly more common in northern than in southern Europe, and p.(Ala175Asp) (A174D) occurred in patients from Italy, Switzerland and the former Yugoslavia (16% overall), but not from the United Kingdom, France or the USA; p.(Asn335Lys) (N334K) was first described in patients from the former Yugoslavia and Italy, and in the French series its carriers were mainly Turkish immigrants, which suggests a higher frequency in south-eastern Europe [20]. Absolute linkage disequilibrium between A149P and a restriction polymorphism haplotype in 15 homozygotes indicates a single origin with a founder effect, and haplotype analysis also attributed a single founder to A174D, with high frequencies reached through genetic drift [19, 20]. In Turkey, 9 of 13 patients were homozygous for A149P [20]. In India, c.324+1G>A is a founder variant in the Agarwal community, with a shared haplotype [103]. In Turkey, p.(Ala150Pro) and p.(Ala175Asp) predominate, with 87.5% homozygosity [85]. In Italy, the 6.5 kb deletion accounts for 11% of alleles in a small cohort [65].

9.2. Fructose-1,6-bisphosphatase deficiency

The estimated prevalence is 1:350,000 in the Netherlands, according to a conference abstract, and less than 1:900,000 in France; these values rest on small numbers and on clinical ascertainment [8, 86, 139]. About 150 to 190 patients have been published worldwide [8, 9]. The disease has no ethnic predominance, but is more frequent in populations with consanguinity: most reports are of European and North American patients, with many cases in Japan, a high proportion of Turkish patients in the Hamburg and Zurich series, nine patients from six families in Israel (two Jewish, three Arab, one Druze), 14 patients in Saudi Arabia and series in Pakistan, India, Malaysia, China, Egypt and Lebanon [3, 8, 9, 36, 66]. The founder or frequent variants are c.959dup in Japan (46% of alleles) and Central Europe (14%), the exon 2 deletion in patients of Turkish and Armenian ancestry (and in Lebanon), c.841G>A p.(Glu281Lys) in Pakistan, India and Turkey (with different haplotypes), c.472C>T p.(Arg158Trp) in Pakistan and India, c.960delinsGG in Egypt and c.958G>A and c.986T>C in Southern Brazil [38, 58, 66–69]. The Saudi centre following 39 adults reports a relatively high incidence, attributed to consanguinity [92]. For the Japanese insertion, OMIM gives 16 of 22 alleles, a figure that diverges from the original abstract (10 of 22, 46%), adopted here [23, 38].

9.3. Cytosolic PEPCK deficiency and essential fructosuria

No population prevalence of PEPCK-C deficiency has been published, nor can it be derived from existing data [17]. The frequency of c.925G>A in ExAC was 0.98% in Finns and 0.10% overall, with one homozygote, and gnomAD v2.1.1 records 361 heterozygotes and 3 homozygotes; the presence of homozygotes in population databases and the mild phenotype of the Finnish patients led the authors to consider undiagnosed patients or modifiers of severity and penetrance [25, 26]. The p.(Ile45Thr) variant, described in Ashkenazi Jews, has according to the authors a frequency of 0.2% in Europeans [26]. The concentration of 24 Finnish patients diagnosed between 2016 and 2019, 22 of them homozygous for c.925G>A, results from a founder allele «endemic» in that population and should not be generalised; there are additional families from the Arabian Gulf and Latvia [10, 11, 17, 48]. Essential fructosuria has an estimated frequency of 1:130,000, probably an underestimate because it is asymptomatic and because reducing-substance tests have been abandoned; Orphanet classifies the prevalence as unknown, and in the UK Biobank no participant had the known causal genotype [3, 18, 56]. SORD deficiency due to c.757del homozygosity has an estimated frequency of 1:100,000, with about 70% of cases sporadic owing to recurrent gene conversion from a pseudogene on chromosome 15 [3].

9.4. Portugal and Brazil

In Brazil, the study of six unrelated patients from the south of the country with FBPase deficiency (one with consanguineous parents) found only three variants in 11 alleles, including two novel ones, c.958G>A and c.986T>C, linked to specific haplotypes, which the authors consider the most prevalent in the country; five patients were homozygous [69]. In a reference laboratory in Southern Brazil, transferrin IEF identified four patients with HFI among the 14 completed diagnoses in 1546 individuals tested between 2008 and 2017, mainly between 11 months and 3 years of age and in the presence of liver disease [101]. In Portugal, the sources consulted present no epidemiological data; the international SSIEM survey on FBPase deficiency had a co-author from a Portuguese centre, without a number of patients by country in the abstract [107]. The lack of data in the sources consulted does not demonstrate the absence of published data.

9.5. Special populations

The newborn and young infant are the most vulnerable: in HFI, because of exposure to formulas, sucrose for analgesia and oral rotavirus vaccines before diagnosis; in FBPase deficiency, because of scarce glycogen reserves [3, 4, 75]. Below 2 years of age, intravenous medicines containing fructose or sorbitol should be contraindicated unless there is a compelling need [40]. In adults with HFI, hospitalisation, intravenous amiodarone and sugar-containing excipients are the main risks [94, 95]; in adults with FBPase or PEPCK-C deficiency, alcohol and intense exercise are triggers [11, 97]. Patients with HFI who self-restrict fructose may reach adolescence or adulthood undiagnosed, with steatosis and short stature [93]. Steatosis in treated adults (75–94% depending on the method and cohort) and the small increases in blood pressure and glomerular filtration define a population with needs for hepatic and cardiovascular follow-up [72, 79, 81].

9.6. European networks and patient associations

MetabERN, C-FAO subnetwork, coordinated by Terry Derks (Groningen), Sarah Grünert (Freiburg), Diego Martinelli (Rome) and Alessandro Rossi (Naples), with patient representation from the French association AFG, includes disorders of fructose metabolism and gluconeogenesis [31]. Patient associations and resources include Metabolic Support UK, the website of the Boston University HFI laboratory, with lists of tolerated and non-tolerated sugars, the food list of Genetic Metabolic Dietitians International and the Asociación de Afectados por Intolerancia Hereditaria a la Fructosa, in Spain [4, 109, 140].

10. Illustrative Clinical Case

10.1. Hereditary fructose intolerance diagnosed in adolescence through steatosis

Hurlock and colleagues described in 2026 a North American girl born in 2009, referred at 13 years of age to paediatric gastroenterology for mild persistent elevation of transaminases (AST and ALT of 40–50 IU/L), nausea and abdominal pain without jaundice, of two years' duration [93]. She had always had short stature, below the 3rd centile, with a body mass index of 23–24.9 (z-score of 0.99–1.1) and accelerated weight gain in the preceding years; endocrinology found a normal bone age with nearly closed growth plates and attributed the short stature to a familial cause. Investigation for Wilson disease, alpha-1 antitrypsin deficiency, coeliac disease, lysosomal diseases, autoimmune hepatitis and hepatitis C was negative. Ultrasound showed steatosis and transient elastography (FibroScan®) a normal liver stiffness of 6.1 kPa. Because of persistent steatosis of unknown cause, she underwent liver biopsy in March 2024, which showed macrovesicular steatosis in 20–30% of hepatocytes, without inflammation or fibrosis (Figure 1 of the article: A, haematoxylin-eosin with mild macrovesicular steatosis; B, trichrome with normal architecture and no fibrosis; https://pmc.ncbi.nlm.nih.gov/articles/PMC13398793/figure/jpr370197-fig-0001/). Because of the phenotype of steatosis without obesity, a cholestasis and metabolic disease genetic panel was requested, whose result, in April 2025, revealed homozygosity for the pathogenic variant ALDOB NM_000035.4:c.448G>C p.(Ala150Pro) [93].

At the metabolic disease clinic, a targeted history revealed abdominal pain and poor weight gain since 6 years of age, with no follow-up after an earlier referral; at 12 years, episodes of dizziness, tremor and visual disturbances after fruit or sugary foods and drinks; and lifelong avoidance of fruit, desserts and juices, because of the abdominal pain and dizziness that followed. The diet included frequent fast food, meats, few vegetables and 2–3 gallons of milk per week [93]. In June 2025 she started strict avoidance of fructose, sucrose, sorbitol and polysorbate, with glucose self-monitoring and glucose tablets for symptoms. She continued to have symptoms weekly or every few weeks (tremor, dizziness, occasional vomiting) without documented hypoglycaemia. Six months later (November 2025), ultrasound no longer showed steatosis, liver stiffness was 4.4 kPa and AST and ALT had normalised (18 and 17 U/L); height remained just below the 3rd centile [93].

The case shows how self-avoidance of fructose masks the classical picture and prolongs subclinical liver disease and growth faltering, and how a targeted dietary history (aversion to fruit and sweets since childhood) would have brought the diagnosis forward by years. The approach followed — genotyping after biopsy — reverses the recommended order, in which molecular testing precedes and often avoids biopsy [4, 93]. The authors cite a frequency of 1 in 20,000 births in the USA, which differs from the North American carrier-based estimates (1:60,000 with a five-variant panel) [4, 93].

10.2. Complementary case: cytosolic PEPCK deficiency with acute liver failure

Vasiļevska and colleagues described an 8-year-old Latvian girl, with no history other than prolonged neonatal jaundice, who after an infection, fasting and high sucrose intake immediately beforehand developed severe acute hepatic and renal failure, with ALT of 6759 U/L, AST of 9165 U/L, creatinine of 250 µmol/L, urea of 37.92 mmol/L, prothrombin of 30.6% and international normalised ratio of 2.40, fulfilling criteria for paediatric acute liver failure [48]. Plasma glutamine was 3217.1 µmol/L (reference 373–709) and urinary glutamine 2903.5 mmol/mol creatinine (reference 7–137), with normal ammonia; urinary organic acids showed hydroxy-dicarboxylic aciduria and increased Krebs cycle intermediates, including fumarate, without raised ketones. The picture reversed with continuous glucose infusion. Genetic study identified compound heterozygosity PCK1 NM_002591.4:c.925G>A p.(Gly309Arg) and c.1833_1834del p.(Glu611AspfsTer16), the latter proposed as likely pathogenic; her 12-year-old sister, with the same genotype, was asymptomatic [48]. The authors propose the combination of hypoglycaemia, raised glutamine and normal ammonia as suggestive of the diagnosis. The case illustrates intrafamilial variability and the need for an emergency plan for asymptomatic siblings with the same genotype.

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

HFI. With complete restriction of fructose, sucrose, sorbitol and sucralose started early and sustained adherence, neurocognitive development, general health and life expectancy are normal; without adherence, chronic hepatic or renal disease is to be expected [3, 4]. Growth normalises within 2–3 years after the diet is started, but hepatomegaly persists in many patients, even in those treated from birth [30, 76]. Steatosis in treated patients reaches 94% on ultrasound in an Italian paediatric cohort and 75% on magnetic resonance in a Spanish cohort, with intrahepatic triglycerides of 2.5% versus 0.6% in Dutch and Belgian adults [72, 78, 79]. Treated adults have slightly higher systolic blood pressure and glomerular filtration than controls, which raises the hypothesis of a greater long-term cardiovascular risk [4, 81]. The risk of hepatic adenoma and fibrosis is potential and rests on case reports [4, 80]. The chronic kidney disease described resulted from early or chronic exposure or from a persistent tubular defect [4].

FBPase deficiency. Once diagnosed and managed, the course is generally benign, with normal growth and psychomotor and intellectual development, and fasting tolerance improves with age, so that the disease usually ceases to be a problem in adult life [3]. The disease may be lethal in the neonatal period, but appropriate treatment confers a favourable prognosis [23]. In the SSIEM survey, the proportion of patients with fasting tolerance considered normal increased from 30% (1–10 years) to 36% (11–16 years) and 58% (over 16 years), without biochemical proof [107]. Mortality and sequelae are concentrated in neonatal and early childhood crises and in diagnostic delays: two neonatal deaths among 14 Egyptian children, one neonatal death among 7 Malaysian patients, neurological sequelae in a Lebanese patient undiagnosed for 10 years [9, 66, 87]. Two Swedish siblings followed for more than 30 years had a favourable course [70]. Hepatic abnormalities appeared in all 18 patients of a Franco-Belgian series; steatosis may progress to fibrosis, there are no long-term follow-up data and, by analogy with non-alcoholic fatty liver disease and glycogen storage disease type I, the authors consider a risk of adenoma or hepatocellular carcinoma that was not documented in the series [61]. Crises persist in adults in the context of infection, fasting or alcohol [90, 91, 97]. A patient with about 30 admissions before diagnosis developed, despite later adherence, sensorineural hearing loss and early cognitive impairment [134].

PEPCK-C deficiency. Morbidity results from the hypoglycaemic episodes; with appropriate treatment, the abnormalities normalise after each episode, and neurological development may be normal even after acute liver failure [13, 17]. There is at least one death from hypoglycaemic cerebral oedema before diagnosis, and the risk of episodes persists into adulthood [11, 17]. In the synopsis of the 2022 review, 28 of the 32 patients had normal cognition and neurodevelopment, and there was one death at 3.5 years [25]. The first patient described, without effective treatment, died at 2 years and 10 months with cerebral and optic atrophy [25].

Essential fructosuria. The prognosis is that of the general population [3, 56].

11.2. Surveillance of hereditary fructose intolerance

After diagnosis, the initial evaluation includes consultation with a biochemical geneticist or paediatric metabolic specialist to identify metabolic abnormalities, a dietitian experienced in metabolic disease, ophthalmology (best corrected visual acuity and slit-lamp biomicroscopy), hepatic assessment (enzymes, coagulation factors, albumin, bilirubin) and renal assessment (urea, creatinine, cystatin C and electrolytes, especially potassium, phosphorus, calcium and magnesium), genetic counselling and family support [4]. There are no formal surveillance guidelines [4]. Regular collection of the nutritional history is the best method of dietary monitoring; there are no sensitive chemical parameters, except perhaps the transaminases [3]. CDT and sialotransferrins correlate with fructose intake (disialotransferrin with R² of 0.7), unlike ALT and steatosis, but there is no consensus on the best isoform nor a clear correlation with liver damage, tolerance or genotype [72, 100, 141]. None of these tests has definitively proved useful in diagnosis or surveillance [4].

Hepatic surveillance by ultrasound, elastography or spectroscopy in adults and cardiovascular surveillance derive from cohorts of treated patients and not from a formal recommendation [72, 78, 79, 81]. In the adolescent of the clinical case, repeated ultrasound and elastography documented resolution of steatosis six months after the diet was started [93].

11.3. Surveillance of fructose-1,6-bisphosphatase deficiency

At diagnosis, assessment with a metabolic physician and dietitian includes: blood glucose, arterial blood gases, lactate, ketones, urinary organic acids, liver tests, lipid profile, uric acid and CK; breathing (apnoea, dyspnoea); neurological assessment, with electroencephalography if there are seizures and brain magnetic resonance imaging if there are encephalopathy and seizures; investigation for infection in those presenting in crisis; abdominal ultrasound; height, weight, head circumference and nutritional status; development; genetic counselling and family support [8].

GeneReviews does not set intervals for hepatic surveillance; the Franco-Belgian series proposes regarding these patients as having chronic liver disease, with annual hepatic assessment throughout life, including in adults, who often cease to be followed in hepatology, and with six-monthly ultrasound if there is fibrosis; this is an author proposal based on 18 patients, without prospective validation [8, 61].

11.4. Follow-up of cytosolic PEPCK deficiency and essential fructosuria

There is no published surveillance protocol for PEPCK-C deficiency; follow-up focuses on periodic review of the emergency plan and education about triggers (infection, fasting, intense exercise, alcohol, breastfeeding), extended to siblings with the same genotype, and on liver tests after each decompensation [11, 17, 48]. Essential fructosuria requires no follow-up [3].

12. Summary and Final Considerations

Hereditary fructose intolerance, essential fructosuria and the gluconeogenesis defects share a metabolic pathway, but follow opposite clinical logics. In HFI, aldolase B deficiency makes fructose toxic: accumulated fructose-1-phosphate sequesters phosphate, depletes ATP and blocks glycogenolysis and gluconeogenesis, so that hypoglycaemia, vomiting and hepatic and tubular injury appear after ingestion of fructose, sucrose or sorbitol, while fasting is well tolerated. In fructose-1,6-bisphosphatase deficiency and cytosolic PEPCK deficiency, by contrast, the problem is fasting: once glycogen is depleted, the liver does not produce glucose and hypoglycaemia appears with lactic acidosis (FBPase) or with inappropriately low ketosis and urinary fumarate (PEPCK-C), triggered by fever, vomiting, fasting, alcohol or exercise. Essential fructosuria has no clinical consequence.

Diagnosis rests on the dietary history and the timing of hypoglycaemia, on biochemistry collected during the episode (phosphate, uric acid, magnesium and tubular function in HFI; urinary glycerol and glycerol-3-phosphate and pseudohypertriglyceridaemia in FBPase deficiency; Krebs cycle intermediates and glutamine in PEPCK-C deficiency) and on gene sequencing with CNV analysis. Fructose loading tests no longer have a place in the initial investigation. The ALDOB variants p.(Ala150Pro), p.(Ala175Asp) and p.(Asn335Lys) predominate in Europe; in FBPase deficiency there are founder alleles in Japan, Turkey and Armenia, Pakistan and India, Egypt and Southern Brazil; in PEPCK-C deficiency, c.925G>A accounts for the Finnish patients. The proportions of variants detectable by each method are not equivalent to clinical sensitivity, and a negative test in the face of strong suspicion requires CNV analysis or enzyme study.

There are no authorised medicines and no society guidelines. In HFI, treatment is lifelong avoidance of fructose, sucrose, sorbitol and sucralose, with a sugar-free multivitamin, and the greatest risk is iatrogenic: infusions, excipients, sucrose for neonatal analgesia and oral rotavirus vaccines with more than 1000 mg of sucrose. European labelling rules set a zero threshold for intravenous fructose and sorbitol and 5 mg/kg/day for the other routes. In FBPase deficiency, the BIMDG protocol defines crisis treatment — glucose 200 mg/kg as a bolus, high-rate glucose infusion, bicarbonate only with pH below 7.1 or base deficit above 15 mmol/L, insulin for hyperglycaemia — and intervention should begin while blood glucose is still normal; maintenance rests on avoidance of fasting, nocturnal uncooked cornstarch and a written emergency plan, avoiding intravenous glycerol and sorbitol. In PEPCK-C deficiency the same preventive logic applies, with an emergency plan also in adults.

The prognosis with treatment is normal growth, development and life expectancy in HFI and in most patients with FBPase deficiency, but steatosis persists in a large proportion of treated patients with HFI and appears in adults with FBPase deficiency, which justifies prolonged hepatic surveillance. Fructokinase inhibition with PF-06835919 improved fructose tolerance in three patients with HFI in a nine-day study, with no active development programme identified. Cascade testing of siblings, education of families and hospital teams and planned transition to adult care complete the prevention of decompensations and iatrogenic harm.

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