Disorders of Ketolysis and Ketogenesis (ACAT1, OXCT1, SLC16A1, HMGCL, HMGCS2)

Mitochondrial beta-ketothiolase deficiency (alpha-methylacetoacetic aciduria), succinyl-CoA:3-oxoacid CoA transferase deficiency, monocarboxylate transporter 1 deficiency and the SLC16A1 allelic disorders, HMG-CoA lyase deficiency, and mitochondrial HMG-CoA synthase deficiency: ketoacidotic crises and hypoketotic hypoglycaemia as the two faces of ketone body metabolism.

Literature and regulatory information updated: 17 October 2026.

0. Reference Summary Table

This article brings together the five inherited disorders of ketone body metabolism described in humans: three defects of utilisation or transport (ketolysis), which present with ketoacidotic crises, and two defects of synthesis (ketogenesis), which present with hypoketotic hypoglycaemia and encephalopathy [1–3]. None of the five entities has a GeneReviews chapter; the only GeneReviews chapter that covers the SLC16A1 gene is the review of nonsyndromic genetic hyperinsulinism, in which the exercise-induced allelic disorder appears [4].

Table sources: identifiers and transcripts [5, 6]; Orphanet codes and frequencies [7–11]; counts and ages [12–19]; screening [5, 20]; European network [21, 22]. Within MetabERN, the European Reference Network for hereditary metabolic disorders, the C-FAO subnetwork covers disorders of carbohydrate metabolism, fatty acid oxidation, and ketone bodies, and the AOA subnetwork covers aminoacidopathies and organic acidurias. HHF7 denotes familial hyperinsulinaemic hypoglycaemia type 7. The GeneGuidance registry swaps the Orphanet codes of the recessive and dominant SLC16A1 conditions; the mapping adopted here follows the Orphanet database: OMIM 616095 corresponds to ORPHA:438075 and OMIM 245340 to ORPHA:171690 [9, 23].

The SLC16A1 allelic disorders do not belong to the group of ketolytic defects, but they share the gene and enter the differential diagnosis of hypoglycaemia and exercise intolerance.

1. Introduction

1.1. Ketone bodies and their place in energy metabolism

The principal ketone bodies are acetoacetate and 3-hydroxybutyrate, kept in equilibrium by 3-hydroxybutyrate dehydrogenase; acetone forms from acetoacetate by nonenzymatic decarboxylation and is eliminated in exhaled air [1]. They are produced in hepatic mitochondria, mainly from fatty acids and to a lesser extent from ketogenic amino acids such as leucine, and during fasting they are an important fuel for cardiac and skeletal muscle and for the brain, which does not oxidise fatty acids; after prolonged fasting they can meet up to two-thirds of the brain's energy needs [1, 2]. Hepatic synthesis (ketogenesis) depends on two mitochondrial enzymes acting in series, mitochondrial HMG-CoA synthase and HMG-CoA lyase; peripheral utilisation (ketolysis) depends on transport across membranes by the monocarboxylate transporters and on two extrahepatic mitochondrial enzymes, succinyl-CoA:3-oxoacid CoA transferase (SCOT) and mitochondrial acetoacetyl-CoA thiolase (T2) [1, 3].

This organisation gives rise to two opposite biochemical phenotypes. In ketogenesis defects, fasting or intercurrent illness causes hypoglycaemia with inappropriately low ketone bodies, because the lack of an alternative fuel accelerates glucose consumption; in ketolysis and transport defects, normally produced ketone bodies accumulate in the blood and cause ketoacidotic crises, often with normal glucose, lactate, and ammonia [1, 2]. Early diagnosis and treatment lead to a favourable prognosis in most series [2].

1.2. Historical overview and molecular milestones

The first disorder of the group to be described was T2 deficiency. In 1971, Daum, Lamm, Mamer, and Scriver reported in the Lancet a child with intermittent metabolic acidosis and a block in isoleucine catabolism, with accumulation of alpha-methylacetoacetate and alpha-methyl-beta-hydroxybutyrate [29]; the full description was published in 1973 [30]. Human T2 cDNA was cloned in 1990 by Fukao and colleagues, who described a 427–amino acid precursor with a 33-residue mitochondrial leader peptide and found, in fibroblasts from four patients, reduced messenger RNA in two and normal levels in two, indicating different molecular mechanisms [31]; molecular studies of the two original families followed in 1993 [32].

SCOT deficiency was described in 1972 by Tildon and Cornblath in an infant with severe intermittent ketoacidosis who died at 6 months, with undetectable transferase activity in brain, muscle, kidney, and fibroblasts [33]. The cDNA was cloned in 1996, the locus (OXCT1) was mapped to 5p13, and the first pathogenic variant was identified in the homozygous state, the stop-creating substitution S283X in historical nomenclature, now NM_000436.4:c.848C>G p.(Ser283Ter); the absence of expression in liver cells confirmed that SCOT does not act in the liver [6, 34].

HMG-CoA lyase deficiency was described in 1976 by Faull and colleagues, in a letter to the New England Journal of Medicine, in a patient from Western Australia with hypoglycaemia and acidosis [35, 36]. The patient had been well until 7 months of age, when, after diarrhoea and vomiting, he developed lethargy, pallor, dehydration, cyanosis, and apnoea requiring resuscitation within 24 hours; at 4 years and 7 months his development was satisfactory [37]. The first four reported patients received a provisional diagnosis of Reye syndrome, and for years the disorder was classified as an organic acidaemia before it was also recognised as a fatty acid oxidation disorder [37, 38]. The HMGCL gene was cloned in 1993: the 298-residue mature protein is preceded by a 27-residue mitochondrial transit peptide, and the first variant characterised was a 2–base pair deletion at codon Ser-69 in two French-Canadian Acadian siblings [39].

Mitochondrial HMG-CoA synthase deficiency was the last enzyme defect to be recognised: Thompson, Hsu, Pitt, Treacy, and Stanley described fasting hypoketotic coma in a child in 1997 [40], and in 2001 Aledo and colleagues identified the first HMGCS2 variants (G212R and R500H in historical nomenclature, = NM_005518.4:c.634G>A p.(Gly212Arg) and NM_005518.4:c.1499G>A p.(Arg500His)) and showed that the gene is expressed mainly in the liver, which makes enzymatic confirmation difficult and places diagnosis at the molecular level [41].

Ketone body transport entered human pathology by two routes. In 2007, Otonkoski and colleagues showed that SLC16A1 promoter variants cause autosomal dominant exercise-induced hyperinsulinism through failure to silence the transporter in beta cells [24]. In 2014, van Hasselt and colleagues used exome sequencing to identify a homozygous frameshift variant in SLC16A1 in a patient with severe recurrent ketoacidosis and, among 96 patients with a suspected ketolytic defect, seven further inactivating variants in the homozygous and heterozygous state, establishing MCT1 deficiency as a cause of ketoacidosis [42]. The myopathic form due to lactate transporter defect had been described by Fishbein in 1986 [27].

1.3. Nomenclature and definition of the entities

T2 deficiency appears in the literature under several names: beta-ketothiolase (or 3-oxothiolase) deficiency, mitochondrial acetoacetyl-CoA thiolase deficiency, alpha-methylacetoacetic aciduria, and, in the reviews by Grünert and Sass, 2-methylacetoacetyl-CoA thiolase deficiency (MAT or MATD), a name that highlights the enzyme's dual role in ketolysis and isoleucine catabolism [5, 12]. The abbreviation BKTD (beta-ketothiolase deficiency) is used in newborn screening studies [43, 44]. It is defined by biallelic ACAT1 variants or by absent or reduced T2 activity, with a phenotype of intermittent ketoacidotic crises under ketogenic stress [12, 45].

SCOT deficiency is defined by biallelic OXCT1 variants or by deficient transferase activity in lymphocytes or fibroblasts; permanent ketosis, even when the patient is well, is considered pathognomonic of severe genotypes [3, 13]. MCT1 deficiency is defined by loss-of-function variants in SLC16A1, in the homozygous or heterozygous state, with recurrent ketoacidosis and no specific biochemical marker [42, 46].

HMG-CoA lyase deficiency (HMGCLD, 3-hydroxy-3-methylglutaric aciduria) affects both ketogenesis and the last step of leucine catabolism, which gives it a diagnostic urinary signature [1, 16]. Mitochondrial HMG-CoA synthase deficiency (HMGCS2D) is the only defect that affects hepatic ketogenesis exclusively and therefore produces no specific metabolites outside of crises [5, 47].

Outside the clinical scope of this article is cytosolic acetoacetyl-CoA thiolase deficiency (ACAT2), an enzyme of isoprenoid and cholesterol synthesis, reported in 1984 in two patients with intellectual disability and persistent ketosis, with a diagnosis considered uncertain [1, 48]. Idiopathic ketotic hypoglycaemia, HSD10 disease (HSD17B10), and the other causes of elevated C5-OH are treated as differential diagnoses. The classic organic acidaemias, beta-oxidation defects, glutaric aciduria type II, biotinidase and holocarboxylase synthetase deficiencies, the glycogen storage diseases, congenital hyperinsulinism, GLUT1 deficiency, and pyruvate dehydrogenase complex deficiency form part of the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. Physiology of ketone body synthesis, transport, and utilisation

In hepatic mitochondria, mitochondrial HMG-CoA synthase condenses acetoacetyl-CoA and acetyl-CoA into 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), which HMG-CoA lyase cleaves into acetyl-CoA and acetoacetate [1]. HMG-CoA also derives from leucine catabolism, so both deficiencies impair ketogenesis, but only lyase deficiency causes accumulation of leucine pathway intermediates [1]. HMG-CoA is also an intermediate in cholesterol synthesis; the cytoplasmic form of the synthase, which takes part in that pathway, complicates the enzyme assay of the mitochondrial isoform [1, 37].

Ketone bodies cross the inner mitochondrial membrane via the mitochondrial pyruvate carrier and cell membranes via the monocarboxylate transporters (MCTs). Export from the hepatocyte is facilitated by MCT1 and/or MCT7 (encoded by SLC16A1 and SLC16A6), and MCT1 mediates entry into target cells (heart, muscle, neurons) and passage across the blood–brain barrier [1]. In extrahepatic mitochondria, SCOT transfers CoA from succinyl-CoA to acetoacetate, forming acetoacetyl-CoA, which T2 cleaves into two molecules of acetyl-CoA [1]. SCOT is not expressed in the liver and has no known function other than ketolysis; it is the rate-limiting enzyme of ketone body utilisation [1, 2, 34]. T2, by contrast, is also expressed in the liver, where it takes part in ketogenesis, and it cleaves 2-methylacetoacetyl-CoA in the isoleucine pathway [1, 12].

The second reaction of ketolysis can be partly catalysed by medium-chain 3-ketoacyl-CoA thiolase (T1), which explains why patients with T2 deficiency do not have permanent ketosis, unlike patients with severe SCOT deficiency [1]. Because patients with T2 deficiency present with ketoacidosis rather than hypoketosis, T1 appears to substitute for T2 better in ketogenesis than in ketolysis [1].

2.2. HMGCS2 and mitochondrial HMG-CoA synthase deficiency

The HMGCS2 gene (1p12, 10 exons) encodes the rate-limiting enzyme of hepatic ketogenesis, the only one specific to it, which catalyses the first irreversible step of the pathway [5, 49]. In the deficiency, beta-oxidation continues, but acetyl-CoA is not converted to ketone bodies; the excess is diverted to omega-oxidation, with dicarboxylic aciduria, and to metabolites such as 4-hydroxy-6-methyl-2-pyrone (4-HMP), and the ratio of acetylcarnitine (C2) to free carnitine (C0) increases [5, 50]. The enzyme is expressed mainly in the liver but also in the colon, muscle, heart, pancreas, and testes [51].

Proposed mechanisms for the hyperammonaemia, present in about one-third of decompensations, include increased protein catabolism to sustain gluconeogenesis and hyperacetylation of carbamoyl phosphate synthetase 1 and ornithine transcarbamylase by excess acetyl-CoA, with inactivation of sirtuin 5 through NAD⁺/NADH imbalance; Hmgcs2⁻/⁻ mice show mitochondrial protein hyperacetylation [5, 52].

By 2025, about 100 patients and 77 variants had been described [51]. Variants cluster in exons 2 and 4; NM_005518.4:c.1201G>T p.(Glu401Ter) is the most common in Chinese patients, and c.634G>A p.(Gly212Arg), the G212R of Aledo 2001, is the most prevalent in Europeans [6, 41, 49]. In the review of 75 patients by Grünert and colleagues, p.(Gly212Arg) was the only recurrent variant, present in six families [18]. In the Vietnamese cohort of 19 patients, c.559+1G>A was present in 11 (57.9%) and c.1090T>A p.(Phe364Ile) in 10 (55.5%); c.1502G>C p.(Arg501Pro), common in Thai patients, yields a normal amount of protein but no activity, through loss of the salt bridge between Arg501 and Asp101 [49, 52]. Exon 1 deletions have been described in two families, which calls for quantitative copy-number analysis [50].

The two 2025 reviews disagree on genotype–phenotype correlation. Decru and colleagues found a correlation between severity and the number of truncating variants, and a review cited by Nguyen associated biallelic truncating variants with higher mortality [19, 49]; the review by Grünert and colleagues found no correlation [18]. The existence of asymptomatic biallelic individuals in several families shows that exposure to metabolic stress weighs more than genotype [18, 52].

2.3. HMGCL and HMG-CoA lyase deficiency

HMGCL maps to 1p36.11 and has 9 exons [16, 17]. The crystal structure of the enzyme shows a TIM barrel with a C-terminal cavity formed by eight beta strands, where 3-hydroxyglutarate and Mg²⁺ bind; substrate binding involves Asn311 and Lys313, a G loop facilitates the Cys266–Cys323 disulfide bridge, and Arg41 interacts with the acyl-CoA carbonyl, promoting enolisation of the product [37]. Activity is highest in the liver and has not been detected in the heart or adult brain; pancreatic expression is consistent with the pancreatitis described in some patients, and the striatum shows particular vulnerability to oxidative damage by 3-hydroxy-3-methylglutarate [37].

The pathophysiology combines ketone body deficiency with accumulation of leucine metabolites. Counterregulation of hypoglycaemia is impaired because the disorder simultaneously affects leucine catabolism and the utilisation of acetyl-CoA from lipid oxidation; acetyl-CoA accumulation can deplete free CoA, and the hyperammonaemia has been attributed to inhibition of N-acetylglutamate synthase or to insufficient Krebs cycle intermediates [36, 53]. Ketone bodies reduce muscle proteolysis during fasting, so their absence may also contribute to hyperammonaemia [37]. White matter is diffusely abnormal even in asymptomatic patients, possibly because of deficient myelination, since ketone bodies are a substrate for synthesis of myelin cholesterol [1, 54].

In the review of 118 patients with a published genotype, variants were distributed across all 9 exons and noncoding regions; 72.9% were homozygous and 20.3% compound heterozygous, only one variant was identified in 5.1%, and none in 1.7%, despite unequivocal enzyme deficiency in fibroblasts [16]. In one homozygote, paternal uniparental isodisomy of chromosome 1 was confirmed [16]. The most frequent variant was NM_000191.3:c.109G>T p.(Glu37Ter), the historical E37X, in 36 patients (30.5%; 28 homozygous), originating mainly from Brazil, Spain, Portugal, and Morocco; next came c.122G>A p.(Arg41Gln), R41Q, in 12 (10.2%), mostly Saudi but also Turkish and Italian, and the splice variant c.876+1G>C in 6 (5.5%), common in Turkish patients [6, 16]. The Saudubray chapter writes the Iberian variant as "c.109G>A"; this change is incompatible with the stop codon (GAG to TAG requires G>T), and the correct form, validated in VariantValidator, is c.109G>T [1, 6, 37].

Mitchell and colleagues showed in 1998 that codons 41 and 42 are a hotspot for causal variants (R41Q, R41X, D42E, D42G, D42H), which accounted for 26% (21/82) of the alleles in their series; among nine Saudi probands, six were homozygous for R41Q and two for F305fs(-2) [55]. In the Saudi cohort of Alfadhel and colleagues, p.(Arg41Gln) was present in 48 of 62 patients (77.4%), followed by c.206_207del p.(Ser69Cysfs*11) in 5 (8.1%) and c.914_915del p.(Phe305Tyrfs*10) in 2 (3.2%), as described in the article [17]. In northern Portugal, E37X accounted for 84.1% of the alleles of 11 patients, with one V168fs(-2) allele, one novel D204N allele (c.610G>A), and one unidentified allele [56]. The historical V168fs(-2), described as c.504_505delCT, is normalised under the 3' alignment rule to NM_000191.3:c.505_506del p.(Ser169LeufsTer8) [6]. In Taiwan, the substitution p.Arg165Gln and two splice variants with exon 3 skipping have been described [37, 57].

The 2020 review also recorded nomenclature corrections: the deletion c.27del, with predicted frameshift p.(Arg10Glyfs*24); the variant designated p.Val168Valfs8, which may cause skipping of exon 5 or exons 5–6; the "C-to-T" substitution of Zafeiriou 2007, which corresponds to c.796C>T; c.438T>G, corrected from p.(Ser46Arg) to p.(Ser146Arg); the intron 1–4 deletion NG_013061.1:g.9326_13806del; and an 84–base pair in-frame deletion [16]. In 2025, a complex deep intronic variant, c.60+42_60+44delins-708_-478inv, was described that escaped targeted sequencing and was resolved only by genome and RNA sequencing (section 10) [58].

Enzyme activity was undetectable in 10 patients and between 0.7% and 13.7% of normal in 16 others in Gibson's 1988 review; parents have intermediate activity in leukocytes or fibroblasts, but in some families obligate heterozygotes had normal values, so the enzyme assay cannot be used to identify carriers [37, 59]. The genotype–phenotype relationship is weak: manifestations depend more on exposure to stress and on the consequences of hypoglycaemia than on residual activity [1, 16, 60].

2.4. OXCT1 and SCOT deficiency

OXCT1 (5p13.1) has 17 exons; by 2025, about 61 cases and about 41 variants had been described (29 missense, 6 nonsense, 3 intronic, 2 insertions, and 1 exonic deletion) [14]. Pathogenic variants cluster in structural regions of the protein [13]. Expression of mutant cDNA has been used to grade residual activity and classify the genotype as severe or mild, a distinction that predicts permanent or episodic ketosis and the usefulness of home monitoring for ketonuria [3, 5].

In Saudi Arabia, 17 patients from nine consanguineous families were homozygous for NM_000436.4:c.1402C>T p.(Arg468Cys); the variant lies far from the active site, abolishes a salt bridge with Glu312, and is temperature-sensitive (12% of wild-type activity at 37 °C and 51% at 30 °C), which relates to decompensation during fever; it has also been described in a Tunisian patient, suggesting an ancient Arab founder [6, 61]. Exonic deletions require quantitative methods: a homozygous 10,881–base pair deletion of exons 4–7 (chr5:g.41842776_41853656del, GRCh38) was identified by exome sequencing and confirmed by quantitative polymerase chain reaction (PCR), and a deletion of exons 8–16 had previously been described in compound heterozygosity with c.1118T>G p.(Ile373Ser) [14].

OXCT1 heterozygotes can develop severe ketoacidosis. Between 2008 and 2012, four patients with severe ketoacidosis had a single variant (p.R281C and p.T435N in the published notation, = NM_000436.4:c.841C>T p.(Arg281Cys) and NM_000436.4:c.1304C>A p.(Thr435Asn); p.W213* and c.493delG in the published designation), with no large deletions on multiplex ligation-dependent probe amplification (MLPA) and wild-type alleles on cDNA; between 2013 and 2014, among six patients with severe ketoacidosis (pH ≤7.25 and total ketone bodies ≥10 mmol/L) and nonspecific organic acids, two more were heterozygous [62]. The R281C and T435N variants are temperature-sensitive [62].

2.5. ACAT1 and T2 deficiency

ACAT1 maps to 11q22.3–q23.1, spans about 27 kb, has 12 exons, and has a TATA-less housekeeping-type promoter [43, 63]. The 2019 update compiled 105 disease-associated variants in 149 patients from 134 nuclear families, with homozygosity in 50.8% of families; variants were found in every exon, especially exon 11 (15), exon 6 (11), and exon 5 (9) [63]. Of the 30 missense variants tested in fibroblasts, all had activity ≤25% of wild type; the variants mapped onto the crystal structure almost all affect internal residues and reduce folding efficiency and stability, and only p.(Cys126Ser) and p.(Tyr219His), whose side chains point toward the active site, had normal stability with no activity [5, 63]. Five exonic variants alter splicing, such as c.380C>T p.(Ala127Val), which activates a cryptic acceptor, and c.949G>A p.(Asp317Asn), located in an exonic enhancer and causing exon 10 skipping [12, 63].

In the review of 244 patients, 164 had ACAT1 analysis: 51.8% were homozygous and 47.6% compound heterozygous; only 29 of the 67 homozygotes with available information had consanguineous parents [12]. The most frequent variant, NM_000019.4:c.622C>T p.(Arg208Ter) (historical R208X), was present in at least 36 individuals of Vietnamese, Dutch, and Turkish origin; c.1006-1G>C, which causes exon 11 skipping, in 12; and c.949G>A in 10 [6, 12]. In Vietnam, R208X was found in the homozygous state in six and the heterozygous state in two of eight patients and was not found in 400 controls; in two Dutch patients it occurred on a different haplotype [64]. In the series of 41 patients from northern Vietnam, c.622C>T accounted for 66% and c.1006-1G>C for 19% of alleles, with haplotypes consistent with a common ancient founder in the Kinh ethnic group [65]. In China, the same c.622C>T accounted for 17.2% and c.1006-1G>C for 8.6% of alleles, and c.1124A>G p.(Asn375Ser) activates a cryptic splice donor; c.578T>G p.(Met193Arg) and c.455G>C p.(Gly152Ala), common in other populations, were absent [6, 43]. In Turkey, c.158G>A p.(Gly53Glu) was the most frequent variant (42.1% of cases) in a series of 20 patients [6, 66].

Genotype does not correlate with clinical phenotype, but it does shape the biochemical phenotype: patients with at least one allele with residual activity ("mild") have crises as severe and frequent as those with a severe genotype, but subtler isoleucine metabolites, even during crises, which reduces detection by newborn screening where mild variants predominate, as in Japan [45, 63]. The MLPA assay developed for ACAT1 detects exon deletions that sequencing does not identify [5].

2.6. SLC16A1: MCT1 deficiency and allelic disorders

MCT1 is ubiquitous and is the most abundant lactate transporter in glia. Loss of function reduces peripheral uptake of ketone bodies, which accumulate in the blood in catabolic states with hormonal counterregulation; gluconeogenesis is intact, so hypoglycaemia is atypical [26]. MCT1 also transports lactate, including in the glia–neuron shuttle, and in animal and cell models its reduction impairs learning and long-term memory, which may explain the learning difficulties better than the crises themselves [1, 26]. Fibroblasts from a homozygous patient showed an altered bioenergetic profile, suggesting secondary mitochondrial dysfunction [67].

In the founding series, mutational status (homozygosity or heterozygosity) correlated with the severity of ketoacidosis, with MCT1 protein levels, and with transport capacity [42]. Reported variants include NM_003051.4:c.982C>T p.(Arg328Ter) in the heterozygous state in two British half-brothers, also present in their healthy mother and in a half-sister [6, 46]; c.218del p.(Gly73ValfsTer8) and c.1079del p.(Ala360GlyfsTer19) in the homozygous state [6, 68]; c.747_750del in the homozygous state in a Spanish patient [67]; and two novel homozygous variants, p.(Gly25Val) and p.(Leu403Phe), in three Palestinian children [15]. Symptomatic heterozygotes suggest a dominant-negative effect or incomplete penetrance; relatives carrying the proband's variant are often asymptomatic, pointing to additional factors [26, 68].

In exercise-induced hyperinsulinism, SLC16A1 promoter variants increase protein binding to regulatory elements and stimulate transcription 3- to 10-fold in reporter constructs in beta cells, where the gene is normally silenced; ectopic MCT1 allows pyruvate uptake and pyruvate-stimulated insulin secretion, and patients' fibroblasts have elevated transcripts without altered transport [5, 24]. Linkage analysis in two families with ten affected members gave a LOD score of 3.6 on chromosome 1, and all 13 patients identified had promoter variants [24]. The myopathic form follows dominant inheritance; in some heterozygotes, muscle lactate clearance is reduced to about 50% [26–28]. Overlap between the ketoacidotic and myopathic forms is limited and has no known explanation [26].

2.7. Normalised reference variants

The variants in the table were validated in VariantValidator (GRCh38, MANE Select transcript) on 17 October 2026; the historical nomenclature column links current nomenclature to the earlier literature [6].

Sources for the context column: [12, 16–18, 34, 43, 46, 49, 52, 56, 61, 65, 66, 68]. The Nguyen 2025 studies used NM_005518.3 for HMGCS2 and NM_000191.2 for HMGCL; the c. numbering of the variants above is identical in the validated versions [6].

2.8. Correlations, penetrance, and modifiers

In all five disorders, genotype poorly explains the clinical phenotype; crisis frequency depends mainly on exposure to catabolic stress (infection, fasting, vomiting), and asymptomatic biallelic individuals have been identified through family screening [1, 12, 16, 18]. Genotype relates better to the severity of the biochemical abnormalities: permanent ketosis in severe OXCT1 genotypes, subtle isoleucine metabolites in mild ACAT1 genotypes, and severity of ketoacidosis proportional to the loss of MCT1 [1, 42, 63]. Simple heterozygosity for OXCT1 or SLC16A1 increases the risk of ketoacidosis when stress is sufficient, whereas heterozygotes for ACAT1, HMGCL, and HMGCS2 have no described disease [1, 46, 62]. In 2026 preclinical studies, sodium–glucose cotransporter 2 (SGLT2) inhibitors increased ketogenesis by acting as direct allosteric activators of hepatic HMGCS2; the relevance to these disorders has not been studied [69].

3. Clinical Spectrum and Manifestations by System

3.1. Two patterns of decompensation

Ketolysis and transport defects present as crises of severe ketoacidosis in early childhood, with normal health and pH between crises. Triggers are fasting and infections with food refusal and vomiting; the child has tachypnoea from the acidosis, dehydration from vomiting and osmotic diuresis, and decreased consciousness when acidosis is severe, and some patients have seizures [1]. In most, glucose, lactate, and ammonia are normal, but there may be hypoglycaemia, hyperglycaemia, or mild hyperammonaemia [1, 45, 70]. The acidaemia is disproportionate to the ketosis: in a Japanese infant with SCOT deficiency, 3-hydroxybutyrate was similar to that of children admitted for idiopathic ketotic hypoglycaemia, but pH and bicarbonate were significantly lower, which the authors attribute to rapid accumulation of ketone bodies before renal compensation [71].

Ketogenesis defects present as encephalopathy with hypoketotic hypoglycaemia, with or without hyperammonaemia, and hepatomegaly [1]. Hypoglycaemia is a late manifestation, and normoglycaemic crises with encephalopathy and severe acidosis occur, especially in HMG-CoA synthase deficiency [5, 49, 72].

3.2. T2 (beta-ketothiolase) deficiency

The systematic review by Grünert and Sass compiled 244 patients published through November 2019, with metabolic, enzymatic, or genetic documentation; the median age at report was 6.0 years (from the neonatal period to 36 years), and parental consanguinity was 33.3% [12]. In the 205 symptomatic patients, first symptoms appeared between 2 days and 8 years (median 12 months): 3.4% in the neonatal period, 43.4% in the first year after the neonatal period, and 35.6% in the second year; all manifested the disease in the first decade and more than 82% in the first two years [12]. Of the 221 patients with available information, 89.6% had at least one crisis, 33.0% more than one, 11.8% between three and six, and 1.4% more than nine; 10.4% were asymptomatic at the time of report [12]. The Saudubray chapter states that most patients have a single episode and that ketoacidosis is very rare after mid-childhood [1]; Fukao and colleagues describe the first crisis as usually occurring between 6 months and 3 years of age, with fewer than three crises in most patients [45].

Crises include severe metabolic acidosis (pH <7.0), ketosis, and altered alertness progressing to coma; six patients had a metabolic stroke-like presentation, and hypo- or hyperglycaemia, mild hyperammonaemia, elevated transaminases, and secondary carnitine deficiency have been described [12]. Many required intensive care and ventilation, and at least 11 required haemodialysis or peritoneal dialysis; one patient had a long QT interval in the first episode and another a resuscitated cardiac arrest [12]. Mortality was 8.9% (21/235), mostly during the first decompensation, between 7 months and 8 years (median 16 months) [12]. Only four children first presented with chronic neurological symptoms, and of the 28 diagnosed while asymptomatic (newborn or family screening), three later had a crisis despite presymptomatic diagnosis [12].

In the series of 41 patients from northern Vietnam (2005–2016), crises began in most between 6 and 18 months, recurrence occurred in 43%, and 28% had hyperglycaemia during the crisis, up to 23.3 mmol/L; there were five deaths and two cases of neurological sequelae, and neither age at onset, crisis frequency, nor genotype predicted outcome [65]. In the French series of 26 patients, 6 (23%) had neurological abnormalities: two never had ketoacidosis but developed extrapyramidal signs with putaminal involvement, two before the first crisis, one more than ten years after the initial decompensation, and one immediately after a severe crisis [73]. Grünert and colleagues described, in 32 patients from five countries, decompensation in 63% and major intellectual disability in 7% [70]. In China, 62% of 29 patients were symptomatic (2 neonatal, 13 after the neonatal period, mean 10.5 months), with triggers that included infections, diarrhoea, and an inflammatory response to vaccination (two severe crises after vaccines, one fatal) [43]; in a Chinese series of 76 patients, neurological involvement reached 38.0% (19/50), rarely permanent [74]. In Turkey, 20 patients from 11 families (consanguinity 81.8%) had neurological involvement in 10% and mortality of 5% [66]; in Palestine, 12 patients from eight consanguineous families had crises triggered by gastroenteritis or respiratory infection, and one had hypotonia and delay before the first crisis [75].

Neurologic injury can arise before the first episode of ketoacidosis, as a consequence of a severe episode, or independently of crises; the predominant hypothesis is toxicity of isoleucine-derived acyl-CoA esters to the basal ganglia [1, 12, 73]. Crisis frequency decreases with age and usually stops before adolescence [44]. In adults, Zhen and colleagues described in 2024 a 34-year-old man with diabetic ketoacidosis and elevated glycated haemoglobin (HbA1c), the first case of established diabetes in T2 deficiency; stress hyperglycaemia with normal HbA1c is, by contrast, common in paediatric crises [76].

3.3. SCOT deficiency

In the systematic review of 44 patients (34 published and 10 new), all had severe ketoacidotic episodes; first symptoms appeared between 36 hours and 3 years (median 7 months), about 70% in the first year and about one-quarter in the neonatal period [13]. Two patients died, and 92% of survivors had normal psychomotor development without neurological abnormalities; the disease can be diagnosed only by enzymatic or molecular study and is probably underdiagnosed [13]. Some patients required mechanical ventilation and continuous renal replacement therapy for acidosis refractory to fluids and bicarbonate [5]. The Saudubray chapter notes that nearly 50% of patients become acidotic in the first days of life and the rest in the first two years, and that almost all survive without sequelae [1].

The Saudi cohort homozygous for p.(Arg468Cys) showed a later pattern: of 17 patients followed for a median of 11 years, 15 (88.2%) were symptomatic, with a first crisis between 6 months and 4 years (median 2 years) and only three in the first year; two remained asymptomatic at 8 and 19 years, and two (11.8%) died in the first crisis, at 2.5 and 3 years [61]. Crises ceased in 73.3%, with the last between 2 and 13 years (median 6), and no patient had crises after age 13 except during pregnancy; adults tolerated fasts longer than 12 hours, and neurodevelopment was normal in all [61]. In the emergency department, SCOT deficiency is often mistaken for severe gastroenteritis with dehydration and ketoacidosis, with no investigation after recovery [61].

3.4. MCT1 deficiency

MCT1 deficiency should be considered in the presence of recurrent episodes of ketoacidosis with hyperventilation or cyclic vomiting in the first years of life, triggered by infection or fasting, with normal or borderline glucose [26, 42]. Crises are preceded by food refusal and vomiting, with dehydration and, when severe, decreased consciousness and inadequate respiratory effort; hypoglycaemia is infrequent, and the spectrum includes lactic as well as ketotic acidosis [5, 67]. Homozygotes present earlier, with developmental delay and more severe ketoacidosis; by 2025 only 17 patients had been identified [15]. All homozygotes described in the Saudubray chapter had developmental delay and several had epilepsy, with abnormal signal in the subcortical U fibres, basal ganglia, and thalami, and two sisters had agenesis of the corpus callosum [1, 77, 78]. Heterozygotes have less severe and later-onset crises, sometimes initially interpreted as cyclic vomiting [1, 46].

A 2026 systematic review compiled eight genetically confirmed patients, with onset between 2 months and 11.5 years, recurrent vomiting, lethargy, hypotonia, and high anion gap acidosis with normal lactate and ammonia; some had seizures, developmental and speech delay, or paroxysmal dystonia, and no mortality was reported [68]. The review has methodological limitations: it includes a case with a final diagnosis of GLUT1 deficiency and omits the 2014 founding series, so it serves mainly to describe the general pattern [68]. In three Palestinian children, hyperuricemia accompanied the crises [15]. Some patients with MCT1 loss of function have cramps, stiffness, or exertional fatigue and episodes of elevated creatine kinase (CK) and rhabdomyolysis, with normal electromyography and muscle histology between episodes [26, 27].

Exercise-induced hyperinsulinism, a dominant allelic disorder, manifests as hyperinsulinaemic hypoglycaemia during anaerobic exercise or after a pyruvate load, in childhood or later; a history of severe hypoglycaemia after anaerobic exercise is the suggestive clue [4, 24]. In a 41-year-old man, a generalised tonic–clonic seizure with severe hypoglycaemia after strenuous exercise led to a prolonged fasting test with exercise that demonstrated hyperinsulinaemic hypoglycaemia, and a variant of uncertain significance (VUS) in SLC16A1 was identified [79].

3.5. HMG-CoA lyase deficiency

The systematic review of 211 patients (through September 2019) included 46 patients of Turkish origin, 20 Portuguese, 13 Brazilians of Portuguese ancestry, 19 Saudis, and 12 Spaniards, with consanguinity of 49% and median follow-up of 48 months [16]. Of the 165 with acute symptoms, onset was neonatal in 42.4% (11 symptomatic on the first day), in the first year in 39.4%, in the second year in 7.9%, and after the second year in 10.8%, with a median of 4 months; the latest presentation occurred at 29 years, with death in the initial crisis [16]. Of the 171 with available information, 95.3% had at least one crisis and eight had more than ten [16]. Mortality was 16.1% (34/211), between 72 hours and 40 years of age (median 9.5 months), mostly during decompensations; one woman died at 24 years during her second pregnancy, one child died during sleep at 13 months without prior symptoms, one previously asymptomatic 29-year-old adult died of septic shock, and one 7-month-old infant died of cardiomyopathy with arrhythmias [16]. In the series of 37 patients from Belgium, Germany, the Netherlands, Switzerland, and Turkey, 94% had acute decompensation, 50% with neonatal onset and only 8% after the first year; six died, and half had normal cognitive development [60].

The crisis includes persistent vomiting, rapid progression from lethargy and hypotonia to coma, pallor, dehydration, tachypnoea or apnoea, seizures (including myoclonus), hypothermia, and moderate hepatomegaly; without ventilation, apnoea can be fatal, and the first episode may be lethal [16, 37]. In the newborn, seizures, lethargy, or tachypnoea can appear in the first days, even before the first feed, because birth itself is a catabolic event [37]. Hypoglycaemia can be extreme, with initial glucose levels of 0.2–1.8 mmol/L and many below 0.4 mmol/L; one patient died in a second episode with glucose below 0.1 mmol/L after a dietary change that increased leucine intake [37]. A pH below 7.0 is not unusual in newborns, lactate can reach 10 to 20 mmol/L, and hyperammonaemia occurred in about half the patients in Gibson's review, with values of 388–1370 µmol/L in three patients and above 2000 µmol/L in one [37, 59]. Transaminases usually rise only mildly, but peaks of aspartate aminotransferase (AST) of 11,736 IU/L at 7 months, and of AST 21,992 U/L with alanine aminotransferase (ALT) of 18,213 U/L and an international normalised ratio (INR) of 9.8 in fulminant liver failure at 9 months, initially attributed to paracetamol poisoning, have been recorded [16, 36]. None of the patients in the Atlas had ketonuria during crises [37].

In the Saudi cohort of 62 patients from 54 families (three Riyadh centres, 1987–2018, all with a molecular diagnosis and consanguinity in every family), diagnosis was neonatal in 43.5%; at presentation, there was hypoketotic hypoglycaemia in 61.3%, metabolic acidosis in 79.0%, both in 64.5%, seizures in 27.4%, and coma in five, and fever or illness triggered decompensation in 80.6%; all were alive at last follow-up (27 months to 32 years) [17]. In the Australian cohort of ten patients, presentations included hypoglycaemia with acidosis, hyperammonaemia on day 3, weight loss greater than 10% between days 4 and 6, isolated developmental delay at 2.5 years, liver failure at 9 months, and mild vomiting with diagnosis by screening on day 7 [36]. Among 17 Chinese patients, 76.5% were diagnosed in the first year, and coma was the initial manifestation in 58.9% [80]. In Brazil, among 15 patients (13 of Portuguese ancestry), there was hypoglycaemia in 12, seizures in 10, acidosis in 9, vomiting in 6, and hepatomegaly in 5 [81].

Extraneurologic complications are rare: dilated cardiomyopathy with arrhythmias in three patients (two fatal), left ventricular noncompaction in one, and pancreatitis in two, one of them a 5-year-old girl with intractable vomiting, abdominal pain, and recurrent hypoglycaemia [16, 37, 82]. In the Saudi cohort, hepatomegaly was recorded in 19.4%, fatty liver in 16.1%, and gallstones in 6.5% [17]. Adult-onset forms include a 36-year-old woman with seizures and severe leukoencephalopathy and a 29-year-old man with sudden coma, profound hypoglycaemia, hyperammonaemia, and acidosis without ketosis [17, 83, 84]. Coexistence with diabetes has been described: a 36-year-old man with type 2 diabetes presented with confusion and shock, acidosis, hyperammonaemia, hyperosmolar hyperglycaemia, and hypoketosis, in a setting in which dextrose was limited by the hyperglycaemia and intravenous lipids were contraindicated [85]; there are also reports of type 1 diabetes in a Portuguese patient and type 2 diabetes in Spanish adults [86, 87].

3.6. Mitochondrial HMG-CoA synthase deficiency

In the review of 75 patients (59 published and 16 unpublished), 91% had acute decompensation, mostly in the first year but after the neonatal period; 8% died, mostly in the initial crisis, and 98% of survivors had normal development [18]. The review of 95 cases by Decru and colleagues places onset between 3 months and 6 years, mostly before 3 years, with greater severity before 1 year and first decompensation mostly after gastroenteritis [19]. The crisis includes lethargy progressing to coma, acidotic breathing, hepatomegaly, vomiting, and sometimes shock or seizures, with hypoketotic or nonketotic hypoglycaemia, dicarboxylic aciduria without appropriate ketonuria, elevated transaminases, acidosis, hyperammonaemia in about one-third, and marked hypertriglyceridaemia with low high-density lipoprotein (HDL) cholesterol [5, 19]. The pattern mimics a beta-oxidation defect or glutaric aciduria type II, leading to misdiagnosis [5]. The Saudubray chapter describes episodes between 5 months and 6 years, hepatomegaly that regresses, rare hyperammonaemia, and sometimes ketonuria, with rapid recovery on intravenous glucose in most [1, 50].

At the Vietnam National Children's Hospital (October 2018 to October 2024), 19 patients from 14 families included 16 symptomatic patients and three asymptomatic siblings identified by family screening, normal at 5–14 years, whereas their younger siblings had had a crisis at 5–14 months [49]. The first crisis occurred between 10 days and 28 months (median 7 months), triggered by poor feeding in 93.8%, vomiting in 56.3%, diarrhoea in 25.0%, and fever in 18.8%; there was lethargy or coma in 81.3%, tachypnoea in 68.8%, hepatomegaly in 56.3%, shock in 37.5%, and seizures in 18.8% [49]. Transaminases were elevated in all, acidosis was present in 75% (median pH 7.18), and hypoglycaemia in 56.3% (median glucose 2.2 mmol/L); four patients were normoglycaemic, one had hyperglycaemia of 24.5 mmol/L with acidosis and ketonuria resembling diabetic ketoacidosis, ammonia was elevated in five (up to 983 µmol/L), and CK in four of seven [49]. Also described are a Japanese case with severe acidosis and fatty liver without hypoglycaemia, steatorrhea, dyslipidaemia, and hypophosphataemic encephalopathy in Thai patients, and a metabolic stroke-like presentation with refractory seizures and basal ganglia lesions in a 2-year-old Palestinian boy [88–90].

3.7. Neuroimaging

In T2 deficiency, imaging in 71 patients was normal in 52.1%; the most common abnormalities were T2 hyperintensities of the basal ganglia (globi pallidi, putamen, lentiform and caudate nuclei, and also the substantia nigra), lesions of the internal and external capsules, atrophy, and white matter foci, with no consistent association with clinical features [12]. A 2026 case documented progression of pallidal lesions to the putamina and cerebral peduncles in a 2-year-old girl with euglycaemic ketoacidosis, with punctate hypointensities on susceptibility-weighted imaging suggestive of microcystic degeneration and microhaemorrhage, after a normal baseline magnetic resonance imaging (MRI) scan 17 months earlier [91].

In HMG-CoA lyase deficiency, MRI in 60 patients (biased toward symptomatic patients) was normal in only two; white matter abnormalities were almost universal and atrophy with ventricular dilatation was frequent, with isolated cases of basal ganglia lesions, ischaemic lesions, subdural haematoma or hygroma, and occipital porencephaly [16]. In the Saudi cohort, 25.8% had periventricular and deep white matter hyperintensities [17]. In the Atlas, MRI at 2.5 years in a child diagnosed in the first month showed increased signal in the frontal white matter, and at 9 years in another child extensive increased subcortical signal consistent with dysmyelination (Atlas Figs. 46.10 and 46.11) [37].

In homozygous MCT1 deficiency, MRI shows diffuse symmetric abnormalities of the subcortical white matter, basal ganglia, and thalami and, in some patients, agenesis of the corpus callosum [67, 77]. In HMG-CoA synthase deficiency, 3 of 11 comatose patients in the Vietnamese cohort had abnormal MRI (symmetric hyperintensities of the caudate nuclei and putamina, of the deep periventricular white matter, or ventricular dilatation) [49].

3.8. Summary of cohorts

The systematic reviews compile patients dating back to the 1970s and suffer from publication bias toward severe cases; the prognosis for those born today with early diagnosis may be better [16].

4. Clinical Recognition and Red Flags

4.1. When to suspect

In the newborn, acetonuria is always abnormal and is a sign of metabolic disease, because serum ketone bodies reach only 0.5–1 mmol/L in early neonatal life [92]. Neonatal ketoacidosis with hyperglycaemia can mimic neonatal diabetes and suggests a ketolysis defect; a newborn with severe hypoglycaemia without ketonuria, acidosis, hyperammonaemia, or lethargy in the first days suggests HMG-CoA lyase deficiency [37, 92]. In the bedside protocol of the Saudubray chapter, an intoxication-type presentation with ketoacidosis, marked ketonuria, normal or elevated ammonia, and normal or elevated glucose points to organic acidurias and ketolysis defects, and an energy-deficiency presentation with nonketotic acidosis, elevated ammonia and lactate, and low glucose points to beta-oxidation and ketogenesis defects [92].

In infants and young children, suspicion arises with recurrent crises of severe ketoacidosis with normal glucose and lactate, which are highly suggestive of a ketolytic defect or MCT1 deficiency, and with severe fasting hypoglycaemia without ketosis, which, if accompanied by acidosis, suggests HMG-CoA lyase or HMG-CoA synthase deficiency [92]. A diagnosis of "fasting ketoacidosis" or idiopathic ketotic hypoglycaemia should be questioned when there is concomitant severe metabolic acidosis [92]. Acidemia disproportionate to the ketosis should raise suspicion of a ketone body utilisation defect [71]. A Reye syndrome–like presentation, acute liver failure in childhood, acute or subacute dystonia after decompensation, leukoencephalopathy with U-fibre involvement, or agenesis of the corpus callosum with recurrent ketoacidosis are other settings in which these disorders belong on the list [37, 92].

In adolescents and adults, presentation is rare but possible: hypoketotic hypoglycaemic coma or leukoencephalopathy with seizures in HMG-CoA lyase deficiency, and ketoacidosis in the setting of diabetes in T2 deficiency [76, 83, 84]. In women with known disease, pregnancy, morning sickness, and hyperemesis are triggers [16, 93]. Asymptomatic biallelic individuals identified within families are at risk in situations of major stress, such as serious illness, accidents, or military training [52].

4.2. Red flags and emergency signs

The early sign to look for in ketolysis defects is tachypnoea; hypoglycaemia is late, so intervention should occur even with normal glucose [94]. In HMG-CoA lyase deficiency, early signs are subtle (lethargy, hypotonia), refusal to drink is frequent and early, and blood glucose should not be used for reassurance or to delay treatment [72]. The New England Consortium (NEC) protocol calls for intravenous treatment in the presence of any of the following: vomiting, hypoglycaemia, poor oral intake, dehydration, decreased alertness, or acidosis, and warns that ketones cannot be used to assess dehydration in this disorder [53]. In the emergency version of the British protocol (BIMDG, British Inherited Metabolic Disease Group), treatment is started if the child is unwell or vomiting, with hypoglycaemia (<2.6 mmol/L), acidosis or hyperventilation (base deficit >10 mmol/L), or drowsiness [95].

4.3. Newborn screening

In the USA, 3-hydroxy-3-methylglutaric aciduria (HMG-CoA lyase deficiency) and beta-ketothiolase deficiency are core conditions of the RUSP, in the December 2025 version; 2-methyl-3-hydroxybutyric aciduria and 3-methylglutaconic aciduria are secondary conditions, and SCOT, HMG-CoA synthase, and MCT1 deficiencies are not listed [20]. The RUSP is a recommended list, and each state decides its own panel [20]. In 2011, T2 deficiency was screened for by all state programmes [96]. In Australia, screening has potentially detected HMG-CoA lyase deficiency since 1998, with sampling on day 2 and results by day 8 [36]. In Italy, T2 deficiency has been part of the national panel since the Ministerial Decree of 13 October 2016 [44]. The UK programme, since January 2015, includes phenylketonuria, congenital hypothyroidism, sickle cell disease, cystic fibrosis, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, maple syrup urine disease, isovaleric acidaemia, glutaric aciduria type 1, and homocystinuria, and does not include these disorders [97]. The Saudi authors recommend newborn screening targeted at the p.(Arg41Gln) variant in their population [17]. The sources consulted do not describe the screening panels of Portugal or Brazil for these disorders.

Screening has limitations specific to each disorder. In T2 deficiency, C5:1 and C5-OH can be normal even during crises, and genotypes with residual activity are often missed, so normal screening does not exclude the disease [3, 12, 63]. In HMG-CoA lyase deficiency, the disease can manifest before the result is available: of the six Australian patients born after 1998, two presented clinically before the result, two had symptoms at recall, and two were not detected, even on retrospective reanalysis [36]. In HMG-CoA synthase deficiency, the C2/C0 ratio in dried blood spots was abnormal in only 2 of 6 samples [19]. SCOT and MCT1 deficiencies have no screening marker [5].

For an elevated C5-OH, the American College of Medical Genetics and Genomics (ACMG) ACT Sheet, updated in July 2022, directs the clinician to inform the family, assess clinical status the same day (poor feeding, vomiting, lethargy), consult a paediatric metabolic specialist, evaluate the newborn for hypoglycaemia, ketonuria, and metabolic acidosis and transfer to hospital if these are present or if the newborn is unwell, initiate confirmatory testing, advise on the need for urgent treatment of acidosis, and report the final diagnosis to the programme [98]. The ACT Sheet emphasises that HMG-CoA lyase and holocarboxylase synthetase deficiencies can present acutely in the neonatal period and that avoiding fasting is essential [98].

5. Diagnosis: Criteria, Testing, and Algorithms

5.1. Diagnostic criteria

No formal diagnostic criteria have been published by scientific societies for any of the five disorders. In the practice of the systematic reviews, diagnosis rests on metabolic documentation (a characteristic organic acid and acylcarnitine profile), enzymatic documentation (absent or reduced activity in fibroblasts, lymphocytes, or lymphoblasts), or genetic documentation (biallelic pathogenic or likely pathogenic variants) [12, 16]. A diagnosis based on metabolites alone, without enzymatic or molecular confirmation, is insufficient in T2 deficiency, because HSD10 disease (HSD17B10) produces a similar profile; two published siblings were excluded from the review for this reason [12, 43]. In SCOT, MCT1, and HMG-CoA synthase deficiencies, diagnosis is now essentially molecular [1, 13, 41].

5.2. The critical sample and fuel ratios

Samples collected during hypoglycaemia or ketoacidosis, before treatment, are the most valuable, because the biochemistry of several of these defects normalises when the patient is well [1, 63]. Simultaneous measurement of glucose, free fatty acids (FFAs), and ketone bodies (KBs) is needed to interpret hypoketotic states and must be read according to age and fasting duration [3, 99]. An FFA/total KB ratio greater than 2.5 indicates a ketogenesis or beta-oxidation defect, and a ratio below 0.3 suggests a ketolysis defect [1, 3]. In the fasting test criteria, beta-oxidation and ketogenesis defects show glucose <2.8 mmol/L with elevated FFAs, low KBs, FFA/KB >2 (normal <1), and a glucose × total KB product (both in mmol/L) <4; in ketolysis defects, KBs are already elevated at baseline, rise sharply with fasting, and the glucose × total KB product is >10 [99]. The 3-hydroxybutyrate/acetoacetate ratio is normally greater than 1 after an overnight fast and less than 1 in the postprandial period [99].

The urine ketone dipstick becomes positive when plasma acetoacetate is ≥0.1 mmol/L (total KBs >0.2 mmol/L) [92]. As a general rule, hyperketosis above 6 mmol/L of total KBs with bicarbonate <18 mmol/L is not physiologic, whereas ketosis without acidosis, hyperlactataemia, or hypoglycaemia is probably nutritional [92]. Absence of ketonuria in a hypoglycaemic patient means hypoketosis, but the presence of ketones can be misleading, and blood FFAs and 3-hydroxybutyrate may be needed; after treatment with glucose and fluids, urine is negative for ketones except in HMG-CoA lyase deficiency [38]. For sample collection, FFAs require 0.3 mL in a fluoride-heparin tube; 3-hydroxybutyrate and acetoacetate, like lactate and pyruvate, require 1 mL of blood mixed immediately with 0.5 mL of 18% perchloric acid on ice, refrigerated centrifugation, and freezing of the supernatant at −20 °C; carnitine, 1–2 mL in EDTA on ice; and urine, at least 5 mL frozen at −20 °C [99].

5.3. Fasting test

The fasting test now has restricted indications: unexplained hypoglycaemia after a baseline workup that has excluded beta-oxidation defects and adrenal insufficiency, or assessment of fasting tolerance during treatment. It is performed only in a specialised metabolic unit, stopping if glucose falls below 2.6 mmol/L, if bicarbonate falls below 15 mmol/L, or if neurological symptoms appear, with blood samples at 0, 8, 12, 16, 20, and 24 hours and urine collected in 8-hour periods [99]. The glucagon test has been abandoned in fasting hypoglycaemia, because it is dangerous when glycogen is depleted [1, 99]. The table reproduces normal values at the end of the fast.

Source: Table 3.6 of the Saudubray chapter on diagnostic procedures [99]. At the end of the fast or during hypoglycaemia, the following are normal: insulin <3 mU/L with glucose <2.8 mmol/L, cortisol >120 ng/mL, adrenocorticotropic hormone (ACTH) <80 pg/mL, and growth hormone (GH) >10 ng/mL [99].

5.4. Biochemistry by entity

Sources: [1, 5, 19, 36, 37, 43, 50, 63, 66, 99, 100].

In T2 deficiency, excretion of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine is characteristic, but 2-methylacetoacetate degrades rapidly, especially in urine that is not fresh, and mild forms may show abnormalities only under stress, for example after an isoleucine load [1, 63]. In the Turkish series, plasma C5-OH was elevated in 100% of acute samples and 97.1% of stable samples, C5:1 in 85.7% and 73.5%, and C4OH only during crises (28.6%); urinary 2-methyl-3-hydroxybutyrate and tiglylglycine were elevated in all acute samples and less often in remission, which supports longitudinal assessment with several markers [66]. In the Chinese series of 76 patients, urinary 2-methyl-3-hydroxybutyrate was detected in 100% (66/66) and blood C4OH in 96.3% (26/27) [74]. HSD10 disease gives a similar pattern but without 2-methylacetoacetate [1, 101].

In HMG-CoA lyase deficiency, urinary 3-hydroxy-3-methylglutarate reaches 10,000–20,000 mmol/mol creatinine during crises and 200–4000 between crises, against a normal value below 100 mmol/mol (somewhat higher in young infants); on gas chromatography–mass spectrometry, di- and tri-trimethylsilyl derivatives form, both of which must be included in quantification, and 3-methylcrotonic acid and its isomer 3-methyl-3-butenoic acid are artefacts of the technique [37]. 3-Methylglutarylcarnitine was identified in 1986 as a diagnostic metabolite in plasma and urine [102]. Plasma glycine was persistently elevated in one treated patient, and C5-OH but not C6DC remained elevated [58]. The acylcarnitine table in the Atlas chapter introducing fatty acid oxidation disorders (Table 34.1) gives control values for this disease that are higher than the patient range, an internal inconsistency that precludes its use; usable reference values are those of each laboratory and of published cases (section 5.5) [38].

In HMG-CoA synthase deficiency, Pitt and colleagues described in 2015 seven novel organic acids during crisis that normalise on recovery; cutoffs of adipic acid >200 and 4-HMP >20 µmol/mmol creatinine flagged all eight crisis samples from five patients, with a positive predictive value of 80% (95% confidence interval [CI], 35–100%), and some patients with ketosis from other causes had elevated 4-HMP [50]. In the review of 95 cases, 4-HMP was detected in 33 of 35 acute urine samples (usually only retrospectively), dicarboxylic aciduria in 54 of 56, and the plasma C2/C0 ratio was abnormal in 16 of 18 (88.9%) acute samples but in only 2 of 6 (33%) dried blood samples; the authors recommend that laboratories look for 4-HMP and elevated C2/C0 when there is dicarboxylic aciduria without appropriate ketonuria [19]. 4-HMP is not routinely available in all laboratories, no Vietnamese patient fully met the criterion of elevated C2/C0 with dicarboxylic aciduria, and the C2/C0 >3 cutoff is of uncertain value outside decompensation [49, 52]. Elevated C8–C12 acylcarnitines during fasting can cause confusion with MCAD deficiency, but C10:1 is normal and there is no suberylglycine or hexanoylglycine [52]. A combination of organic acids, low free carnitine, and an altered acylcarnitine profile after carnitine supplementation was proposed as suggestive in 2006 [103].

In SCOT deficiency, persistent ketonuria in the postprandial state is suggestive in severe genotypes; organic acids and acylcarnitines are nonspecific, and their normality does not exclude the diagnosis, which is the main reason for diagnostic delay [1, 5]. In the Saudi p.(Arg468Cys) cohort, acylcarnitines were normal in all, and no permanent ketonuria was observed [61]. In MCT1 deficiency, severe recurrent high anion gap metabolic acidosis due to accumulation of ketones in blood and urine is the key finding, and the absence of a metabolic profile is precisely the scenario in which SLC16A1 should be sequenced after T2 and SCOT have been excluded [26, 46, 68].

5.5. Newborn screening: markers, second-tier testing, and false negatives

Published values illustrate the magnitude: in the Chinese T2 deficiency series, C4OH had a mean of 1.38 ± 0.94 µmol/L (reference 0.02–0.3), C5-OH 1.36 ± 0.87 (0.06–0.5), and C5:1 0.37 ± 0.28 (0–0.05); in one patient, C4OH normalised at recall at 2 weeks, leading to discharge from the programme, and rose again at 11 months [43]. In the Australian patients with HMG-CoA lyase deficiency, initial C5-OH ranged from 0.02 µmol/L (normal) to 2.2 µmol/L (reference <0.2), and one patient with very low total and free carnitine had low levels of all acylcarnitines [36]. In T2 deficiency, second-tier testing made it possible to exclude malonic aciduria (C3DC) in cases with mild elevations, and C4OH, which also rises in other disorders, should be part of a combined strategy [44].

5.6. Enzyme studies

T2 activity is measured in fibroblasts (lymphocytes are less reliable); the assay is complicated by the other thiolases, and the specific substrate, 2-methylacetoacetyl-CoA, is difficult to synthesise, so the assay is run with and without potassium, which activates T2 but not the other thiolases [1, 12]. In the 2020 review, 105 patients had reduced or absent T2 activity in fibroblasts, lymphocytes, or lymphoblasts [12]. HMG-CoA lyase activity is measured in leukocytes, lymphoblasts, or fibroblasts and was reduced or absent in all 114 patients studied [16]; it cannot be used to identify carriers [37]. SCOT can be measured in lymphocytes or fibroblasts; in one Saudi patient, fibroblast activity was 1.2 nmol/min/mg (normal 2.6–8.6) [1, 61]. The HMG-CoA synthase assay requires a liver biopsy and is complicated by the cytoplasmic isoenzyme [1, 49]. MCT1 transport has no routine clinical assay described in the sources [68].

5.7. Molecular testing and its limitations

The first-line molecular test is a panel of energy and intermediary metabolism genes that includes all five genes, or exome or genome sequencing, with copy-number variant analysis [44, 49, 52]. The limitations are concrete: sequencing does not detect exon deletions in ACAT1, OXCT1, and HMGCS2, which require MLPA, quantitative PCR, or coverage analysis [5, 14, 50]; the SLC16A1 promoter variants responsible for exercise-induced hyperinsulinism are missed by coding-only exomes and panels [5]; and deep intronic variants, such as the HMGCL variant described in 2025, escape targeted and exome sequencing and require genome and RNA sequencing [58]. A negative targeted test does not exclude an unequivocal biochemical diagnosis [58]. In 5.1% of patients with HMG-CoA lyase deficiency, only one variant was identified, and in 1.7%, none [16]. The choice of phenotype terms weighs on exome analysis: in a Thai case, the exome was negative with the terms "hyperammonaemia" and "acidosis," and reanalysis three years later with the term "hypoglycaemia" identified the HMGCS2 variant; exome reanalysis every 1–2 years adds 10–15% more diagnoses [52].

The report should state the gene, the transcript and its version (NM_000019.4, NM_000436.4, NM_003051.4, NM_000191.3, or NM_005518.4), the HGVS description at the cDNA and protein levels, zygosity, and classification according to ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) criteria [6]. Variants of uncertain significance are frequent in these rare disorders: in Italian screening, two of the three newborns with T2 deficiency were homozygous for missense VUS (c.983C>T p.(Ala328Val) and c.764A>T p.(Glu255Val)), interpreted using population frequency data, in silico predictors, and, for the second, the existence of other pathogenic substitutions at the same codon (PM5 criterion) [44]. Parental segregation analysis, enzyme activity, and RNA studies help with reclassification: in a cohort cited by Menkovic and colleagues, 50% of intronic or splice VUS were reclassified as likely pathogenic by RNA studies, and in the HMGCL case, negligible gene expression (Z = −22.7) allowed the PVS1 criterion to be applied [58]. When simple heterozygosity for OXCT1 or SLC16A1 is found in a patient with ketoacidosis, the variant may be causal on its own (section 2.8), so the absence of a second variant does not close the investigation [46, 62].

5.8. Practical algorithm

In a child with decompensation, the first step is to collect the critical sample (glucose, blood gases with anion gap, lactate, ammonia, FFAs, 3-hydroxybutyrate and acetoacetate, acylcarnitines, carnitine, amino acids, insulin, cortisol, and urine for organic acids and ketones) before giving glucose [99, 105]. If there is ketoacidosis with normal glucose, lactate, and ammonia and an FFA/KB ratio <0.3, organic acids and acylcarnitines point to T2 (2-methyl-3-hydroxybutyrate, tiglylglycine, C5:1, C5-OH, C4OH); if they are nonspecific, molecular study of ACAT1, OXCT1, and SLC16A1 with deletion analysis follows [1, 46, 92]. If there is hypoketotic hypoglycaemia with FFA/KB >2.5, the presence of 3-hydroxy-3-methylglutarate indicates HMG-CoA lyase deficiency; a normal acylcarnitine profile with very high fatty acids and unrevealing organic acids (or with 4-HMP and dicarboxylic acids) points to HMG-CoA synthase, and the remaining branches to beta-oxidation and carnitine transport defects [1, 19, 38]. The presence of ketosis does not exclude HMG-CoA synthase deficiency, and normoglycaemia does not exclude any of the ketogenesis defects [1, 49]. For an elevated C5-OH on screening, the ACMG algorithm applies: glucose, electrolytes, blood gases and ammonia, urine organic acids and plasma acylcarnitines (in the newborn and the mother), plasma amino acids and serum biotinidase, consideration of holocarboxylase synthetase deficiency, and, when indicated, enzymatic and molecular testing [98].

5.9. Prenatal and preimplantation diagnosis

When the familial variants are known, prenatal diagnosis is molecular [1]. In HMG-CoA lyase deficiency, activity can be measured in chorionic villi or amniocytes, and the diagnosis has been made by analysis of metabolites in maternal urine at 23 weeks; 3-hydroxy-3-methylglutarate can be measured directly in amniotic fluid by isotope dilution [1, 37, 106]. In T2 and SCOT deficiencies, activity can be measured in chorionic villi (T2) or in cultured amniocytes (T2 or SCOT) [1]. Preimplantation genetic testing depends on prior identification of both of the couple's variants; the sources consulted do not describe its specific application in these disorders.

6. Differential Diagnosis

6.1. Comparison table

Sources: [1, 4, 24, 36, 38, 61, 68, 76, 92, 98, 101, 107–109].

6.2. Recurrent ketoacidosis: ketolysis, organic acidaemias, diabetes, and endocrine causes

Classic organic acidaemia and a ketolytic defect are distinguished by ammonia and lactate, which are increased in the organic acidaemias and normal or low in ketolytic defects, and by the organic acid profile [92]. Organic acidaemias and ketolytic defects can be associated with hyperglycaemia and glycosuria and mimic diabetes; the hyperglycaemia corrects within hours with insulin, and in adults with hyperglycaemia, HbA1c separates stress hyperglycaemia from established diabetes [76, 92]. In Vietnam, 28% of patients with T2 deficiency had hyperglycaemia during the crisis [65]. Adrenal insufficiency, including as-yet undiagnosed X-linked adrenoleukodystrophy, can cause a ketoacidotic crisis with hypoglycaemia and is always in the differential [92]. Glycogen storage disease III and glycogen synthase deficiency cause recurrent ketotic hypoglycaemia but not severe ketoacidosis [92].

Before labelling hypoglycaemia with ketosis as idiopathic, the following should be excluded: drugs (beta-blockers, alcohol), liver disease, adrenal insufficiency, hypopituitarism or isolated growth hormone deficiency, glycogen storage diseases, Fanconi-Bickel syndrome, gluconeogenesis defects, defects of ketone body utilisation or transport, organic acidaemias, maple syrup urine disease, and some beta-oxidation defects in which ketone bodies are formed [1]. Glycogen storage disease IXa is a relatively common and easily missed cause of ketotic hypoglycaemia, which may explain the higher prevalence of idiopathic ketotic hypoglycaemia in boys [1, 108]. Idiopathic ketotic hypoglycaemia is the most common cause of hypoglycaemia in nondiabetic children between 6 months and 6 years; it is more frequent in underweight children or those with relative macrocephaly and after intrauterine growth restriction, has rare neurological sequelae, and in most cases stops occurring by age 7 [1]. In acute hypoglycaemia in this entity, lactate and alanine are low and branched-chain amino acids are elevated [1, 109]. It represents the lower tail of the distribution of fasting tolerance, and stable isotope studies have attributed the hypoglycaemia to a failure of hepatic glucose production rather than to increased oxidation [1, 110, 111].

6.3. Elevated C5-OH and isoleucine profiles

C5-OH comprises two species with the same mass, 3-hydroxyisovalerylcarnitine and 2-methyl-3-hydroxybutyrylcarnitine, and its elevation on screening requires distinguishing among 3-methylcrotonyl-CoA carboxylase deficiency (infant or maternal), HMG-CoA lyase deficiency, T2 deficiency, multiple carboxylase deficiency (holocarboxylase synthetase and biotinidase), HSD10 disease, the 3-methylglutaconic acidurias, and MT-ATP6 mitochondrial disease; 3-methylcrotonyl-CoA carboxylase deficiency is the most common [1, 98]. Confirmation requires urine organic acids in the infant and the mother, plasma acylcarnitines, and serum biotinidase [1, 98]. In T2 deficiency, C5:1 is also elevated [98]. HSD10 disease presents in most cases with a severe progressive neurological phenotype (rigidity, dystonia, choreoathetosis, cortical blindness, atrophy, and white matter and basal ganglia abnormalities) rather than ketoacidotic crises, but a 6-year-old boy was diagnosed during a severe ketoacidotic crisis without neurological symptoms, mimicking T2 deficiency; 2-methyl-3-hydroxybutyrate and tiglylglycine are markedly elevated without 2-methylacetoacetate, especially after an oral isoleucine load of 100 mg/kg [43, 101]. 3-Hydroxyisovalerate increases in ketosis and with valproate, and 3-methylglutaconic acid in uraemia, in pregnancy, and in T2 deficiency itself [100]. Severe isovaleric acidaemia shares the predisposition of HMG-CoA lyase deficiency to encephalopathy with hypoglycaemia, acidosis, and hyperammonaemia, whereas 3-methylcrotonyl-CoA carboxylase and 3-methylglutaconyl-CoA hydratase deficiencies include many asymptomatic individuals [36].

6.4. Hypoketotic hypoglycaemia: ketogenesis, beta-oxidation, and hyperinsulinism

Severe fasting hypoglycaemia without ketosis suggests a beta-oxidation defect when there is no severe acidosis, and HMG-CoA lyase, HMG-CoA synthase, or cytosolic phosphoenolpyruvate carboxykinase deficiency when there is acidosis; absence of ketonuria during hypoglycaemia also occurs in hyperinsulinism, citrin deficiency, and growth hormone deficiency in infancy [92]. Elevation of CK and uric acid during hypoglycaemia is a red flag for a beta-oxidation defect [38]. In HMG-CoA lyase deficiency, the specific aciduria resolves the differential; the absence of ketonuria also distinguishes it from propionic and methylmalonic acidaemias [37]. HMG-CoA synthase deficiency is confused with beta-oxidation defects, glutaric aciduria type II, glycogen storage diseases, organic acidaemias, and, when hyperglycaemia is present, diabetic ketoacidosis; in the Vietnamese cohort, 14 probands had incorrect initial diagnoses, including one with a glutaric aciduria type II profile, and the crisis mimics sepsis or acute encephalopathy [5, 49]. In a Thai newborn, elevated leucine/isoleucine and valine on screening led to a provisional diagnosis of maple syrup urine disease and exchange transfusion, before the absence of 2-hydroxyisocaproate made that diagnosis unlikely [52]. Congenital hyperinsulinism, the most common cause of recurrent hypoglycaemia in early infancy (about 1/40,000–1/50,000 live births, 1/10,000 in consanguineous regions), is distinguished by the response to glucagon and a glucose requirement above 8 mg/kg/min [107]. In exercise-induced hyperinsulinism, the hypoglycaemia is nonketotic and occurs after anaerobic exercise [4].

6.5. MCT1 deficiency and GLUT1 deficiency

MCT1 deficiency should be suspected in children with unexplained recurrent metabolic acidosis and normal metabolic markers, and the 2026 systematic review inadvertently included a case that turned out to be GLUT1 deficiency, which illustrates the clinical overlap among epilepsy, developmental delay, and white matter abnormalities [68]. The distinction has therapeutic consequences: the ketogenic diet is the treatment for GLUT1 deficiency and is dangerous in MCT1 deficiency (section 7.8) [1, 68].

7. Treatment and Risk Management Strategies

7.1. Principles and framework of the recommendations

There is no approved specific treatment for any of the five disorders, nor any formal guideline from a scientific society (Society for the Study of Inborn Errors of Metabolism, MetabERN, or ACMG) dedicated to ketogenesis and ketolysis defects [5, 22]. The available recommendations are emergency protocols (BIMDG, revised in 2016 for children and in 2018 for adults with HMG-CoA lyase deficiency; NEC, undated), the ACMG ACT Sheet for elevated C5-OH (2022), and practices described by groups of centres (Australia 2023, Vietnam 2025, Saudi Arabia 2021–2022) [17, 36, 49, 53, 61, 72, 93, 94, 98]. In all of them, fasting avoidance is the cornerstone: in the 2020 systematic reviews, avoiding fasting was probably the main factor in preventing decompensations, and there are no controlled trials from which to draw conclusions about the need for a special diet or carnitine [12, 16]. The treatment common to both families of disorders is the provision of glucose in sufficient quantity to suppress lipolysis and ketogenesis, which treats hypoglycaemia in ketogenesis defects and prevents production of ketone bodies that the body cannot use in ketolysis defects [1, 5].

7.2. Treatment of acute decompensation

7.2.1. Oral emergency regimen at home

In children who are relatively well, without vomiting or respiratory distress, the British protocols for ketone defects (SCOT and T2) and for HMG-CoA lyase deficiency use a glucose polymer solution given every 2 hours; each dose is the daily volume divided by 12, and if there is nausea, smaller and more frequent volumes or continuous nasogastric tube feeding can be given [72, 94]. One heaped 5-mL spoon corresponds to about 7 g of polymer, and electrolytes can be added by making up the oral rehydration solution with the polymer solution [94]. In HMG-CoA lyase deficiency, refusal to drink is a common early symptom, and early use of a nasogastric tube may avoid the intravenous route [72]. In adults with HMG-CoA lyase deficiency, the regimen is generally 200 mL of 25% polymer solution every 2 hours [93]. The Australian protocol uses maltodextrin to provide about 120% of estimated energy requirements, with carbohydrate every 1–3 hours [36].

Sources: [72, 93, 94].

In SCOT, T2, and MCT1 deficiencies, the Saudubray chapter recommends carbohydrate drinks at the first sign of illness and hospital admission if they are vomited or if there is moderate or marked ketonuria [1]. Decompensation is rapid in early childhood [1].

7.2.2. Hospital treatment: glucose and fluids

Initial assessment includes blood gases and pH, glucose (laboratory and capillary), urea and electrolytes, complete blood count, blood culture, ketones (by capillary meter if needed), and ketonuria in ketolytic defects [94], and glucose, blood gases, electrolytes, ammonia, ketonuria, urinalysis, transaminases and alkaline phosphatase, prothrombin time and activated partial thromboplastin time, organic acids, and cultures in HMG-CoA lyase deficiency [53]. Intravenous (IV) glucose is given even when blood glucose is normal, to suppress ketogenesis [76, 94].

In the British paediatric protocol, common to ketone defects and HMG-CoA lyase deficiency, glucose 200 mg/kg is given immediately over a few minutes (2 mL/kg of 10% glucose or 1 mL/kg of 20%) along with a normal saline bolus of 10 mL/kg (20 mL/kg if there is poor perfusion or shock, repeated if needed); 10% glucose at 5 mL/kg/h is used only until the next solution is prepared, which is 0.45% NaCl with 10% glucose at a volume of deficit plus maintenance (100 mL/kg for the first 10 kg, 50 mL/kg for the next 10 kg, and 20 mL/kg thereafter), correcting the deficit over 24 hours [72, 94]. Potassium is added once there is urine output and the serum potassium is known; the patient is reassessed every 4–6 hours (Glasgow Coma Scale, blood pressure, blood gases, glucose, urea, and electrolytes), and oral feeding is reintroduced as soon as the child is alert and not vomiting; in HMG-CoA lyase deficiency, the infusion is maintained for at least 24 hours before review [72, 94]. The NEC protocol for HMG-CoA lyase deficiency specifies that glucose should never be less than 10%, at 1.5 times maintenance to provide 7–8 mg/kg/min, and treats hypoglycaemia with a bolus of 25% dextrose 2 mL/kg followed by the same infusion [53].

In adults with HMG-CoA lyase deficiency, the British protocol calls for priority triage, correction of dehydration with 0.9% NaCl, initial correction of hypoglycaemia with 50 mL of 50% dextrose over 30 minutes, and 10% dextrose at 2 mL/kg/h (e.g., 140 mL/h in a 70-kg adult), with a glucose target of 6–10 mmol/L; hypoglycaemia sets in rapidly if venous access fails, and IV dextrose is continued until normal oral feeding is tolerated [93]. The same protocol includes treatment of infection, analgesia, an antipyretic, an antiemetic, and monitoring for hypokalaemia and refeeding syndrome [93].

For crises of HMG-CoA lyase deficiency, the Atlas describes parenteral 20% glucose with IV insulin to maintain blood glucose between 6 and 8 mmol/L [37]. The Australian group uses glucose infusion rates above endogenous production: 6–9 mg/kg/min in infants, 5 mg/kg/min in children, and 2.5 mg/kg/min in adults [36]. In HMG-CoA synthase deficiency, the Vietnamese cohort used 10% dextrose at 8–10 mg/kg/min with early oral feeding [49]. In newborns with hypoglycaemia of any cause, the Saudubray chapter on emergency treatment indicates a glucose bolus of 0.2–0.5 g/kg followed by an infusion of 10% glucose with electrolytes (about 10 mg/kg/min), after the critical samples have been collected [105].

7.2.3. Insulin

Hyperglycaemia is treated not by reducing glucose but by adding insulin: the British paediatric protocol starts insulin, according to the local protocol, if glucose remains above 8 mmol/L, and the adult protocol above 10 mmol/L [72, 93, 94]. Saudubray's drug table lists IV insulin 0.05–0.2 IU/kg/h, always with glucose-containing solutions, for decompensation in organic acidurias and beta-oxidation defects [112]. In the Vietnamese cohort, a patient with HMG-CoA synthase deficiency and hyperglycaemia of 24.5 mmol/L received insulin 0.05 IU/kg/h for 4 hours [49].

7.2.4. Sodium bicarbonate and electrolyte correction

Correction of acidosis is the point on which protocols diverge most. The British protocol does not use bicarbonate routinely: only if the pH is below 7.1, the base deficit is greater than 15 mmol/L, or the pH is falling rapidly (in HMG-CoA lyase deficiency, after blood glucose and perfusion have been corrected), with a half correction calculated as 0.15 × weight (kg) × base deficit (mmol/L), in mmol, given over at least 30 minutes, using 8.4% bicarbonate (1 mmol/mL) diluted at least 1:5 in 5% glucose; repeated doses are rarely needed and should prompt consideration of sepsis [72, 94]. The NEC protocol for HMG-CoA lyase deficiency treats acidosis aggressively when bicarbonate is below 16 mmol/L, with IV sodium bicarbonate 1 mEq/kg (no maximum dose defined in the source), and warns that conservative treatment can have tragic consequences [53]. The Saudubray chapter indicates IV bicarbonate in ketolytic defects if ketoacidosis is severe (pH <7.1) and allows it in milder acidosis, with frequent electrolyte monitoring because of the risk of severe and potentially fatal hypernatraemia [1]. In newborns with severe ketoacidosis, repeated bicarbonate boluses can induce hypernatraemia, oedema, and cerebral haemorrhage, and sodium bicarbonate can replace one-quarter to one-half of sodium requirements in the first 6–12 hours, through a separate (Y-site) line to avoid precipitation with calcium [105]. Hypokalaemia is another risk: in a 5-year-old boy with MCT1 deficiency, bicarbonate in dextrose-containing fluids led to a potassium of 1.7 mmol/L [68].

When acidosis is refractory, the series describe mechanical ventilation and continuous renal replacement therapy: in SCOT deficiency, renal replacement was needed in some patients in the 2021 review, and in HMG-CoA synthase deficiency, seven of the 19 Vietnamese patients underwent continuous venovenous haemofiltration for 19–82 hours during the first crisis [5, 49]. In the T2 deficiency review, at least 11 patients underwent haemodialysis or peritoneal dialysis [12].

7.2.5. Hyperammonaemia

In HMG-CoA lyase deficiency with hyperammonaemia, the Atlas states that sodium benzoate or phenylacetate and L-arginine are useful and that exchange transfusion or peritoneal dialysis may be needed in infants; the sources consulted do not give doses of these drugs for this disorder [37]. One case of hyperammonaemia above 2000 µmol/L was treated with peritoneal dialysis [16]. In HMG-CoA synthase deficiency, a patient with ammonia of 983 µmol/L was treated with sodium benzoate, and sodium benzoate and renal replacement were used in severe hyperammonaemia [5, 49]. Carglumic acid, listed in Saudubray's table for hyperammonaemia in organic acidurias (100–250 mg/kg/day in 4 doses), has no described use in these disorders in the sources consulted [112].

7.2.6. Lipids, carnitine, and adjunctive measures during crisis

In HMG-CoA lyase deficiency, the NEC protocol prohibits lipids in any form [53]. In the same protocol, carnitine is given orally at 100–200 mg/kg/day in 3 doses or IV at 30–50 mg/kg/day [53]; in the Vietnamese HMG-CoA synthase deficiency cohort, 13 of 16 patients received L-carnitine during the first crisis [49]. Ondansetron 0.15 mg/kg IV over 15 minutes, up to 3 times daily (a dosage matching that of the Portuguese SmPC for Zofran® for chemotherapy-induced nausea and vomiting from 6 months to 17 years, which limits each IV dose to 8 mg [113]), is indicated for persistent vomiting in the Saudubray chapter on emergency treatment, in the general context of inherited metabolic diseases and not specifically for these disorders [105]. Sodium D,L-3-hydroxybutyrate as rescue therapy in ketogenesis defects is discussed in section 7.5.2.

7.3. Comparison of acute protocols

Sources: [36, 49, 53, 72, 93, 94]. The differences reflect centre practice rather than direct comparisons; none of the regimens has been tested against another.

7.4. Chronic treatment and prevention

7.4.1. Diet and fasting avoidance

In ketolysis defects and MCT1 deficiency, the Saudubray chapter recommends regular, frequent meals in the first year and thereafter no fasting longer than 12 hours, with high carbohydrate intake during any stress (surgery, infection) [1]. Mild protein restriction is generally recommended in T2 deficiency, on the hypothesis that isoleucine metabolites are toxic to the basal ganglia, but outcomes did not correlate with protein intake, and several patients had normal development without a diet [1, 73]. In the 2020 review of T2 deficiency (163 patients with available information), 82.2% followed a specific diet at least temporarily: 52.7% an isoleucine- or protein-restricted diet, usually with mild restriction (up to 2 g/kg/day of protein), and 28.8% protein and fat restriction, 41 of the 47 only during crises; none used a special amino acid mixture, and 17.8% never had restrictions [12]. Ketogenic diets should be avoided in all three ketolysis disorders, and a low-fat diet is not necessary [1]. SGLT2 inhibitors should be avoided in T2 deficiency because of the risk of ketoacidosis [5, 76].

In SCOT deficiency, the practices described include avoiding prolonged fasting and excessive fat intake, mild protein restriction (2.0 g/kg/day in one reported child), L-carnitine if needed, an emergency card, and home monitoring for ketonuria in mild genotypes [5]. A 2025 review adds raw starch, fat restriction, and oral bicarbonate, and notes that immature pancreatic amylase before 12 months limits starch digestion [14]. In the Saudi p.(Arg468Cys) cohort, all were instructed to avoid fasting, restrict protein, and take carnitine, but adherence was partial: among the 7 patients with full or partial adherence, crises resolved in 5, and among the 8 nonadherent patients, on a normal diet and without carnitine, they resolved in 6 and 2 never had crises; finding no correlation between chronic management and outcome, the authors conclude that dietary restriction and carnitine may not be necessary in adulthood, but that prompt treatment of crises must continue for life [61].

In MCT1 deficiency, the supportive measures described are avoiding fasting and prolonged exertion, frequent meals, hydration, and caregiver education; in the report by Balasubramaniam, crises were treated with IV dextrose at 9 mg/kg/min, with glucose polymers at home and mild protein restriction during illness [46, 68]. Triggers should be identified even in heterozygotes [5].

In HMG-CoA lyase deficiency, the Saudubray chapter recommends moderate protein or leucine restriction and acknowledges less agreement on a low-fat diet; some patients have normal development without restriction [1, 84]. The Atlas describes a high-carbohydrate diet with cornstarch, glucose polymers during intercurrent illness, cornstarch at bedtime, frequent meals in infancy, and permission to sleep through the night only after the absence of hypoglycaemia has been documented; fat restriction may reduce urinary metabolites, and 3-hydroxybutyrate infusion prevented fasting hypoglycaemia in one patient [37]. In the 2020 review (117 patients with available information), only 7.7% had no restrictions; of the 105 with details, 43.8% were on a leucine- or protein-restricted diet and 54.3% on a diet restricted in leucine or protein and in fat; many of the patients on leucine restriction received a leucine-free amino acid mixture, and the diet was liberalised in some during childhood [16]. In the Saudi cohort, the diet was leucine-restricted in 60% and protein-restricted in 22.6% (with a leucine-free formula), with poor adherence and no apparent difference in outcome between diets [17]. In the Australian cohort, only one patient used a branched-chain amino acid–free formula in infancy; the rest followed a moderate-protein, low-fat, carbohydrate-supplemented diet, liberalised with age, with current protein intake of 0.5–3.4 g/kg/day and fat between 8% and 30% of energy; the three adults had been free of acute episodes for 11–22 years [36].

The Australian group published practice recommendations for HMG-CoA lyase deficiency, based on the authors' opinion and experience, which constitute the most detailed document available [36].

Source: Table 3 of Thompson and colleagues [36]. Nighttime uncooked cornstarch (1–1.5 g/kg/day) was used in three children and in no adults in the cohort, so it is an option rather than routine [36]. A low-fat, low-protein diet carries a risk of deficiencies of essential fatty acids, fat-soluble vitamins, calcium, iron, and vitamin B12, which warrant regular lifelong micronutrient monitoring [36].

In HMG-CoA synthase deficiency, after genetic confirmation, the Vietnamese cohort applied fasting avoidance with feeds every 3 hours from 0 to 4 months and a maximum fast of 8 hours between 4 and 12 months, a regular schedule thereafter, carbohydrate-rich fluids every 3–4 hours during illness, and 10% dextrose at 1.5 times maintenance during illness, poor intake, or preoperative fasting, with L-carnitine and maltodextrin; relapses fell from 11 in seven patients before diagnosis to 2 in two patients afterward, and all were alive, 18 of 19 with normal development [49]. For ketogenesis defects, the Saudubray chapter recommends avoiding fasting and maintaining high carbohydrate intake during any metabolic stress, with glucose infusion if drinks are refused or vomited [1]. Prognosis is generally good with these measures, and some centres use carnitine only during intercurrent illness [52].

7.4.2. Emergency plans and education

After discharge, parents should know how to recognise early signs and start home treatment, with an emergency card describing the regimen; if decompensations are recurrent, gastrostomy and/or a totally implantable venous access device may be considered [105]. All the Australian patients had maltodextrin-based emergency plans, with IV dextrose if not tolerated [36]. The Duke case illustrates the risk of the interval before diagnosis: the confirmatory result was reported on a Friday afternoon, and the infant decompensated the following weekend (section 10) [58]. The Chinese authors recommend greater caution in administering vaccines, because the inflammatory response can trigger a decompensation that is clinically indistinguishable from a vaccine reaction; this is the authors' opinion, without a guideline [43].

7.5. Drugs

7.5.1. Levocarnitine

L-carnitine (levocarnitine, the international nonproprietary name; Carnitor® in the USA, with a Food and Drug Administration [FDA] label) replenishes carnitine stores and removes toxic acyl-CoA intermediates as acylcarnitines; the racemic mixture should not be used [112]. In these disorders, its use rests on the secondary carnitine deficiency documented in some patients (T2 deficiency, HMG-CoA lyase deficiency with very low free carnitine, HMG-CoA synthase deficiency with low free carnitine in 7 of 16 Vietnamese patients) and on a hypothesised detoxifying effect and preservation of free CoA, but its value has not been demonstrated [1, 12, 16, 36, 49]. In the T2 deficiency review, 65.9% of patients received oral L-carnitine at least temporarily, usually between 50 and 200 mg/kg/day; in the HMG-CoA lyase deficiency review, 78% [12, 16]. There is no published consensus on the optimal dose; the Australian group typically uses 100 mg/kg/day in childhood, reduced on a mg/kg basis with age by analogy with glutaric aciduria type 1 and methylmalonic acidaemia, and in the Saudi cohort the dose was 50–100 mg/kg/day [17, 36].

Sources: [36, 53, 112, 114, 115]. The recommended doses are those of the NEC protocol and the clinical series; the labels are shown for comparison and differ from each other: the Portuguese SmPC allows higher doses than the FDA label up to age 2 and lower mg/kg doses from 6 to 12 years, and does not set the 3 g/day maximum [114, 115]. The FDA label indicates levocarnitine for primary systemic carnitine deficiency and for the acute and chronic treatment of patients with an inborn error of metabolism resulting in secondary carnitine deficiency, with no known contraindications [114]. The adverse effects described are transient nausea, vomiting, abdominal cramps, and diarrhoea, body odor, and seizures (with or without preexisting epilepsy, with increased frequency in patients with epilepsy); hypersensitivity reactions include rash, urticaria, and facial oedema and, with the IV route, especially in dialysis, anaphylaxis, laryngeal oedema, and bronchospasm [114]. Levocarnitine increases the INR in patients treated with warfarin [114]. Monitoring includes blood chemistry, vital signs, plasma carnitine, and clinical status; plasma carnitine should be measured before starting the IV form and monitored weekly and monthly [114]. For gastrointestinal effects, the label advises spacing doses and slow ingestion; with new or more frequent seizures, a relationship with the drug should be considered [114]. In ketogenesis defects, carnitine is sometimes prescribed empirically until a beta-oxidation defect has been excluded, weighing the risk in VLCAD (very-long-chain acyl-CoA dehydrogenase) deficiency [52].

7.5.2. Sodium D,L-3-hydroxybutyrate and ketone esters

Sodium 3-hydroxybutyrate, usually racemic (D,L), provides the ketone body that patients with a ketogenesis defect cannot produce; Saudubray's drug table lists 300–2000 mg/kg/day orally, in 3 to 6 doses, for glycogen storage disease III, glutaric aciduria type II, other beta-oxidation defects, and ketogenesis defects [112, 116]. The main evidence comes from glutaric aciduria type II (a retrospective cohort of 23 patients), in which benefit can take weeks to months [116, 117]. In ketogenesis defects, experience comes from case reports and series: Bhattacharya and colleagues described in 2020 three catastrophic decompensations (carnitine-acylcarnitine translocase deficiency, HMG-CoA lyase deficiency, and carnitine palmitoyltransferase 2 deficiency) with rapid and sustained recovery after intensive therapy with adjunctive sodium D,L-3-hydroxybutyrate [118]. In the Australian cohort, four to five patients with HMG-CoA lyase deficiency received 900 mg/kg/day with dextrose-containing fluids in the acute phase; acute use was associated with cognitive preservation after herniation, absence of decompensation during a prolonged herpetic infection, and recovery from liver failure with cognitive restoration within 12 hours, but prolonged use (every 4 hours, from 6 weeks to 2 years of age in one patient) did not show efficacy [36]. The Sydney centre has used ketone body salts as rescue in ketone body synthesis defects since 2010, with pharmacy committee approval and federal notification, and the product is supplied by a UK manufacturer [36]. In the Duke infant, a synthetic 3-hydroxybutyrate marketed as a supplement was introduced at 3 months at about 400 mg/kg/day [58].

This is off-label use: no marketing authorisations or orphan designations were found at the EMA (European Medicines Agency) for 3-hydroxybutyrate in these disorders [36, 119]. The salts carry a sodium load; ketone esters avoid that load, provide only the physiologic D isomer, and achieve higher D-3-hydroxybutyrate concentrations, but they have no described use in these disorders; both salts and esters can cause nausea and abdominal pain [1, 116, 120]. The L-3-hydroxybutyrate in the racemic mixture may be relevant to myelin synthesis, according to animal data [36].

7.5.3. Other drugs and single-case treatments

In a Palestinian infant with severe SCOT deficiency due to a homozygous OXCT1 deletion, dependent on IV glucose for weeks despite bicarbonate and high-dose uncooked cornstarch, the addition of pancrelipase (Creon®) 5000 IU with each starch feed at about 4 months of age allowed IV glucose to be stopped within 3 days; pancrelipase was discontinued at 11 months [14]. This is a single case and an off-label use, whose rationale is the immaturity of pancreatic amylase before 12 months [14]. Oral sodium bicarbonate was used chronically in this infant (up to 10 mEq/kg/day, then 3.2 mEq/kg/day at 12 months) and in six Saudi patients with persistent acidosis [14, 61]. One patient with HMG-CoA lyase deficiency received long-term diazoxide (25 mg every 8 hours) [16].

In exercise-induced hyperinsulinism, the first measure is avoidance or modification of anaerobic exercise; diazoxide (Proglycem® in the USA, labelled for hypoglycaemia due to hyperinsulinism without a genetic subtype) produces only a partial response, and the GeneReviews framework for hyperinsulinism includes IV glucose with a target above 70 mg/dL (3.9 mmol/L), diazoxide with a thiazide, glucagon, and octreotide [4, 5]. In the 2025 adult patient, subcutaneous octreotide reduced exercise-induced hyperinsulinaemia and hypoglycaemia in a dose-dependent manner [79]. Diazoxide has no role in ketoacidotic MCT1 deficiency [5].

7.6. Regulatory status

Sources: [5, 14, 36, 114, 119, 121]. In Portugal, levocarnitine is authorised as Disocor® 1000 mg/10 ml oral solution (Medinfar), indicated for carnitine deficiency resulting from inborn errors of metabolism, with the age-based doses in section 7.5.1 [115].

7.7. Treatment evidence: trials and observational studies

A ClinicalTrials.gov search on 17 October 2026, using the terms for the five disorders, found no interventional trials directed at them; the only registered studies that cover them are genomic newborn screening programmes (BabyDetect, in Liège, completed; Early Check, in the USA, active but not recruiting) and a selective screening study in Kazakhstan of unknown status [121]. A negative search does not prove that no studies exist. The evidence on treatment is therefore observational.

Sources: [12, 14, 16, 36, 49, 61, 117, 118]. None of these studies has a randomised control group or confidence intervals for therapeutic outcomes; before-and-after comparisons confound the effect of the intervention with that of age, which by itself reduces crisis frequency, and the systematic reviews mix very different treatment eras. Indirect comparison of outcomes across cohorts of different disorders, populations, and eras is not legitimate. The results support fasting avoidance and early treatment of crises, and leave open the need for protein restriction, fat restriction, and carnitine.

7.8. Agents and situations to avoid

Ketogenic diets are contraindicated in beta-oxidation, ketogenesis, and ketolysis defects, as in acute intermittent porphyria and pyruvate carboxylase deficiency [1]. In MCT1 deficiency, a 5-year-old girl with refractory absence epilepsy developed vomiting, hypoglycaemia (2.6 mmol/L), and acidosis (pH 7.19, bicarbonate 12.8 mmol/L, anion gap 22 mmol/L) after starting a 2:1 and then a 3:1 ketogenic diet, which was discontinued [68, 122]. SGLT2 inhibitors should be avoided in T2 deficiency [76]. In HMG-CoA lyase deficiency, IV lipids are prohibited by the NEC protocol, and the Greek perioperative report avoided propofol (a lipid emulsion), local anaesthesia (because rescue with lipid emulsion would be impossible), and lactated Ringer's solution [53, 123]. Prolonged fasting, excess alcohol, and, in T2 deficiency, high protein intake are described triggers [44, 93]. The glucagon test is dangerous in the fasting state with depleted glycogen [1].

7.9. Pregnancy, lactation, perioperative care, and transition

Pregnancy in HMG-CoA lyase deficiency is high risk. Of the eight pregnancies reported in five women, five produced healthy offspring; one woman with recurrent decompensations in her first pregnancy died in her second, at 9 weeks, from maternal decompensation, and another had an intrauterine death at 10 weeks during a decompensation and termination of her second pregnancy at 6 weeks [1, 16, 124]. In series of metabolic diseases in pregnancy, decompensations during pregnancy and the postpartum period were frequent, and preconception counselling and joint obstetric–metabolic management are considered essential [124]. In T2 deficiency, four pregnancies in three women were uncomplicated, with healthy offspring (one cesarean delivery for fetal bradycardia) [12]. In SCOT deficiency, two Saudi sisters had different pregnancies: one with recurrent ketoacidosis associated with severe nausea and vomiting and several admissions, the other without crises, both with normal deliveries [61]. In any ketogenesis or ketolysis defect, IV glucose is indicated during labor and in illnesses with vomiting [1]. The British adult protocol includes morning sickness among the triggers [93]. The sources consulted contain no data on lactation in these disorders; the levocarnitine label reports no harm in animal studies and no adequate studies in human pregnancy, recommending use only when the need has been established [114].

Perioperatively, advance planning with the metabolic team and IV glucose whenever there is fasting are the general rules [1, 5]. The first anaesthetic report in HMG-CoA lyase deficiency describes a 14.5-year-old girl with acute cholecystitis after a fatty meal: a deviation from the metabolic protocol caused lactic acidosis and hypoglycaemia, treated in intensive care with bicarbonate (70 mEq over 2 hours, for a bicarbonate of 15 mEq/L), L-carnitine, and 10% dextrose with electrolytes at 150 mL/h; laparoscopic cholecystectomy was performed with midazolam, fentanyl, cisatracurium, and sevoflurane, without propofol or local anaesthesia, with 0.9% NaCl and 10% dextrose and continuous monitoring of blood gases and glucose, and she was discharged on day 3 [123]. The recommendations in that report are opinion [123].

Transition to adulthood requires the adolescent to understand fasting avoidance, the sick-day plan, and the pregnancy plan and to avoid excess alcohol [36]. Ketoacidotic crises become rare after mid-childhood in ketolytic defects, but adults with HMG-CoA lyase deficiency can have severe decompensations, such as cerebellar tonsillar herniation in a patient without medical follow-up for 14 years [1, 36]. In adults with diabetes, managing hyperglycaemia with insulin allows glucose intake to be maintained [76, 85].

7.10. Developments in the past twelve months

Sources: [20, 58, 66, 68, 69, 71, 74, 80, 90, 91, 123, 125]. No clinical trials, regulatory opinions, or authorisations in these disorders were identified in the period [119, 121]. In the abstracts of the Beijing series, the protein designations of the novel variants do not match the published nucleotide changes, so they are not reproduced here [125].

7.11. Available recommendations and divergences

Sources: [1, 36, 53, 72, 93, 94, 98]. The sources agree on fasting avoidance, early glucose, and intervention before hypoglycaemia; they diverge on the bicarbonate threshold, the glucose infusion rate, and fat and protein restriction. The choice between the BIMDG and NEC bicarbonate thresholds should weigh the risk of hypernatraemia and hypokalaemia against that of refractory acidosis, with frequent electrolyte monitoring in both cases [1, 68].

8. Reproductive Options and Family Counselling

8.1. Inheritance patterns and recurrence risks

T2, SCOT, HMG-CoA lyase, and HMG-CoA synthase deficiencies and MCT1 deficiency due to biallelic loss of function are autosomal recessive: when both parents are heterozygous, each pregnancy has a 25% chance of an affected child, 50% of a carrier, and 25% of a noncarrier [1, 107]. In sudden infant deaths with suspected hypoglycaemia, the possibility of a genetic disorder with a recurrence risk of up to 25% should be considered [107]. Paternal uniparental isodisomy of chromosome 1, described in a patient homozygous for an HMGCL variant, means that only the father is a carrier and that the recurrence risk is much lower than 25%; confirmation of segregation in both parents is therefore part of counselling [16].

The OXCT1 and SLC16A1 genes require different counselling. Heterozygotes can develop severe ketoacidosis under ketogenic stress, so carrier parents and siblings are not necessarily unaffected [1, 46, 62]. In MCT1 deficiency with a monoallelic variant, transmission is in practice dominant with incomplete penetrance: the p.(Arg328Ter) variant was present in two affected half-brothers, their healthy mother, and a half-sister [46]; each child of a carrier has a 50% chance of inheriting the variant, but the probability of developing crises has not been quantified. Exercise-induced hyperinsulinism and the myopathic form of SLC16A1 are autosomal dominant, with a 50% risk for each child of an affected individual [4, 24, 26]. In T2, HMG-CoA lyase, and HMG-CoA synthase deficiencies, carrier parents are asymptomatic [17, 49, 61].

8.2. Cascade testing and asymptomatic siblings

The existence of asymptomatic biallelic individuals in several families with HMG-CoA synthase deficiency justifies testing patients' siblings [5, 18]. In the Vietnamese cohort, three older siblings diagnosed through family screening were normal at 5–14 years, and in the Thai family an asymptomatic 13-year-old brother had urinary 4-HMP and dicarboxylic acids after an 8-hour fast and was advised to avoid fasting [49, 52]. In T2 deficiency, 28 patients were diagnosed before symptoms through newborn or family screening, and three of them later had a crisis [12]; in HMG-CoA lyase deficiency, a patient diagnosed presymptomatically through family screening decompensated in the third year [16]. Testing of minor siblings is clinically actionable, because diagnosis allows fasting avoidance and an emergency plan to be instituted, and it also identifies OXCT1 and SLC16A1 carriers with their own risk. The enzyme assay cannot detect HMGCL carriers, so cascade testing is molecular [37]. In populations with founder variants, targeted testing for the variant (p.(Arg41Gln) in Saudi Arabia, p.(Arg468Cys) in Arab patients with SCOT deficiency) is proposed by the cohort authors [17, 61].

8.3. Consanguinity and founder populations

Parental consanguinity was 33.3% in T2 deficiency and 49% in HMG-CoA lyase deficiency in the systematic reviews, and 100% in the Saudi (HMG-CoA lyase) and Palestinian (T2) cohorts [12, 16, 17, 75]. Absence of consanguinity does not exclude homozygosity: only 29 of the 67 homozygotes for ACAT1 variants with available information had related parents, and 18 homozygotes for HMGCL variants came from nonconsanguineous unions, reflecting founder variants such as p.(Glu37Ter) in Portugal and Brazil [12, 16, 56].

8.4. Prenatal and preimplantation diagnosis

Once both familial variants have been identified, molecular prenatal diagnosis is possible on chorionic villi or amniocytes and, in T2, SCOT, and HMG-CoA lyase deficiencies, enzymatic study; in HMG-CoA lyase deficiency, the maternal urine metabolite profile has been used [1, 37, 106, 107]. Preimplantation genetic testing requires the same variants; the sources consulted do not report its use in these disorders. Because the prognosis with early diagnosis and fasting avoidance is favourable in most cases of T2, SCOT, and HMG-CoA synthase deficiency, an alternative to prenatal diagnosis is immediate neonatal diagnosis, with a feeding plan from birth, especially in HMG-CoA lyase deficiency, in which half of crises begin in the first days [16, 60, 106].

8.5. Counselling content

Counselling should explain the inheritance pattern of each gene and the particular situation of OXCT1 and SLC16A1 heterozygotes; the unpredictability of phenotype from genotype; the risk concentrated in the first crisis and its prevention; the need for critical samples in subsequent crises; the risk of pregnancy in women with HMG-CoA lyase deficiency and the need for preconception planning; and the availability of prenatal diagnosis and sibling testing [16, 62, 63, 124].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency and what each figure measures

Counts of published cases are lower bounds, because SCOT, MCT1, and HMG-CoA synthase deficiencies can be diagnosed only by enzymatic or molecular study and are probably underdiagnosed [5, 13]. Screening-based incidences underestimate T2 deficiency, because mild genotypes escape the markers [43, 63]; the difference between China (≈1/1,000,000) and Vietnam (1/190,000) has been attributed to ethnic origin and awareness of the disease [43]. The Orphanet entry for HMG-CoA synthase deficiency, with 9 cases, is outdated relative to the 2025 series [11, 18].

9.2. Ancestry and founder effects

T2 deficiency is panethnic: of the 213 patients with known origin in the 2020 review, 36.6% were of European ancestry, 20.2% Vietnamese (mostly Kinh), 13.1% Turkish, 6.1% Indian (mostly from Hyderabad), 5.6% Chinese, 3.8% Japanese, and 2.8% Tunisian [12]. The p.(Arg208Ter) variant is a founder variant in the Kinh ethnic group but also occurs in Dutch and Turkish patients on a different haplotype [12, 64, 65].

HMG-CoA lyase deficiency is the most common organic acidaemia in the Iberian Peninsula and Saudi Arabia [1, 16]. In Portugal, the experience of the northern group identified it as the most frequent organic aciduria, with p.(Glu37Ter) in 84.1% of the alleles of 11 patients [56]. In Brazil, 13 of 15 patients at a reference laboratory had Portuguese ancestry, and the E37X and V168fs(-2) variants were the common ones in Iberian ancestry [81]. The 2020 review included 20 Portuguese patients and 13 Brazilians of Portuguese ancestry, and p.(Glu37Ter) was the most common variant, distributed across Brazil, Spain, Portugal, and Morocco [16]. In Saudi Arabia, p.(Arg41Gln) accounts for 77.4% of the Riyadh cohort and, in earlier studies, more than 94% of pathogenic alleles [17, 55]. In Turkey, c.876+1G>C is common [16]. A Portuguese patient with HMG-CoA lyase deficiency and type 1 diabetes was described in 2023 [86].

In SCOT deficiency, p.(Arg468Cys) appears to be an ancient Arab founder variant [61]; in HMG-CoA synthase deficiency, p.(Gly212Arg) is the recurrent European variant, p.(Glu401Ter) the Chinese, p.(Arg501Pro) the Thai, and c.559+1G>A and p.(Phe364Ile) the Vietnamese variants [18, 49, 89].

9.3. Special populations

Adults with these disorders include patients diagnosed in childhood and patients with a late first manifestation (HMG-CoA lyase deficiency at 29 and 36 years, and a case at 54 years cited in the Saudi cohort) [17, 83, 84]. Coexistence with type 1 or type 2 diabetes requires coordination between endocrinology and the metabolic team, because insulin therapy becomes the means of maintaining glucose intake without hyperglycaemia [76, 85, 86]. Women of childbearing age with HMG-CoA lyase deficiency constitute the group at highest maternal risk [16]. Newborns of mothers with metabolic disease and infants of mothers with gestational diabetes deserve attention: a Vietnamese patient with HMG-CoA synthase deficiency, born to a mother with insulin-treated gestational diabetes, had a crisis on day 10 [49].

9.4. Reference networks and patient organisations

In Europe, these patients fall within MetabERN, under the C-FAO subnetwork (disorders of carbohydrate metabolism, fatty acid oxidation, and ketone bodies) and, for T2 deficiency and HMG-CoA lyase deficiency as organic acidurias, also under the AOA subnetwork [21, 22]. The European registry E-IMD (European registry and network for Intoxication type Metabolic Diseases) covers organic acidurias and urea cycle disorders [127]. Patient organisations include the Organic Acidemia Association in the USA, with pages for beta-ketothiolase deficiency and HMG-CoA lyase deficiency, Metabolic Support UK and Climb in the United Kingdom, and, in Portugal, APOFEN, the Portuguese Association for Phenylketonuria and other inherited metabolic diseases [107, 128–130]. The sources consulted did not identify a Brazilian organisation specific to these disorders.

10. Illustrative Clinical Case

10.1. HMG-CoA lyase deficiency detected by newborn screening, with a deep intronic variant

Menkovic and colleagues, from Duke University (USA), published in November 2025 the case of an adopted boy, born at 37 weeks, with limited prenatal and family history [58]. Newborn screening on a dried blood spot on day 2 showed elevation of the isobaric pair C4-DC/C5-OH (0.94 and 1.06 µmol/L on initial analysis and repeat; cutoff <0.78 µmol/L). Confirmatory urine organic acids, collected on day 35, showed marked elevation of 3-hydroxy-3-methylglutaric, 3-methylglutaconic, and 3-hydroxyisovaleric acids, consistent with HMG-CoA lyase deficiency (Fig. 1 of the article, total ion chromatogram). The family, informed late on a Friday afternoon and instructed to go to the emergency department in the event of lethargy, vomiting, poor feeding, irritability, hypotonia, or unresponsiveness, brought the child to the emergency department the following weekend, on day 38, with lethargy and projectile vomiting [58].

Lactate was elevated and ammonia normal; on day 39, plasma acylcarnitines showed C5-OH/C3-DC of 0.31 µmol/L (normal <0.07) and C6-DC of 0.39 µmol/L (normal <0.15), and amino acids showed a mildly elevated glycine that rose rapidly during admission (Fig. 2 of the article) [58]. Acute treatment consisted of IV 10% dextrose at 1.5 times maintenance (8 mg/kg/min) and withholding of protein. This was followed by levocarnitine (200 mg/day orally and 450 mg/day from the metabolic formula) and a diet with a leucine-free formula, infant formula to meet leucine requirements, and a carbohydrate-only supplement to reduce fat to about 30% of energy; at 3 months, a synthetic 3-hydroxybutyrate was introduced at about 400 mg/kg/day, with a positive clinical effect according to the parents. At 2 years, the metabolic formula provided 540 kcal, 9.75 g of protein, and 250 mg of leucine, and a vegan diet 18 g/day, for a total protein intake of 28 g/day (1.5 g/kg/day). The sick-day formula provided 540 kcal, 8.25 g of protein, 125 mg of leucine, and 92.97 g of carbohydrate, with dietary protein withheld for 24–48 hours [58].

The genetic workup was the most instructive aspect. A single-nucleotide polymorphism microarray showed regions of homozygosity exceeding 27.6% of the genome, consistent with first- or second-degree parental relatedness, including the HMGCL locus. Targeted HMGCL sequencing, in two laboratories and with deletion/duplication analysis, was negative. Genome sequencing identified a homozygous complex deep intronic variant, c.60+42_60+44delins-708_-478inv, consisting of a 3–base pair deletion with insertion, in inverted orientation, of a duplicated 231–base pair segment located upstream of the gene (diagram in Fig. 3 of the article, accessed at https://pmc.ncbi.nlm.nih.gov/articles/PMC12662037/figure/f0015/). The variant, initially of uncertain significance, was reclassified as likely pathogenic when RNA sequencing showed negligible HMGCL expression (Z = −22.7; reference −2.0 to 2.0), which allowed the PVS1 criterion to be applied according to the ClinGen splicing recommendations [58].

The course up to 3 years included two hospitalisations for gastroenteritis, treated with IV dextrose, carnitine, and the sick-day formula, without acidosis or hypoglycaemia; growth was normal, cognitive development close to that expected for age, with normal motor development and a mild expressive language delay improving with speech therapy, and follow-up was through twice-yearly clinic visits [58]. Plasma glycine remained mildly elevated and C5-OH persistently elevated, unlike C6-DC [58].

The case illustrates three points already described: decompensation can occur in the interval between screening and confirmation, a negative targeted molecular test does not exclude an unequivocal biochemical diagnosis, and RNA studies resolve noncoding variants. Some of the management in this report is not routine in the recommendations: chronic 3-hydroxybutyrate is an off-label use without demonstrated long-term efficacy, and leucine restriction with a leucine-free formula is not adopted by all centres [1, 36].

10.2. Brief cases of the other entities

T2 deficiency detected by Italian screening: a term female newborn (2830 g, 2019) had C5:1 of 0.15 µmol/L (cutoff 0.03), C4DC/C5-OH of 1.01 µmol/L (0.43), and C3DC/C4OH of 3.99 µmol/L (0.50); second-tier testing showed tiglylglycine and 2-methyl-3-hydroxybutyrate and increased D- and L-C4OH enantiomers without C3DC, and molecular analysis identified in ACAT1 (NM_000019.4) the variants c.417del p.(Met141Cysfs*7) and c.472A>G p.(Asn158Asp), with enzyme activity below 1 nmol/(min·mg) (normal 9.00–30.30). With fat and protein control, feeds every 3 hours in the first month, and carnitine, she had a single decompensation with ketonuria during sapovirus gastroenteritis, treated with IV 10% glucose, and at 5 years her examination, growth, and development were normal [44].

Severe SCOT deficiency: a 3-month-old Palestinian infant of consanguineous parents presented after a viral infection with respiratory distress, hypotonia, and hypoactivity, with pH 6.7, bicarbonate 3 mmol/L, and pCO₂ 16.7 mmHg, glucose almost always normal, and persistent ketonuria even when hydrated and fed; he required ventilation for 2 days and remained dependent on IV glucose for weeks, with severe acidosis 12–24 hours after each attempt to stop it, until pancrelipase was introduced with the cornstarch. Exome sequencing identified a homozygous 10,881–base pair deletion of OXCT1 exons 4–7, with healthy heterozygous parents [14].

MCT1 deficiency: a 5-year-old Egyptian boy of nonconsanguineous parents, with three previous crises and isolated speech delay, admitted for drowsiness and refractory vomiting and diarrhoea, had pH 6.8 and bicarbonate 5.2 mmol/L with normal glucose, lactate, and ammonia; sodium bicarbonate in dextrose-containing fluids caused hypokalaemia of 1.7 mmol/L, corrected with potassium and a reduction in bicarbonate, and he recovered within 10 days [68].

HMG-CoA synthase deficiency: a 2480-g Thai female newborn became comatose on day 7 with diarrhoea, glucose 1.1 mmol/L, pH below 6.8, bicarbonate 3.3 mmol/L, ammonia 1081 µmol/L, 3-hydroxybutyrate of 0.2 mmol/L, and urine without ketones; elevated leucine/isoleucine and valine led to a provisional diagnosis of maple syrup urine disease and exchange transfusion. The initial exome was negative; reanalysis with the term "hypoglycaemia" identified homozygosity for p.(Arg501Pro) in HMGCS2, also present in an asymptomatic 13-year-old brother [52].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis by entity

In T2 deficiency, of the 204 survivors with data in the 2020 review, 77.0% had normal development without neurological abnormalities, 2.5% normal cognition with neurological signs (ataxia, hypotonia, choreoathetosis, dystonia, nystagmus), 19.6% developmental delay, mainly motor, and 6.3% movement disorders; seizures outside crises occurred in only two survivors, and mortality was 8.9%, concentrated in the first crisis [12]. The Saudubray chapter estimates that about 20% of patients have some intellectual or neurological problem, including extrapyramidal disorders that can arise without ketoacidosis [1]. Nonneurologic complications are rare (growth delay in some, one alleged fatal cardiomyopathy with limited data) [12]. The course is generally favourable compared with other organic acidurias, provided the fatal risk of the first crisis is controlled [12].

In SCOT deficiency, 2 of 44 patients died and 92% of survivors had normal development; in the Saudi cohort, 2 of 17 died in the first crisis, crises ceased in 73.3% (last crisis at 2–13 years), and neurodevelopment was normal in all [13, 61]. In MCT1 deficiency, all homozygotes described through 2022 had cognitive impairment and/or abnormal neuroimaging, probably unrelated to the crises; in heterozygotes, the prognosis with early diagnosis is generally favourable [1, 26].

In HMG-CoA lyase deficiency, the 2020 review found, among 139 evaluable patients, normal development in 62.6%, mild abnormalities in 6.5%, and overt delay or neurological abnormalities in 31.7% (18 with severe disability), with seizures in 9.0%; mortality was 16.1% [16]. Neurologic problems are more common than in HMG-CoA synthase deficiency, especially in patients with neonatal onset, who also have more recurrent episodes of encephalopathy in late childhood or adulthood [1]. In the Saudi cohort, all were alive, but with seizures in 27.4%, learning difficulties in 24.1%, speech delay in 11.3%, developmental delay in 9.7%, microcephaly in 6.5%, and white matter hyperintensities in 25.8% [17]. In the Australian cohort, intellect was normal in 6 of 9 patients with data, and admissions since diagnosis ranged from 0 to 12 [36].

In HMG-CoA synthase deficiency, 8% of the 75 patients died, mostly in the initial crisis, and 98% of survivors had normal development; most have no further episodes of encephalopathy [1, 18]. In the Vietnamese cohort, all were alive (5 months to 14 years), and 18 of 19 had normal development [49].

In all entities, crisis frequency decreases with age: ketoacidosis is very rare after mid-childhood in ketolytic defects, and no Saudi patient with SCOT deficiency had crises after age 13 except during pregnancy [1, 61]. The relevant exception is HMG-CoA lyase deficiency, with decompensations and deaths described in adulthood [16, 84].

11.2. Surveillance

No published guideline or consensus defines surveillance intervals for these disorders; the sources consulted describe only centre practices (twice-yearly visits in one case, regular micronutrient monitoring on restrictive diets, carnitine monitoring according to the label) [36, 58, 114]. The table brings together the follow-up elements supported by the sources; where no interval has been published, this is stated.

The values and intervals in the table match those of the protocols in section 7; the absence of standardised intervals is a gap in the sources, and surveillance intensity can be reduced with age in ketolytic defects, in which crises become rare, but not in HMG-CoA lyase deficiency [1, 16, 61].

12. Summary and Concluding Remarks

Ketolysis and ketogenesis defects are five rare autosomal recessive disorders that reflect the two sides of ketone body metabolism. T2 (ACAT1), SCOT (OXCT1), and MCT1 (SLC16A1) deficiencies prevent the utilisation or entry of ketone bodies into tissues and manifest, mainly in the first two years, as crises of severe ketoacidosis with generally normal glucose, lactate, and ammonia, triggered by fasting and infection; HMG-CoA lyase (HMGCL) and mitochondrial HMG-CoA synthase (HMGCS2) deficiencies prevent hepatic synthesis and manifest as hypoketotic hypoglycaemia with encephalopathy, acidosis, hepatomegaly, and sometimes hyperammonaemia [1, 2]. OXCT1 and SLC16A1 heterozygotes can have ketoacidosis under stress, and the SLC16A1 gene also causes two dominant allelic disorders, exercise-induced hyperinsulinism and a myopathy due to lactate transporter defect [24, 46, 62].

Diagnosis depends on the critical sample collected during the crisis, before glucose is given, and on joint interpretation of glucose, free fatty acids, and ketone bodies. HMG-CoA lyase deficiency has a diagnostic urinary signature and is a core newborn screening condition in the USA; T2 deficiency has characteristic markers that fail in mild genotypes; SCOT, MCT1, and HMG-CoA synthase deficiencies depend on molecular testing, which should include deletion analysis and, when suspicion persists, genome and RNA sequencing [19, 20, 58, 63]. Founder variants guide testing in specific populations, among them HMGCL p.(Glu37Ter) in Portugal, Spain, and Brazil, p.(Arg41Gln) in Saudi Arabia, and ACAT1 p.(Arg208Ter) in Vietnam [17, 56, 65].

Treatment rests on fasting avoidance, an emergency plan with glucose polymers, and early IV glucose, given even with normal blood glucose, with bicarbonate and insulin according to criteria that differ between the British and North American protocols [53, 72, 94]. Protein restriction, fat restriction, carnitine, and sodium D,L-3-hydroxybutyrate are widely used but supported only by observational evidence, with no registered clinical trials; ketogenic diets are contraindicated [1, 12, 16, 36, 121]. With early diagnosis, most patients with T2, SCOT, or HMG-CoA synthase deficiency have normal development, and crises become rare with age; HMG-CoA lyase deficiency carries a greater burden of neurological sequelae and risk in adulthood and pregnancy, and homozygous MCT1 deficiency is associated with developmental delay independent of crises [1, 12, 13, 16, 18]. There are no formal guidelines or published surveillance intervals, and management relies on emergency protocols, centre practices, and the MetabERN network [22].

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