Methylmalonate Semialdehyde Dehydrogenase Deficiency

Mendelian MONDO:0013579 Pathograph 12 Show in embeddings browser Organic Aciduria Inborn Error of Metabolism

Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency is an ultra-rare autosomal recessive inborn error caused by biallelic variants in ALDH6A1. The enzyme sits at the point where two otherwise separate catabolic routes converge: valine degradation yields (S)-methylmalonate semialdehyde and thymine degradation yields the (R)-enantiomer, and MMSDH oxidatively decarboxylates both to propionyl-CoA. Loss of the enzyme therefore blocks a single shared step of valine and pyrimidine catabolism and produces a characteristic but strikingly inconsistent urinary profile: 3-hydroxyisobutyric acid, 3-hydroxypropionic acid, 3-aminoisobutyric acid, beta-alanine and - in some patients only, and only transiently - methylmalonic acid. The established disorder is biochemical. The clinical picture is not: reported patients range from an entirely healthy newborn-screening ascertainment to severe developmental delay with abnormal myelination, and to death from hepatoencephalopathy after a febrile illness. Fewer than a dozen molecularly confirmed patients have been published, none with segregation data, and the ClinGen Aminoacidopathy Gene Curation Expert Panel classifies the ALDH6A1-disease relationship as Limited. This entry therefore models the enzymatic block and its metabolite consequences as established, and keeps the neurological, hepatic and mitochondrial findings on deliberately detached, low-confidence branches. Not to be confused with HIBADH deficiency, the other primary cause of 3-hydroxyisobutyric aciduria, which blocks the immediately upstream step of the same valine pathway.

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1
Inheritance
6
Pathophys.
12
Phenotypes
2
Gaps
12
Pathograph
1
Genes
1
Medical Actions
3
Differentials
8
References
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
organic acidurias branched chain amino acids
👪

Inheritance

1
Autosomal recessive inheritance with unresolved clinical penetrance HP:0000007
Reported patients are homozygous or compound heterozygous for ALDH6A1 missense variants, several of them ascertained through consanguineous unions. Biallelic variants establish the biochemical phenotype, but do not predict clinical outcome: the index patient of the original 1985 report was developing normally at four years of age, while other biallelic patients have had severe developmental delay or died in early childhood. No segregation evidence is available in any published family.
Autosomal recessive inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE
Show evidence (3 references)
PMID:23835272 SUPPORT Human Clinical
"Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency is a rare autosomal recessive disorder with varied metabolite abnormalities"
Establishes autosomal recessive inheritance for the disorder.
PMID:3939535 SUPPORT Human Clinical
"The patient is now aged 4 years and has developed normally."
The first reported patient was biochemically affected but clinically normal, supporting incomplete clinical penetrance.
CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z SUPPORT Other
"No supporting segregation information is available."
Records that no published family provides segregation evidence for the inheritance model.
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Discussions and Knowledge Gaps

2
Do the neurological, hepatic and growth findings reported in ALDH6A1 patients arise from the enzyme deficiency, or are they ascertainment artefacts of investigating children who were referred for those problems?
KNOWLEDGE GAP OPEN gap_mmsdh_clinical_causality
Attached to
pathophysiology#Reported neurological association of uncertain causality phenotypes#Global developmental delay phenotypes#Abnormal myelination phenotypes#Hepatic encephalopathy
Every reported patient bar one was ascertained because of a clinical problem, and the exception - the 1985 index patient, found through newborn screening for an unrelated reason - was developing normally at four years. With fewer than ten molecularly confirmed patients, no segregation data and no population screening, the disorder's clinical penetrance is not estimable and the direction of the association cannot be resolved. ClinGen's Limited classification rests on exactly this ambiguity.
Proposed experiments
Unbiased ascertainment through untargeted metabolomic screening
exp_mmsdh_unbiased_ascertainment
Identify ALDH6A1 biallelic individuals from large unselected biobank and newborn-screening metabolomic datasets rather than from clinical referral, then phenotype them with standardized developmental, hepatic and neuroimaging assessments against variant-negative relatives. This is the only design that can separate the disorder's true clinical spectrum from referral bias.
Show evidence (2 references)
CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z SUPPORT Other
"In summary, there is limited evidence to support this gene-disease relationship."
The expert-panel classification that frames this gap.
CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z SUPPORT Other
"Although more evidence, genetic and experimental, is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship."
States precisely that the causal role is unestablished rather than refuted.
Why does a single, well-defined enzymatic block produce a different metabolite profile in every reported patient, and what determines which metabolites accumulate in a given individual?
KNOWLEDGE GAP OPEN gap_mmsdh_metabolite_variability
Attached to
pathophysiology#Accumulation of upstream valine- and thymine-pathway metabolites phenotypes#Methylmalonic aciduria
Among molecularly confirmed patients the clinical and biochemical phenotype is highly variable: methylmalonic acid has been persistent in some, transient in another, and absent in others, and the fifth reported case diverges clinically from the earlier ones. Residual enzyme activity, relative valine versus thymine flux, and the observed dissociation between plasma and urinary beta-alanine are all candidate explanations, none tested. The three earliest reported patients also had essentially non-overlapping urinary profiles, but only the first of those was confirmed at the cDNA level, so that particular contrast is at least as consistent with three different disorders as with variability within this one and is not the basis of this gap. The practical consequence is that the disorder has no reliable biochemical screening signature.
Proposed experiments
Residual-activity and stable-isotope flux correlation across genotypes
exp_mmsdh_flux_genotype_correlation
Express each reported ALDH6A1 missense allele, measure residual activity against both (R)- and (S)-methylmalonate semialdehyde, and pair this with stable-isotope valine and thymine flux studies in patient fibroblasts. Testing whether allele-specific enantiomer preference predicts the individual metabolite profile would convert an unexplained heterogeneity into a genotype-phenotype rule.
Show evidence (3 references)
PMID:23835272 SUPPORT Human Clinical
"highly variable clinical and biochemical phenotype"
States the variability directly, in a report whose own case is confirmed by biallelic ALDH6A1 variants and reduced MMSDH enzyme activity.
PMID:32151545 SUPPORT Human Clinical
"clinical phenotypes diverge from prior cases"
A second molecularly confirmed case whose phenotype diverges from the earlier ones.
PMID:32151545 SUPPORT Human Clinical
"Plasma amino acids showed an elevated concentration of β-aminoisobutyrate with undetectable β-alanine."
Documents a plasma/urine dissociation that any explanation of the variability must account for.
⚙

Pathophysiology

6
ALDH6A1-dependent methylmalonate semialdehyde dehydrogenase deficiency
Mechanism confidence: Established
Biallelic ALDH6A1 variants reduce or abolish the activity of mitochondrial methylmalonate semialdehyde dehydrogenase. Six missense alleles affecting residues conserved across mammals have been reported. Direct enzymatic confirmation was historically impossible because the substrate is too unstable to assay; the first successful fibroblast assay was reported in 2013, and reduced protein has separately been shown by Western blot.
ALDH6A1 hgnc:7179 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALDH6A1 (hgnc:7179). hgnc:7179 is a gene from the HUGO Gene Nomenclature Committee.
methylmalonate-semialdehyde dehydrogenase activity GO:0004491 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased methylmalonate-semialdehyde dehydrogenase activity, annotated with methylmalonate-semialdehyde dehydrogenase (acylating, NAD) activity (GO:0004491). GO:0004491 is a molecular function from the Gene Ontology. ↓ DECREASED
mitochondrial matrix GO:0005759 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves mitochondrial matrix (GO:0005759). GO:0005759 is a cellular component from the Gene Ontology.
Downstream
Convergent block of valine and thymine catabolism Loss of enzyme activity blocks the single reaction that both catabolic routes must pass through.
Show evidence (4 references)
CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z SUPPORT Other
"The disease mechanism appears to be biallelic loss-of-function, with a deficiency in the MMSDH protein leading to an increase in valine metabolites such as 3-hydroxyisobutyric acid"
ClinGen expert-panel statement of the biallelic loss-of-function disease mechanism.
PMID:23835272 SUPPORT In Vitro
"Subsequent MMSDH enzyme assay demonstrated reduced activity in patient fibroblasts, measuring 2.5 standard deviations below the mean."
First direct demonstration of reduced MMSDH enzyme activity in a molecularly confirmed patient.
PMID:32151545 SUPPORT In Vitro
"Western blotting of patient fibroblast extracts demonstrated a large reduction of methylmalonate semialdehyde dehydrogenase (MMSD) protein."
Independent protein-level confirmation of enzyme deficiency.
+ 1 more reference
Convergent block of valine and thymine catabolism
Mechanism confidence: Established
MMSDH is the convergence point of two independent catabolic routes. Valine degradation produces (S)-3-hydroxyisobutyric acid, which 3-hydroxyisobutyrate dehydrogenase oxidizes to (S)-methylmalonate semialdehyde; thymine degradation produces (R)-3-aminoisobutyric acid, which is deaminated to the (R)-enantiomer. MMSDH oxidatively decarboxylates both enantiomers to propionyl-CoA, and both are affected by the deficiency. Because one enzyme serves two pathways, the disorder is simultaneously an aminoacidopathy and a pyrimidine-catabolism defect - which is why the urine profile mixes valine-derived and thymine-derived metabolites.
L-valine catabolic process GO:0006574 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased L-valine catabolic process (GO:0006574). GO:0006574 is a biological process from the Gene Ontology. ↓ DECREASED thymine catabolic process GO:0006210 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased thymine catabolic process (GO:0006210). GO:0006210 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Accumulation of upstream valine- and thymine-pathway metabolites Substrate and precursor metabolites upstream of the block accumulate and are excreted.
Semialdehyde shunting toward beta-alanine and malonyl-CoA Blocked semialdehyde is proposed to be diverted into an alternative disposal route rather than simply accumulating.
Show evidence (3 references)
PMID:32151545 SUPPORT Human Clinical
"Methylmalonate semialdehyde dehydrogenase deficiency (MMSDD; MIM 614105) is a rare autosomal recessive defect of valine and pyrimidine catabolism."
Establishes that the single enzyme block affects both valine and pyrimidine catabolism.
PMID:23835272 SUPPORT Other
"Metabolism of valine produces the intermediate (S)-3-hydroxyisobutyric acid (HIBA), which is oxidized to (S)-methylmalonic semialdehyde"
States the valine-derived arm feeding the blocked reaction.
PMID:3939535 SUPPORT Human Clinical
"both R- and S-methylmalonic semialdehydes seem to be equally affected"
Supports that the deficiency affects both enantiomeric substrates, i.e. both feeder pathways.
Accumulation of upstream valine- and thymine-pathway metabolites
Mechanism confidence: Established
The block produces a composite organic aciduria and aminoaciduria drawing on both feeder pathways: 3-hydroxyisobutyric and 3-hydroxypropionic acids, 3-aminoisobutyric acid and beta-alanine. Methylmalonic acid is elevated in some patients only, and in the one patient in whom it was followed longitudinally it was transient rather than persistent. The single most important curation caveat for this disorder is that the metabolite pattern has differed in essentially every reported patient, so no fixed profile can be treated as diagnostic. Whether any of these metabolites is toxic is unknown, which is why this node is not linked to a toxic-metabolite or energy-deficit mechanism.
Downstream
Elevated urinary 3-hydroxyisobutyric acid 3-Hydroxyisobutyric aciduria is the most consistent biochemical expression of the block and the finding that has prompted diagnosis in every reported patient.
Methylmalonic aciduria Methylmalonic acid is raised in a minority of patients and may be transient, which is why it cannot be used to rule the diagnosis in or out.
Show evidence (3 references)
PMID:23835272 SUPPORT Human Clinical
"varied metabolite abnormalities, including accumulation of 3-hydroxyisobutyric, 3-hydroxypropionic, 3-aminoisobutyric and methylmalonic acids, as well as β-alanine"
Enumerates the accumulating metabolites and flags their variability.
PMID:10947204 SUPPORT Human Clinical
"The urine metabolic pattern was strikingly different in all, including beta-alanine, 3-hydroxypropionic acid, both isomers of 3-amino- and 3-hydroxyisobutyric acids in one and 3-hydroxyisobutyric and lactic acids in a second, and mild methylmalonic aciduria in a third patient."
Documents the disparate urinary profiles of the three earliest reported patients. Read narrowly: the same report found MMSDH coding-region alterations in the first patient only, so the second and third patients are not molecularly confirmed and their profiles cannot be attributed to this enzyme block. Cited for the first patient's composite profile, not as a measure of within-disease variability; see PMID:23835272 and PMID:32151545 for variability among confirmed cases.
PMID:32151545 SUPPORT Human Clinical
"Urine organic acid assessment identified excess 3-hydroxyisobutyrate and 3-hydroxypropionate, while urine amino acid analysis identified elevated concentrations of β-aminoisobutyrate and β-alanine."
Independent confirmation of the composite organic-acid and amino-acid pattern.
Semialdehyde shunting toward beta-alanine and malonyl-CoA
Mechanism confidence: Provisional
Metabolomic profiling of fibroblasts from one patient found an over-representation of fatty acids and acylcarnitines. The authors proposed that blocked methylmalonate semialdehyde is diverted to beta-alanine and then to malonyl-CoA, increasing fatty acid synthesis. This is an inference from a metabolite pattern in a single patient's cells, not a demonstrated flux, so the node is provisional and is not used to explain any clinical finding.
Show evidence (1 reference)
PMID:32151545 SUPPORT In Vitro
"Metabolomic profiles from patient fibroblasts demonstrated over-representation of fatty acids and fatty acylcarnitines"
The observed metabolomic finding; the shunt itself is an interpretation the authors hedge as presumptive.
Fibroblast mitochondrial dysfunction
Mechanism confidence: Provisional
Fibroblasts from one patient showed increased superoxide production, reduced oxygen consumption and reduced ATP production. The authors note this as a finding worth checking in future patients rather than an established component of the disease. It is one plausible bridge between the enzymatic block and the neurological findings, but nothing links the two directly, so no causal edge to the clinical arm is asserted here.
Show evidence (2 references)
PMID:32151545 SUPPORT In Vitro
"Patient cells displayed compromised mitochondrial function with increased superoxide production, reduced oxygen consumption, and reduced ATP production."
Single-patient in vitro observation of mitochondrial dysfunction.
PMID:32151545 SUPPORT In Vitro
"Recognition of mitochondrial dysfunction and novel metabolites in this patient provide the opportunity to assess future patients for secondary changes that may influence clinical outcome."
The authors themselves frame the finding as a hypothesis to be tested in future patients.
Reported neurological association of uncertain causality
Mechanism confidence: Hypothetical
Developmental delay and, in one patient, abnormal myelination on brain MRI have been reported in molecularly confirmed patients. No mechanism connects the accumulating metabolites to neuronal or myelin injury, and other biallelic patients have been neurologically normal - the first reported patient was developing normally at four years, and the fifth had a normal brain MRI. ClinGen explicitly leaves open whether the extra-biochemical symptoms belong to the disorder. This node is deliberately detached from the established biochemical chain and must not be read as a mechanism.
brain white matter UBERON:0003544 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain white matter (UBERON:0003544). UBERON:0003544 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (3 references)
PMID:23835272 SUPPORT Human Clinical
"We report a child with severe developmental delays, abnormal myelination on brain MRI"
Case-level association of the genotype with delay and abnormal myelination.
CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z SUPPORT Other
"There is the question of whether the additional symptoms of some individuals are related to this disorder, although that is unrelated to the biochemical abnormality and the response to modified diet seems to indicate a connection."
Expert-panel statement that causal attribution of the clinical symptoms is unresolved. Quoted in full so the panel's own counterweight - the reported response to a modified diet - travels with the uncertainty rather than being cut at the comma.
PMID:32151545 REFUTE Human Clinical
"She was nondysmorphic, had a normal brain MRI, and showed mild hypotonia."
Counterexample - a molecularly confirmed patient without the neuroimaging abnormality.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Methylmalonate Semialdehyde Dehydrogenase Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

12
Digestive 1
Gastroesophageal reflux HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32151545 SUPPORT Human Clinical
"Gastroesophageal reflux occurred with feeding."
Documents reflux in one patient.
Genitourinary 5
Elevated urinary 3-hydroxyisobutyric acid Elevated urinary 3-hydroxyisobutyric acid level HP:6000607 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated urinary 3-hydroxyisobutyric acid level (HP:6000607). HP:6000607 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21863277 SUPPORT Human Clinical
"We present two unrelated patients who presented with developmental delay and increased urinary concentrations of 3-hydroxyisobutyric acid."
Documents the phenotype in two molecularly confirmed patients.
PMID:21863277 SUPPORT Human Clinical
"which may present with only slightly increased urinary levels of 3-hydroxyisobutyric acid, if a patient is metabolically stable"
Establishes that the magnitude of elevation is state-dependent.
Elevated urinary 3-hydroxypropionic acid Elevated urine 3-hydroxypropionic acid level HP:0034661 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated urine 3-hydroxypropionic acid level (HP:0034661). HP:0034661 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32151545 SUPPORT Human Clinical
"Urine organic acid assessment identified excess 3-hydroxyisobutyrate and 3-hydroxypropionate"
Documents 3-hydroxypropionate elevation in a molecularly confirmed patient.
Beta-aminoisobutyric aciduria Elevated urinary 3-aminoisobutyric acid HP:0045034 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated urinary 3-aminoisobutyric acid (HP:0045034). HP:0045034 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23835272 SUPPORT Human Clinical
"accumulation of 3-hydroxyisobutyric, 3-hydroxypropionic, 3-aminoisobutyric and methylmalonic acids"
Lists 3-aminoisobutyric acid among the accumulating metabolites.
Beta-alaninuria HP:0020079 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Beta-alaninuria (HP:0020079). HP:0020079 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:3939535 SUPPORT Human Clinical
"A new metabolic disorder characterised by the excessive excretion of beta-alanine, 3-hydroxypropionic acid, R- and S-3-amino- and 3-hydroxyisobutyric acids"
The original description of the biochemical phenotype, including beta-alanine excretion.
Methylmalonic aciduria HP:0012120 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Methylmalonic aciduria (HP:0012120). HP:0012120 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23835272 SUPPORT Human Clinical
"transient/variable elevations in lactate, methylmalonic acid, 3-hydroxyisobutyric and 3-aminoisobutyric acids"
Methylmalonic aciduria in a patient with biallelic ALDH6A1 variants confirmed by exome and Sanger sequencing and a corresponding reduction in MMSDH enzyme activity, so the finding is attributable to this disorder. The earlier PMID:10947204 patient with mild methylmalonic aciduria is not cited here: that report states "No abnormalities of the MMSDH cDNA were detected in the other patients", so the case is not molecularly confirmed.
Metabolism 1
Increased circulating lactate concentration HP:0002151 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating lactate concentration (HP:0002151). HP:0002151 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23835272 SUPPORT Human Clinical
"transient/variable elevations in lactate, methylmalonic acid, 3-hydroxyisobutyric and 3-aminoisobutyric acids"
Documents transient lactate elevation.
Musculoskeletal 1
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32151545 SUPPORT Human Clinical
"She was nondysmorphic, had a normal brain MRI, and showed mild hypotonia."
Documents mild hypotonia in one patient.
Nervous System 3
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21863277 SUPPORT Human Clinical
"We present two unrelated patients who presented with developmental delay and increased urinary concentrations of 3-hydroxyisobutyric acid."
Case-level evidence for developmental delay in two patients.
PMID:3939535 REFUTE Human Clinical
"The patient is now aged 4 years and has developed normally."
A biallelic patient with normal development; prevents treating delay as a disease-wide phenotype.
Abnormal myelination HP:0012447 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal myelination (HP:0012447). HP:0012447 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23835272 SUPPORT Human Clinical
"We report a child with severe developmental delays, abnormal myelination on brain MRI"
Single-case report of abnormal myelination.
PMID:32151545 REFUTE Human Clinical
"She was nondysmorphic, had a normal brain MRI, and showed mild hypotonia."
A molecularly confirmed patient with a normal brain MRI, which argues against treating abnormal myelination as an established phenotype of the disorder rather than a single-case finding.
Hepatic encephalopathy HP:0002480 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatic encephalopathy (HP:0002480). HP:0002480 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21863277 SUPPORT Human Clinical
"One patient developed a febrile illness and subsequently died from a hepatoencephalopathy at 2 years of age."
The single reported fatal outcome.
Growth 1
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32151545 SUPPORT Human Clinical
"was admitted at two weeks of age for failure to thrive"
Documents failure to thrive as the presenting problem in one patient.
🧬

Genetic Associations

1
Biallelic ALDH6A1 missense variants
Gene: ALDH6A1 hgnc:7179 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ALDH6A1 (hgnc:7179). hgnc:7179 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (6 references)
PMID:10947204 SUPPORT Human Clinical
"revealing homozygosity for a 1336G > A transversion, which leads to substitution of arginine for highly conserved glycine at amino acid 446"
The first molecularly characterized allele.
PMID:21863277 SUPPORT Human Clinical
"suggested homozygosity for the missense mutation c.785 C > A (S262Y) in exon 7 which was not found in 210 control alleles"
Second reported allele, with control-cohort screening.
PMID:21863277 SUPPORT Human Clinical
"a different missense mutation, c.184 C > T (P62S), which was also identified in 1/530 control chromosomes"
Records the control-chromosome observation that tempers the pathogenicity claim for this allele.
+ 3 more references
💊

Medical Actions

1
Valine-restricted diet
Action: dietary interventionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is dietary intervention (NCIT:C15447). NCIT:C15447 is a clinical intervention from the NCI Thesaurus. Ontology label: Dietary Intervention NCIT:C15447
Platform: Behavioral / lifestyle
Restriction of dietary valine reduces substrate flux into the blocked pathway. In the one patient in whom it has been reported in detail it reduced the abnormal analytes and was accompanied by improved growth and reduced reflux. This is a single uncontrolled observation, not demonstrated efficacy, and there is no evidence at all bearing on whether it alters neurological outcome.
Mechanism Target:
MODULATES Accumulation of upstream valine- and thymine-pathway metabolites — Limiting valine intake reduces flux into the valine-derived arm of the block and lowers the accumulating metabolites. It cannot address the thymine-derived arm.
Show evidence (1 reference)
PMID:32151545 SUPPORT Human Clinical
"Management with valine restriction led to reduced concentration of abnormal analytes in blood and urine"
Single-patient evidence that the intervention lowers the target metabolites.
Show evidence (1 reference)
PMID:32151545 SUPPORT Human Clinical
"improved growth, and reduced gastroesophageal reflux"
The accompanying clinical improvement, uncontrolled and in one patient only.
🔬

Biochemical Markers

4
Urinary 3-hydroxyisobutyric acid (INCREASED)
Context: The most consistent analyte; magnitude depends on metabolic state.
Pathograph Readouts
Readout Of Accumulation of upstream valine- and thymine-pathway metabolites Positive Diagnostic
Increased urinary 3-hydroxyisobutyrate is the principal readout of the valine-derived arm of the block.
Show evidence (1 reference)
PMID:32151545 SUPPORT Human Clinical
"Urine organic acid assessment identified excess 3-hydroxyisobutyrate and 3-hydroxypropionate"
Establishes the analyte and its direction.
Urinary 3-hydroxypropionic acid (INCREASED)
Context: Accompanies 3-hydroxyisobutyrate in several patients.
Pathograph Readouts
Readout Of Accumulation of upstream valine- and thymine-pathway metabolites Positive Diagnostic
A secondary organic-acid readout of the same block.
Show evidence (1 reference)
CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z SUPPORT Other
"persistently elevated 3-hydroxypropionate, 3-hydroxyisobutyrate, and β-aminoisobutyrate levels in patients with this condition"
ClinGen records persistent elevation of this analyte in affected patients.
Beta-aminoisobutyric acid (INCREASED)
Context: Elevated in both plasma and urine; the readout that distinguishes this disorder from a pure valine-pathway defect.
Pathograph Readouts
Readout Of Convergent block of valine and thymine catabolism Positive Diagnostic
Elevated beta-aminoisobutyrate reports the thymine-derived arm of the block, which an isolated valine-pathway defect such as HIBADH deficiency would not produce.
Show evidence (1 reference)
PMID:32151545 SUPPORT Human Clinical
"Plasma amino acids showed an elevated concentration of β-aminoisobutyrate with undetectable β-alanine."
Documents plasma elevation of beta-aminoisobutyrate, with the notable dissociation from beta-alanine.
Beta-alanine (INCREASED)
Context: Urinary excretion is elevated, but plasma beta-alanine was undetectable in the one patient in whom both were measured, so the compartments must not be conflated.
Pathograph Readouts
Readout Of Accumulation of upstream valine- and thymine-pathway metabolites Positive Diagnostic
Urinary beta-alanine excretion is part of the original biochemical signature of the disorder.
Show evidence (1 reference)
PMID:32151545 SUPPORT Human Clinical
"urine amino acid analysis identified elevated concentrations of β-aminoisobutyrate and β-alanine"
Documents urinary beta-alanine elevation.
🔬

Diagnosis

3
Urine organic acid and amino acid analysis
The entry point to diagnosis. Urine organic acids show 3-hydroxyisobutyrate with variable 3-hydroxypropionate and methylmalonate; urine and plasma amino acids show beta-aminoisobutyrate and beta-alanine. Because the profile differs between patients and elevations can be mild in a stable patient, a normal-looking screen does not exclude the diagnosis.
urine organic acid analysis
Results: Composite organic aciduria with beta-aminoisobutyrate and beta-alanine; the pattern is variable between patients and over time.
Show evidence (1 reference)
PMID:32151545 SUPPORT Human Clinical
"Urine organic acid assessment identified excess 3-hydroxyisobutyrate and 3-hydroxypropionate, while urine amino acid analysis identified elevated concentrations of β-aminoisobutyrate and β-alanine."
Describes the biochemical work-up that identified the disorder.
ALDH6A1 sequencing
Sequencing ALDH6A1 is the practical confirmatory test, and for three decades it was the only one available, because the substrate instability made the enzyme assay impracticable. Exome sequencing has been the route to diagnosis where the biochemical picture was ambiguous.
molecular genetic testing
Results: Biallelic ALDH6A1 missense variants.
Show evidence (2 references)
PMID:21863277 SUPPORT Human Clinical
"Mutation analysis in the ALDH6A1 gene can reveal a cause of 3-hydroxyisobutyric aciduria"
Establishes gene sequencing as the diagnostic route.
PMID:23835272 SUPPORT Human Clinical
"Compound heterozygous mutations were identified by exome sequencing and confirmed by Sanger sequencing"
Documents exome sequencing as the diagnostic modality in a clinically ambiguous case.
MMSDH enzyme assay in cultured fibroblasts
Available only in specialist laboratories. Long considered impossible because methylmalonate semialdehyde is too unstable; a working fibroblast assay was first reported in 2013 and showed activity 2.5 standard deviations below the mean, which is a reduction rather than an absence.
enzyme activity assay
Results: Reduced MMSDH activity in cultured fibroblasts.
Show evidence (1 reference)
PMID:23835272 SUPPORT In Vitro
"Furthermore, this is the first report to demonstrate a corresponding reduction in MMSDH enzyme activity."
Establishes the enzyme assay as a confirmatory test and dates its first successful use.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population rate has been estimated. Case counts are the only available measure and differ between sources depending on whether biochemically suspected but molecularly unconfirmed patients are counted. ClinGen's 2026 reevaluation counted at least five probands across four publications.
Show evidence (2 references)
CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z SUPPORT Other
"Variants in this gene have been reported in at least 5 probands in 4 publications"
Provides the most recent curated count of molecularly confirmed probands.
PMID:32151545 SUPPORT Human Clinical
"Four prior MMSDD cases are published."
Independently confirms the single-digit published case count as of 2020.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Methylmalonate Semialdehyde Dehydrogenase Deficiency:

HIBADH deficiency
Overlapping Features The other primary cause of 3-hydroxyisobutyric aciduria. HIBADH catalyses the immediately upstream step of the same valine pathway, so the two disorders produce overlapping urinary 3-hydroxyisobutyrate. The discriminators are that HIBADH deficiency does not affect thymine catabolism (so beta-aminoisobutyrate and beta-alanine should not be raised) and that HIBADH enzyme activity is normal in MMSDH deficiency. Measuring HIBADH activity is exactly how MMSDH deficiency was established in two of the reported patients.
Show evidence (2 references)
PMID:35174513 SUPPORT Human Clinical
"the only previously recognized primary cause had been a deficiency of methylmalonic semialdehyde dehydrogenase, the enzyme that is immediately downstream of HIBADH in the valine catabolic pathway and is encoded by the ALDH6A1 gene"
States the precise pathway relationship between the two differential diagnoses.
PMID:21863277 SUPPORT In Vitro
"included tests of the HIBADH enzyme in fibroblast homogenates, which yielded normal activities"
Documents the enzymatic discrimination between the two disorders.
Other causes of 3-hydroxyisobutyric aciduria
Overlapping Features 3-Hydroxyisobutyric aciduria is a biochemical finding with several mechanisms, not a disease. Respiratory-chain defects are an established alternative cause, so an isolated 3-hydroxyisobutyrate elevation should not be equated with an ALDH6A1 defect.
Show evidence (1 reference)
PMID:21863277 SUPPORT Human Clinical
"individuals with 3-hydroxyisobutyryic aciduria represent a heterogeneous group with different underlying mechanisms, including respiratory chain defects or deficiency of methylmalonate semialdehyde dehydrogenase"
Establishes the heterogeneous causation of the presenting biochemical finding.
Classical methylmalonic acidemia
Overlapping Features Patients with the methylmalonic-aciduria variant of the MMSDH phenotype can be mistaken for methylmalonyl-CoA mutase or cobalamin-pathway disorders. In MMSDH deficiency the methylmalonate elevation is mild and may be transient, and it is accompanied by 3-hydroxyisobutyrate and beta-aminoisobutyrate, which the classical methylmalonic acidemias do not produce.
Show evidence (1 reference)
PMID:23835272 SUPPORT Human Clinical
"transient/variable elevations in lactate, methylmalonic acid, 3-hydroxyisobutyric and 3-aminoisobutyric acids"
Shows the co-occurring metabolites that separate this disorder from classical methylmalonic acidemia.
{ }

Source YAML

click to show 
name: Methylmalonate Semialdehyde Dehydrogenase Deficiency
creation_date: '2026-08-18T00:00:00Z'
category: Mendelian
synonyms:
- MMSDH deficiency
- MMSDD
- MMSDHD
- ALDH6A1 deficiency
- Methylmalonic semialdehyde dehydrogenase deficiency
- Developmental delay due to methylmalonate semialdehyde dehydrogenase deficiency
description: >-
  Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency is an ultra-rare
  autosomal recessive inborn error caused by biallelic variants in ALDH6A1. The
  enzyme sits at the point where two otherwise separate catabolic routes
  converge: valine degradation yields (S)-methylmalonate semialdehyde and
  thymine degradation yields the (R)-enantiomer, and MMSDH oxidatively
  decarboxylates both to propionyl-CoA. Loss of the enzyme therefore blocks a
  single shared step of valine and pyrimidine catabolism and produces a
  characteristic but strikingly inconsistent urinary profile: 3-hydroxyisobutyric
  acid, 3-hydroxypropionic acid, 3-aminoisobutyric acid, beta-alanine and - in
  some patients only, and only transiently - methylmalonic acid.

  The established disorder is biochemical. The clinical picture is not: reported
  patients range from an entirely healthy newborn-screening ascertainment to
  severe developmental delay with abnormal myelination, and to death from
  hepatoencephalopathy after a febrile illness. Fewer than a dozen molecularly
  confirmed patients have been published, none with segregation data, and the
  ClinGen Aminoacidopathy Gene Curation Expert Panel classifies the
  ALDH6A1-disease relationship as Limited. This entry therefore models the
  enzymatic block and its metabolite consequences as established, and keeps the
  neurological, hepatic and mitochondrial findings on deliberately detached,
  low-confidence branches.

  Not to be confused with HIBADH deficiency, the other primary cause of
  3-hydroxyisobutyric aciduria, which blocks the immediately upstream step of
  the same valine pathway.
classifications:
  icimd_category:
  - classification_value: organic_acidurias
    notes: >-
      MONDO places methylmalonate semialdehyde dehydrogenase deficiency under
      inborn organic aciduria, and the presenting abnormality is an organic
      aciduria on urine organic-acid analysis.
    evidence:
    - reference: PMID:21863277
      reference_title: 3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 3-hydroxyisobutyric aciduria is an organic aciduria with a poorly understood biochemical basis.
      explanation: Classifies the presenting biochemical abnormality as an organic aciduria.
  - classification_value: branched_chain_amino_acids
    notes: >-
      The enzyme block is on the L-valine catabolic pathway, placing the
      disorder among the branched-chain amino acid disorders as well.
    evidence:
    - reference: PMID:10947204
      reference_title: Molecular characterization of methylmalonate semialdehyde dehydrogenase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These data provide the first molecular characterization of an inborn
        error of metabolism specific to the L-valine catabolic pathway.
      explanation: Places the disorder specifically in branched-chain (valine) amino acid catabolism.
disease_term:
  preferred_term: methylmalonate semialdehyde dehydrogenase deficiency
  term:
    id: MONDO:0013579
    label: methylmalonate semialdehyde dehydrogenase deficiency
parents:
- Organic Aciduria
- Inborn Error of Metabolism
inheritance:
- name: Autosomal recessive inheritance with unresolved clinical penetrance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    Reported patients are homozygous or compound heterozygous for ALDH6A1
    missense variants, several of them ascertained through consanguineous
    unions. Biallelic variants establish the biochemical phenotype, but do not
    predict clinical outcome: the index patient of the original 1985 report was
    developing normally at four years of age, while other biallelic patients
    have had severe developmental delay or died in early childhood. No
    segregation evidence is available in any published family.
  evidence:
  - reference: PMID:23835272
    reference_title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency is a rare
      autosomal recessive disorder with varied metabolite abnormalities
    explanation: Establishes autosomal recessive inheritance for the disorder.
  - reference: PMID:3939535
    reference_title: Excessive excretion of beta-alanine and of 3-hydroxypropionic, R- and S-3-aminoisobutyric, R- and S-3-hydroxyisobutyric and S-2-(hydroxymethyl)butyric acids probably due to a defect in the metabolism of the corresponding malonic semialdehydes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient is now aged 4 years and has developed normally.
    explanation: The first reported patient was biochemically affected but clinically normal, supporting incomplete clinical penetrance.
  - reference: CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z
    reference_title: ALDH6A1 / methylmalonate semialdehyde dehydrogenase deficiency (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: No supporting segregation information is available.
    explanation: Records that no published family provides segregation evidence for the inheritance model.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population rate has been estimated. Case counts are the only available
    measure and differ between sources depending on whether biochemically
    suspected but molecularly unconfirmed patients are counted. ClinGen's 2026
    reevaluation counted at least five probands across four publications.
  evidence:
  - reference: CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z
    reference_title: ALDH6A1 / methylmalonate semialdehyde dehydrogenase deficiency (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Variants in this gene have been reported in at least 5 probands in 4 publications
    explanation: Provides the most recent curated count of molecularly confirmed probands.
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Four prior MMSDD cases are published.
    explanation: Independently confirms the single-digit published case count as of 2020.
pathophysiology:
- name: ALDH6A1-dependent methylmalonate semialdehyde dehydrogenase deficiency
  conforms_to: metabolic_intoxication_decompensation#Enzymatic Block in Intermediary Metabolism
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Biallelic ALDH6A1 variants reduce or abolish the activity of mitochondrial
    methylmalonate semialdehyde dehydrogenase. Six missense alleles affecting
    residues conserved across mammals have been reported. Direct enzymatic
    confirmation was historically impossible because the substrate is too
    unstable to assay; the first successful fibroblast assay was reported in
    2013, and reduced protein has separately been shown by Western blot.
  genes:
  - preferred_term: ALDH6A1
    term:
      id: hgnc:7179
      label: ALDH6A1
  molecular_functions:
  - preferred_term: methylmalonate-semialdehyde dehydrogenase activity
    term:
      id: GO:0004491
      label: methylmalonate-semialdehyde dehydrogenase (acylating, NAD) activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  evidence:
  - reference: CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z
    reference_title: ALDH6A1 / methylmalonate semialdehyde dehydrogenase deficiency (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The disease mechanism appears to be biallelic loss-of-function, with a
      deficiency in the MMSDH protein leading to an increase in valine
      metabolites such as 3-hydroxyisobutyric acid
    explanation: ClinGen expert-panel statement of the biallelic loss-of-function disease mechanism.
  - reference: PMID:23835272
    reference_title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Subsequent MMSDH enzyme assay demonstrated reduced activity in patient
      fibroblasts, measuring 2.5 standard deviations below the mean.
    explanation: First direct demonstration of reduced MMSDH enzyme activity in a molecularly confirmed patient.
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Western blotting of patient fibroblast extracts demonstrated a large
      reduction of methylmalonate semialdehyde dehydrogenase (MMSD) protein.
    explanation: Independent protein-level confirmation of enzyme deficiency.
  - reference: PMID:23835272
    reference_title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Confirmation by enzyme assay has until now not been possible, due to the
      extreme instability of the enzyme substrate.
    explanation: Explains why enzymatic confirmation was unavailable for the first three decades of reported cases.
  downstream:
  - target: Convergent block of valine and thymine catabolism
    description: >-
      Loss of enzyme activity blocks the single reaction that both catabolic
      routes must pass through.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:10947204
      reference_title: Molecular characterization of methylmalonate semialdehyde dehydrogenase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These data provide the first molecular characterization of an inborn
        error of metabolism specific to the L-valine catabolic pathway.
      explanation: Links the molecular lesion directly to a block of the valine catabolic pathway.
- name: Convergent block of valine and thymine catabolism
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    MMSDH is the convergence point of two independent catabolic routes. Valine
    degradation produces (S)-3-hydroxyisobutyric acid, which 3-hydroxyisobutyrate
    dehydrogenase oxidizes to (S)-methylmalonate semialdehyde; thymine
    degradation produces (R)-3-aminoisobutyric acid, which is deaminated to the
    (R)-enantiomer. MMSDH oxidatively decarboxylates both enantiomers to
    propionyl-CoA, and both are affected by the deficiency. Because one enzyme
    serves two pathways, the disorder is simultaneously an aminoacidopathy and a
    pyrimidine-catabolism defect - which is why the urine profile mixes
    valine-derived and thymine-derived metabolites.
  biological_processes:
  - preferred_term: L-valine catabolic process
    term:
      id: GO:0006574
      label: L-valine catabolic process
    modifier: DECREASED
  - preferred_term: thymine catabolic process
    term:
      id: GO:0006210
      label: thymine catabolic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: (S)-methylmalonate semialdehyde
    term:
      id: CHEBI:62413
      label: (S)-methylmalonate semialdehyde
    modifier: INCREASED
  - preferred_term: (R)-methylmalonate semialdehyde
    term:
      id: CHEBI:141212
      label: (R)-methylmalonate semialdehyde
    modifier: INCREASED
  - preferred_term: propionyl-CoA
    term:
      id: CHEBI:15539
      label: propionyl-CoA
  evidence:
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Methylmalonate semialdehyde dehydrogenase deficiency (MMSDD; MIM 614105)
      is a rare autosomal recessive defect of valine and pyrimidine catabolism.
    explanation: Establishes that the single enzyme block affects both valine and pyrimidine catabolism.
  - reference: PMID:23835272
    reference_title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Metabolism of valine produces the intermediate (S)-3-hydroxyisobutyric
      acid (HIBA), which is oxidized to (S)-methylmalonic semialdehyde
    explanation: States the valine-derived arm feeding the blocked reaction.
  - reference: PMID:3939535
    reference_title: Excessive excretion of beta-alanine and of 3-hydroxypropionic, R- and S-3-aminoisobutyric, R- and S-3-hydroxyisobutyric and S-2-(hydroxymethyl)butyric acids probably due to a defect in the metabolism of the corresponding malonic semialdehydes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: both R- and S-methylmalonic semialdehydes seem to be equally affected
    explanation: Supports that the deficiency affects both enantiomeric substrates, i.e. both feeder pathways.
  downstream:
  - target: Accumulation of upstream valine- and thymine-pathway metabolites
    description: >-
      Substrate and precursor metabolites upstream of the block accumulate and
      are excreted.
    causal_link_type: DIRECT
    evidence:
    - reference: CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z
      reference_title: ALDH6A1 / methylmalonate semialdehyde dehydrogenase deficiency (Limited)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        which is consistent with the finding of persistently elevated
        3-hydroxypropionate, 3-hydroxyisobutyrate, and β-aminoisobutyrate levels
        in patients with this condition
      explanation: ClinGen links the enzyme's biochemical function to the observed metabolite accumulation.
  - target: Semialdehyde shunting toward beta-alanine and malonyl-CoA
    description: >-
      Blocked semialdehyde is proposed to be diverted into an alternative
      disposal route rather than simply accumulating.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32151545
      reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        presumably due to methylmalonate semialdehyde shunting to β-alanine and
        subsequently to malonyl-CoA with ensuing increase of fatty acid synthesis
      explanation: The authors propose, but do not demonstrate, the shunt; the causal link is typed as indirect and the node is marked provisional.
- name: Accumulation of upstream valine- and thymine-pathway metabolites
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  description: >-
    The block produces a composite organic aciduria and aminoaciduria drawing on
    both feeder pathways: 3-hydroxyisobutyric and 3-hydroxypropionic acids,
    3-aminoisobutyric acid and beta-alanine. Methylmalonic acid is elevated in
    some patients only, and in the one patient in whom it was followed
    longitudinally it was transient rather than persistent. The single most
    important curation caveat for this disorder is that the metabolite pattern
    has differed in essentially every reported patient, so no fixed profile can
    be treated as diagnostic. Whether any of these metabolites is toxic is
    unknown, which is why this node is not linked to a toxic-metabolite or
    energy-deficit mechanism.
  chemical_entities:
  - preferred_term: 3-hydroxyisobutyric acid
    term:
      id: CHEBI:18064
      label: 3-hydroxyisobutyric acid
    modifier: INCREASED
  - preferred_term: 3-hydroxypropionic acid
    term:
      id: CHEBI:33404
      label: 3-hydroxypropionic acid
    modifier: INCREASED
  - preferred_term: 3-aminoisobutyric acid
    term:
      id: CHEBI:27389
      label: 3-aminoisobutyric acid
    modifier: INCREASED
  - preferred_term: beta-alanine
    term:
      id: CHEBI:16958
      label: beta-alanine
    modifier: INCREASED
  - preferred_term: methylmalonic acid
    term:
      id: CHEBI:30860
      label: methylmalonic acid
    modifier: INCREASED
  evidence:
  - reference: PMID:23835272
    reference_title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      varied metabolite abnormalities, including accumulation of
      3-hydroxyisobutyric, 3-hydroxypropionic, 3-aminoisobutyric and
      methylmalonic acids, as well as β-alanine
    explanation: Enumerates the accumulating metabolites and flags their variability.
  - reference: PMID:10947204
    reference_title: Molecular characterization of methylmalonate semialdehyde dehydrogenase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The urine metabolic pattern was strikingly different in all, including
      beta-alanine, 3-hydroxypropionic acid, both isomers of 3-amino- and
      3-hydroxyisobutyric acids in one and 3-hydroxyisobutyric and lactic acids
      in a second, and mild methylmalonic aciduria in a third patient.
    explanation: >-
      Documents the disparate urinary profiles of the three earliest reported
      patients. Read narrowly: the same report found MMSDH coding-region
      alterations in the first patient only, so the second and third patients
      are not molecularly confirmed and their profiles cannot be attributed to
      this enzyme block. Cited for the first patient's composite profile, not
      as a measure of within-disease variability; see PMID:23835272 and
      PMID:32151545 for variability among confirmed cases.
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urine organic acid assessment identified excess 3-hydroxyisobutyrate and
      3-hydroxypropionate, while urine amino acid analysis identified elevated
      concentrations of β-aminoisobutyrate and β-alanine.
    explanation: Independent confirmation of the composite organic-acid and amino-acid pattern.
  downstream:
  - target: Elevated urinary 3-hydroxyisobutyric acid
    description: >-
      3-Hydroxyisobutyric aciduria is the most consistent biochemical expression
      of the block and the finding that has prompted diagnosis in every reported
      patient.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21863277
      reference_title: 3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Mutation analysis in the ALDH6A1 gene can reveal a cause of
        3-hydroxyisobutyric aciduria
      explanation: Directly connects ALDH6A1 deficiency to the 3-hydroxyisobutyric aciduria phenotype.
  - target: Methylmalonic aciduria
    description: >-
      Methylmalonic acid is raised in a minority of patients and may be
      transient, which is why it cannot be used to rule the diagnosis in or out.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23835272
      reference_title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        transient/variable elevations in lactate, methylmalonic acid,
        3-hydroxyisobutyric and 3-aminoisobutyric acids
      explanation: Documents the elevation as transient and variable rather than a fixed feature.
- name: Semialdehyde shunting toward beta-alanine and malonyl-CoA
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Metabolomic profiling of fibroblasts from one patient found an
    over-representation of fatty acids and acylcarnitines. The authors proposed
    that blocked methylmalonate semialdehyde is diverted to beta-alanine and
    then to malonyl-CoA, increasing fatty acid synthesis. This is an inference
    from a metabolite pattern in a single patient's cells, not a demonstrated
    flux, so the node is provisional and is not used to explain any clinical
    finding.
  chemical_entities:
  - preferred_term: malonyl-CoA
    term:
      id: CHEBI:15531
      label: malonyl-CoA
    modifier: INCREASED
  - preferred_term: beta-alanine
    term:
      id: CHEBI:16958
      label: beta-alanine
    modifier: INCREASED
  evidence:
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Metabolomic profiles from patient fibroblasts demonstrated
      over-representation of fatty acids and fatty acylcarnitines
    explanation: The observed metabolomic finding; the shunt itself is an interpretation the authors hedge as presumptive.
- name: Fibroblast mitochondrial dysfunction
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Fibroblasts from one patient showed increased superoxide production, reduced
    oxygen consumption and reduced ATP production. The authors note this as a
    finding worth checking in future patients rather than an established
    component of the disease. It is one plausible bridge between the enzymatic
    block and the neurological findings, but nothing links the two directly, so
    no causal edge to the clinical arm is asserted here.
  evidence:
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient cells displayed compromised mitochondrial function with increased
      superoxide production, reduced oxygen consumption, and reduced ATP
      production.
    explanation: Single-patient in vitro observation of mitochondrial dysfunction.
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Recognition of mitochondrial dysfunction and novel metabolites in this
      patient provide the opportunity to assess future patients for secondary
      changes that may influence clinical outcome.
    explanation: The authors themselves frame the finding as a hypothesis to be tested in future patients.
- name: Reported neurological association of uncertain causality
  biological_scale: ORGANISM
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Developmental delay and, in one patient, abnormal myelination on brain MRI
    have been reported in molecularly confirmed patients. No mechanism connects
    the accumulating metabolites to neuronal or myelin injury, and other
    biallelic patients have been neurologically normal - the first reported
    patient was developing normally at four years, and the fifth had a normal
    brain MRI. ClinGen explicitly leaves open whether the extra-biochemical
    symptoms belong to the disorder. This node is deliberately detached from the
    established biochemical chain and must not be read as a mechanism.
  locations:
  - preferred_term: brain white matter
    term:
      id: UBERON:0003544
      label: brain white matter
  evidence:
  - reference: PMID:23835272
    reference_title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a child with severe developmental delays, abnormal myelination
      on brain MRI
    explanation: Case-level association of the genotype with delay and abnormal myelination.
  - reference: CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z
    reference_title: ALDH6A1 / methylmalonate semialdehyde dehydrogenase deficiency (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      There is the question of whether the additional symptoms of some
      individuals are related to this disorder, although that is unrelated to
      the biochemical abnormality and the response to modified diet seems to
      indicate a connection.
    explanation: >-
      Expert-panel statement that causal attribution of the clinical symptoms is
      unresolved. Quoted in full so the panel's own counterweight - the reported
      response to a modified diet - travels with the uncertainty rather than
      being cut at the comma.
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: She was nondysmorphic, had a normal brain MRI, and showed mild hypotonia.
    explanation: Counterexample - a molecularly confirmed patient without the neuroimaging abnormality.
phenotypes:
- category: Biochemical
  name: Elevated urinary 3-hydroxyisobutyric acid
  description: >-
    The most consistent biochemical feature and the finding that leads to
    investigation. It may be only slightly raised when the patient is
    metabolically stable, so a mild elevation does not exclude the diagnosis.
  context: Established biochemical phenotype; not a clinical-severity assertion.
  phenotype_term:
    preferred_term: Elevated urinary 3-hydroxyisobutyric acid level
    term:
      id: HP:6000607
      label: Elevated urinary 3-hydroxyisobutyric acid level
  evidence:
  - reference: PMID:21863277
    reference_title: 3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present two unrelated patients who presented with developmental delay
      and increased urinary concentrations of 3-hydroxyisobutyric acid.
    explanation: Documents the phenotype in two molecularly confirmed patients.
  - reference: PMID:21863277
    reference_title: 3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      which may present with only slightly increased urinary levels of
      3-hydroxyisobutyric acid, if a patient is metabolically stable
    explanation: Establishes that the magnitude of elevation is state-dependent.
- category: Biochemical
  name: Elevated urinary 3-hydroxypropionic acid
  description: Raised urinary 3-hydroxypropionate accompanies the 3-hydroxyisobutyrate elevation in several patients.
  context: Established biochemical phenotype; frequency across patients unquantified.
  phenotype_term:
    preferred_term: Elevated urine 3-hydroxypropionic acid level
    term:
      id: HP:0034661
      label: Elevated urine 3-hydroxypropionic acid level
  evidence:
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urine organic acid assessment identified excess 3-hydroxyisobutyrate and
      3-hydroxypropionate
    explanation: Documents 3-hydroxypropionate elevation in a molecularly confirmed patient.
- category: Biochemical
  name: Beta-aminoisobutyric aciduria
  description: >-
    3-Aminoisobutyric acid is the thymine-derived precursor upstream of the
    block; its urinary elevation is the biochemical signature of the
    pyrimidine-catabolism arm of the disorder.
  context: Established biochemical phenotype reflecting the thymine-catabolism arm.
  phenotype_term:
    preferred_term: Elevated urinary 3-aminoisobutyric acid
    term:
      id: HP:0045034
      label: Elevated urinary 3-aminoisobutyric acid
  evidence:
  - reference: PMID:23835272
    reference_title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      accumulation of 3-hydroxyisobutyric, 3-hydroxypropionic, 3-aminoisobutyric
      and methylmalonic acids
    explanation: Lists 3-aminoisobutyric acid among the accumulating metabolites.
- category: Biochemical
  name: Beta-alaninuria
  description: Elevated beta-alanine was a defining feature of the original 1985 report and recurs in later patients.
  context: Established biochemical phenotype; plasma beta-alanine may be normal or undetectable despite urinary elevation.
  phenotype_term:
    preferred_term: Beta-alaninuria
    term:
      id: HP:0020079
      label: Beta-alaninuria
  evidence:
  - reference: PMID:3939535
    reference_title: Excessive excretion of beta-alanine and of 3-hydroxypropionic, R- and S-3-aminoisobutyric, R- and S-3-hydroxyisobutyric and S-2-(hydroxymethyl)butyric acids probably due to a defect in the metabolism of the corresponding malonic semialdehydes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A new metabolic disorder characterised by the excessive excretion of
      beta-alanine, 3-hydroxypropionic acid, R- and S-3-amino- and
      3-hydroxyisobutyric acids
    explanation: The original description of the biochemical phenotype, including beta-alanine excretion.
- category: Biochemical
  name: Methylmalonic aciduria
  description: >-
    Present in a minority of patients and transient in at least one. Its absence
    does not exclude the diagnosis, and its presence invites confusion with the
    classical methylmalonic acidemias.
  context: Inconsistent biochemical phenotype; deliberately not treated as diagnostic.
  phenotype_term:
    preferred_term: Methylmalonic aciduria
    term:
      id: HP:0012120
      label: Methylmalonic aciduria
  evidence:
  - reference: PMID:23835272
    reference_title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      transient/variable elevations in lactate, methylmalonic acid,
      3-hydroxyisobutyric and 3-aminoisobutyric acids
    explanation: >-
      Methylmalonic aciduria in a patient with biallelic ALDH6A1 variants
      confirmed by exome and Sanger sequencing and a corresponding reduction in
      MMSDH enzyme activity, so the finding is attributable to this disorder.
      The earlier PMID:10947204 patient with mild methylmalonic aciduria is not
      cited here: that report states "No abnormalities of the MMSDH cDNA were
      detected in the other patients", so the case is not molecularly confirmed.
- category: Neurologic
  name: Global developmental delay
  description: >-
    Reported in several molecularly confirmed patients, but absent in others,
    and never shown to be caused by the enzyme deficiency. Ascertainment through
    neurologic investigation is a live alternative explanation for the
    association.
  context: Reported association; causal attribution to ALDH6A1 deficiency unresolved.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:21863277
    reference_title: 3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present two unrelated patients who presented with developmental delay
      and increased urinary concentrations of 3-hydroxyisobutyric acid.
    explanation: Case-level evidence for developmental delay in two patients.
  - reference: PMID:3939535
    reference_title: Excessive excretion of beta-alanine and of 3-hydroxypropionic, R- and S-3-aminoisobutyric, R- and S-3-hydroxyisobutyric and S-2-(hydroxymethyl)butyric acids probably due to a defect in the metabolism of the corresponding malonic semialdehydes.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: The patient is now aged 4 years and has developed normally.
    explanation: A biallelic patient with normal development; prevents treating delay as a disease-wide phenotype.
- category: Neurologic
  name: Abnormal myelination
  description: >-
    Abnormal myelination on brain MRI was described in a single patient. Another
    molecularly confirmed patient had a normal brain MRI.
  context: Single-patient neuroimaging finding; not generalizable on current evidence.
  phenotype_term:
    preferred_term: Abnormal myelination
    term:
      id: HP:0012447
      label: Abnormal myelination
  evidence:
  - reference: PMID:23835272
    reference_title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a child with severe developmental delays, abnormal myelination
      on brain MRI
    explanation: Single-case report of abnormal myelination.
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: She was nondysmorphic, had a normal brain MRI, and showed mild hypotonia.
    explanation: >-
      A molecularly confirmed patient with a normal brain MRI, which argues
      against treating abnormal myelination as an established phenotype of the
      disorder rather than a single-case finding.
- category: Neurologic
  name: Hypotonia
  description: Mild hypotonia was present in the fifth reported patient during infancy.
  context: Single-patient finding.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She was nondysmorphic, had a normal brain MRI, and showed mild hypotonia.
    explanation: Documents mild hypotonia in one patient.
- category: Gastrointestinal
  name: Failure to thrive
  description: >-
    Failure to thrive prompted admission at two weeks of age in the fifth
    reported patient, and improved on valine restriction.
  context: Single-patient finding that responded to dietary treatment.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      was admitted at two weeks of age for failure to thrive
    explanation: Documents failure to thrive as the presenting problem in one patient.
- category: Gastrointestinal
  name: Gastroesophageal reflux
  description: >-
    Feeding-associated reflux in the fifth reported patient. Notable because it
    improved with valine restriction, which is one of the few observations
    linking a clinical finding to the metabolic block.
  context: Single-patient finding; treatment-responsive.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Gastroesophageal reflux occurred with feeding.
    explanation: Documents reflux in one patient.
- category: Hepatic
  name: Hepatic encephalopathy
  description: >-
    One patient died at two years of age from hepatoencephalopathy following a
    febrile illness. This is the only reported death and the only report of
    hepatic involvement; whether it belongs to the disorder is unknown.
  context: Single fatal case; causal attribution to ALDH6A1 deficiency unresolved.
  phenotype_term:
    preferred_term: Hepatic encephalopathy
    term:
      id: HP:0002480
      label: Hepatic encephalopathy
  evidence:
  - reference: PMID:21863277
    reference_title: 3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient developed a febrile illness and subsequently died from a
      hepatoencephalopathy at 2 years of age.
    explanation: The single reported fatal outcome.
- category: Metabolic
  name: Increased circulating lactate concentration
  description: Transient and variable lactate elevation was documented in one patient alongside the organic aciduria.
  context: Transient finding in one patient.
  phenotype_term:
    preferred_term: Increased circulating lactate concentration
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  evidence:
  - reference: PMID:23835272
    reference_title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      transient/variable elevations in lactate, methylmalonic acid,
      3-hydroxyisobutyric and 3-aminoisobutyric acids
    explanation: Documents transient lactate elevation.
biochemical:
- name: Urinary 3-hydroxyisobutyric acid
  presence: INCREASED
  context: The most consistent analyte; magnitude depends on metabolic state.
  biomarker_term:
    preferred_term: 3-hydroxyisobutyric acid
    term:
      id: CHEBI:18064
      label: 3-hydroxyisobutyric acid
  readouts:
  - target: Accumulation of upstream valine- and thymine-pathway metabolites
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Increased urinary 3-hydroxyisobutyrate is the principal readout of the
      valine-derived arm of the block.
  evidence:
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urine organic acid assessment identified excess 3-hydroxyisobutyrate and
      3-hydroxypropionate
    explanation: Establishes the analyte and its direction.
- name: Urinary 3-hydroxypropionic acid
  presence: INCREASED
  context: Accompanies 3-hydroxyisobutyrate in several patients.
  biomarker_term:
    preferred_term: 3-hydroxypropionic acid
    term:
      id: CHEBI:33404
      label: 3-hydroxypropionic acid
  readouts:
  - target: Accumulation of upstream valine- and thymine-pathway metabolites
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: A secondary organic-acid readout of the same block.
  evidence:
  - reference: CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z
    reference_title: ALDH6A1 / methylmalonate semialdehyde dehydrogenase deficiency (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      persistently elevated 3-hydroxypropionate, 3-hydroxyisobutyrate, and
      β-aminoisobutyrate levels in patients with this condition
    explanation: ClinGen records persistent elevation of this analyte in affected patients.
- name: Beta-aminoisobutyric acid
  presence: INCREASED
  context: >-
    Elevated in both plasma and urine; the readout that distinguishes this
    disorder from a pure valine-pathway defect.
  biomarker_term:
    preferred_term: 3-aminoisobutyric acid
    term:
      id: CHEBI:27389
      label: 3-aminoisobutyric acid
  readouts:
  - target: Convergent block of valine and thymine catabolism
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Elevated beta-aminoisobutyrate reports the thymine-derived arm of the
      block, which an isolated valine-pathway defect such as HIBADH deficiency
      would not produce.
  evidence:
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plasma amino acids showed an elevated concentration of β-aminoisobutyrate
      with undetectable β-alanine.
    explanation: Documents plasma elevation of beta-aminoisobutyrate, with the notable dissociation from beta-alanine.
- name: Beta-alanine
  presence: INCREASED
  context: >-
    Urinary excretion is elevated, but plasma beta-alanine was undetectable in
    the one patient in whom both were measured, so the compartments must not be
    conflated.
  biomarker_term:
    preferred_term: beta-alanine
    term:
      id: CHEBI:16958
      label: beta-alanine
  readouts:
  - target: Accumulation of upstream valine- and thymine-pathway metabolites
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Urinary beta-alanine excretion is part of the original biochemical signature of the disorder.
  evidence:
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      urine amino acid analysis identified elevated concentrations of
      β-aminoisobutyrate and β-alanine
    explanation: Documents urinary beta-alanine elevation.
genetic:
- name: Biallelic ALDH6A1 missense variants
  gene_term:
    preferred_term: ALDH6A1
    term:
      id: hgnc:7179
      label: ALDH6A1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    All reported disease alleles are missense and affect residues conserved
    across mammals: c.1336G>A (p.Gly446Arg), c.785C>A (p.Ser262Tyr), c.184C>T
    (p.Pro62Ser), c.514T>C (p.Tyr172His), c.1603C>T (p.Arg535Cys) and c.1261C>T
    (p.Pro421Ser). Most patients are homozygous, several through consanguinity;
    one is compound heterozygous. The disease mechanism is biallelic loss of
    function. Two caveats matter for variant interpretation: p.Pro62Ser was also
    seen once in 530 control chromosomes, and p.Pro421Ser was reported as a
    variant of uncertain significance whose pathogenicity rests on the
    accompanying protein and metabolite data rather than on the sequence change
    alone.
  evidence:
  - reference: PMID:10947204
    reference_title: Molecular characterization of methylmalonate semialdehyde dehydrogenase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      revealing homozygosity for a 1336G > A transversion, which leads to
      substitution of arginine for highly conserved glycine at amino acid 446
    explanation: The first molecularly characterized allele.
  - reference: PMID:21863277
    reference_title: 3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      suggested homozygosity for the missense mutation c.785 C > A (S262Y) in
      exon 7 which was not found in 210 control alleles
    explanation: Second reported allele, with control-cohort screening.
  - reference: PMID:21863277
    reference_title: 3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a different missense mutation, c.184 C > T (P62S), which was also
      identified in 1/530 control chromosomes
    explanation: Records the control-chromosome observation that tempers the pathogenicity claim for this allele.
  - reference: PMID:23835272
    reference_title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      within exon 6 (c.514 T > C; p. Tyr172His) and exon 12 (c.1603C > T; p.
      Arg535Cys) of ALDH6A1
    explanation: The only reported compound-heterozygous genotype.
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ALDH6A1 gene sequencing identified a homozygous variant of uncertain
      significance, c.1261C > T (p.Pro421Ser).
    explanation: Documents the sixth allele and its VUS classification.
  - reference: CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z
    reference_title: ALDH6A1 / methylmalonate semialdehyde dehydrogenase deficiency (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: At least six unique missense variants have been reported in humans.
    explanation: Confirms that the reported allelic spectrum is entirely missense.
diagnosis:
- name: Urine organic acid and amino acid analysis
  diagnosis_term:
    preferred_term: urine organic acid analysis
  description: >-
    The entry point to diagnosis. Urine organic acids show 3-hydroxyisobutyrate
    with variable 3-hydroxypropionate and methylmalonate; urine and plasma amino
    acids show beta-aminoisobutyrate and beta-alanine. Because the profile
    differs between patients and elevations can be mild in a stable patient, a
    normal-looking screen does not exclude the diagnosis.
  results: >-
    Composite organic aciduria with beta-aminoisobutyrate and beta-alanine; the
    pattern is variable between patients and over time.
  evidence:
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urine organic acid assessment identified excess 3-hydroxyisobutyrate and
      3-hydroxypropionate, while urine amino acid analysis identified elevated
      concentrations of β-aminoisobutyrate and β-alanine.
    explanation: Describes the biochemical work-up that identified the disorder.
- name: ALDH6A1 sequencing
  diagnosis_term:
    preferred_term: molecular genetic testing
  description: >-
    Sequencing ALDH6A1 is the practical confirmatory test, and for three decades
    it was the only one available, because the substrate instability made the
    enzyme assay impracticable. Exome sequencing has been the route to diagnosis
    where the biochemical picture was ambiguous.
  results: Biallelic ALDH6A1 missense variants.
  evidence:
  - reference: PMID:21863277
    reference_title: 3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutation analysis in the ALDH6A1 gene can reveal a cause of
      3-hydroxyisobutyric aciduria
    explanation: Establishes gene sequencing as the diagnostic route.
  - reference: PMID:23835272
    reference_title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compound heterozygous mutations were identified by exome sequencing and
      confirmed by Sanger sequencing
    explanation: Documents exome sequencing as the diagnostic modality in a clinically ambiguous case.
- name: MMSDH enzyme assay in cultured fibroblasts
  diagnosis_term:
    preferred_term: enzyme activity assay
  description: >-
    Available only in specialist laboratories. Long considered impossible
    because methylmalonate semialdehyde is too unstable; a working fibroblast
    assay was first reported in 2013 and showed activity 2.5 standard deviations
    below the mean, which is a reduction rather than an absence.
  results: Reduced MMSDH activity in cultured fibroblasts.
  evidence:
  - reference: PMID:23835272
    reference_title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, this is the first report to demonstrate a corresponding
      reduction in MMSDH enzyme activity.
    explanation: Establishes the enzyme assay as a confirmatory test and dates its first successful use.
differential_diagnoses:
- name: HIBADH deficiency
  description: >-
    The other primary cause of 3-hydroxyisobutyric aciduria. HIBADH catalyses
    the immediately upstream step of the same valine pathway, so the two
    disorders produce overlapping urinary 3-hydroxyisobutyrate. The
    discriminators are that HIBADH deficiency does not affect thymine catabolism
    (so beta-aminoisobutyrate and beta-alanine should not be raised) and that
    HIBADH enzyme activity is normal in MMSDH deficiency. Measuring HIBADH
    activity is exactly how MMSDH deficiency was established in two of the
    reported patients.
  evidence:
  - reference: PMID:35174513
    reference_title: "3-Hydroxyisobutyric acid dehydrogenase deficiency: Expanding the clinical spectrum and quantitation of D- and L-3-Hydroxyisobutyric acid by an LC-MS/MS method."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the only previously recognized primary cause had been a deficiency of
      methylmalonic semialdehyde dehydrogenase, the enzyme that is immediately
      downstream of HIBADH in the valine catabolic pathway and is encoded by the
      ALDH6A1 gene
    explanation: States the precise pathway relationship between the two differential diagnoses.
  - reference: PMID:21863277
    reference_title: 3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      included tests of the HIBADH enzyme in fibroblast homogenates, which
      yielded normal activities
    explanation: Documents the enzymatic discrimination between the two disorders.
- name: Other causes of 3-hydroxyisobutyric aciduria
  description: >-
    3-Hydroxyisobutyric aciduria is a biochemical finding with several
    mechanisms, not a disease. Respiratory-chain defects are an established
    alternative cause, so an isolated 3-hydroxyisobutyrate elevation should not
    be equated with an ALDH6A1 defect.
  evidence:
  - reference: PMID:21863277
    reference_title: 3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      individuals with 3-hydroxyisobutyryic aciduria represent a heterogeneous
      group with different underlying mechanisms, including respiratory chain
      defects or deficiency of methylmalonate semialdehyde dehydrogenase
    explanation: Establishes the heterogeneous causation of the presenting biochemical finding.
- name: Classical methylmalonic acidemia
  description: >-
    Patients with the methylmalonic-aciduria variant of the MMSDH phenotype can
    be mistaken for methylmalonyl-CoA mutase or cobalamin-pathway disorders. In
    MMSDH deficiency the methylmalonate elevation is mild and may be transient,
    and it is accompanied by 3-hydroxyisobutyrate and beta-aminoisobutyrate,
    which the classical methylmalonic acidemias do not produce.
  evidence:
  - reference: PMID:23835272
    reference_title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      transient/variable elevations in lactate, methylmalonic acid,
      3-hydroxyisobutyric and 3-aminoisobutyric acids
    explanation: Shows the co-occurring metabolites that separate this disorder from classical methylmalonic acidemia.
treatments:
- name: Valine-restricted diet
  description: >-
    Restriction of dietary valine reduces substrate flux into the blocked
    pathway. In the one patient in whom it has been reported in detail it
    reduced the abnormal analytes and was accompanied by improved growth and
    reduced reflux. This is a single uncontrolled observation, not demonstrated
    efficacy, and there is no evidence at all bearing on whether it alters
    neurological outcome.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Accumulation of upstream valine- and thymine-pathway metabolites
    treatment_effect: MODULATES
    description: >-
      Limiting valine intake reduces flux into the valine-derived arm of the
      block and lowers the accumulating metabolites. It cannot address the
      thymine-derived arm.
    evidence:
    - reference: PMID:32151545
      reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Management with valine restriction led to reduced concentration of
        abnormal analytes in blood and urine
      explanation: Single-patient evidence that the intervention lowers the target metabolites.
  evidence:
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      improved growth, and reduced gastroesophageal reflux
    explanation: The accompanying clinical improvement, uncontrolled and in one patient only.
references:
- reference: PMID:3939535
  title: Excessive excretion of beta-alanine and of 3-hydroxypropionic, R- and S-3-aminoisobutyric, R- and S-3-hydroxyisobutyric and S-2-(hydroxymethyl)butyric acids probably due to a defect in the metabolism of the corresponding malonic semialdehydes.
  findings: []
- reference: PMID:10947204
  title: Molecular characterization of methylmalonate semialdehyde dehydrogenase deficiency.
  findings: []
- reference: PMID:21863277
  title: 3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase.
  findings: []
- reference: PMID:23835272
  title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
  findings: []
- reference: PMID:32151545
  title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
  findings: []
- reference: PMID:34176136
  title: 3-Hydroxyisobutyrate dehydrogenase (HIBADH) deficiency-A novel disorder of valine metabolism.
  findings: []
- reference: PMID:35174513
  title: "3-Hydroxyisobutyric acid dehydrogenase deficiency: Expanding the clinical spectrum and quantitation of D- and L-3-Hydroxyisobutyric acid by an LC-MS/MS method."
  findings: []
- reference: CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z
  title: ALDH6A1 / methylmalonate semialdehyde dehydrogenase deficiency (Limited)
  findings: []
discussions:
- discussion_id: gap_mmsdh_clinical_causality
  prompt: >-
    Do the neurological, hepatic and growth findings reported in ALDH6A1
    patients arise from the enzyme deficiency, or are they ascertainment
    artefacts of investigating children who were referred for those problems?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Reported neurological association of uncertain causality
  - phenotypes#Global developmental delay
  - phenotypes#Abnormal myelination
  - phenotypes#Hepatic encephalopathy
  rationale: >-
    Every reported patient bar one was ascertained because of a clinical
    problem, and the exception - the 1985 index patient, found through newborn
    screening for an unrelated reason - was developing normally at four years.
    With fewer than ten molecularly confirmed patients, no segregation data and
    no population screening, the disorder's clinical penetrance is not estimable
    and the direction of the association cannot be resolved. ClinGen's Limited
    classification rests on exactly this ambiguity.
  evidence:
  - reference: CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z
    reference_title: ALDH6A1 / methylmalonate semialdehyde dehydrogenase deficiency (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In summary, there is limited evidence to support this gene-disease relationship.
    explanation: The expert-panel classification that frames this gap.
  - reference: CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z
    reference_title: ALDH6A1 / methylmalonate semialdehyde dehydrogenase deficiency (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although more evidence, genetic and experimental, is needed to support a
      causal role, no convincing evidence has emerged that contradicts the
      gene-disease relationship.
    explanation: States precisely that the causal role is unestablished rather than refuted.
  proposed_experiments:
  - experiment_id: exp_mmsdh_unbiased_ascertainment
    name: Unbiased ascertainment through untargeted metabolomic screening
    description: >-
      Identify ALDH6A1 biallelic individuals from large unselected biobank and
      newborn-screening metabolomic datasets rather than from clinical referral,
      then phenotype them with standardized developmental, hepatic and
      neuroimaging assessments against variant-negative relatives. This is the
      only design that can separate the disorder's true clinical spectrum from
      referral bias.
- discussion_id: gap_mmsdh_metabolite_variability
  prompt: >-
    Why does a single, well-defined enzymatic block produce a different
    metabolite profile in every reported patient, and what determines which
    metabolites accumulate in a given individual?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Accumulation of upstream valine- and thymine-pathway metabolites
  - phenotypes#Methylmalonic aciduria
  rationale: >-
    Among molecularly confirmed patients the clinical and biochemical phenotype
    is highly variable: methylmalonic acid has been persistent in some,
    transient in another, and absent in others, and the fifth reported case
    diverges clinically from the earlier ones. Residual enzyme activity,
    relative valine versus thymine flux, and the observed dissociation between
    plasma and urinary beta-alanine are all candidate explanations, none tested.
    The three earliest reported patients also had essentially non-overlapping
    urinary profiles, but only the first of those was confirmed at the cDNA
    level, so that particular contrast is at least as consistent with three
    different disorders as with variability within this one and is not the basis
    of this gap. The practical consequence is that the disorder has no reliable
    biochemical screening signature.
  evidence:
  - reference: PMID:23835272
    reference_title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: highly variable clinical and biochemical phenotype
    explanation: >-
      States the variability directly, in a report whose own case is confirmed
      by biallelic ALDH6A1 variants and reduced MMSDH enzyme activity.
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: clinical phenotypes diverge from prior cases
    explanation: A second molecularly confirmed case whose phenotype diverges from the earlier ones.
  - reference: PMID:32151545
    reference_title: "Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Plasma amino acids showed an elevated concentration of β-aminoisobutyrate
      with undetectable β-alanine.
    explanation: Documents a plasma/urine dissociation that any explanation of the variability must account for.
  proposed_experiments:
  - experiment_id: exp_mmsdh_flux_genotype_correlation
    name: Residual-activity and stable-isotope flux correlation across genotypes
    description: >-
      Express each reported ALDH6A1 missense allele, measure residual activity
      against both (R)- and (S)-methylmalonate semialdehyde, and pair this with
      stable-isotope valine and thymine flux studies in patient fibroblasts.
      Testing whether allele-specific enantiomer preference predicts the
      individual metabolite profile would convert an unexplained heterogeneity
      into a genotype-phenotype rule.
notes: >-
  New entry curated for the WP-001 metabolic worklist row 1.2.17.01 (ALDH6A1,
  MONDO:0013579, OMIM:614105, ORPHA:289307). Note that the worklist row cites
  OMIM 603178, which is the ALDH6A1 *gene* MIM; the phenotype MIM is 614105, and
  MONDO:0013579 carries the latter as its xref.

  Curation stance: the enzymatic block and its metabolite consequences are
  curated as ESTABLISHED; every clinical finding is kept on PROVISIONAL or
  HYPOTHETICAL nodes with no causal edge from the biochemical chain, because
  ClinGen classifies the gene-disease relationship as Limited and explicitly
  leaves open whether the extra-biochemical symptoms belong to the disorder. No
  phenotype `frequency:` bands are assigned - with fewer than ten published
  patients and clinical ascertainment throughout, any band would be fabricated.
  Only the enzyme node declares `conforms_to`
  (`metabolic_intoxication_decompensation#Enzymatic Block in Intermediary
  Metabolism`); the module's toxic-metabolite, decompensation and encephalopathy
  nodes are deliberately NOT claimed, since metabolite toxicity and acute
  decompensation are not evidenced for this disorder.

  NEC note: "3-hydroxyisobutyric aciduria" names a biochemical finding with at
  least three causes - ALDH6A1 deficiency, HIBADH deficiency (a separate WP-001
  row, 1.2.25.01) and respiratory-chain defects. Literature retrieved under that
  phrase must be checked for which enzyme it concerns before use. Curated
  against the ALDH6A1 identity anchors (MONDO RO:0004003 -> HGNC:7179,
  OMIM:614105, Orphanet:289307), all three of which agree.

  Deferred to a second pass: Orphanet provenance (ORPHA:289307 is not in
  references_cache and needs an Orphadata refresh), imaging_findings for the
  single abnormal-myelination case, and prevalence beyond the literature count.
📚

References & Deep Research

References

8
PMID:3939535
Excessive excretion of beta-alanine and of 3-hydroxypropionic, R- and S-3-aminoisobutyric, R- and S-3-hydroxyisobutyric and S-2-(hydroxymethyl)butyric acids probably due to a defect in the metabolism of the corresponding malonic semialdehydes.
No top-level findings curated for this source.
PMID:10947204
Molecular characterization of methylmalonate semialdehyde dehydrogenase deficiency.
No top-level findings curated for this source.
PMID:21863277
3-Hydroxyisobutyrate aciduria and mutations in the ALDH6A1 gene coding for methylmalonate semialdehyde dehydrogenase.
No top-level findings curated for this source.
PMID:23835272
Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
No top-level findings curated for this source.
PMID:32151545
Clinical, biochemical, mitochondrial, and metabolomic aspects of methylmalonate semialdehyde dehydrogenase deficiency: Report of a fifth case.
No top-level findings curated for this source.
PMID:34176136
3-Hydroxyisobutyrate dehydrogenase (HIBADH) deficiency-A novel disorder of valine metabolism.
No top-level findings curated for this source.
PMID:35174513
3-Hydroxyisobutyric acid dehydrogenase deficiency: Expanding the clinical spectrum and quantitation of D- and L-3-Hydroxyisobutyric acid by an LC-MS/MS method.
No top-level findings curated for this source.
CGGV:assertion_57ca1521-9336-4769-bc55-240089dab917-2026-01-09T170000.000Z
ALDH6A1 / methylmalonate semialdehyde dehydrogenase deficiency (Limited)
No top-level findings curated for this source.