3-Methylglutaconic Aciduria Type I

Mendelian MONDO:0009610 Pathograph 20 Show in embeddings browser Organic Aciduria Inborn Error of Metabolism

3-Methylglutaconic aciduria type I (MGA1) is an autosomal recessive defect of leucine catabolism caused by biallelic pathogenic variants in AUH, which encodes mitochondrial 3-methylglutaconyl-CoA hydratase. The established phenotype is biochemical: deficient enzyme activity causes persistent urinary 3-methylglutaconic acid, variably accompanied by 3-methylglutaric and 3-hydroxyisovaleric acids, and can produce an elevated C5-OH newborn-screening signal. Clinical penetrance is unresolved. Long-term newborn-screened individuals have remained asymptomatic without treatment, whereas small, clinically ascertained series and case reports describe nonspecific pediatric neurodevelopmental findings and a possible adult-onset progressive leukoencephalopathy. Ascertainment bias prevents treating those neurologic findings as established consequences of the biochemical defect. MGA1 is the disorder historically termed primary 3-methylglutaconic aciduria; secondary 3-methylglutaconic acidurias arise through other mitochondrial mechanisms rather than an AUH-dependent leucine-pathway block.

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1
Inheritance
4
Pathophys.
8
Phenotypes
3
Gaps
20
Pathograph
1
Genes
2
Medical Actions
4
Differentials
15
References
🏷

Classifications

ICIMD (Inherited Metabolic Disorders)
organic acidurias
👪

Inheritance

1
Autosomal recessive inheritance with incomplete clinical penetrance HP:0000007
Biallelic AUH variants establish the biochemical disorder, but a specific clinical phenotype is not consistently expressed. Complete enzyme absence and long follow-up after newborn-screening detection can be compatible with normal development and absence of neurologic symptoms.
Autosomal recessive inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE
Show evidence (2 references)
PMID:12655555 SUPPORT Human Clinical
"Complete absence of 3-methylglutaconyl-CoA hydratase/AUH appears to be compatible with normal development in some cases."
Biallelic loss of AUH function does not invariably produce a clinical phenotype.
PMID:36341175 SUPPORT Human Clinical
"all four patients diagnosed through NBS (including three with over 18 years of clinical follow-up) remain asymptomatic in the absence of treatment"
Long-term untreated follow-up directly supports incomplete clinical penetrance.
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Discussions and Knowledge Gaps

3
Does AUH deficiency cause a reproducible childhood clinical phenotype, or do the reported developmental, behavioral, and severe neurologic findings primarily reflect ascertainment and coincidental comorbidity?
CONTROVERSY OPEN controversy_mga1_childhood_clinical_phenotype
Attached to
pathophysiology#Reported pediatric neurodevelopmental association of uncertain causality phenotypes#Delayed speech and language development phenotypes#Severe global developmental delay
Clinically ascertained cases report heterogeneous pediatric findings, but four newborn-screened patients, including three followed for more than 18 years without treatment, remained asymptomatic. The current evidence cannot estimate clinical penetrance or separate AUH effects from background neurodevelopmental variation.
Proposed experiments
Family-controlled longitudinal natural-history study
exp_mga1_family_controlled_natural_history
Follow all molecularly confirmed individuals identified through screening, including untreated participants and variant-negative relatives, with standardized cognition, language, motor, psychiatric, metabolite, and MRI assessments. Prespecified family-control comparisons would quantify penetrance while limiting ascertainment bias.
Show evidence (2 references)
PMID:36341175 SUPPORT Human Clinical
"there is no clear evidence of a specific childhood-onset clinical phenotype associated with this disorder"
Defines the central controversy about childhood clinical attribution.
PMID:21840233 SUPPORT Human Clinical
"We describe two siblings with 3-methylglutaconic aciduria type I with phenotypic heterogeneity."
Shows why selected pediatric reports cannot define a consistent phenotype.
Is adult-onset progressive leukoencephalopathy a causal late manifestation of AUH deficiency, and if so, what biochemical mechanism injures white matter?
CONTROVERSY OPEN controversy_mga1_adult_leukoencephalopathy
Attached to
pathophysiology#Reported adult leukoencephalopathy association of uncertain causality imaging_findings#Extensive cerebral white-matter disease on adult MRI phenotypes#Progressive ataxia phenotypes#Leukoencephalopathy
Adult case reports show a recurring ataxia/leukoencephalopathy pattern, and one patient had marked CSF 3-hydroxyisovalerate enrichment, but there are too few unbiased adult observations to establish causality. No validated chain links the diagnostic metabolites to myelin or axonal injury.
Proposed experiments
Adult biochemical-screening, MRI, and CNS-metabolite study
exp_mga1_adult_screening_mri_metabolomics
Screen large adult biobank cohorts for the MGA1 biochemical and molecular phenotype independently of neurologic symptoms, then compare blinded MRI, neurologic examinations, plasma/CSF metabolites, and longitudinal change with matched controls. Patient-derived neural cultures could then test candidate metabolites at measured human CNS concentrations.
Show evidence (2 references)
PMID:20855850 SUPPORT Human Clinical
"In both patients, MRI revealed extensive white matter disease."
Supports recurrence of the adult imaging association in the small clinical series.
PMID:36341175 SUPPORT Human Clinical
"will be required to conclusively prove or disprove the association with adult-onset leukoencephalopathy"
Directly supports keeping the association unresolved.
Do leucine restriction or levocarnitine alter biochemical markers, neurologic penetrance, or long-term imaging outcomes in MGA1?
KNOWLEDGE GAP OPEN gap_mga1_treatment_effectiveness
Attached to
treatments#Leucine-restricted diet treatments#Levocarnitine supplementation
Treatment reports are uncontrolled and often begin in asymptomatic infants. Untreated newborn-screened individuals have also remained asymptomatic for more than 18 years, so normal development under treatment cannot establish efficacy. Intensive restriction carries nutritional and adherence burdens.
Proposed experiments
Prospective treatment-and-observation registry
exp_mga1_treatment_registry
Use a multicenter protocol with standardized diet, carnitine status, urinary metabolites, neurodevelopment, neurologic examination, and MRI. Compare prespecified treated and conservatively observed groups with adjustment for indication and ascertainment; randomized treatment would be considered only if an actionable clinical phenotype is first established.
Show evidence (2 references)
PMID:36341175 SUPPORT Human Clinical
"The burdens of sustained treatment (particularly with intensive dietary leucine restriction) in asymptomatic individuals may be of little benefit"
Establishes the uncertainty and burden underlying the treatment gap.
PMID:38077954 SUPPORT Human Clinical
"Treatments such as dietary leucine restriction and carnitine supplementation may have little effect on MGCA1 in childhood"
A modern untreated case and literature review question benefit while calling for further study.
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Pathophysiology

4
AUH-dependent 3-methylglutaconyl-CoA hydratase deficiency
Biallelic pathogenic variants in AUH reduce or abolish mitochondrial 3-methylglutaconyl-CoA hydratase activity. The enzyme catalyzes conversion of 3-methylglutaconyl-CoA to 3-hydroxy-3-methylglutaryl-CoA in leucine degradation.
AUH hgnc:890 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves AUH (hgnc:890). hgnc:890 is a gene from the HUGO Gene Nomenclature Committee.
L-leucine catabolic process GO:0006552 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased L-leucine catabolic process (GO:0006552). GO:0006552 is a biological process from the Gene Ontology. ↓ DECREASED
methylglutaconyl-CoA hydratase activity GO:0004490 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased methylglutaconyl-CoA hydratase activity (GO:0004490). GO:0004490 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
Leucine-pathway organic-acid accumulation The hydratase block causes the characteristic primary 3-methylglutaconic aciduria biochemical profile.
Show evidence (2 references)
PMID:12434311 SUPPORT In Vitro
"we show that 3-methylglutaconyl-CoA hydratase is encoded by the AUH gene"
Establishes AUH as the gene encoding the deficient enzyme.
PMID:16640564 SUPPORT In Vitro
"The only missense mutation found in MGA1 phenotypes, c.719C>T, leading to the amino acid exchange A240V, produces an enzyme with only 9% of the wild-type 3-MG-CoA hydratase activity."
Functional expression data show severe loss of hydratase activity from an AUH missense allele.
Leucine-pathway organic-acid accumulation
The AUH-dependent leucine-catabolism block produces persistent urinary 3-methylglutaconic acid, with variable 3-hydroxyisovaleric and 3-methylglutaric acids. These metabolites are diagnostic readouts. Their toxicity and any causal connection to neurologic disease have not been demonstrated, so this node does not conform to a toxic-metabolite or energy-deficit mechanism module.
Downstream
3-Methylglutaconic aciduria Persistent urinary 3-methylglutaconic acid is the defining phenotypic expression of the biochemical block.
Show evidence (2 references)
PMID:36341175 SUPPORT Human Clinical
"causes the accumulation of urinary 3-methylglutaconate, with or without 3-hydroxyisovalerate and 3-methylglutarate"
Establishes the invariant and variable components of the biochemical profile.
PMID:16640564 SUPPORT Human Clinical
"excessive urinary excretion of 3-methylglutaconic acid, 3-methylglutaric acid and 3-hydroxyisovaleric acid"
Independently supports the characteristic urine organic-acid pattern.
Reported adult leukoencephalopathy association of uncertain causality
A small number of adults with biochemical and genetic MGA1 have been reported with progressive ataxia and extensive cerebral white-matter disease. The causal path from AUH deficiency or its metabolites to white-matter injury is unknown, and ascertainment bias remains a viable explanation. This clinical-association node is intentionally detached from the established biochemical causal chain.
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.
Downstream
Leukoencephalopathy Extensive white-matter disease is the defining imaging observation in the reported adult cases.
Progressive ataxia Progressive ataxia was the shared presenting feature of two reported adults.
Optic atrophy Optic atrophy was present in one of the two reported adults.
Spasticity Spasticity was present in one of the two reported adults.
Dementia Dementia was present in one of the two reported adults.
Show evidence (2 references)
PMID:20855850 SUPPORT Human Clinical
"In both patients, MRI revealed extensive white matter disease."
Supports the reported adult association in two patients.
PMID:36341175 SUPPORT Human Clinical
"It is unclear whether the clinical features seen in reported patients are caused by the biochemical abnormalities, or whether they simply represent an ascertainment bias in patients that come to clinical attention."
Directly states why the reported association cannot yet be modeled as established causation.
Reported pediatric neurodevelopmental association of uncertain causality
Delayed speech, learning problems, and severe early neuromotor impairment have been reported in individual children with biochemical MGA1. Familial discordance, asymptomatic newborn-screened individuals, and the absence of a consistent childhood phenotype make causal attribution uncertain. This node is intentionally detached from the established biochemical causal chain.
Downstream
Delayed speech and language development Expressive speech delay is reported in some children, but penetrance and causal attribution are unknown.
Severe global developmental delay Severe psychomotor delay and neurologic impairment have been reported in an individual infant.
Show evidence (2 references)
PMID:21840233 SUPPORT Human Clinical
"The index case was a 14-year-old female with learning disability, attention deficit-hyperactivity and early onset subclinical leukoencephalopathy."
Documents neurodevelopmental findings in one molecularly confirmed sibling.
PMID:36341175 SUPPORT Human Clinical
"there is no clear evidence of a specific childhood-onset clinical phenotype associated with this disorder"
Qualifies the pediatric reports as associations of uncertain causality.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for 3-Methylglutaconic Aciduria Type I 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

8
Eye 1
Optic atrophy HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20855850 SUPPORT Human Clinical
"One patient additionally had optic atrophy, the other spasticity and dementia."
Supports a case-level observation only.
Musculoskeletal 1
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20855850 SUPPORT Human Clinical
"One patient additionally had optic atrophy, the other spasticity and dementia."
Supports a case-level observation only.
Nervous System 5
Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21840233 SUPPORT Human Clinical
"Her 9-year-old brother had severe expressive speech delay and delay in speech sound development with normal cognitive functions."
Case-level evidence for expressive speech delay.
PMID:36341175 SUPPORT Human Clinical
"there is no clear evidence of a specific childhood-onset clinical phenotype associated with this disorder"
Prevents interpreting speech delay as an established disease-wide phenotype.
Severe 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 (1 reference)
PMID:10070612 SUPPORT Human Clinical
"progressive neurological impairments presented as quadriplegia, athetoid movements and severe psychomotor retardation from 4 months of age"
Supports the severe case while not implying a frequency estimate.
Progressive ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251), qualified as course progressive. HP:0001251 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:20855850 SUPPORT Human Clinical
"presented in adulthood with progressive ataxia."
Directly supports progressive ataxia in the two adult cases.
PMID:36341175 SUPPORT Human Clinical
"It is unclear whether the clinical features seen in reported patients are caused by the biochemical abnormalities, or whether they simply represent an ascertainment bias in patients that come to clinical attention."
Qualifies causal attribution.
Leukoencephalopathy HP:0002352 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukoencephalopathy (HP:0002352), qualified as course progressive. HP:0002352 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:20855850 SUPPORT Human Clinical
"In both patients, MRI revealed extensive white matter disease."
Supports the reported adult imaging phenotype.
PMID:36341175 SUPPORT Human Clinical
"will be required to conclusively prove or disprove the association with adult-onset leukoencephalopathy"
Makes the uncertainty explicit.
Dementia HP:0000726 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dementia (HP:0000726). HP:0000726 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20855850 SUPPORT Human Clinical
"One patient additionally had optic atrophy, the other spasticity and dementia."
Supports a case-level observation only.
Other 1
3-Methylglutaconic aciduria HP:0003535 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is 3-Methylglutaconic aciduria (HP:0003535). HP:0003535 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36341175 SUPPORT Human Clinical
"causes the accumulation of urinary 3-methylglutaconate"
Establishes the defining biochemical phenotype without assigning a frequency band.
🧬

Genetic Associations

1
Biallelic AUH pathogenic variants
Gene: AUH hgnc:890 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is AUH (hgnc:890). hgnc:890 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:12655555 SUPPORT Human Clinical
"Molecular analyses in five patients from four independent families revealed homozygosity or compound heterozygosity for mutations in the AUH gene"
Establishes the biallelic molecular basis.
PMID:21840233 SUPPORT Human Clinical
"homozygous deletion of exons 1-3 within the AUH gene"
Documents an intragenic deletion allele.
PMID:35457240 SUPPORT Human Clinical
"two microdeletions in compound heterozygosity encompassing the AUH gene, which confirmed the diagnosis"
Shows that compound structural variants can underlie MGA1.
💊

Medical Actions

2
Leucine-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
Leucine restriction has been proposed from pathway logic and used in case reports, but no controlled evidence demonstrates neurologic benefit. Sustained intensive restriction may offer little benefit to asymptomatic individuals on current evidence and should not be represented as routine therapy; any use requires individualized metabolic-dietitian oversight.
Mechanism Target:
MODULATES Leucine-pathway organic-acid accumulation — Restriction is intended to reduce leucine substrate flux into the blocked pathway; clinical benefit is unproven.
Show evidence (2 references)
PMID:20855850 SUPPORT Other
"Dietary treatment with leucine restriction may be considered."
Supports only a proposal, not demonstrated efficacy.
PMID:36341175 SUPPORT Human Clinical
"The burdens of sustained treatment (particularly with intensive dietary leucine restriction) in asymptomatic individuals may be of little benefit, and likely to result in poor compliance."
Directly supports avoiding routine intensive restriction in asymptomatic individuals.
Levocarnitine supplementation
Action: carnitine supplementationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is carnitine supplementation, annotated with Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. Ontology label: Nutritional Support NCIT:C15433
Levocarnitine has been given with protein or leucine restriction in pediatric reports. These uncontrolled observations do not establish clinical benefit or a universal indication, and long-term asymptomatic outcomes are also reported without treatment.
Show evidence (3 references)
PMID:35457240 SUPPORT Human Clinical
"The patient was then supplemented with levocarnitine and protein intake was slowly decreased."
Documents use in one case without proving efficacy.
PMID:34333924 SUPPORT Human Clinical
"After being treated with leucine diet restriction and L-carnitine, 4 patients with AUH gene variation who were from asymptomatic phase developed normally"
Describes normal development under combined treatment but lacks an untreated comparison.
PMID:36341175 SUPPORT Human Clinical
"remain asymptomatic in the absence of treatment"
Shows that normal outcome cannot be attributed to supplementation from uncontrolled treated cases.
🔬

Biochemical Markers

6
Urinary 3-methylglutaconic acid (INCREASED)
Context: Persistent defining biochemical feature; magnitude varies.
Pathograph Readouts
Readout Of Leucine-pathway organic-acid accumulation Positive Diagnostic
Increased urinary 3-methylglutaconic acid is the defining readout of the AUH-dependent leucine block.
Show evidence (1 reference)
PMID:36341175 SUPPORT Human Clinical
"causes the accumulation of urinary 3-methylglutaconate"
Establishes the defining urinary metabolite.
Urinary 3-methylglutaric acid (INCREASED)
Context: Variably accompanies 3-methylglutaconic acid and may be absent.
Pathograph Readouts
Readout Of Leucine-pathway organic-acid accumulation Positive Diagnostic
Increased urinary 3-methylglutaric acid can accompany the primary 3-MGA profile.
Show evidence (1 reference)
PMID:36341175 SUPPORT Human Clinical
"with or without 3-hydroxyisovalerate and 3-methylglutarate"
Supports its variable rather than obligatory presence.
Urinary 3-hydroxyisovaleric acid (INCREASED)
Context: Variably accompanies 3-methylglutaconic acid and may be absent.
Pathograph Readouts
Readout Of Leucine-pathway organic-acid accumulation Positive Diagnostic
Increased urinary 3-hydroxyisovaleric acid can accompany the primary 3-MGA profile.
Show evidence (1 reference)
PMID:36341175 SUPPORT Human Clinical
"with or without 3-hydroxyisovalerate and 3-methylglutarate"
Supports its variable rather than obligatory presence.
Blood 3-hydroxyisovalerylcarnitine (C5-OH) (INCREASED)
Context: Newborn-screening clue; nonspecific and not predictive of outcome.
Pathograph Readouts
Readout Of Leucine-pathway organic-acid accumulation Positive Diagnostic
Elevated C5-OH can flag disturbed leucine metabolism but does not identify MGA1 by itself.
Show evidence (2 references)
PMID:35457240 SUPPORT Human Clinical
"detection of increased 3-hydroxyisovalerylcarnitine levels at newborn screening"
Documents C5-OH as the screening signal in a confirmed MGA1 case.
PMID:40937535 SUPPORT Human Clinical
"C5-OH concentrations of patients with different IEMs reported in the literature were insufficiently distinctive to differentiate between these diseases."
Establishes that C5-OH is nonspecific across inborn errors of metabolism.
3-methylglutaconyl-CoA hydratase activity in fibroblasts (DECREASED)
Context: Confirmatory functional measurement when molecular results are incomplete or discordant.
Pathograph Readouts
Readout Of AUH-dependent 3-methylglutaconyl-CoA hydratase deficiency Negative Diagnostic
Markedly reduced fibroblast enzyme activity directly reports the proximal enzymatic lesion.
Show evidence (1 reference)
PMID:21840233 SUPPORT In Vitro
"The diagnosis was confirmed by a demonstration of 3-methylglutaconyl-CoA hydratase enzyme deficiency in the cultured skin fibroblasts"
Cultured-fibroblast testing directly demonstrates the proximal enzyme deficiency.
Cerebrospinal-fluid 3-hydroxyisovaleric acid (INCREASED)
Context: Single late-onset adult case; not an established routine biomarker.
Pathograph Readouts
Readout Of Leucine-pathway organic-acid accumulation Positive
CSF enrichment demonstrates CNS exposure but does not establish neurotoxicity.
Show evidence (1 reference)
PMID:16541463 SUPPORT Human Clinical
"In the cerebrospinal fluid, the 3HIVA concentration was 10 times higher than in the plasma of the patient"
Documents CSF enrichment in one adult with late-onset leukoencephalopathy.
🔬

Diagnosis

5
C5-OH newborn-screening signal
Elevated 3-hydroxyisovalerylcarnitine can lead to detection of MGA1, but it is shared with other metabolic disorders and cannot establish the diagnosis or predict clinical outcome.
newborn screening
Results: Elevated C5-OH requiring confirmatory biochemical and molecular evaluation.
Show evidence (2 references)
PMID:35457240 SUPPORT Human Clinical
"detection of increased 3-hydroxyisovalerylcarnitine levels at newborn screening"
Supports C5-OH-based detection.
PMID:40937535 SUPPORT Human Clinical
"C5-OH concentrations of patients with different IEMs reported in the literature were insufficiently distinctive to differentiate between these diseases."
Supports the required cross-disease nonspecificity caveat.
Urine organic-acid analysis
Demonstrates persistent 3-methylglutaconic acid, with or without 3-methylglutaric and 3-hydroxyisovaleric acids. The pattern establishes biochemical suspicion but must be distinguished from secondary 3-MGA-urias.
urine chemistry measurement NCIT:C61044 NCI Thesaurus (NCIT)
Results: Increased urinary 3-methylglutaconic acid with variable 3-methylglutaric and 3-hydroxyisovaleric acids.
Show evidence (1 reference)
PMID:36341175 SUPPORT Human Clinical
"causes the accumulation of urinary 3-methylglutaconate, with or without 3-hydroxyisovalerate and 3-methylglutarate"
Defines the current biochemical diagnostic pattern.
Biallelic AUH testing with copy-number analysis
Molecular confirmation identifies biallelic pathogenic AUH variants. If sequencing or a targeted panel is negative or incomplete despite a compelling biochemical profile, deletion/duplication or broader structural-variant analysis should be considered because compound AUH-encompassing microdeletions are reported.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic AUH variants, including sequence or copy-number variants.
Show evidence (3 references)
PMID:12655555 SUPPORT Human Clinical
"revealed homozygosity or compound heterozygosity for mutations in the AUH gene"
Supports biallelic molecular confirmation.
PMID:35457240 SUPPORT Human Clinical
"A next-generation sequencing (NGS) panel for 3-methylglutaconic aciduria failed to establish a definitive diagnosis."
Demonstrates that a targeted sequencing panel can miss the causal structural variants.
PMID:35457240 SUPPORT Human Clinical
"single nucleotide polymorphism array analysis disclosed the presence of two microdeletions in compound heterozygosity encompassing the AUH gene, which confirmed the diagnosis"
Supports copy-number escalation when biochemical and sequencing results conflict.
Fibroblast 3-methylglutaconyl-CoA hydratase assay
A functional assay can demonstrate markedly deficient hydratase activity, especially when molecular testing is incomplete or reveals variants needing functional confirmation.
clinical laboratory procedure NCIT:C25294 NCI Thesaurus (NCIT)
Results: Markedly decreased 3-methylglutaconyl-CoA hydratase activity in cultured fibroblasts.
Show evidence (1 reference)
PMID:21840233 SUPPORT In Vitro
"The diagnosis was confirmed by a demonstration of 3-methylglutaconyl-CoA hydratase enzyme deficiency in the cultured skin fibroblasts"
Directly supports functional confirmation in cultured fibroblasts.
Leucine loading as a primary-versus-secondary biochemical discriminator
In a specialist study of 21 patients with different 3-MGA-urias, urinary 3-methylglutaconic acid increased after leucine loading only in AUH defect. This is evidence for pathway discrimination, not a routine first-line test or a substitute for molecular confirmation.
clinical laboratory procedure NCIT:C25294 NCI Thesaurus (NCIT)
Results: Selective post-load increase of urinary 3-methylglutaconic acid in AUH deficiency.
Show evidence (1 reference)
PMID:24757000 SUPPORT Human Clinical
"After leucine loading urinary 3-methylglutaconic acid levels increased only in the patients with an AUH defect."
Demonstrates biochemical discrimination of primary MGA1 from secondary 3-MGA-urias.
🩻

Imaging Findings

2
Extensive cerebral white-matter disease on adult MRI
Extensive cerebral white-matter disease was observed on MRI in two adults with the MGA1 biochemical phenotype and progressive ataxia.
Mri Extensive Reported adult-onset cases; association with MGA1 remains unproven.
Leukoencephalopathy HP:0002352 Human Phenotype Ontology (HP) brain white matter UBERON:0003544 Uberon multi-species anatomy ontology (UBERON) Leukoencephalopathy HP:0002352 Human Phenotype Ontology (HP)
Show evidence (2 references)
PMID:20855850 SUPPORT Human Clinical
"In both patients, MRI revealed extensive white matter disease."
Direct evidence for the adult MRI observation.
PMID:36341175 SUPPORT Human Clinical
"Longer-term follow-up of patients detected via NBS (or biochemical screening of large cohorts of asymptomatic adult individuals) will be required to conclusively prove or disprove the association with adult-onset leukoencephalopathy."
Qualifies the disease attribution of the imaging pattern.
Mild deep white-matter abnormalities on childhood follow-up MRI
Mild deep white-matter abnormalities were found on follow-up MRI in one 10-year-old who had earlier presented with isolated febrile seizures.
Mri Single pediatric follow-up observation; attribution uncertain.
Cerebral white-matter abnormality HP:0002500 Human Phenotype Ontology (HP) brain white matter UBERON:0003544 Uberon multi-species anatomy ontology (UBERON) Cerebral white-matter abnormality HP:0002500 Human Phenotype Ontology (HP)
Show evidence (1 reference)
PMID:20855850 SUPPORT Human Clinical
"Follow-up MRI in a 10-year-old boy, who presented earlier with isolated febrile seizures, showed mild abnormalities in deep white matter."
Directly supports the single pediatric imaging observation.
📈

Progression

3
Biochemical detection in infancy
Age: Newborn period
MGA1 can be detected in an asymptomatic infant through elevated C5-OH and a characteristic urine organic-acid profile. Detection does not predict later clinical disease.
Show evidence (1 reference)
PMID:35457240 SUPPORT Human Clinical
"detection of increased 3-hydroxyisovalerylcarnitine levels at newborn screening, which were associated with increased urinary excretion of 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and 3-methylglutaric acid"
Documents biochemical detection through newborn screening and confirmatory urine metabolites.
Childhood course
Age: Infancy through adolescence
The best available long-term newborn-screening cohort found no specific childhood-onset clinical phenotype. Speech, learning, behavioral, and severe neurologic findings have been reported in clinically ascertained cases, but their causal attribution to AUH deficiency is uncertain.
Show evidence (3 references)
PMID:36341175 SUPPORT Human Clinical
"there is no clear evidence of a specific childhood-onset clinical phenotype associated with this disorder"
Directly supports the conservative childhood natural-history framing.
PMID:21840233 SUPPORT Human Clinical
"We describe two siblings with 3-methylglutaconic aciduria type I with phenotypic heterogeneity."
Illustrates heterogeneous reported pediatric findings without establishing disease-wide penetrance.
PMID:38077954 SUPPORT Human Clinical
"She is now two years and six months old, and her physical growth and psychomotor development have progressed normally."
Adds a contemporary untreated newborn-screened case with normal early-childhood development.
Reported adult neurologic course
Age: Adulthood to late adulthood
Several clinically ascertained adults have developed slowly progressive ataxia and extensive white-matter disease, sometimes with optic atrophy, spasticity, or dementia. The number of cases is very small, and long-term newborn-screened cohorts have not yet proved that this association is causal.
Show evidence (2 references)
PMID:20855850 SUPPORT Human Clinical
"Two unrelated patients with the characteristic biochemical findings of 3- methylglutaconic aciduria type I presented in adulthood with progressive ataxia."
Documents the adult neurologic presentation in two clinically ascertained patients.
PMID:36341175 SUPPORT Human Clinical
"Longer-term follow-up of patients detected via NBS (or biochemical screening of large cohorts of asymptomatic adult individuals) will be required to conclusively prove or disprove the association with adult-onset leukoencephalopathy."
Qualifies the adult association as unproven rather than an inevitable disease phase.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population prevalence estimate is available. A 2022 cohort review described fewer than 30 published cases; case counts vary across reviews because of duplicate reports and uncertain clinical ascertainment.
Show evidence (1 reference)
PMID:36341175 SUPPORT Human Clinical
"It is an ultra-rare condition, with <30 cases published in the literature."
Provides the most recent explicit literature-count characterization.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from 3-Methylglutaconic Aciduria Type I:

Secondary 3-methylglutaconic acidurias
Overlapping Features TAZ/Barth, SERAC1/MEGDEL, OPA3/Costeff, DNAJC19/DCMA, TMEM70-related disease, and other mitochondrial disorders can produce persistent 3-methylglutaconic aciduria without an AUH-dependent leucine-catabolism block.
Distinguishing Features
  • Biallelic AUH variants and deficient 3-methylglutaconyl-CoA hydratase establish primary MGA1.
  • Secondary disorders are classified by their causal protein and syndrome-specific phenotype rather than by a numbered 3-MGA type.
  • In a specialist series, leucine loading increased urinary 3-methylglutaconic acid only in AUH defect.
Show evidence (2 references)
PMID:23296368 SUPPORT Other
"One should distinguish between "primary 3-methylglutaconic aciduria" formerly known as type I (3-methylglutaconyl-CoA hydratase deficiency, AUH defect) due to defective leucine catabolism and the--currently known--three groups of "secondary 3-methylglutaconic aciduria"."
Establishes the mechanism-based primary-versus-secondary distinction.
PMID:24757000 SUPPORT Human Clinical
"After leucine loading urinary 3-methylglutaconic acid levels increased only in the patients with an AUH defect."
Provides a biochemical discriminator supporting the mechanistic distinction.
3-hydroxy-3-methylglutaryl-CoA lyase deficiency
Overlapping Features HMGCL deficiency is an adjacent leucine-pathway disorder that can produce C5-OH, 3-methylglutaconic acid, 3-methylglutaric acid, and 3-hydroxyisovaleric acid. Unlike the uncertain clinical penetrance of MGA1, HMGCL deficiency can cause severe acute hypoketotic metabolic crises.
Distinguishing Features
  • Urinary 3-hydroxy-3-methylglutaric acid is a discriminating HMGCL-deficiency marker not expected in the core MGA1 profile.
  • Acute vomiting, acidosis, and hypoketotic hypoglycemia support HMGCL deficiency rather than uncomplicated MGA1.
  • HMGCL enzyme or molecular testing, rather than AUH testing, confirms the diagnosis.
Show evidence (2 references)
PMID:32685354 SUPPORT Human Clinical
"Patients with HMGCLD present with a diagnostic urinary pattern of elevated organic acids such as 3‐hydroxyisovaleric acid (3HIV‐A), 3‐methylglutaconic acid (3MGC‐A), 3‐hydroxy‐3‐methylglutaric acid (3H3MG‐A), 3‐methylglutaric acid (3MG‐A) and in some cases 3‐methylcrotonylglycine."
Establishes the overlapping profile and the distinguishing 3-hydroxy-3-methylglutaric acid marker.
PMID:32685354 SUPPORT Human Clinical
"Patients may suffer from severe attacks of metabolic decompensation with lethargy, seizures, hypotonia, vomiting and acidosis with hypoketotic hypoglycemia that may result in irreversible neurological damage."
Supports the acute hypoketotic-crisis distinction from MGA1.
Other disorders with an elevated C5-OH screening signal
Overlapping Features 3-methylcrotonyl-CoA carboxylase deficiency, beta-ketothiolase deficiency, multiple carboxylase deficiencies, and several other organic and mitochondrial disorders share the isobaric C5-OH screening transition. C5-OH alone therefore cannot identify MGA1.
Distinguishing Features
  • Resolve the signal with urine organic acids, enzyme assays, and molecular testing rather than C5-OH magnitude.
  • Confirm primary MGA1 with the characteristic urine profile plus deficient AUH activity or biallelic AUH variants.
Show evidence (4 references)
PMID:32685354 SUPPORT Human Clinical
"3‐methylcrotonyl‐CoA carboxylase deficiency"
Identifies 3MCC deficiency in the shared isobaric acylcarnitine differential.
PMID:32685354 SUPPORT Human Clinical
"β‐ketothiolase deficiency"
Identifies beta-ketothiolase deficiency in the shared isobaric acylcarnitine differential.
PMID:32685354 SUPPORT Human Clinical
"multiple carboxylase deficiency"
Identifies multiple carboxylase deficiency in the shared isobaric acylcarnitine differential.
+ 1 more reference
Not-otherwise-specified 3-methylglutaconic aciduria
Overlapping Features Significant, persistent 3-methylglutaconic aciduria can remain unexplained after AUH deficiency and known secondary syndromes are excluded. Such cases should not be assigned MGA1 without AUH or enzyme confirmation.
Distinguishing Features
  • No confirmatory biallelic AUH variants or deficient AUH enzyme activity.
  • Known secondary 3-MGA syndromes have been excluded but the pathomechanism remains unresolved.
Show evidence (1 reference)
PMID:23296368 SUPPORT Other
"should be referred to as "not otherwise specified (NOS) 3-MGA-uria" until elucidation of the underlying pathomechanism enables proper (possibly extended) classification."
Supports retaining an unresolved NOS category rather than misclassifying it as MGA1.
{ }

Source YAML

click to show 
name: 3-Methylglutaconic Aciduria Type I
creation_date: '2026-07-08T00:00:00Z'
category: Mendelian
synonyms:
- 3-Methylglutaconyl-CoA hydratase deficiency
- 3-MG-CoA hydratase deficiency
- AUH defect
- MGA1
- MGCA1
- Primary 3-methylglutaconic aciduria
description: >-
  3-Methylglutaconic aciduria type I (MGA1) is an autosomal recessive defect of
  leucine catabolism caused by biallelic pathogenic variants in AUH, which
  encodes mitochondrial 3-methylglutaconyl-CoA hydratase. The established
  phenotype is biochemical: deficient enzyme activity causes persistent urinary
  3-methylglutaconic acid, variably accompanied by 3-methylglutaric and
  3-hydroxyisovaleric acids, and can produce an elevated C5-OH newborn-screening
  signal. Clinical penetrance is unresolved. Long-term newborn-screened
  individuals have remained asymptomatic without treatment, whereas small,
  clinically ascertained series and case reports describe nonspecific pediatric
  neurodevelopmental findings and a possible adult-onset progressive
  leukoencephalopathy. Ascertainment bias prevents treating those neurologic
  findings as established consequences of the biochemical defect. MGA1 is the
  disorder historically termed primary 3-methylglutaconic aciduria; secondary
  3-methylglutaconic acidurias arise through other mitochondrial mechanisms
  rather than an AUH-dependent leucine-pathway block.
classifications:
  icimd_category:
  - classification_value: organic_acidurias
    notes: >-
      ICIMD places AUH-related MGA1 among the organic acidurias caused by a block
      in branched-chain amino-acid catabolism.
    evidence:
    - reference: PMID:36341175
      reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        3-Methylglutaconyl-CoA hydratase deficiency (MGA1) is a defect in leucine catabolism
      explanation: Supports classification as an intermediary-metabolism organic aciduria of leucine catabolism.
disease_term:
  preferred_term: 3-methylglutaconic aciduria type 1
  term:
    id: MONDO:0009610
    label: 3-methylglutaconic aciduria type 1
parents:
- Organic Aciduria
- Inborn Error of Metabolism
inheritance:
- name: Autosomal recessive inheritance with incomplete clinical penetrance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    Biallelic AUH variants establish the biochemical disorder, but a specific
    clinical phenotype is not consistently expressed. Complete enzyme absence
    and long follow-up after newborn-screening detection can be compatible with
    normal development and absence of neurologic symptoms.
  evidence:
  - reference: PMID:12655555
    reference_title: Mutations in the AUH gene cause 3-methylglutaconic aciduria type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Complete absence of 3-methylglutaconyl-CoA hydratase/AUH appears to be
      compatible with normal development in some cases.
    explanation: Biallelic loss of AUH function does not invariably produce a clinical phenotype.
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      all four patients diagnosed through NBS (including three with over
      18 years of clinical follow-up) remain asymptomatic in the absence of treatment
    explanation: Long-term untreated follow-up directly supports incomplete clinical penetrance.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence estimate is available. A 2022 cohort review
    described fewer than 30 published cases; case counts vary across reviews
    because of duplicate reports and uncertain clinical ascertainment.
  evidence:
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It is an ultra-rare condition, with <30 cases published in the literature.
    explanation: Provides the most recent explicit literature-count characterization.
progression:
- phase: Biochemical detection in infancy
  age_range: Newborn period
  notes: >-
    MGA1 can be detected in an asymptomatic infant through elevated C5-OH and a
    characteristic urine organic-acid profile. Detection does not predict later
    clinical disease.
  evidence:
  - reference: PMID:35457240
    reference_title: "3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      detection of increased 3-hydroxyisovalerylcarnitine levels at newborn
      screening, which were associated with increased urinary excretion of
      3-methylglutaconic acid, 3-hydroxyisovaleric acid, and 3-methylglutaric acid
    explanation: Documents biochemical detection through newborn screening and confirmatory urine metabolites.
- phase: Childhood course
  age_range: Infancy through adolescence
  notes: >-
    The best available long-term newborn-screening cohort found no specific
    childhood-onset clinical phenotype. Speech, learning, behavioral, and severe
    neurologic findings have been reported in clinically ascertained cases, but
    their causal attribution to AUH deficiency is uncertain.
  evidence:
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there is no clear evidence of a specific childhood-onset clinical phenotype associated with this disorder
    explanation: Directly supports the conservative childhood natural-history framing.
  - reference: PMID:21840233
    reference_title: Phenotypic heterogeneity in two siblings with 3-methylglutaconic aciduria type I caused by a novel intragenic deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe two siblings with 3-methylglutaconic aciduria type I with phenotypic heterogeneity.
    explanation: Illustrates heterogeneous reported pediatric findings without establishing disease-wide penetrance.
  - reference: PMID:38077954
    reference_title: Asymptomatic 3-methylglutaconic aciduria type 1 detected by high C5-OH on newborn screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She is now two years and six months old, and her physical growth and
      psychomotor development have progressed normally.
    explanation: Adds a contemporary untreated newborn-screened case with normal early-childhood development.
- phase: Reported adult neurologic course
  age_range: Adulthood to late adulthood
  notes: >-
    Several clinically ascertained adults have developed slowly progressive
    ataxia and extensive white-matter disease, sometimes with optic atrophy,
    spasticity, or dementia. The number of cases is very small, and long-term
    newborn-screened cohorts have not yet proved that this association is causal.
  evidence:
  - reference: PMID:20855850
    reference_title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two unrelated patients with the characteristic biochemical findings of
      3- methylglutaconic aciduria type I presented in adulthood with progressive ataxia.
    explanation: Documents the adult neurologic presentation in two clinically ascertained patients.
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Longer-term follow-up of patients detected via NBS (or biochemical screening
      of large cohorts of asymptomatic adult individuals) will be required to
      conclusively prove or disprove the association with adult-onset leukoencephalopathy.
    explanation: Qualifies the adult association as unproven rather than an inevitable disease phase.
pathophysiology:
- name: AUH-dependent 3-methylglutaconyl-CoA hydratase deficiency
  conforms_to: metabolic_intoxication_decompensation#Enzymatic Block in Intermediary Metabolism
  mechanism_confidence: ESTABLISHED
  description: >-
    Biallelic pathogenic variants in AUH reduce or abolish mitochondrial
    3-methylglutaconyl-CoA hydratase activity. The enzyme catalyzes conversion of
    3-methylglutaconyl-CoA to 3-hydroxy-3-methylglutaryl-CoA in leucine
    degradation.
  genes:
  - preferred_term: AUH
    term:
      id: hgnc:890
      label: AUH
  molecular_functions:
  - preferred_term: methylglutaconyl-CoA hydratase activity
    term:
      id: GO:0004490
      label: methylglutaconyl-CoA hydratase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: L-leucine catabolic process
    term:
      id: GO:0006552
      label: L-leucine catabolic process
    modifier: DECREASED
  cellular_components:
  - preferred_term: mitochondrial matrix
    term:
      id: GO:0005759
      label: mitochondrial matrix
  evidence:
  - reference: PMID:12434311
    reference_title: 3-Methylglutaconic aciduria type I is caused by mutations in AUH.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: we show that 3-methylglutaconyl-CoA hydratase is encoded by the AUH gene
    explanation: Establishes AUH as the gene encoding the deficient enzyme.
  - reference: PMID:16640564
    reference_title: Biochemical characterization of human 3-methylglutaconyl-CoA hydratase and its role in leucine metabolism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The only missense mutation found in MGA1 phenotypes, c.719C>T, leading to
      the amino acid exchange A240V, produces an enzyme with only 9% of the
      wild-type 3-MG-CoA hydratase activity.
    explanation: Functional expression data show severe loss of hydratase activity from an AUH missense allele.
  downstream:
  - target: Leucine-pathway organic-acid accumulation
    description: The hydratase block causes the characteristic primary 3-methylglutaconic aciduria biochemical profile.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12434311
      reference_title: 3-Methylglutaconic aciduria type I is caused by mutations in AUH.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This results in elevated urinary levels of 3-methylglutaconic acid,
        3-methylglutaric acid, and 3-hydroxyisovaleric acid.
      explanation: Directly links the AUH-dependent enzyme deficiency to the urine organic-acid profile.
- name: Leucine-pathway organic-acid accumulation
  mechanism_confidence: ESTABLISHED
  description: >-
    The AUH-dependent leucine-catabolism block produces persistent urinary
    3-methylglutaconic acid, with variable 3-hydroxyisovaleric and
    3-methylglutaric acids. These metabolites are diagnostic readouts. Their
    toxicity and any causal connection to neurologic disease have not been
    demonstrated, so this node does not conform to a toxic-metabolite or
    energy-deficit mechanism module.
  chemical_entities:
  - preferred_term: 3-methylglutaconic acid
    term:
      id: CHEBI:144330
      label: 3-methylglutaconic acid
    modifier: INCREASED
  - preferred_term: 3-methylglutaric acid
    term:
      id: CHEBI:68566
      label: 3-methylglutaric acid
    modifier: INCREASED
  - preferred_term: 3-hydroxyisovaleric acid
    term:
      id: CHEBI:37084
      label: 3-hydroxyisovaleric acid
    modifier: INCREASED
  evidence:
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      causes the accumulation of urinary 3-methylglutaconate, with or without
      3-hydroxyisovalerate and 3-methylglutarate
    explanation: Establishes the invariant and variable components of the biochemical profile.
  - reference: PMID:16640564
    reference_title: Biochemical characterization of human 3-methylglutaconyl-CoA hydratase and its role in leucine metabolism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      excessive urinary excretion of 3-methylglutaconic acid, 3-methylglutaric
      acid and 3-hydroxyisovaleric acid
    explanation: Independently supports the characteristic urine organic-acid pattern.
  downstream:
  - target: 3-Methylglutaconic aciduria
    description: Persistent urinary 3-methylglutaconic acid is the defining phenotypic expression of the biochemical block.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36341175
      reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: causes the accumulation of urinary 3-methylglutaconate
      explanation: Directly connects the established accumulation mechanism to the biochemical phenotype.
- name: Reported adult leukoencephalopathy association of uncertain causality
  mechanism_confidence: HYPOTHETICAL
  description: >-
    A small number of adults with biochemical and genetic MGA1 have been
    reported with progressive ataxia and extensive cerebral white-matter
    disease. The causal path from AUH deficiency or its metabolites to
    white-matter injury is unknown, and ascertainment bias remains a viable
    explanation. This clinical-association node is intentionally detached from
    the established biochemical causal chain.
  locations:
  - preferred_term: brain white matter
    term:
      id: UBERON:0003544
      label: brain white matter
  evidence:
  - reference: PMID:20855850
    reference_title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In both patients, MRI revealed extensive white matter disease.
    explanation: Supports the reported adult association in two patients.
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is unclear whether the clinical features seen in reported patients are
      caused by the biochemical abnormalities, or whether they simply represent
      an ascertainment bias in patients that come to clinical attention.
    explanation: Directly states why the reported association cannot yet be modeled as established causation.
  downstream:
  - target: Leukoencephalopathy
    description: Extensive white-matter disease is the defining imaging observation in the reported adult cases.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20855850
      reference_title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In both patients, MRI revealed extensive white matter disease.
      explanation: Links the provisional clinical-association node to the reported imaging phenotype.
  - target: Progressive ataxia
    description: Progressive ataxia was the shared presenting feature of two reported adults.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20855850
      reference_title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: presented in adulthood with progressive ataxia.
      explanation: Directly supports the shared adult presentation.
  - target: Optic atrophy
    description: Optic atrophy was present in one of the two reported adults.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20855850
      reference_title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: One patient additionally had optic atrophy, the other spasticity and dementia.
      explanation: Supports optic atrophy as a case-level, not disease-wide, association.
  - target: Spasticity
    description: Spasticity was present in one of the two reported adults.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20855850
      reference_title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: One patient additionally had optic atrophy, the other spasticity and dementia.
      explanation: Supports spasticity as a case-level association.
  - target: Dementia
    description: Dementia was present in one of the two reported adults.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20855850
      reference_title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: One patient additionally had optic atrophy, the other spasticity and dementia.
      explanation: Supports dementia as a case-level association.
- name: Reported pediatric neurodevelopmental association of uncertain causality
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Delayed speech, learning problems, and severe early neuromotor impairment
    have been reported in individual children with biochemical MGA1. Familial
    discordance, asymptomatic newborn-screened individuals, and the absence of a
    consistent childhood phenotype make causal attribution uncertain. This node
    is intentionally detached from the established biochemical causal chain.
  evidence:
  - reference: PMID:21840233
    reference_title: Phenotypic heterogeneity in two siblings with 3-methylglutaconic aciduria type I caused by a novel intragenic deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The index case was a 14-year-old female with learning disability,
      attention deficit-hyperactivity and early onset subclinical leukoencephalopathy.
    explanation: Documents neurodevelopmental findings in one molecularly confirmed sibling.
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there is no clear evidence of a specific childhood-onset clinical phenotype associated with this disorder
    explanation: Qualifies the pediatric reports as associations of uncertain causality.
  downstream:
  - target: Delayed speech and language development
    description: Expressive speech delay is reported in some children, but penetrance and causal attribution are unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21840233
      reference_title: Phenotypic heterogeneity in two siblings with 3-methylglutaconic aciduria type I caused by a novel intragenic deletion.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Her 9-year-old brother had severe expressive speech delay and delay in
        speech sound development with normal cognitive functions.
      explanation: Documents speech delay in a molecularly confirmed child while preserving normal cognition.
  - target: Severe global developmental delay
    description: Severe psychomotor delay and neurologic impairment have been reported in an individual infant.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10070612
      reference_title: "3-Methylglutaconic aciduria type I: clinical heterogeneity as a neurometabolic disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        progressive neurological impairments presented as quadriplegia, athetoid
        movements and severe psychomotor retardation from 4 months of age
      explanation: Supports a severe pediatric case report, not a general MGA1 phenotype.
phenotypes:
- name: 3-Methylglutaconic aciduria
  description: Persistent increased urinary 3-methylglutaconic acid is the defining biochemical phenotype.
  context: Established biochemical phenotype; not a clinical-penetrance assertion.
  phenotype_term:
    preferred_term: 3-Methylglutaconic aciduria
    term:
      id: HP:0003535
      label: 3-Methylglutaconic aciduria
  evidence:
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: causes the accumulation of urinary 3-methylglutaconate
    explanation: Establishes the defining biochemical phenotype without assigning a frequency band.
- name: Delayed speech and language development
  description: >-
    Expressive speech delay has been reported in individual children. Current
    cohort evidence does not establish it as a penetrant consequence of AUH
    deficiency.
  context: Reported pediatric cases; causal attribution uncertain.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:21840233
    reference_title: Phenotypic heterogeneity in two siblings with 3-methylglutaconic aciduria type I caused by a novel intragenic deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her 9-year-old brother had severe expressive speech delay and delay in
      speech sound development with normal cognitive functions.
    explanation: Case-level evidence for expressive speech delay.
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there is no clear evidence of a specific childhood-onset clinical phenotype associated with this disorder
    explanation: Prevents interpreting speech delay as an established disease-wide phenotype.
- name: Severe global developmental delay
  description: >-
    Severe psychomotor retardation with quadriplegia and athetoid movements was
    described in one infant; its generalizability and causal relationship to
    AUH deficiency remain uncertain.
  context: Single severe pediatric case; causal attribution uncertain.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:10070612
    reference_title: "3-Methylglutaconic aciduria type I: clinical heterogeneity as a neurometabolic disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      progressive neurological impairments presented as quadriplegia, athetoid
      movements and severe psychomotor retardation from 4 months of age
    explanation: Supports the severe case while not implying a frequency estimate.
- name: Progressive ataxia
  description: Progressive ataxia was the shared presenting feature of two reported adults.
  context: Reported adult-onset cases; disease association not yet proven.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20855850
    reference_title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: presented in adulthood with progressive ataxia.
    explanation: Directly supports progressive ataxia in the two adult cases.
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is unclear whether the clinical features seen in reported patients are
      caused by the biochemical abnormalities, or whether they simply represent
      an ascertainment bias in patients that come to clinical attention.
    explanation: Qualifies causal attribution.
- name: Leukoencephalopathy
  description: >-
    Extensive white-matter disease was present in reported adults and mild deep
    white-matter abnormalities in one child; the association with AUH deficiency
    remains unproven.
  context: Reported adult and pediatric cases; causal attribution uncertain.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20855850
    reference_title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In both patients, MRI revealed extensive white matter disease.
    explanation: Supports the reported adult imaging phenotype.
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      will be required to conclusively prove or disprove the association with adult-onset leukoencephalopathy
    explanation: Makes the uncertainty explicit.
- name: Optic atrophy
  description: Optic atrophy occurred in one reported adult case.
  context: Single reported adult; causal attribution uncertain.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:20855850
    reference_title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One patient additionally had optic atrophy, the other spasticity and dementia.
    explanation: Supports a case-level observation only.
- name: Spasticity
  description: Spasticity occurred in one reported adult case.
  context: Single reported adult; causal attribution uncertain.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:20855850
    reference_title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One patient additionally had optic atrophy, the other spasticity and dementia.
    explanation: Supports a case-level observation only.
- name: Dementia
  description: Dementia occurred in one reported adult case.
  context: Single reported adult; causal attribution uncertain.
  phenotype_term:
    preferred_term: Dementia
    term:
      id: HP:0000726
      label: Dementia
  evidence:
  - reference: PMID:20855850
    reference_title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One patient additionally had optic atrophy, the other spasticity and dementia.
    explanation: Supports a case-level observation only.
imaging_findings:
- name: Extensive cerebral white-matter disease on adult MRI
  modality: MRI
  imaging_finding_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  located_in:
    preferred_term: brain white matter
    term:
      id: UBERON:0003544
      label: brain white matter
  spatial_extent: EXTENSIVE
  diagnostic: false
  context: Reported adult-onset cases; association with MGA1 remains unproven.
  description: >-
    Extensive cerebral white-matter disease was observed on MRI in two adults
    with the MGA1 biochemical phenotype and progressive ataxia.
  evidence:
  - reference: PMID:20855850
    reference_title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In both patients, MRI revealed extensive white matter disease.
    explanation: Direct evidence for the adult MRI observation.
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Longer-term follow-up of patients detected via NBS (or biochemical screening
      of large cohorts of asymptomatic adult individuals) will be required to
      conclusively prove or disprove the association with adult-onset leukoencephalopathy.
    explanation: Qualifies the disease attribution of the imaging pattern.
- name: Mild deep white-matter abnormalities on childhood follow-up MRI
  modality: MRI
  imaging_finding_term:
    preferred_term: Cerebral white-matter abnormality
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  phenotype_term:
    preferred_term: Cerebral white-matter abnormality
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  located_in:
    preferred_term: brain white matter
    term:
      id: UBERON:0003544
      label: brain white matter
  diagnostic: false
  context: Single pediatric follow-up observation; attribution uncertain.
  description: >-
    Mild deep white-matter abnormalities were found on follow-up MRI in one
    10-year-old who had earlier presented with isolated febrile seizures.
  evidence:
  - reference: PMID:20855850
    reference_title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Follow-up MRI in a 10-year-old boy, who presented earlier with isolated
      febrile seizures, showed mild abnormalities in deep white matter.
    explanation: Directly supports the single pediatric imaging observation.
biochemical:
- name: Urinary 3-methylglutaconic acid
  presence: INCREASED
  context: Persistent defining biochemical feature; magnitude varies.
  biomarker_term:
    preferred_term: 3-methylglutaconic acid
    term:
      id: CHEBI:144330
      label: 3-methylglutaconic acid
  readouts:
  - target: Leucine-pathway organic-acid accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased urinary 3-methylglutaconic acid is the defining readout of the AUH-dependent leucine block.
  evidence:
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: causes the accumulation of urinary 3-methylglutaconate
    explanation: Establishes the defining urinary metabolite.
- name: Urinary 3-methylglutaric acid
  presence: INCREASED
  context: Variably accompanies 3-methylglutaconic acid and may be absent.
  biomarker_term:
    preferred_term: 3-methylglutaric acid
    term:
      id: CHEBI:68566
      label: 3-methylglutaric acid
  readouts:
  - target: Leucine-pathway organic-acid accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased urinary 3-methylglutaric acid can accompany the primary 3-MGA profile.
  evidence:
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with or without 3-hydroxyisovalerate and 3-methylglutarate
    explanation: Supports its variable rather than obligatory presence.
- name: Urinary 3-hydroxyisovaleric acid
  presence: INCREASED
  context: Variably accompanies 3-methylglutaconic acid and may be absent.
  biomarker_term:
    preferred_term: 3-hydroxyisovaleric acid
    term:
      id: CHEBI:37084
      label: 3-hydroxyisovaleric acid
  readouts:
  - target: Leucine-pathway organic-acid accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased urinary 3-hydroxyisovaleric acid can accompany the primary 3-MGA profile.
  evidence:
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with or without 3-hydroxyisovalerate and 3-methylglutarate
    explanation: Supports its variable rather than obligatory presence.
- name: Blood 3-hydroxyisovalerylcarnitine (C5-OH)
  presence: INCREASED
  context: Newborn-screening clue; nonspecific and not predictive of outcome.
  biomarker_term:
    preferred_term: 3-hydroxyisovalerylcarnitine
    term:
      id: CHEBI:73027
      label: 3-hydroxyisovalerylcarnitine
  readouts:
  - target: Leucine-pathway organic-acid accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Elevated C5-OH can flag disturbed leucine metabolism but does not identify MGA1 by itself.
  evidence:
  - reference: PMID:35457240
    reference_title: "3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: detection of increased 3-hydroxyisovalerylcarnitine levels at newborn screening
    explanation: Documents C5-OH as the screening signal in a confirmed MGA1 case.
  - reference: PMID:40937535
    reference_title: "Evaluation of Newborn Screening for Diseases Using C5-OH as a Marker: Systematic Review of the Literature and Evaluation of 17 Years of C5-OH Screening in the Netherlands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      C5-OH concentrations of patients with different IEMs reported in the
      literature were insufficiently distinctive to differentiate between these diseases.
    explanation: Establishes that C5-OH is nonspecific across inborn errors of metabolism.
- name: 3-methylglutaconyl-CoA hydratase activity in fibroblasts
  presence: DECREASED
  context: Confirmatory functional measurement when molecular results are incomplete or discordant.
  biomarker_term:
    preferred_term: methylglutaconyl-CoA hydratase activity
    term:
      id: GO:0004490
      label: methylglutaconyl-CoA hydratase activity
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  readouts:
  - target: AUH-dependent 3-methylglutaconyl-CoA hydratase deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Markedly reduced fibroblast enzyme activity directly reports the proximal enzymatic lesion.
  evidence:
  - reference: PMID:21840233
    reference_title: Phenotypic heterogeneity in two siblings with 3-methylglutaconic aciduria type I caused by a novel intragenic deletion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The diagnosis was confirmed by a demonstration of 3-methylglutaconyl-CoA
      hydratase enzyme deficiency in the cultured skin fibroblasts
    explanation: Cultured-fibroblast testing directly demonstrates the proximal enzyme deficiency.
- name: Cerebrospinal-fluid 3-hydroxyisovaleric acid
  presence: INCREASED
  context: Single late-onset adult case; not an established routine biomarker.
  biomarker_term:
    preferred_term: 3-hydroxyisovaleric acid
    term:
      id: CHEBI:37084
      label: 3-hydroxyisovaleric acid
  readouts:
  - target: Leucine-pathway organic-acid accumulation
    relationship: READOUT_OF
    direction: POSITIVE
    interpretation: CSF enrichment demonstrates CNS exposure but does not establish neurotoxicity.
  evidence:
  - reference: PMID:16541463
    reference_title: NMR spectroscopic studies on the late onset form of 3-methylglutaconic aciduria type I and other defects in leucine metabolism.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the cerebrospinal fluid, the 3HIVA concentration was 10 times higher
      than in the plasma of the patient
    explanation: Documents CSF enrichment in one adult with late-onset leukoencephalopathy.
genetic:
- name: Biallelic AUH pathogenic variants
  gene_term:
    preferred_term: AUH
    term:
      id: hgnc:890
      label: AUH
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    Reported pathogenic alleles include sequence variants affecting AUH
    function and intragenic or gene-encompassing deletions. The clinical outcome
    cannot be predicted from residual activity or variant class; copy-number
    analysis is important when a strong biochemical phenotype is not explained
    by routine sequencing.
  evidence:
  - reference: PMID:12655555
    reference_title: Mutations in the AUH gene cause 3-methylglutaconic aciduria type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular analyses in five patients from four independent families
      revealed homozygosity or compound heterozygosity for mutations in the AUH gene
    explanation: Establishes the biallelic molecular basis.
  - reference: PMID:21840233
    reference_title: Phenotypic heterogeneity in two siblings with 3-methylglutaconic aciduria type I caused by a novel intragenic deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: homozygous deletion of exons 1-3 within the AUH gene
    explanation: Documents an intragenic deletion allele.
  - reference: PMID:35457240
    reference_title: "3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      two microdeletions in compound heterozygosity encompassing the AUH gene,
      which confirmed the diagnosis
    explanation: Shows that compound structural variants can underlie MGA1.
diagnosis:
- name: C5-OH newborn-screening signal
  diagnosis_term:
    preferred_term: newborn screening
  description: >-
    Elevated 3-hydroxyisovalerylcarnitine can lead to detection of MGA1, but it
    is shared with other metabolic disorders and cannot establish the diagnosis
    or predict clinical outcome.
  results: Elevated C5-OH requiring confirmatory biochemical and molecular evaluation.
  evidence:
  - reference: PMID:35457240
    reference_title: "3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: detection of increased 3-hydroxyisovalerylcarnitine levels at newborn screening
    explanation: Supports C5-OH-based detection.
  - reference: PMID:40937535
    reference_title: "Evaluation of Newborn Screening for Diseases Using C5-OH as a Marker: Systematic Review of the Literature and Evaluation of 17 Years of C5-OH Screening in the Netherlands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      C5-OH concentrations of patients with different IEMs reported in the
      literature were insufficiently distinctive to differentiate between these diseases.
    explanation: Supports the required cross-disease nonspecificity caveat.
- name: Urine organic-acid analysis
  diagnosis_term:
    preferred_term: urine chemistry measurement
    term:
      id: NCIT:C61044
      label: Urine Chemistry Measurement
  description: >-
    Demonstrates persistent 3-methylglutaconic acid, with or without
    3-methylglutaric and 3-hydroxyisovaleric acids. The pattern establishes
    biochemical suspicion but must be distinguished from secondary 3-MGA-urias.
  results: Increased urinary 3-methylglutaconic acid with variable 3-methylglutaric and 3-hydroxyisovaleric acids.
  evidence:
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      causes the accumulation of urinary 3-methylglutaconate, with or without
      3-hydroxyisovalerate and 3-methylglutarate
    explanation: Defines the current biochemical diagnostic pattern.
- name: Biallelic AUH testing with copy-number analysis
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Molecular confirmation identifies biallelic pathogenic AUH variants. If
    sequencing or a targeted panel is negative or incomplete despite a
    compelling biochemical profile, deletion/duplication or broader
    structural-variant analysis should be considered because compound
    AUH-encompassing microdeletions are reported.
  results: Biallelic pathogenic AUH variants, including sequence or copy-number variants.
  evidence:
  - reference: PMID:12655555
    reference_title: Mutations in the AUH gene cause 3-methylglutaconic aciduria type I.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      revealed homozygosity or compound heterozygosity for mutations in the AUH gene
    explanation: Supports biallelic molecular confirmation.
  - reference: PMID:35457240
    reference_title: "3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A next-generation sequencing (NGS) panel for 3-methylglutaconic aciduria
      failed to establish a definitive diagnosis.
    explanation: Demonstrates that a targeted sequencing panel can miss the causal structural variants.
  - reference: PMID:35457240
    reference_title: "3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      single nucleotide polymorphism array analysis disclosed the presence of
      two microdeletions in compound heterozygosity encompassing the AUH gene,
      which confirmed the diagnosis
    explanation: Supports copy-number escalation when biochemical and sequencing results conflict.
- name: Fibroblast 3-methylglutaconyl-CoA hydratase assay
  diagnosis_term:
    preferred_term: clinical laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  description: >-
    A functional assay can demonstrate markedly deficient hydratase activity,
    especially when molecular testing is incomplete or reveals variants needing
    functional confirmation.
  results: Markedly decreased 3-methylglutaconyl-CoA hydratase activity in cultured fibroblasts.
  evidence:
  - reference: PMID:21840233
    reference_title: Phenotypic heterogeneity in two siblings with 3-methylglutaconic aciduria type I caused by a novel intragenic deletion.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The diagnosis was confirmed by a demonstration of 3-methylglutaconyl-CoA
      hydratase enzyme deficiency in the cultured skin fibroblasts
    explanation: Directly supports functional confirmation in cultured fibroblasts.
- name: Leucine loading as a primary-versus-secondary biochemical discriminator
  diagnosis_term:
    preferred_term: clinical laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  description: >-
    In a specialist study of 21 patients with different 3-MGA-urias, urinary
    3-methylglutaconic acid increased after leucine loading only in AUH defect.
    This is evidence for pathway discrimination, not a routine first-line test
    or a substitute for molecular confirmation.
  results: Selective post-load increase of urinary 3-methylglutaconic acid in AUH deficiency.
  evidence:
  - reference: PMID:24757000
    reference_title: Leucine Loading Test is Only Discriminative for 3-Methylglutaconic Aciduria Due to AUH Defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After leucine loading urinary 3-methylglutaconic acid levels increased only in the patients with an AUH defect.
    explanation: Demonstrates biochemical discrimination of primary MGA1 from secondary 3-MGA-urias.
differential_diagnoses:
- name: Secondary 3-methylglutaconic acidurias
  description: >-
    TAZ/Barth, SERAC1/MEGDEL, OPA3/Costeff, DNAJC19/DCMA, TMEM70-related disease,
    and other mitochondrial disorders can produce persistent
    3-methylglutaconic aciduria without an AUH-dependent leucine-catabolism
    block.
  distinguishing_features:
  - Biallelic AUH variants and deficient 3-methylglutaconyl-CoA hydratase establish primary MGA1.
  - Secondary disorders are classified by their causal protein and syndrome-specific phenotype rather than by a numbered 3-MGA type.
  - In a specialist series, leucine loading increased urinary 3-methylglutaconic acid only in AUH defect.
  evidence:
  - reference: PMID:23296368
    reference_title: "Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      One should distinguish between "primary 3-methylglutaconic aciduria"
      formerly known as type I (3-methylglutaconyl-CoA hydratase deficiency,
      AUH defect) due to defective leucine catabolism and the--currently
      known--three groups of "secondary 3-methylglutaconic aciduria".
    explanation: Establishes the mechanism-based primary-versus-secondary distinction.
  - reference: PMID:24757000
    reference_title: Leucine Loading Test is Only Discriminative for 3-Methylglutaconic Aciduria Due to AUH Defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After leucine loading urinary 3-methylglutaconic acid levels increased only in the patients with an AUH defect.
    explanation: Provides a biochemical discriminator supporting the mechanistic distinction.
- name: 3-hydroxy-3-methylglutaryl-CoA lyase deficiency
  description: >-
    HMGCL deficiency is an adjacent leucine-pathway disorder that can produce
    C5-OH, 3-methylglutaconic acid, 3-methylglutaric acid, and
    3-hydroxyisovaleric acid. Unlike the uncertain clinical penetrance of MGA1,
    HMGCL deficiency can cause severe acute hypoketotic metabolic crises.
  distinguishing_features:
  - Urinary 3-hydroxy-3-methylglutaric acid is a discriminating HMGCL-deficiency marker not expected in the core MGA1 profile.
  - Acute vomiting, acidosis, and hypoketotic hypoglycemia support HMGCL deficiency rather than uncomplicated MGA1.
  - HMGCL enzyme or molecular testing, rather than AUH testing, confirms the diagnosis.
  evidence:
  - reference: PMID:32685354
    reference_title: A newborn screening approach to diagnose 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients with HMGCLD present with a diagnostic urinary pattern of elevated
      organic acids such as 3‐hydroxyisovaleric acid (3HIV‐A),
      3‐methylglutaconic acid (3MGC‐A), 3‐hydroxy‐3‐methylglutaric acid
      (3H3MG‐A), 3‐methylglutaric acid (3MG‐A) and in some cases
      3‐methylcrotonylglycine.
    explanation: Establishes the overlapping profile and the distinguishing 3-hydroxy-3-methylglutaric acid marker.
  - reference: PMID:32685354
    reference_title: A newborn screening approach to diagnose 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients may suffer from severe attacks of metabolic decompensation with
      lethargy, seizures, hypotonia, vomiting and acidosis with hypoketotic
      hypoglycemia that may result in irreversible neurological damage.
    explanation: Supports the acute hypoketotic-crisis distinction from MGA1.
- name: Other disorders with an elevated C5-OH screening signal
  description: >-
    3-methylcrotonyl-CoA carboxylase deficiency, beta-ketothiolase deficiency,
    multiple carboxylase deficiencies, and several other organic and
    mitochondrial disorders share the isobaric C5-OH screening transition.
    C5-OH alone therefore cannot identify MGA1.
  distinguishing_features:
  - Resolve the signal with urine organic acids, enzyme assays, and molecular testing rather than C5-OH magnitude.
  - Confirm primary MGA1 with the characteristic urine profile plus deficient AUH activity or biallelic AUH variants.
  evidence:
  - reference: PMID:32685354
    reference_title: A newborn screening approach to diagnose 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 3‐methylcrotonyl‐CoA carboxylase deficiency
    explanation: Identifies 3MCC deficiency in the shared isobaric acylcarnitine differential.
  - reference: PMID:32685354
    reference_title: A newborn screening approach to diagnose 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: β‐ketothiolase deficiency
    explanation: Identifies beta-ketothiolase deficiency in the shared isobaric acylcarnitine differential.
  - reference: PMID:32685354
    reference_title: A newborn screening approach to diagnose 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: multiple carboxylase deficiency
    explanation: Identifies multiple carboxylase deficiency in the shared isobaric acylcarnitine differential.
  - reference: PMID:32685354
    reference_title: A newborn screening approach to diagnose 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In order to distinguish between these disorders, a patient must be recalled
      for urine sampling and/or analysis of enzyme activities.
    explanation: Supports biochemical resolution beyond the screening marker.
- name: Not-otherwise-specified 3-methylglutaconic aciduria
  description: >-
    Significant, persistent 3-methylglutaconic aciduria can remain unexplained
    after AUH deficiency and known secondary syndromes are excluded. Such cases
    should not be assigned MGA1 without AUH or enzyme confirmation.
  distinguishing_features:
  - No confirmatory biallelic AUH variants or deficient AUH enzyme activity.
  - Known secondary 3-MGA syndromes have been excluded but the pathomechanism remains unresolved.
  evidence:
  - reference: PMID:23296368
    reference_title: "Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      should be referred to as "not otherwise specified (NOS) 3-MGA-uria" until
      elucidation of the underlying pathomechanism enables proper (possibly extended) classification.
    explanation: Supports retaining an unresolved NOS category rather than misclassifying it as MGA1.
treatments:
- name: Leucine-restricted diet
  description: >-
    Leucine restriction has been proposed from pathway logic and used in case
    reports, but no controlled evidence demonstrates neurologic benefit.
    Sustained intensive restriction may offer little benefit to asymptomatic
    individuals on current evidence and should not be represented as routine
    therapy; any use requires individualized metabolic-dietitian oversight.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Leucine-pathway organic-acid accumulation
    treatment_effect: MODULATES
    description: Restriction is intended to reduce leucine substrate flux into the blocked pathway; clinical benefit is unproven.
  evidence:
  - reference: PMID:20855850
    reference_title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Dietary treatment with leucine restriction may be considered.
    explanation: Supports only a proposal, not demonstrated efficacy.
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The burdens of sustained treatment (particularly with intensive dietary
      leucine restriction) in asymptomatic individuals may be of little benefit,
      and likely to result in poor compliance.
    explanation: Directly supports avoiding routine intensive restriction in asymptomatic individuals.
- name: Levocarnitine supplementation
  description: >-
    Levocarnitine has been given with protein or leucine restriction in pediatric
    reports. These uncontrolled observations do not establish clinical benefit
    or a universal indication, and long-term asymptomatic outcomes are also
    reported without treatment.
  treatment_term:
    preferred_term: carnitine supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
  evidence:
  - reference: PMID:35457240
    reference_title: "3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was then supplemented with levocarnitine and protein intake was slowly decreased.
    explanation: Documents use in one case without proving efficacy.
  - reference: PMID:34333924
    reference_title: "[Analysis of six children with 3-methylglutaconic aciduria]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After being treated with leucine diet restriction and L-carnitine, 4
      patients with AUH gene variation who were from asymptomatic phase developed normally
    explanation: Describes normal development under combined treatment but lacks an untreated comparison.
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      remain asymptomatic in the absence of treatment
    explanation: Shows that normal outcome cannot be attributed to supplementation from uncontrolled treated cases.
references:
- reference: PMID:10070612
  title: "3-Methylglutaconic aciduria type I: clinical heterogeneity as a neurometabolic disease."
  findings: []
- reference: PMID:12434311
  title: 3-Methylglutaconic aciduria type I is caused by mutations in AUH.
  findings: []
- reference: PMID:12655555
  title: Mutations in the AUH gene cause 3-methylglutaconic aciduria type I.
  findings: []
- reference: PMID:16541463
  title: NMR spectroscopic studies on the late onset form of 3-methylglutaconic aciduria type I and other defects in leucine metabolism.
  findings: []
- reference: PMID:16640564
  title: Biochemical characterization of human 3-methylglutaconyl-CoA hydratase and its role in leucine metabolism.
  findings: []
- reference: PMID:20855850
  title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
  findings: []
- reference: PMID:21840233
  title: Phenotypic heterogeneity in two siblings with 3-methylglutaconic aciduria type I caused by a novel intragenic deletion.
  findings: []
- reference: PMID:23296368
  title: "Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature."
  findings: []
- reference: PMID:24757000
  title: Leucine Loading Test is Only Discriminative for 3-Methylglutaconic Aciduria Due to AUH Defect.
  findings: []
- reference: PMID:32685354
  title: A newborn screening approach to diagnose 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.
  findings: []
- reference: PMID:34333924
  title: "[Analysis of six children with 3-methylglutaconic aciduria]."
  findings: []
- reference: PMID:35457240
  title: "3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature."
  findings: []
- reference: PMID:36341175
  title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
  findings: []
- reference: PMID:38077954
  title: Asymptomatic 3-methylglutaconic aciduria type 1 detected by high C5-OH on newborn screening.
  findings: []
- reference: PMID:40937535
  title: "Evaluation of Newborn Screening for Diseases Using C5-OH as a Marker: Systematic Review of the Literature and Evaluation of 17 Years of C5-OH Screening in the Netherlands."
  findings: []
discussions:
- discussion_id: controversy_mga1_childhood_clinical_phenotype
  prompt: >-
    Does AUH deficiency cause a reproducible childhood clinical phenotype, or do
    the reported developmental, behavioral, and severe neurologic findings
    primarily reflect ascertainment and coincidental comorbidity?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Reported pediatric neurodevelopmental association of uncertain causality
  - phenotypes#Delayed speech and language development
  - phenotypes#Severe global developmental delay
  rationale: >-
    Clinically ascertained cases report heterogeneous pediatric findings, but
    four newborn-screened patients, including three followed for more than 18
    years without treatment, remained asymptomatic. The current evidence cannot
    estimate clinical penetrance or separate AUH effects from background
    neurodevelopmental variation.
  evidence:
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there is no clear evidence of a specific childhood-onset clinical phenotype associated with this disorder
    explanation: Defines the central controversy about childhood clinical attribution.
  - reference: PMID:21840233
    reference_title: Phenotypic heterogeneity in two siblings with 3-methylglutaconic aciduria type I caused by a novel intragenic deletion.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe two siblings with 3-methylglutaconic aciduria type I with phenotypic heterogeneity.
    explanation: Shows why selected pediatric reports cannot define a consistent phenotype.
  proposed_experiments:
  - experiment_id: exp_mga1_family_controlled_natural_history
    name: Family-controlled longitudinal natural-history study
    description: >-
      Follow all molecularly confirmed individuals identified through screening,
      including untreated participants and variant-negative relatives, with
      standardized cognition, language, motor, psychiatric, metabolite, and MRI
      assessments. Prespecified family-control comparisons would quantify
      penetrance while limiting ascertainment bias.
- discussion_id: controversy_mga1_adult_leukoencephalopathy
  prompt: >-
    Is adult-onset progressive leukoencephalopathy a causal late manifestation
    of AUH deficiency, and if so, what biochemical mechanism injures white matter?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - pathophysiology#Reported adult leukoencephalopathy association of uncertain causality
  - imaging_findings#Extensive cerebral white-matter disease on adult MRI
  - phenotypes#Progressive ataxia
  - phenotypes#Leukoencephalopathy
  rationale: >-
    Adult case reports show a recurring ataxia/leukoencephalopathy pattern, and
    one patient had marked CSF 3-hydroxyisovalerate enrichment, but there are too
    few unbiased adult observations to establish causality. No validated chain
    links the diagnostic metabolites to myelin or axonal injury.
  evidence:
  - reference: PMID:20855850
    reference_title: "3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In both patients, MRI revealed extensive white matter disease.
    explanation: Supports recurrence of the adult imaging association in the small clinical series.
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      will be required to conclusively prove or disprove the association with adult-onset leukoencephalopathy
    explanation: Directly supports keeping the association unresolved.
  proposed_experiments:
  - experiment_id: exp_mga1_adult_screening_mri_metabolomics
    name: Adult biochemical-screening, MRI, and CNS-metabolite study
    description: >-
      Screen large adult biobank cohorts for the MGA1 biochemical and molecular
      phenotype independently of neurologic symptoms, then compare blinded MRI,
      neurologic examinations, plasma/CSF metabolites, and longitudinal change
      with matched controls. Patient-derived neural cultures could then test
      candidate metabolites at measured human CNS concentrations.
- discussion_id: gap_mga1_treatment_effectiveness
  prompt: >-
    Do leucine restriction or levocarnitine alter biochemical markers, neurologic
    penetrance, or long-term imaging outcomes in MGA1?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Leucine-restricted diet
  - treatments#Levocarnitine supplementation
  rationale: >-
    Treatment reports are uncontrolled and often begin in asymptomatic infants.
    Untreated newborn-screened individuals have also remained asymptomatic for
    more than 18 years, so normal development under treatment cannot establish
    efficacy. Intensive restriction carries nutritional and adherence burdens.
  evidence:
  - reference: PMID:36341175
    reference_title: "3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The burdens of sustained treatment (particularly with intensive dietary
      leucine restriction) in asymptomatic individuals may be of little benefit
    explanation: Establishes the uncertainty and burden underlying the treatment gap.
  - reference: PMID:38077954
    reference_title: Asymptomatic 3-methylglutaconic aciduria type 1 detected by high C5-OH on newborn screening.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatments such as dietary leucine restriction and carnitine supplementation may have little effect on MGCA1 in childhood
    explanation: A modern untreated case and literature review question benefit while calling for further study.
  proposed_experiments:
  - experiment_id: exp_mga1_treatment_registry
    name: Prospective treatment-and-observation registry
    description: >-
      Use a multicenter protocol with standardized diet, carnitine status,
      urinary metabolites, neurodevelopment, neurologic examination, and MRI.
      Compare prespecified treated and conservatively observed groups with
      adjustment for indication and ascertainment; randomized treatment would be
      considered only if an actionable clinical phenotype is first established.
notes: >-
  Comprehensive re-review of the WP-001 AUH entry. The record deliberately
  separates the established biochemical lesion from two detached, provisional
  clinical-association branches. It does not apply the toxic-metabolite/energy-deficit
  or acute-decompensation module nodes because metabolite toxicity, energy failure,
  and acute crises are not established. Phenotype frequencies
  are omitted because the published cohorts are small and ascertainment-biased.
📚

References & Deep Research

References

15
PMID:10070612
3-Methylglutaconic aciduria type I: clinical heterogeneity as a neurometabolic disease.
No top-level findings curated for this source.
PMID:12434311
3-Methylglutaconic aciduria type I is caused by mutations in AUH.
No top-level findings curated for this source.
PMID:12655555
Mutations in the AUH gene cause 3-methylglutaconic aciduria type I.
No top-level findings curated for this source.
PMID:16541463
NMR spectroscopic studies on the late onset form of 3-methylglutaconic aciduria type I and other defects in leucine metabolism.
No top-level findings curated for this source.
PMID:16640564
Biochemical characterization of human 3-methylglutaconyl-CoA hydratase and its role in leucine metabolism.
No top-level findings curated for this source.
PMID:20855850
3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy.
No top-level findings curated for this source.
PMID:21840233
Phenotypic heterogeneity in two siblings with 3-methylglutaconic aciduria type I caused by a novel intragenic deletion.
No top-level findings curated for this source.
PMID:23296368
Inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature: proper classification and nomenclature.
No top-level findings curated for this source.
PMID:24757000
Leucine Loading Test is Only Discriminative for 3-Methylglutaconic Aciduria Due to AUH Defect.
No top-level findings curated for this source.
PMID:32685354
A newborn screening approach to diagnose 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.
No top-level findings curated for this source.
PMID:34333924
[Analysis of six children with 3-methylglutaconic aciduria].
No top-level findings curated for this source.
PMID:35457240
3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature.
No top-level findings curated for this source.
PMID:36341175
3-Methylglutaconyl-CoA hydratase deficiency: When ascertainment bias confounds a biochemical diagnosis.
No top-level findings curated for this source.
PMID:38077954
Asymptomatic 3-methylglutaconic aciduria type 1 detected by high C5-OH on newborn screening.
No top-level findings curated for this source.
PMID:40937535
Evaluation of Newborn Screening for Diseases Using C5-OH as a Marker: Systematic Review of the Literature and Evaluation of 17 Years of C5-OH Screening in the Netherlands.
No top-level findings curated for this source.