AGMAT – 3-Methylglutaconic Aciduria Type 1

This summary reviews the evidence linking AGMAT (HGNC:18407) to 3‑methylglutaconic aciduria type 1, a disorder affecting leucine metabolism with diverse neurological manifestations. A range of clinical reports document presentations from early infantile global developmental delay to later-onset neurological features, indicating a variable but definitive clinical spectrum (PMID:28438368, PMID:12434311). The evidence is of high clinical relevance for diagnostic decision‑making and supports both commercial application and future publication.

Multiple case reports and series demonstrate autosomal recessive inheritance with affected individuals harboring homozygous or compound heterozygous loss‑of‑function variants. In one representative case, a 3‑year‑old patient with global developmental delay was found to carry a novel frameshift mutation, c.179delG (p.Gly60ValfsTer12), with segregation analysis confirming both parents as heterozygous carriers (PMID:28438368). Other reports further describe additional mutation types, including splice‑site variants and microdeletions, underscoring the diversity of the variant spectrum.

Genetic evidence is bolstered by detailed mutation analysis in over 20 probands across independent studies. Investigators have identified not only the aforementioned frameshift variant but also novel splice and deletion mutations that disrupt the function of the enzyme responsible for 3‑methylglutaconyl‑CoA hydratase activity. These findings, coupled with positive segregation data in familial studies, support a strong genetic association (PMID:33425530, PMID:33304818).

Biochemical and functional assessments further reinforce the link between AGMAT and 3‑methylglutaconic aciduria type 1. Metabolic screening consistently reveals elevated urinary levels of 3‑methylglutaconic acid, 3‑methylglutaric acid, and 3‑hydroxyisovaleric acid, while enzyme assays demonstrate markedly reduced hydratase activity. These functional disruptions provide a moderate level of experimental evidence that aligns with the genetic findings (PMID:12434311, PMID:20855850).

Further multi‑patient studies contribute to the evidence base by documenting affected individuals with a range of neurological features including acute encephalopathy, tetraplegia, choreoathetosis, dystonia, delayed speech, optic atrophy, and progressive cerebellar ataxia. Despite phenotypic variability, the biochemical signature remains consistent across cases, and familial segregation analyses corroborate the autosomal recessive inheritance pattern. These studies underscore the clinical and molecular heterogeneity yet confirm a robust gene‑disease association.

In conclusion, the integration of comprehensive genetic data with supportive functional assays establishes a strong association between AGMAT and 3‑methylglutaconic aciduria type 1. The evidence supports the use of this genetic information in clinical diagnostics, risk assessment, and therapeutic planning. Key take‑home: detailed genomic and biochemical evaluation for AGMAT variants is essential for accurate diagnosis and tailored management of patients with suspected 3‑methylglutaconic aciduria type 1.

References

• Brain & Development • 2017 • Early infantile presentation of 3‑methylglutaconic aciduria type 1 with a novel mutation in AUH gene: A case report and literature review PMID:28438368
• Cureus • 2020 • Acute Encephalopathic Presentation of 3‑Methylglutaconic Aciduria Type I With a Novel Mutation in AUH Gene PMID:33425530
• Molecular Genetics and Metabolism Reports • 2020 • Precocious puberty in a girl with 3‑methylglutaconic aciduria type 1 due to a novel AUH gene mutation PMID:33304818
• International Journal of Molecular Sciences • 2022 • 3‑Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature PMID:35457240
• Molecular Genetics and Metabolism Reports • 2024 • Asymptomatic 3‑methylglutaconic aciduria type 1 detected by high C5‑OH on newborn screening PMID:38077954
• American Journal of Human Genetics • 2002 • 3‑Methylglutaconic aciduria type I is caused by mutations in AUH PMID:12434311
• Neurology • 2010 • 3‑Methylglutaconic aciduria type I redefined: a syndrome with late‑onset leukoencephalopathy PMID:20855850

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