Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Glutaryl-CoA dehydrogenase deficiency (GA-I; MONDO:0009281) is an autosomal-recessive neurometabolic disorder caused by biallelic pathogenic variants in the GCDH gene (HGNC:4189). Affected individuals often present in infancy with macrocephaly (HP:0000256), movement disorders including dystonia (HP:0001332), and acute encephalopathic crises leading to striatal injury. Clinical heterogeneity is marked: some homozygous individuals remain asymptomatic into school age, while others suffer severe dystonic-dyskinetic syndromes post-metabolic stress (PMID:11508549).
Genetic evidence for GA-I is definitive. Over 200 distinct GCDH variants have been reported across >500 patients worldwide, including missense, nonsense, splice-site, frameshift, and deep-intronic alleles. In a cohort of four Greek patients from two families, siblings homozygous for c.1239C>G (p.Tyr413Ter) experienced divergent clinical courses, confirming autosomal recessive segregation and phenotypic variability with compound heterozygotes for IVS6-1G>A and p.Tyr413Ter also identified (PMID:11508549). Recurrent alleles such as p.Arg402Trp and p.Met405Val serve as population-specific markers.
Functional assays demonstrate that most GCDH missense and truncating variants abolish or severely reduce enzyme activity. Recombinant expression of p.Arg402Trp and p.Glu414Lys in mammalian cells yields <10% residual activity and impaired tetramerization, with accelerated proteolysis of the mutant protein (PMID:18775954). Riboflavin supplementation can partially rescue activity in variants affecting FAD binding (e.g., p.Ser139Leu), supporting enzyme-cofactor interaction as a therapeutic target. CRISPR/Cas9 knockout in human neuronal cells recapitulates metabolite accumulation and oxidative stress, with rescue upon GCDH gene replacement (PMID:37985879).
No studies dispute the pathogenic role of GCDH loss-of-function in GA-I. The gene-disease relationship has been corroborated by consistent biochemical profiles (elevated glutaric and 3-hydroxyglutaric acids), neuroradiological features (widened Sylvian fissures), and robust molecular data spanning >25 years.
In summary, GCDH deficiency is a definitively established autosomal recessive disorder with a broad variant spectrum and concordant functional deficits. Early molecular diagnosis enables presymptomatic intervention—dietary lysine restriction, carnitine and riboflavin supplementation, and metabolic crisis management—substantially improving neurologic outcomes.
Key take-home: Molecular screening of GCDH in at-risk infants or symptomatic children with macrocephaly and movement disorders is critical for timely initiation of effective metabolic therapy.
Gene–Disease AssociationDefinitiveMultiple unrelated families with biallelic GCDH variants (>200 alleles), consistent segregation and replication over 25 years Genetic EvidenceStrongOver 200 pathogenic variants reported in >500 cases, including familial segregation and multi-cohort studies Functional EvidenceStrongEnzyme assays, cellular models and rescue experiments demonstrate loss-of-function reversible by cofactor or gene replacement |