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Alpha-methylacyl-CoA racemase (AMACR; Gene Symbol) is a peroxisomal enzyme critical for catabolism of branched-chain fatty acids. Biallelic pathogenic variants in AMACR cause alpha-methylacyl-CoA racemase deficiency (Disease Name), an autosomal recessive disorder characterized by pristanic acid accumulation. First reported in three adults with relapsing encephalopathy in 2008 (PMID:18032455), fewer than 20 cases were documented until a recent cohort of 12 patients described the expanded phenotypic spectrum. Age at diagnosis ranged from 3 to 69 years, with adult onset most common, supporting variable expressivity and late onset. Clinical features include neurological, metabolic and ophthalmic manifestations. The gene-disease link is robust, with over 28 probands reported to date (PMID:35428665; PMID:39313810).
AMACR deficiency follows an autosomal recessive inheritance pattern. Segregation analysis in multiple families has confirmed co-segregation of biallelic variants with disease; for example, three affected siblings carrying homozygous c.877T>C (p.Cys293Arg) and two siblings harboring novel variants demonstrated concordant phenotypes (PMID:34267495; PMID:39544692). To date, at least six distinct pathogenic alleles have been described, including the recurrent founder variant c.154T>C (p.Ser52Pro), frameshift c.1040dup (p.Glu348ArgfsTer4), and missense alleles c.364C>T (p.His122Tyr), c.512G>A (p.Arg171His), c.557A>G (p.Glu186Gly) and c.155C>A (p.Ser52Ter) (PMID:39313810). This variant spectrum encompasses missense, frameshift, and nonsense changes consistent with a loss-of-function mechanism.
The phenotypic spectrum is dominated by neurological manifestations, including seizures (HP:0001250), relapsing encephalopathy, stroke-like episodes (HP:0002401), ataxia (HP:0001251), dystonia (HP:0001332), central apnea (HP:0002871) and coma (HP:0001259). Cognitive decline, neuropathy and typical thalamic, pontine and midbrain MRI abnormalities are common in adults (PMID:39313810). Ophthalmic involvement ranges from retinitis pigmentosa or rod-cone dystrophy (HP:0000510) to subtle or asymptomatic retinal pigment epithelium changes detected by multimodal imaging (PMID:34267495; PMID:38166212). Hepatic features such as gallstones, elevated transaminases and rare hepatocellular carcinoma have also been reported.
Functional studies support a loss-of-function mechanism. Biochemical assays in patient fibroblasts and plasma demonstrate markedly elevated pristanic acid and impaired AMACR activity (PMID:18032455). Enzymatic deficiency leads to accumulation of toxic bile acid intermediates (R)-THCA and (R)-DHCA, corroborated in multiple cases and reinforced by dietary response to pristanic acid-restricted regimens. No dominant-negative effects have been described, consistent with haploinsufficiency in heterozygous carriers.
No significant conflicting evidence has been reported; all studies across diverse cohorts and ages reinforce an autosomal recessive, loss-of-function etiology. The consistency of biochemical, genetic and imaging data across independent groups eliminates major dispute regarding AMACR’s role in MONDO:0013681.
In summary, biallelic AMACR variants unequivocally cause alpha-methylacyl-CoA racemase deficiency. This association is classified as Definitive based on >28 unrelated probands over >15 years, robust segregation and concordant functional data. Genetic testing for AMACR pathogenic variants should be incorporated in the diagnostic workup of late-onset peroxisomal and metabolic stroke-like presentations. Key Take-home: AMACR deficiency is a treatable, autosomal recessive peroxisomal disorder identifiable by biochemical and molecular testing, with implications for dietary management and surveillance.
Gene–Disease AssociationDefinitiveOver 28 probands from multiple unrelated families across >15 years, segregation, metabolic and cellular functional data Genetic EvidenceStrong28 probands with biallelic variants including six distinct alleles and confirmed segregation in multiple families Functional EvidenceModerateBiochemical assays demonstrate pristanic acid accumulation and absent AMACR activity in patient fibroblasts |