ACY1 – Aminoacylase 1 Deficiency

ACY1 (HGNC:177) has been implicated in aminoacylase 1 deficiency (MONDO_0012368), a rare inborn error of metabolism characterized by abnormal urinary excretion of N-acetylated amino acids and diverse neurological manifestations. Multiple independent case reports have described patients with neurological features ranging from autistic behavior to intellectual disability and motor delay, establishing a consistent clinical phenotype (PMID:20480396).

The genetic evidence spans at least 15 unrelated probands, with several studies reporting homozygous and compound heterozygous mutations. A recurrent variant, c.1057C>T (p.Arg353Cys), is observed in multiple cases and serves as a key diagnostic marker, with additional reports identifying frameshift, exon‐skipping, and other missense variants that affect enzyme function (PMID:24117009).

Segregation analyses in affected families have further supported the autosomal‐recessive inheritance of ACY1 deficiency. For instance, families with affected siblings and parental carrier status provide strong segregation evidence, bolstering the overall genetic association (PMID:38234346).

Functional studies reinforce the genetic data by demonstrating that ACY1 mutations lead to markedly reduced enzyme activity. Assays in EBV-transformed lymphoblasts, fibroblasts, and in vitro overexpression models consistently show loss of catalytic function and reduced protein levels, aligning with the clinical biochemical phenotype and confirming a loss-of-function mechanism (PMID:16274666, PMID:16465618).

While some studies have raised questions regarding the complete spectrum of clinical outcomes and the direct causal role of ACY1 impairment, the convergent genetic, segregation, and functional evidence across multiple independent cohorts strongly supports a pathogenic role in aminoacylase 1 deficiency. Overall, the evidence reliably supports a strong gene–disease association that informs both diagnostic decision-making and commercial genetic testing approaches.

Key take‑home sentence: The comprehensive integration of genetic and functional data firmly establishes ACY1 deficiency as a strong gene–disease association, critical for accurate diagnosis and future research efforts.

References

• Journal of inherited metabolic disease • 2010 • Aminoacylase 1 deficiency associated with autistic behavior PMID:20480396
• Clinical genetics • 2014 • Aminoacylase I deficiency due to ACY1 mRNA exon skipping PMID:24117009
• AME case reports • 2024 • Aminoacylase 1 deficiency: case report on three affected siblings PMID:38234346
• Metabolic brain disease • 2016 • Expanding the phenotype in aminoacylase 1 (ACY1) deficiency: characterization of the molecular defect in a 63-year-old woman with generalized dystonia PMID:26686503
• American journal of human genetics • 2006 • Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism PMID:16465618

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