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!
This summary outlines the association between ACER3 and leukodystrophy based on multiple independent studies. Detailed genetic analyses and functional assessments have implicated biallelic mutations in ACER3 as causative for a progressive leukodystrophy phenotype presenting in early childhood. Affected individuals display a constellation of clinical features including leukodystrophy, peripheral neuropathy, spasticity, developmental regression, and dystonia (PMID:26792856, PMID:34281620).
Genetic evidence comprises case reports and multipatient investigations where patients were found to be homozygous or compound heterozygous for ACER3 variants. In one seminal report, a homozygous c.98A>G (p.Glu33Gly) mutation was detected and shown to abolish the enzyme’s catalytic function, a finding confirmed by subsequent segregation analyses in family members (PMID:26792856). In a later study, three novel ACER3 mutations were identified with clear segregation in affected relatives, broadening the mutation spectrum and reinforcing the gene‐disease association (PMID:34281620).
The variants described encompass both missense and loss‑of‑function types. The c.98A>G (p.Glu33Gly) mutation, for instance, exemplifies a missense change that disrupts a critical residue for enzymatic activity. The recurrent nature of such variants and their consistent segregation in affected families provide substantial genetic evidence supporting the disease mechanism in an autosomal recessive pattern.
Functional studies have underscored the pathogenicity of ACER3 mutations. Enzymatic assays, including LC‑MS/MS analyses and yeast complementation experiments, have demonstrated that the loss of ACER3 catalytic activity leads to the accumulation of several sphingolipid substrates, a biochemical abnormality that is in direct concordance with the clinical phenotype observed in patients (PMID:26792856). Such experimental data validate a loss‑of‑function mechanism as the underlying cause of the leukodystrophy.
Integratively, both the robust genetic evidence—highlighted by multiple probands, segregation in families, and heterogeneity of variant types—and the consistent functional data yield a strong clinical validity for the association between ACER3 and leukodystrophy. The concurrent findings from independent studies provide critical information to guide diagnostic decision‑making and potential commercial genetic testing applications.
Key take‑home sentence: Incorporating ACER3 mutation screening in patients with early‑onset leukodystrophy is essential for accurate diagnosis, improved management, and further elucidation of disease pathogenesis.
Gene–Disease AssociationStrongMultiple independent studies report homozygous and compound heterozygous variants in ACER3 in unrelated probands (at least 4 probands across studies PMID:26792856, PMID:34281620) with clear familial segregation and concordant functional evidence. Genetic EvidenceStrongThe identification of both missense and loss‑of‑function variants, including c.98A>G (p.Glu33Gly), in multiple probands with segregation in families supports a robust genetic underpinning. Functional EvidenceStrongEnzymatic activity assays and yeast rescue experiments confirm that ACER3 mutations abolish catalytic function, resulting in sphingolipid accumulation that mirrors the leukodystrophy phenotype. |