ACER1 – Farber Lipogranulomatosis

This summary evaluates the association between ACER1 (HGNC:18356) and Farber lipogranulomatosis (MONDO_0009218), a rare lysosomal storage disorder primarily characterized by the pathological accumulation of ceramide that leads to multi‐system deterioration including respiratory failure (PMID:12638942). The disease follows an autosomal recessive inheritance pattern, as evidenced by affected individuals born to consanguineous parents and multiple instances where biallelic pathogenic variants in ACER1 have been reported in independent studies.

Genetic evidence is supported by multiple case reports and series. In one influential study, two Japanese patients were evaluated and found to harbor novel missense and small deletion mutations. Notably, the missense variant c.703G>C (p.Gly235Arg) was identified and serves as a representative change; additional studies reported further private mutations, including splice and deletion variants, that altogether affirm the mutational spectrum of ACER1 in Farber disease (PMID:12638942, PMID:11241842). Although explicit counts of affected relatives with segregating variants were not provided, the recurrence of these findings across several families bolsters the association.

Experimental and functional data further substantiate the role of ACER1 deficiency in the disease. Functional assays conducted in COS‑1 cells have demonstrated that expression of mutant acid ceramidase cDNA—including the variant c.703G>C (p.Gly235Arg)—results in a dramatic decrease of enzyme activity to 35%, 2%, and 37% of control values, respectively (PMID:12638942). These observations confirm that the molecular defects lead to significant loss of function and are consistent with the disease phenotype, reinforcing the pathogenic mechanism likely based on haploinsufficiency.

In terms of clinical validity, the body of evidence—including multiple independent probands from study cohorts, functional assays exhibiting concordant reductions in enzyme activity, and consistent identification of ACER1 mutations across different ethnic populations—supports a ClinGen category of Strong. The rationale is built upon the identification of pathogenic variants in more than two unrelated probands in separate studies and the experimental demonstration of their deleterious impact on enzyme function (PMID:31240154).

While some studies have discussed the limitations associated with genotype‐phenotype correlations due to the genetic privacy of many mutations, there is no conflicting evidence that refutes the association between ACER1 variants and Farber lipogranulomatosis. Instead, the convergent evidence from both genetic and functional studies underscores the clinical relevance of ACER1 testing for diagnostic decision‑making and therapeutic considerations.

Key take‑home: Robust genetic and functional data affirm that mutations in ACER1, such as c.703G>C (p.Gly235Arg), are strongly associated with Farber lipogranulomatosis, thereby supporting its use in clinical diagnosis and guiding future research.

References

• Journal of inherited metabolic disease • 2002 • Mutation analysis of the acid ceramidase gene in Japanese patients with Farber disease PMID:12638942
• JIMD reports • 2019 • Hematopoietic stem cell transplant does not prevent neurological deterioration in infants with Farber disease: Case report and literature review PMID:31240154
• Human mutation • 2001 • Molecular analysis of acid ceramidase deficiency in patients with Farber disease PMID:11241842

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