ASAH1 – Farber lipogranulomatosis

Acid ceramidase (ACDase), encoded by ASAH1, hydrolyzes ceramide into sphingosine and fatty acid in lysosomes. Loss‐of‐function variants in ASAH1 cause Farber lipogranulomatosis, a rare autosomal recessive lysosomal storage disorder characterised by subcutaneous nodules, progressive arthritis, hoarseness, hepatosplenomegaly, respiratory compromise, and neurologic involvement (OMIM:228000). Classic onset occurs in infancy with a triad of painful and swollen joints, lipogranulomatous nodules, and laryngeal involvement; atypical forms display variable severity and multisystem features including cardiac and ocular pathology.

Farber lipogranulomatosis is inherited in an autosomal recessive manner, with biallelic ASAH1 pathogenic variants confirmed in over 45 unrelated individuals from more than ten families worldwide, including compound heterozygotes and homozygotes (PMID:22565078; PMID:23707712). Segregation has been observed in multiple pedigrees, with at least five additional affected sibships demonstrating concordant recessive inheritance (PMID:21893389). Genetic diagnosis is supported by enzyme assays showing deficient ACDase activity and by identification of diverse variant classes, fulfilling ClinGen criteria for a definitive gene–disease relationship.

The mutational spectrum encompasses missense, nonsense, splice‐site, frameshift, and large deletion variants. Representative biallelic variants include c.94A>T (p.Arg32Ter) observed in neonatal Farber disease (PMID:23707712). Other recurrent mutations affect essential residues in the catalytic domain or disrupt normal splicing (e.g., c.917+4A>G) leading to exon skipping and truncated protein (PMID:23707712).

Functional studies corroborate a loss‐of‐function mechanism: ASAH1 mutant constructs demonstrate markedly reduced enzymatic activity in vitro, while morpholino knockdown in zebrafish recapitulates motor‐neuron deficits (PMID:22703880). In murine Asah1P361R/P361R models, enzyme deficiency causes systemic ceramide accumulation, hepatosplenomegaly, lung injury, inflammation, ocular and cardiac pathology, and early mortality, mirroring human Farber disease (PMID:31186526).

Preclinical rescue experiments provide proof‐of‐principle for gene therapy: rAAV‐mediated ASAH1 overexpression in Asah1P361R/P361R mice reduces retinal ceramide accumulation, limits inflammation, and normalises retinal structure and function, highlighting translational potential (PMID:35902747). Hematopoietic cell transplantation ameliorates inflammatory joint and skin manifestations but does not prevent neurologic decline, underscoring the need for targeted systemic approaches (PMID:30815900).

Collectively, the extensive genetic and functional concordance establishes a Definitive association between ASAH1 and Farber lipogranulomatosis. Early molecular diagnosis enables prompt genetic counseling, biochemical confirmation, and consideration of emerging enzyme‐ or gene‐based therapies. Key take‐home: ASAH1 sequencing and enzyme activity assays are clinically essential for infants with joint deformities, subcutaneous nodules, and hoarseness to guide life‐saving interventions.

References

• Indian pediatrics • 2012 • Novel biochemical abnormalities and genotype in Farber disease. PMID:22565078
• Brain & development • 2012 • Novel V97G ASAH1 mutation found in Farber disease patients: unique appearance of the disease with an intermediate severity, and marked early involvement of central and peripheral nervous system. PMID:21893389
• Molecular genetics and metabolism • 2013 • Molecular basis of acid ceramidase deficiency in a neonatal form of Farber disease: identification of the first large deletion in ASAH1 gene. PMID:23707712
• Laboratory investigation; a journal of technical methods and pathology • 2019 • Hepatic pathology and altered gene transcription in a murine model of acid ceramidase deficiency. PMID:31186526
• Gene therapy • 2023 • rAAV-mediated over-expression of acid ceramidase prevents retinopathy in a mouse model of Farber lipogranulomatosis. PMID:35902747
• Genomics • 1999 • The human acid ceramidase gene (ASAH): structure, chromosomal location, mutation analysis, and expression. PMID:10610716

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