ABHD12 – PHARC syndrome

ABHD12 is mutated in PHARC syndrome, a rare early-onset autosomal recessive neurodegenerative disorder characterized by demyelinating polyneuropathy, sensorineural hearing loss, cerebellar ataxia, retinitis pigmentosa (rod-cone dystrophy), and early-onset cataracts. PHARC was first described in 2012 and linked to biallelic loss-of-function variants in ABHD12, encoding an α/β-hydrolase domain–containing serine lipase involved in endocannabinoid metabolism.

Genetic evidence from multiple case reports and cohort studies has identified over 58 affected individuals from 37 unrelated families harboring homozygous or compound heterozygous ABHD12 variants, consistent with autosomal recessive inheritance (PMID:39501272). Segregation analysis in sibships and consanguineous pedigrees confirms co-segregation of biallelic variants with disease phenotypes. Key manifestations include sensory and motor neuropathy, hearing impairment, progressive ataxia, visual loss from rod-cone dystrophy, and cataract formation.

The variant spectrum is dominated by predicted loss-of-function mutations, including nonsense, frameshift, and exon–deletion alleles. A representative novel frameshift mutation, NM_001042472.3:c.601dup (p.Val201GlyfsTer4), has been reported in two affected siblings with PHARC features confirmed by segregation (PMID:37803361).

Functional validation studies demonstrate that ABHD12 mutations abrogate monoacylglycerol lipase activity in transfected cells and that zebrafish abhd12 knockdown morphants recapitulate human PHARC hallmarks—including ataxia, abnormal myelination, retinal disorganization, and lens defects—rescuable by wild-type but not mutant human ABHD12 mRNA (PMID:27890673).

Based on the quantity of cases, robust segregation data, and concordant functional models, the gene–disease relationship reaches a ClinGen clinical validity of Definitive. Genetic evidence is Strong (biallelic LoF variants in >30 families, segregation), and functional evidence is Moderate (in vivo rescue models).

Key take-home: Genetic testing for ABHD12 should be included in multi-gene panels for polyneuropathy, sensorineural hearing loss, cerebellar ataxia, retinal dystrophy, and early-onset cataract to enable timely and accurate diagnosis of PHARC syndrome.

References

• Human Mutation • 2013 • Two novel mutations in ABHD12: expansion of the mutation spectrum in PHARC and assessment of their functional effects. PMID:24027063
• Neurobiology of Disease • 2017 • Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC. PMID:27890673
• Journal of the Neurological Sciences • 2018 • Phenotypical features of two patients diagnosed with PHARC syndrome and carriers of a new homozygous mutation in the ABHD12 gene. PMID:29571850
• BMC Medical Genomics • 2023 • Genetic insights into PHARC syndrome: identification of a novel frameshift mutation in ABHD12. PMID:37803361
• Acta Neurologica Belgica • 2025 • Characterizing and expanding the neurological clinical spectrum of PHARC syndrome: a systematic review. PMID:39501272

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