PHARC syndrome: an overview

PHARC, polyneuropathy, hearing loss, cerebellar ataxia, retinitis pigmentosa and cataracts, or PHARC is a very rare progressive neurodegenerative autosomal recessive disease caused by biallelic mutations in the ABHD12 (a/b-hydrolase domain containing 12) gene, which encodes a lyso-phosphatidylserine (lyso-PS) lipase. The Orpha number for PHARC is ORPHA171848. The clinical picture of PHARC syndrome is very heterogeneous with a wide range of age at onset for each symptom, making a clinical diagnosis very challenging. Differential diagnoses of the disease include Refsum disease, Charcot-Marie-Tooth disease, and Usher syndrome. Many aspects of the disease, such as the biochemistry and pathophysiology, are still not fully understood. We generated a clinical overview of all PHARC patients, including their mutations, described in literature so far. Furthermore, we give an outline of the most recent developments in research on the pathophysiology of PHARC syndrome in an attempt to gain more insight into and increase awareness of the heterogeneity of the disease. We included 58 patients with PHARC from 37 different families with 27 known ABHD12 mutations. The age at onset (from early childhood to late thirties) and the severity of each feature of PHARC varied widely among patients. Demyelinating polyneuropathy was reported in 91% of the patients. In 86% of patients, hearing loss was present and 74% had cerebellar ataxia, the most variable symptom of PHARC. Retinitis pigmentosa and cataracts occurred in 82% and 86% of patients, respectively. Due to the rareness of the disease and the variable clinical phenotype, a diagnosis of PHARC is often delayed and mostly only made after an extensive genetic work-up. Therefore, we recommend adding the ABHD12 gene to diagnostic gene panels for polyneuropathy, cerebellar ataxia, hearing loss, retinal dystrophy, and cataracts. In addition, a full clinical work-up, neurological (with EMG and neuroimaging of the brain) and ophthalmological (with ERG) examination and audiological tests are indispensable to obtain a comprehensive overview of the clinical phenotype as some symptoms in PHARC may be very subtle and easily overlooked if not tested for. In conclusion, we strongly recommend that patients with (suspected) PHARC should be evaluated in a multidisciplinary setting involving ophthalmologists, audiologists, neurologists, and geneticists to ensure the best possible care. Furthermore, we discuss whether PHARC is a spectrum with various incomplete phenotypes even later in life, or whether it is a syndrome in which the clinical symptoms are variable in severity and age of onset.