Criscuolo_2013_Eur.J.Neurol_20_e60

Inherited neurodegenerative pathologies involving peripheral, CNS and eye can be caused by different pathogenetic mechanisms, principally affecting mitochondria, lysosomes and peroxisomes. Recently, a new autosomal recessive neurodegenerative disease, called PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataracts) has been described and linked to impairment of the endocannabinoid metabolism. The 19 patients reported are from 11 kindreds from Norway, Algeria, United Arab Emirates and USA 1. Onset was typically in the teens. All adult patients showed peripheral neuropathy, 16 had sensorineural hearing loss, 13 cataracts and 11 retinitis pigmentosa. Ataxia was absent in six patients, and its onset age was the most variable sign. PHARC is due to mutations in the ABHD12 gene, which encodes a serine hydrolase shown to hydrolyse 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter. Actually little is known about ABHD12 function. Its potential role was suggested using activity-based protein profiling with mouse brain proteome. Approximately 85% of brain 2-AG hydrolase activity can be ascribed to monoacylglycerol lipase (MAGL), and the remaining 15% is mostly catalysed by two uncharacterized enzymes, ABHD6 and ABHD12 2.Interestingly, MAGL, ABHD6 and ABHD12 display distinct cellular expression patterns, suggesting that they may control different pools of 2-AG in the nervous system 3. It is not excluded that ABHD12 could have other so far unidentified substrates, and that PHARC pathogenesis could be associated to a different pathway other than cannabinoid. More recently, PHARC syndrome has been placed in the more general category of the inborn errors of the phospholipids synthesis 4. To search for PHARC mutations in a cohort of 93 unclassified ataxic patients, we selected 15 patients according to the following criteria: possible recessive inheritance and Refsum-like phenotype (ataxia, visual impairment, neuropathy and hearing loss). Mean age at onset +/- SD was 24.8 +/- 15.8 years (range 040 years). Parental consanguinity was present in five. All had ataxia, six had pigmentary retinal degeneration, four optic atrophy, two cataract, and three both cataract and retinitis pigmentosa. Neuropathy was present in 10 patients, hearing loss in eight and hyposmia in four. Magnetic resonance imaging was performed in 13 patients, and showed cerebellar atrophy in five, olivo-ponto-cerebellar atrophy in one, triventricular hydrocephalus and aqueductal stenosis in one. All but one patient were from Southern Italy. After informed consent, we excluded Refsum disease, NARP, FA and mitochondrial inherited ataxia syndrome in all. Despite recessive inheritance pattern, SCA 7 CAG repeat expansion was excluded in four patients. Direct sequencing of the 13 coding exons and the intron-exon boundaries of ABHD12 has been conducted. No mutations were found. Twelve validated SNPs were identified in our population. A heterozygous deletion in the 3'-UTR, c.*324delG, not reported in the database, was found in two patients. This is the first PHARC screening after the original description of the disorder. According to our analysis, ABHD12 mutations are not a frequent cause of ataxia at least in Southern Italy. Further studies on larger groups of patients are necessary to define the frequency of the ABHD12 mutations, which will be useful when performing a focused screening.