Abstract
This study investigated the phenotypic spectrum of PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and early-onset cataract) syndrome caused by biallelic variants in the ABHD12 gene. A total of 15 patients from 12 different families were included, with a mean age of 36.7 years (standard deviation [SD] ± 11.0; range from 17.5 to 53.9) at the most recent examination. The presence and onset of neurological, audiological and ophthalmic symptoms were variable, with no evident order of symptom appearance. The mean best-corrected visual acuity was 1.1 logMAR (SD ± 0.9; range from 0.1 to 2.8; equivalent to 20/250 Snellen) and showed a trend of progressive decline. Different types of cataract were observed in 13 out of 15 patients (87%), which also included congenital forms of cataract. Fundus examination revealed macular involvement in all patients, ranging from alterations of the retinal pigment epithelium to macular atrophy. Intraretinal spicular hyperpigmentation was observed in 7 out of 15 patients (47%). From an ophthalmic perspective, clinical manifestations in patients with PHARC demonstrate variability with regard to their onset and severity. Given the variable nature of PHARC, an early multidisciplinary assessment is recommended to assess disease severity.
Highlights
PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa (RP) and earlyonset cataract) is an acronym for a rare, neurodegenerative disease caused by biallelic variants in the ABHD12 gene [1,2]
ABHD12 is located on chromosome 20 and encodes the α/β-hydrolase domain-containing protein 12 (ABHD12), which is highly expressed in the central nervous system (CNS) and plays a vital role in lipid metabolism
A clinical diagnosis of PHARC was based on the presence of variable combinations of polyneuropathy, HL, ataxia, RP and cataract
Summary
PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa (RP) and earlyonset cataract) is an acronym for a rare, neurodegenerative disease caused by biallelic variants in the ABHD12 gene [1,2]. Disruption of ABHD12 in mice leads to (i) accumulation of lyso-PS in the cerebellum breaching the homeostatic threshold, inducing continuous stimulation of the Purkinje neurons, leading to deregulated cerebellar activity and (ii) increased levels of microglial activation and inflammation [5,6,7]. Accompanying this inflammatory response in mice are behavioral deficits, including sensorimotor defects and hearing loss, which resembles the phenotype described in patients with PHARC syndrome [5,6,7]
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