Genotype‐phenotype correlation in a novel ABHD12 mutation underlying PHARC syndrome

Abstract

PHARC syndrome is a rare neurodegenerative disorder caused by mutations in the ABHD12 gene. It is a genetically heterogeneous and clinically variable disease, which is characterized by demyelinating polyneuropathy, hearing loss, cerebellar ataxia, retinitis pigmentosa, and early‐onset cataract and can easily be misdiagnosed as other neurologic disorders with a similar clinical picture, such as Charcot‐Marie‐Tooth disease and Refsum disease. We describe the genotype‐phenotype correlation of two siblings with a novel genotype underlying PHARC syndrome. The genotype was identified using next‐generation sequencing. We examined both patients by means of thorough history taking and clinical examination, nerve conduction studies (NCS), brain imaging, and optical coherence tomography to establish a genotype‐phenotype correlation. We identified a novel homozygous point mutation (c.784C > T, p.Arg262*) in the ABHD12 gene. This mutation was detected in both siblings, who had bilateral hearing loss and cataracts, signs of cerebellar ataxia, and neuropathy with a primarily demyelinating pattern in NCS. In one case, retinitis pigmentosa was also evident. As PHARC syndrome is a rare autosomal recessive disorder, our findings highlight the importance of an interdisciplinary diagnostic workup with clinical and molecular genetic testing to avoid a misdiagnosis as Charcot‐Marie‐Tooth disease or Refsum disease.

The Phenotypic Spectrum of Patients with PHARC Syndrome Due to Variants in ABHD12: An Ophthalmic Perspective

“…In all patients with available neurological data, demyelinating polyneuropathy was detected in all, with variable presence of ataxia and cerebellar atrophy. These findings are consistent with previous studies on PHARC syndrome [1,11]. The exact etiology of neurologic deficits in patients with PHARC remains unclear, but previous studies have shown that accumulation of lyso-PS in the cerebellum due to disruptive ABHD12 leads to increased levels of microglial activation and neuroinflammation, which is the presumed cause for neurological deficits in abhd12 knockout mice [5][6][7].…”

“…In this retrospective study, we report the genetic and clinical characteristics of 15 patients with PHARC syndrome with variable severity, caused by variants in the ABHD12 gene. This study aimed to expand our clinical knowledge on PHARC syndrome, as it is a rare neurodegenerative disease with less than 50 cases currently described in the literature [11,16]. The advent of next-generation sequencing has made it possible to identify disease-causing variants on novel genes at a rapid pace and the ongoing improvements in this technology may lead to an increased detection of patients with biallelic ABHD12 variants/PHARC syndrome in the future [17].…”

“…Polyneuropathy is typically one of the first findings in patients with PHARC syndrome, which usually manifests in childhood. Early signs of polyneuropathy include distal muscle weakness, sensory disturbances, pes cavus and Achilles tendon contractures [1,9,11]. Sensorineural hearing loss is present in most patients with PHARC, with severity varying from moderate hearing loss to profound deafness [1,8].…”

“…While PHARC syndrome encompasses neurological, auditory and ophthalmic findings, not all of these findings are necessarily present at initial presentation [1,2]. Depending on the presenting symptoms, patients may first be misdiagnosed with other neurodegenerative diseases that give rise to roughly similar phenotypes, such as Charcot-Marie-Tooth, Usher type 3 and adult Refsum disease [1,11].…”

Lipid Dyshomeostasis and Inherited Cerebellar Ataxia

“…Importantly, its mutations are linked to neurodegenerative disorders, such as polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) [16,108]. Although PHARC syndrome can be clinically variable [109][110][111][112], the cerebellum of PHARC subjects is the most atrophied brain region in any case [113].…”