Objective: To provide a systematic review of the neurological manifestations of the PHARC syndrome.

Background: Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataracts (PHARC) syndrome is an autosomal recessive neurodegenerative disease caused by mutations in the ABHD12 gene.

Method: We searched the PubMed database up to January 2023 and included all publications containing reports of patients with clinical and genetic features suggestive of PHARC syndrome.

Results: In our systematic review, we identified 54 unique patients in a total of 12 included publications. The mean age was 36.2 years and men were more commonly affected with a ratio of 1.45:1. The clinical phenotype was variable and the most common manifestations by order of frequency were: hearing loss (87.0%), retinitis pigmentosa (81.5%), cataract (79.6%), polyneuropathy (72.2%) and ataxia (51.9%). Only one-third of the patients had a complete PHARC syndrome with all five cardinal features. In the population with polyneuropathy, most patients (93.8%) had at least one suggestive finding in the neurological examination (pes cavus, hypoesthesia, or hypo/areflexia) and, in the group that performed nerve conduction studies, the majority (92.9%) had a demyelinating polyneuropathy. Ataxia is the least frequent feature of PHARC, being present in only half of the cases. Regarding the patients with ataxia, 28% had gait ataxia, 11% had appendicular ataxia, and 61% had generalized ataxia. Finally, in the subgroup of patients with ataxia that did brain MRI, about half had an unremarkable exam. Pyramidal signs are not a cardinal feature of PHARC syndrome, nonetheless, they were present in 40% of the patients when searched. More than half of those with pyramidal signs had a complete PHARC syndrome, all of them had concurrent polyneuropathy, and all but one had ataxia and cerebellar/vermian atrophy in the brain MRI.

Conclusion: The PHARC syndrome has a highly variable clinical phenotype and the complete syndrome, with all five clinical hallmarks, was only present in a fraction of the reviewed cases. The association of hearing loss and retinitis pigmentosa in a patient with ataxia should make us think of the diagnosis of PHARC, especially in the presence of demyelinating polyneuropathy. Involvement of the pyramidal tract, and its co-occurrence with polyneuropathy and ataxia, could be a new sign that expands the clinical spectrum of PHARC.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-neurological-manifestations-of-pharc-syndrome-a-systematic-review/