Characterizing and expanding the neurological clinical spectrum of PHARC syndrome: a systematic review

PHARC syndrome is an autosomal recessive neurodegenerative disease caused by mutations in the ABHD12 gene and is characterized by five main clinical features: polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataracts. This systematic review aimed to characterize the neurological features of PHARC syndrome and identify potential new clinical features. A systematic search of studies reporting cases of PHARC syndrome was conducted using PubMed/MEDLINE and NLM databases, identifying 57 unique cases. The results showed that hearing loss was the most common initial symptom, with a complete syndrome observed in only 31.6% of reported cases. The mean diagnostic delay from the appearance of the first PHARC-related symptom to diagnosis was 20.5 years. Although pyramidal signs are not classically associated with PHARC syndrome, they were a prevalent feature when assessed. Patients with pyramidal signs were more likely to exhibit an ataxic phenotype (p-value 0.018), a complete syndrome (p-value 0.092), and cerebellar atrophy on MRI (p-value 0.001), compared to those without pyramidal signs. This review further supports the highly variable phenotype of PHARC syndrome and the lack of a clear genotype-phenotype correlation. Further research is needed to clarify the relevance of these findings within the clinical spectrum of PHARC syndrome.