Phenotypic spectrum of variants in the FIG4 gene: variants associated with Charcot-Marie-Tooth 4J and parkinsonism

Abstract

Biallelic variants in the FIG4 gene cause Charcot-Marie-Tooth type 4J (CMT4J) and Yunis-Varon syndrome. There is increasing evidence of phenotypic overlap between CMT4J and Yunis-Varon syndrome, which presents with peripheral neuropathy and central nervous system (CNS) abnormalities, particularly parkinsonism. We aim to extend and specify the phenotype-genotype correlation of the FIG4 variants by presenting four cases of CMT4J, including two with parkinsonism. All patients carried the pathogenic FIG4 variant c.122T>C p.(Ile41Thr) in compound heterozygosity with another variant: c.793C>T p.(Arg265*), c.498-1G>A, or c.447-2A>C. Disease onset occurred in the first or second decade of life. All presented with demyelinating sensorimotor polyneuropathy, distal muscle weakness of the upper and lower limbs, and foot deformity. In one patient, the muscle weakness was asymmetrical. Two patients developed parkinsonism. Our findings expand the phenotypic spectrum of FIG4-related disorders, reinforcing the link between CMT4J and parkinsonism. These insights are crucial for improving genetic diagnosis and advancing potential therapeutic strategies.