FIG4 mutations leading to parkinsonism and a phenotypical continuum between CMT4J and Yunis Varón syndrome.

Background: Charcot-Marie-Tooth disease type 4J (CMT4J) originates from mutations in the FIG4 gene and leads to distal muscle weakness. Two null alleles of FIG4 cause Yunis Varón syndrome with severe central nervous system involvement, cleidocranial dysmorphism, absent thumbs and halluces and early death.

Objectives: To analyse the phenotypic spectrum of FIG4-related disease and explore effects of residual FIG4 protein.

Methods: Phenotyping of five new patients with FIG4-related disease. Western Blot analyses of FIG4 from patient fibroblasts.

Results: Next generation sequencing revealed compound heterozygous variants in FIG4 in five patients. All five patients presented with peripheral neuropathy, various degree of dysmorphism and a central nervous system involvement comprising Parkinsonism in 3/5 patients, cerebellar ataxia (1/5), spasticity of lower limbs (1/5), epilepsy (1/5) and/or cognitive deficits (2/5). Onset varied between the first and the seventh decade. There was no residual FIG4 protein detectable in fibroblasts of the four analysed patients.

Conclusion: This study extends the phenotypic spectrum of FIG4-related disease to Parkinsonism as a feature and demonstrates new phenotypes on a continuum between CMT4J and Yunis Varón syndrome.