Cerebellar Ataxia and Peripheral Neuropathy in a Family With PNPLA8-Associated Disease

Objectives: To describe clinical and genetic findings in 2 siblings with slowly progressive ataxia.

Methods: We studied 2 adult siblings through detailed physical and instrumental examinations. Whole-exome sequencing was used to identify an underlying genetic cause.

Results: Both siblings presented with adolescence-onset ataxia, progressive sensorimotor polyneuropathy, and preserved cognition over time. The onset of symptoms was between 10 and 14 years of age. A brain MRI demonstrated mild cerebellar atrophy in the older brother at age 45 years. Exome sequencing revealed compound heterozygous loss-of-function variants c.2269del (p.(Thr757GlnfsTer10)) and c.2275_2276del (p.(Leu759AlafsTer4)) in PNPLA8. The novel variant c.2269del results in frameshift with a premature stop codon p.(Thr757GlnfsTer10) and loss of normal enzyme function.

Discussion: Our findings support the theory that biallelic loss-of-function PNPLA8 variants are involved in neurodegenerative mitochondrial disease. Compared with patients previously described, these patients' phenotype may be interpreted as a milder phenotype associated with a slight progression of ataxia throughout adulthood.