Progressive cerebellar atrophy and polyneuropathy: expanding the spectrum of PNKP mutations

• DOI: 10.1007/s10048-012-0351-8
• Publication Date: 2012-12-08T02:51:04Z
• Authors: Cathryn Poulton; Renske Oegema; Daphne Heijsman; Jeannette Hoogeboom; Rachel Schot; Hans Stroink; Michèl A. Willemsen; Frans W. Verheijen; Peter van de Spek; Andreas Kremer; Grazia M. S. Mancini
• Keywords: Male; 0301 basic medicine; Adolescent; DCN MP - Plasticity and memory; Siblings; DNA Mutational Analysis; Pedigree; 3. Good health; Radiography; Consanguinity; Phosphotransferases (Alcohol Group Acceptor); Polyneuropathies; 03 medical and health sciences; DNA Repair Enzymes; Cerebellum; Mutation; EMC MGC-02-02-01; Disease Progression; Humans; Child; EMC MGC-02-96-01; Follow-Up Studies; Spinocerebellar Degenerations

We present a neurodegenerative disorder starting in early childhood of two brothers consisting of severe progressive polyneuropathy, severe progressive cerebellar atrophy, microcephaly, mild epilepsy, and intellectual disability. The cause of this rare syndrome was found to be a homozygous mutation (c.1250_1266dup, resulting in a frameshift p.Thr424GlyfsX48) in PNKP, identified by applying homozygosity mapping and whole-genome sequencing. Mutations in PNKP have previously been associated with a syndrome of microcephaly, seizures and developmental delay (MIM 613402), but not with a neurodegenerative disorder. PNKP is a dual-function enzyme with a key role in different pathways of DNA damage repair. DNA repair disorders can result in accelerated cell death, leading to underdevelopment and neurodegeneration. In skin fibroblasts from both affected individuals, we show increased susceptibility to apoptosis under stress conditions and reduced PNKP expression. PNKP is known to interact with DNA repair proteins involved in the onset of polyneuropathy and cerebellar degeneration; therefore, our findings explain this novel phenotype.