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


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.

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We thank Dr. N.G. Jaspers at the Department of Genetics, Erasmus Medical Center for critically reading the manuscript. We acknowledge the collaboration of the members of the patients’ family. We thank J. Meulstee for the help with interpretation of EMG data. We also thank Tom de Vries Lentsch for the figures and Petra Veraart for the genealogical study.

Conflict of interest

The authors declare no conflict of interest.

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Correspondence to Grazia M. S. Mancini.

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Supplementary information is available at the Neurogenetics website.

Cathryn Poulton and Renske Oegema contributed equally to the manuscript.

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Poulton, C., Oegema, R., Heijsman, D. et al. Progressive cerebellar atrophy and polyneuropathy: expanding the spectrum of PNKP mutations. Neurogenetics 14, 43–51 (2013) doi:10.1007/s10048-012-0351-8

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  • DNA repair
  • Microcephaly
  • Polyneuropathy
  • Cerebellar atrophy
  • PNKP
  • MCSZ syndrome