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Neurol Genet. 2015 Oct 22;1(4):e30. doi: 10.1212/NXG.0000000000000030. eCollection 2015 Dec.

Mutation in PNKP presenting initially as axonal Charcot-Marie-Tooth disease.

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Department of Neurology (J.L.P., O.G.P.B., A.S.B.O.), Federal University of São Paulo, São Paulo, Brazil; Department of Microbiology (C.R.R.R., C.F.M.M.), Institute of Biomedical Sciences, and Center for Human Genome and Stem Cell Research (L.I.M.-S., F.K.), Institute of Biosciences, University of São Paulo, São Paulo, Brazil; Mendelics Genomic Analysis (V.D.M., F.K.), São Paulo, Brazil; Department of Neurology (W.M.), University of São Paulo School of Medicine, Ribeirão Preto, Brazil; and Department of Neurology (F.K.), University of São Paulo School of Medicine, São Paulo, Brazil.


PNKP (polynucleotide kinase 3'-phosphatase, OMIM #605610) product is involved in the repair of strand breaks and base damage in the DNA molecule mainly caused by radical oxygen species. Deleterious variants affecting this gene have been previously associated with microcephaly, epilepsy, and developmental delay.(1) According to a previous report, homozygous loss-of-function substitution in PNKP was associated with cerebellar atrophy, neuropathy, microcephaly, epilepsy, and intellectual disability.(2) Recently, whole-exome sequencing (WES) performed in a cohort of Portuguese families with ataxia with oculomotor apraxia (AOA) disclosed pathogenic variants in PNKP in 11 individuals. Other clinical features in that study included neuropathy, dystonia, cognitive impairment, decreased vibration sense, pyramidal signs, mild elevation in α-fetoprotein, and low levels of albumin. This condition was named AOA type 4 (OMIM #616267), as the phenotype of AOA has been previously associated with 3 other genes: APTX, SETX, and PIK3R5.(3) Altogether, these reports demonstrate the great phenotypic diversity associated with PNKP mutations. In this article, we further enlarge this variability by demonstrating that early-onset axonal sensory-motor neuropathy (or axonal Charcot-Marie-Tooth (CMT) disease) followed years later by ataxia without oculomotor apraxia can be caused by deleterious variants in PNKP. Full consent was obtained from the patient and his parents for this publication. This study was approved by institutional ethics committees.

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