Objective: We report on a new case expanding the clinical presentation of PNKP deficiency

Background: PNKP gene encodes for a kinase/phosphatase protein involved in DNA damage response controlled and stabilized by ATM phosphorilation1. PNKP deficiency, thus far described in 40 subjects, has been associated with a pleiotropic neurological phenotype encompassing microcephaly, seizures, developmental delay, ataxia, oculomotor apraxia and polyneuropathy2,3,4. We report on a new presenting phenotype of the disease characterized by a pure generalized chorea.

Method: This 25 year-old girl presented at the age of 2 with subacute onset chorea. On examination she showed: normal psychomotor developmental, mild microcephaly, and generalized chorea mimicking Sydenam’s chorea. Neuroimaging, rheumatological and metabolic diagnostic work-up was inconclusive. In the following years the movement disorder (MD) remained stable with relapses and partial remissions, well controlled by pimozide. She has never presented ocular motility disorders. Cognitive development was normal and she was able to have a normal academic career. At the age of 19 she complained progressive fatigability and asthenia of lower limbs. Clinical and neurophysiological examination revealed a sensory-motor axonal demyelinating neuropathy. In the few following years the neuropathy spread to upper limbs with a distal to proximal progression pattern. At the moment she is able to walk only with orthosis. At the age of 20 brain MRI disclosed cerebellar atrophy. Blood examination showed hypercholesterolemia and hypoalbuminemia. Alpha fetoprotein was normal

Results: Clinical exome revealed a compound heterozygous variant on PNKP gene: c.1253_1269dup and c.1196T>C p.Leu399Pro. Segregation was confirmed in the parents.

Conclusion: PNKP gene should be considered in the differential diagnosis of each early onset  choreic syndrome. The apparent stable clinical course in this condition anticipates of several years a severe ascendant neuropathy. Microcephaly plus chorea are clinical markers of this disease. The present abstract has been presented in two previous meeting:-Ataxia Telangiectasia Clinical Research Conference (29 November1 December 2018, Napoli);-6 th international symposium on paediatric movement disorders (78 February 2019, Barcellona)

References: [1] J.L. Parsons, S.V. Khoronenkova, I.I. Dianova, N. Ternette, B.M. Kessler, P.K. Datta, G.L. Dianov, Phosphorylation of PNKP by ATM prevents its proteasomal degradation and enhances resistance to oxidative stress, Nucleic acids research 40 (2012) 11404-11415 [2] J. Bras, I. Alonso, C. Barbot, M.M. Costa, L. Darwent, T. Orme, J. Sequeiros, J. Hardy, P. Coutinho, R. Guerreiro, Mutations in PNKP cause recessive ataxia with oculomotor apraxia type 4. Am J Hum Genet. 96 (2015) 474-479 [3] J. Shen, E. C. Gilmore, C. A. Marshall, M. Haddadin, J. J. Reynolds, W. Eyaid, A Bodell, K. Allen, B. S. Chang, A. Grix, R. Sean Hill, M. Topcu, K. W. Caldecott, A. J. Barkovich, and C. A. Walsh [4] A. Leal, S. Bogantes-Ledezma, A.B. Ekici, S. Uebe, C. T. Thiel, H. Sticht, M. Berghoff, C. Berghoff, B. Morera, M. Meisterernst, A. Reis, The polynucleotide kinase 3′-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25. Neurogenetics 19 (2018) 1-11

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pnkp-deficiency-mimicking-a-benign-hereditary-chorea-the-misleading-presentation-of-a-neurodegenerative-disorder/