Ataxia oculomotor apraxia type 4 due to a pathogenic variant in PNKP gene

İntroduction: Polynucleotide kinase phosphatase (PNKP) enzyme plays a role in many DNA repair pathways such as base excision repair, single-strand breaks repair and double-strand breaks repair. PNKP gene mutations are classically thought to cause two main phenotypes with overlapping symptoms between them. The first (MCSZ) is characterized by microcephaly (MC), resistant seizures (SZ) and developmental delay. The second is ataxia-oculomotor apraxia 4 (AOA4) is characterized by early-onset cerebellar ataxia, axonal polyneuropathy, and oculomotor apraxia.

Case Presentation: A 14-year-old female patient presented with unsteady gait, which had been present since she started walking and was getting worse. Neurological examination revealed microcephaly, ocular apraxia, absence of tendon reflexes, distally tapering legs and pes cavus. She was receiving special education due to moderate intellectual disability. EMG revealed severe sensorimotor axonal neuropathy. The brain MRI showed cerebellar atrophy. Plasma levels of creatine kinase and cholesterol were normal, while plasma albumin was slightly reduced, and alpha-fetoprotein level was slightly increased. The WES screening revealed homozygous p.Thr424Glyfs⃰49 pathogenic variant in the PNKP gene.

Conclusion: Autosomal recessive PNKP mutation-associated AOA4 should be remembered in patients presenting with ocular apraxia, neuropathy, and progressive cerebellar ataxia. The presence of intellectual disability and microcephaly, as in this patient, indicates the presence of a continuum spectrum of PNKP-related phenotypes, in which the symptoms manifest themselves at varying degrees and over time, rather than two different phenotypes that are clearly separated from each other.