Novel PNKP mutation in siblings with ataxia-oculomotor apraxia type 4

Abstract

The phenotypic and genetic spectrum of ataxia with oculomotor apraxia (AOA) disorders is rapidly evolving and new technologies such as genetic mapping using whole exome sequencing reveal subtle distinctions among the various subtypes. We report a novel PNKP mutation in two siblings with progressive ataxia, abnormal saccades, sensorimotor neuropathy and dystonia consistent with the AOA type 4 phenotype. Laboratory evaluation revealed hypoalbuminemia, hypercholesterolemia with elevated LDL, elevated IgE levels and normal α fetoprotein levels. Eye movement examination demonstrated a marked saccade initiation defect with profound hypometric horizontal saccades. Vertical saccades were also affected but less so. Also present were conspicuous thrusting head movements when attempting to change gaze, but rather than an apraxia these were an adaptive strategy to take advantage of an intact vestibulo-ocular reflex to carry the eyes to a new target of interest. This is demonstrated in accompanying videos.

A Novel Homozygous Variant in the Fork-Head-Associated Domain of Polynucleotide Kinase Phosphatase in a Patient Affected by Late-Onset Ataxia With Oculomotor Apraxia Type 4

“…BMI index was 24.22. LDL increased level (173 mg/dl, nv < 130) confirmed data by Scheiss et al (4), who reported increased LDL and IgE levels in AOA4 patients. The immunoglobulin dosage was not performed.…”

“…Mutations in the DNA repair factor polynucleotide kinase phosphatase (PNKP) have been linked to multiple distinct human inherited syndromes. These include (i) microcephaly with seizures (MCSZ, MIM 613402, also known as early infantile epileptic encephalopathy-10), which is characterized by microcephaly, early-onset, intractable seizures, and developmental delay (1), (ii) progressive cerebellar atrophy and polyneuropathy (2), and (iii) ataxia with oculomotor apraxia type 4 (AOA4) (3,4).…”

From congenital microcephaly to adult onset cerebellar ataxia: Distinct and overlapping phenotypes in patients with PNKP gene mutations

“…Additional features were cognitive impairment (7/10 patients), increased plasma alpha‐fetoprotein and cholesterol (5/11 patients), and decreased albumin (6/11 patients) (Bras et al, ). In recent years, the availability of next‐generation sequencing or whole exome sequencing in the diagnostic procedure allowed the identification of several patients worldwide with MCSZ (Entezam, Razipour, Talebi, Beiraghi Toosi, & Keramatipour, ; Nair et al, ; Nakashima et al, ) or AOA4 phenotype (Paucar et al, ; Schiess, Zee, Siddiqui, Szolics, & El‐Hattab, ; Scholz et al, ; Tzoulis et al, ) or with symptoms encompassing both conditions (Taniguchi‐Ikeda et al, ). In other cases, the presenting clinical phenotype was characterized by the presence of a motor and sensory axonal polyneuropathy, resembling a form of Charcot–Marie–Tooth disease (Leal et al, ; Pedroso et al, ).…”

Ataxia with oculomotor apraxia type 4 detected by next-generation sequencing

“…У обоих выявлены атрофия мозжечка при МРТ, полинейропатия смешанного характера при ЭНМГ, гиперхолестеринемия, гипоальбуминемия, нормальный уровень α-фетопротеина. При NGS найдена новая мутация PNKP с.1189-15_119del18 в гомозиготном состоянии [10]. Особенность -внутрисемейные различия возраста начала и интеллекта.…”