Ataxia with Oculomotor Apraxia Type 4 with PNKP Common “Portuguese” and Novel Mutations in Two Belarusian Families

Abstract

Ataxia with oculomotor apraxia type 4 (AOA4) is a rare autosomal recessive, PNKP-related disorder delineated in 2015 in Portugal. We diagnosed AOA4 by next generation sequencing (NGS) followed by Sanger's sequencing in three boys from two unrelated Belarusian families. In both families, one of the heterozygous PNKP mutations was c.1123G>T, common in Portuguese patients; biallelic mutations, c.1270_1283dup14 and c.1029+2T>C, respectively, were novel. These are the first reported AOA4 Slavic cases and the first with a “Portuguese” PNKP mutation outside Portugal. Distinction in two brothers was microcephaly but their disease was not severe in contrast to PNKP-related “microcephaly, seizures, and developmental delay” and reported cases with features of both phenotypes.

PNKP mutation in a child: is there a firm line between MCSZ and AOA4 phenotype?

“…Consanguinity was likewise reported in that case. Two Belarus families provided the first observed AOA4 in Slavic countries with PNKP mutation, which differ from our case in the absence of cerebellar atrophy, but with signs of early onset epilepsy and AOA [4]. The distinctive feature of our patient is mixed MCSZ-AOA4 phenotype that has some variance from typical AOA (absence of oculomotor apraxia) and from typical MCSZ (absence of epilepsy).…”

“…This is the first pathogenic PNKP-gene mutation to be reported in the Balkan region. This mutation seems to be common in various European heritages (it has been reported in Norway, the Netherlands [3], Germany, and Belarus [4]), and Asian heritages (Iranian, Japanese and Palestinian origins) [5]. The PNKP mutation is the most common cause of AOA in Portugal [1].…”

Novel PNKP mutations associated with reduced DNA single‐strand break repair and severe microcephaly, seizures, and developmental delay

“…A prediction of this model is that MCSZ patients in whom the repair of both oxidative SSBs and TOP1-induced SSBs is defective should exhibit not only neurodevelopmental pathology resulting from unrepaired oxidative SSBs but also neurodegeneration and/ or cerebellar ataxia resulting from unrepaired TOP1induced SSBs that typifies AOA4 and CMT2B2. Whilst cerebellar ataxia was not initially reported in initial MCSZ patients, it has recently been reported in some cases (Entezam et al, 2018;Gatti et al, 2019;Poulton et al, 2012;Rudenskaya et al, 2019;Taniguchi-Ikeda et al, 2018). It will thus be important to assess the current and other MCSZ patients in future, for cerebellar dysfunction and/or other neurodegenerative pathology.…”

The DNA repair enzyme, aprataxin, plays a role in innate immune signaling

“…Biochemical and genetic tests, as well as family history are used for diagnosis (Klockgether, 2007). There are four subtypes of ataxia with oculomotor apraxia (AOA): AOA1 [mutations in APTX (Moreira et al, 2001) and/or PNKP (Bras et al, 2015)]; AOA2 [mutations in SETX (Airoldi et al, 2010)]; AOA3 [mutations in PIK3R5 (Tassan et al, 2012)]; AOA4 [mutations in PNKP (Paucar et al, 2016;Rudenskaya et al, 2019)]. All are associated with early disease onset and elevated alphafetoprotein, while AOA1, AOA2, and AOA4 are further associated with elevated cholesterol and hypoalbuminemia (Papadimitriou et al, 1996;Moreira et al, 2001;Sano et al, 2004;Quinzii et al, 2005;Kijas et al, 2006;Tada et al, 2010;Bogeski et al, 2011;Bras et al, 2015;Paucar et al, 2019;Kato et al, 2021;Coutinho et al, 2023).…”