Two patients with <i><scp>PNKP</scp></i> mutations presenting with microcephaly, seizure, and oculomotor apraxia

Taniguchi‐Ikeda, Mariko; Morisada, Naoya; Inagaki, Hidehito; Ouchi, Yuya; Takami, Yuichi; Tachikawa, Masaji; Satake, Wataru; Kobayashi, Kenzo; Tsuneishi, Syuichi; Takada, Shinako; Yamaguchi, Hiroshi; Nagase, Hiroaki; Nozu, Kandai; Okamoto, Nobuhiko; Nishio, Hisahide; Toda, Tatsushi; Morioka, Ichiro; Wada, Hiroyoshi; Kurahashi, Hiroki; Iijima, Kazumoto

doi:10.1111/cge.13106

Cited by 11 publications

(13 citation statements)

References 5 publications

(7 reference statements)

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“…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, ).…”

Section: Introductionmentioning

confidence: 99%

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

Gatti

Magri

Nanetti

et al. 2019

American J of Med Genetics Pt A

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Pathogenic variants in polynucleotide kinase 3 0 -phosphatase (PNKP) gene have been associated with two distinct clinical presentations: autosomal recessive microcephaly, seizures, and developmental delay (MCSZ; MIM 613402) and ataxia with oculomotor apraxia type 4 (AOA4; MIM 616267). More than 40 patients have been reported so far, and their clinical presentations revealed a continuum phenotypic spectrum ranging from congenital microcephaly and early-onset intractable seizures, to adult onset slowly progressive sensory-motor neuropathy and cerebellar ataxia. We describe three unrelated Italian patients with different phenotypes and novel or recurrent pathogenic variants in PNKP gene. Patient 1, homozygous for the recurrent frameshift variant (p.Thr424Glyfs*49), had an early-onset MCSZ phenotype. Late in the disease progression, cerebellar ataxia and peripheral neuropathy were recognized. Patient 2, homozygous for a frameshift variant (p.Ala429Thrfs*42), presented a phenotype partially consistent with MCSZ including microcephaly and developmental delay, but without seizures. Patient 3 is one of the oldest patients described to date and presented polyneuropathy, and cerebellar signs. Biochemical tests showed abnormalities of cholesterol, albumin, or alpha-fetoprotein plasma levels. The clinical presentation of our patients encompassed early-to-adult-onset manifestations. For these cases, the long clinical follow-up allowed an in-depth phenotypic characterization and a better delineation of the natural history of patients carrying PNKP pathogenic variants. K E Y W O R D S alpha-fetoprotein, cerebellar atrophy, oculomotor apraxia, seizures

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Section: Introductionmentioning

confidence: 99%

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

Gatti

Magri

Nanetti

et al. 2019

American J of Med Genetics Pt A

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“…Smaller introns are associated with a higher likelihood of intron retention (35), a mechanism we proved for two novel variants here. RNA analyses of disease-associated PNKP variants were previously not reported, despite many intronic and splice sites affecting changes described (6,26,28,29,(36)(37)(38)(39)(40)(41)(42)(43). The results of our RNA splicing analyses for one novel silent variant, one known splice donor variant and moreover one variant annotated as missense point toward a likely underappreciated pathomechanism.…”

Section: Discussionmentioning

confidence: 62%

Prenatal phenotype of PNKP-related primary microcephaly associated with variants in the FHA and Phosphatase domain

Neuser

Krey

Schwan³

et al. 2021

Preprint

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Biallelic PNKP variants cause heterogeneous disorders ranging from neurodevelopmental disorder with microcephaly/seizures to adult-onset Charcot-Marie-Tooth disease. To date, only postnatal descriptions exist. We present the first prenatal diagnosis of PNKP-related primary microcephaly. Detailed pathological examination of a male fetus revealed micrencephaly with extracerebral malformations and thus presumed syndromic microcephaly. A recessive disorder was suspected because of previous pregnancy termination for similar abnormalities in a sibling fetus. Prenatal trio exome sequencing identified compound-heterozygosity for the PNKP variants c.498G>A, p.[(=),0?] and c.302C>T, p.(Pro101Leu). Segregation confirmed both variants in the sibling fetus. Through RNA analyses, we characterized skipping of exon 4 affecting the PNKP Forkhead-associated (FHA) and Phosphatase domains (p.Leu67_Lys166del) as the predominant effect of the c.498G>A variant. We retrospectively investigated two unrelated individuals diagnosed with biallelic PNKP-variants to compare prenatal/postnatal phenotypes. Both carry the same splice-donor variant c.1029+2T>C in trans with a variant in the FHA domain (c.311T>C, p.(Leu104Pro) and c.151G>C, p.(Val51Leu), respectively). RNA-seq showed complex splicing events for c.1029+2T>C and c.151G>C. Computational modelling and structural analysis revealed significant clustering of missense variants in the FHA domain, with some variants potentially generating structural damage. Our detailed clinical description extends the PNKP-continuum to the prenatal stage. Investigating possible PNKP-variant effects using RNA and structural modelling, we highlight the mutational complexity and exemplify a framework for variant characterization in this multi-domain protein.

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“…2,9,10 In few reported cases of mixed MCSZ-AOA4 phenotypes, MCSZ features were predominated. 3,4 Though AOA4 with microcephaly and/or epilepsy was not reported previously, we consider the phenotype in the brothers as AOA4 variant. Absence of cerebellar atrophy on MRI and of polyneuropathy may be other distinctions of AOA4 in family 2, or these signs may appear later, like polyneuropathy in Swedish and Norwegian patients, 11,12 like cerebellar signs in Latin American cases with predominant polyneuropathy, 5,6 or like cerebellar atrophy in patient 1.…”

Section: Discussionmentioning

confidence: 97%

“…2 Though different, the diseases have crosspoints, and mixed phenotypes have been reported. 3,4 PNKPrelated cases with predominant congenital or adult-onset axonal polyneuropathy and later-appearing mild AOA4 features adjoin AOA4. 5,6 Some PNKP mutations are shared by different phenotypes.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Two patients with PNKP mutations presenting with microcephaly, seizure, and oculomotor apraxia

Cited by 11 publications

References 5 publications

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

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

Prenatal phenotype of PNKP-related primary microcephaly associated with variants in the FHA and Phosphatase domain

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

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