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PNKP Mutations Identified by Whole-Exome Sequencing in a Norwegian Patient with Sporadic Ataxia and Edema.

ABSTRACT: We identified PNKP mutations in a Norwegian woman with AOA. This patient had the typical findings with cognitive dysfunction, peripheral neuropathy, cerebellar dysarthria, horizontal nystagmus, oculomotor apraxia, and severe truncal and appendicular ataxia. In addition, she had hypoalbuminemia and massive lower limb edema which showed some improvement with treatment. Exome sequencing identified two heterozygous mutations, one in exon 14 (c.1196T>C, p.Leu399Pro) and one in exon 16 (c.1393_1396del, p.Glu465*). This is the first non-Portuguese patient with AOA due to PNKP mutations and provides independent verification that PNKP mutations cause AOA.

SUBMITTER: Tzoulis C

PROVIDER: S-EPMC5243888 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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PNKP Mutations Identified by Whole-Exome Sequencing in a Norwegian Patient with Sporadic Ataxia and Edema.

Tzoulis C C Sztromwasser Paweł P Johansson Stefan S Gjerde Ivar Otto IO Knappskog Per P Bindoff L A LA

Cerebellum (London, England) 20170201 1

We identified PNKP mutations in a Norwegian woman with AOA. This patient had the typical findings with cognitive dysfunction, peripheral neuropathy, cerebellar dysarthria, horizontal nystagmus, oculomotor apraxia, and severe truncal and appendicular ataxia. In addition, she had hypoalbuminemia and massive lower limb edema which showed some improvement with treatment. Exome sequencing identified two heterozygous mutations, one in exon 14 (c.1196T>C, p.Leu399Pro) and one in exon 16 (c.1393_1396del ...[more]

PMID: 27165045

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Project description:ImportanceCerebellar ataxias are a diverse collection of neurologic disorders with causes ranging from common acquired etiologies to rare genetic conditions. Numerous genetic disorders have been associated with chronic progressive ataxia and this consequently presents a diagnostic challenge for the clinician regarding how to approach and prioritize genetic testing in patients with such clinically heterogeneous phenotypes. Additionally, while the value of genetic testing in early-onset and/or familial cases seems clear, many patients with ataxia present sporadically with adult onset of symptoms and the contribution of genetic variation to the phenotype of these patients has not yet been established.ObjectiveTo investigate the contribution of genetic disease in a population of patients with predominantly adult- and sporadic-onset cerebellar ataxia.Design, setting, and participantsWe examined a consecutive series of 76 patients presenting to a tertiary referral center for evaluation of chronic progressive cerebellar ataxia.Main outcomes and measuresNext-generation exome sequencing coupled with comprehensive bioinformatic analysis, phenotypic analysis, and clinical correlation.ResultsWe identified clinically relevant genetic information in more than 60% of patients studied (n = 46), including diagnostic pathogenic gene variants in 21% (n = 16), a notable yield given the diverse genetics and clinical heterogeneity of the cerebellar ataxias.Conclusions and relevanceThis study demonstrated that clinical exome sequencing in patients with adult-onset and sporadic presentations of ataxia is a high-yield test, providing a definitive diagnosis in more than one-fifth of patients and suggesting a potential diagnosis in more than one-third to guide additional phenotyping and diagnostic evaluation. Therefore, clinical exome sequencing is an appropriate consideration in the routine genetic evaluation of all patients presenting with chronic progressive cerebellar ataxia.

Dataset Information

PNKP Mutations Identified by Whole-Exome Sequencing in a Norwegian Patient with Sporadic Ataxia and Edema.

Publications

PNKP Mutations Identified by Whole-Exome Sequencing in a Norwegian Patient with Sporadic Ataxia and Edema.

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