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Prenatal Genetic Testing for Dopa-Responsive Dystonia - Clinical Judgment in the Context of Next Generation Sequencing.

ABSTRACT: We present a family in which the first child was diagnosed with dopa-responsive dystonia based on biochemical findings only. Dopa-responsive dystonia is a severe heterogeneous genetic disease. The possibly involved genes are GCH1 and TH. In their second pregnancy, the parents came for genetic counseling and prenatal diagnosis late, at 12 weeks of gestation. Genetic testing in the affected child was performed, but the results were difficult to interpret. The identified mutations were classified as VOUS - variants of unknown clinical significance. Although possibly causative, a homozygous variant in the TH gene was not reported before in children with dopa-responsive dystonia. Due to limited time, establishing the fetal prognosis was challenging. Our report emphasizes the importance of a multidisciplinary approach in the context of new diagnostic techniques, such as Next Generation Sequencing. We illustrate the fact that behind any laboratory result remains sophisticated clinical judgment. We also describe a previously not reported variant of the TH gene in a child with severe, early-onset dystonia.

SUBMITTER: Nedelea F

PROVIDER: S-EPMC6418328 | biostudies-literature | 2018 Oct-Dec

REPOSITORIES: biostudies-literature

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Prenatal Genetic Testing for Dopa-Responsive Dystonia - Clinical Judgment in the Context of Next Generation Sequencing.

Nedelea Florina F Veduta Alina A Duta Simona S Vayna Ana-Maria AM Panaitescu Anca A Peltecu Gheorghe G Duba Hans-Christoph HC

Journal of medicine and life 20181001 4

We present a family in which the first child was diagnosed with dopa-responsive dystonia based on biochemical findings only. Dopa-responsive dystonia is a severe heterogeneous genetic disease. The possibly involved genes are GCH1 and TH. In their second pregnancy, the parents came for genetic counseling and prenatal diagnosis late, at 12 weeks of gestation. Genetic testing in the affected child was performed, but the results were difficult to interpret. The identified mutations were classified a ...[more]

PMID: 30894892

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Project description:IntroductionAlthough the diurnal fluctuation of motor dysfunction, reversible with small doses of dopamine, is a cornerstone for the phenotype of the autosomal dominant Segawa syndrome, the non-motor symptoms of this neurotransmitter deficiency have still received limited attention.ObjectiveThis study aims to evaluate non-motor symptoms of this dopa-responsive dystonia through an intrafamilial comparative cross-sectional study.MethodsSeventeen individuals with a c.IVS5 + 3insT (c.626 + 3insT) variation in the GTP cyclohydrolase-1 gene (GCH1, HGNC: 4193) and 34 intrafamilial controls were studied using the Beck Depression Inventory-II, the Wiener Matrizen Test 2, the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, the MINI/MINI PLUS Questionnaires, the World Health Organization Quality of Life - BREF Instrument and a drug use assessment questionnaire.ResultsNo significant difference was found between the groups in the prevalence of sleep disorders and in cognitive function. Nevertheless, generalized anxiety disorder (p = 0.050) and attention-deficit/hyperactivity disorder in childhood (p = 0.011) were observed only in individuals without the molecular variation. The group with the GCH1 variation presented a worse perception about how safe they feel in their daily lives (p = 0.034), less satisfaction with themselves (p = 0.049) and with their relationships (p = 0.029), and a higher prevalence of past major depressive episodes before use of L-Dopa (p = 0.046).ConclusionLow dopamine could have been protective against generalized anxiety disorder and attention-deficit/hyperactivity disorder in childhood in Segawa group individuals. The prevalence of depression was higher in individuals with the molecular variant prior to the L-Dopa treatment. Considering it, the penetrance estimates for the variant carriers increased from 58.8% to up to 88% in this large studied family. Additionally, neuropsychiatric tests of all individuals with a molecular diagnosis in an affected family are a valuable instrument for its clinical management.

Dataset Information

Prenatal Genetic Testing for Dopa-Responsive Dystonia - Clinical Judgment in the Context of Next Generation Sequencing.

Publications

Prenatal Genetic Testing for Dopa-Responsive Dystonia - Clinical Judgment in the Context of Next Generation Sequencing.

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