Pediatric writer's cramp in myoclonus-dystonia: Maternal imprinting hides positive family history

Gerrits, M C F; Foncke, E.M.J.; Koelman, J.H.T.M.; Tijssen, Marina A. J.

doi:10.1016/j.ejpn.2008.03.007

Cited by 11 publications

(11 citation statements)

References 24 publications

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“…One individual with a mutation in SGCE (MIM: 604149) had findings of dystonia (MIM: 159900) on exam and her son, who was positive for the mutation, had severe writer's cramp reported on an iterative family history, a reported manifestation of SGCE mutations. 11 Another individual with a PPARG (MIM: 601487) mutation had a family history of lipodystrophy incorrectly diagnosed as Dunnigan type lipodystrophy (MIM: 151660). On exam the participant had lipodystrophy and laboratory abnormalities including mild liver function elevations, mild hypertriglyceridemia with low HDL, and intermittently elevated fasting glucose concentrations with mild hyperinsulinemia.…”

Section: Iterative Phenotypingmentioning

confidence: 99%

Individualized Iterative Phenotyping for Genome-wide Analysis of Loss-of-Function Mutations

Johnston

Lewis

et al. 2015

The American Journal of Human Genetics

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Next-generation sequencing provides the opportunity to practice predictive medicine based on identified variants. Putative loss-offunction (pLOF) variants are common in genomes and understanding their contribution to disease is critical for predictive medicine. To this end, we characterized the consequences of pLOF variants in an exome cohort by iterative phenotyping. Exome data were generated on 951 participants from the ClinSeq cohort and filtered for pLOF variants in genes likely to cause a phenotype in heterozygotes. 103 of 951 exomes had such a pLOF variant and 79 participants were evaluated. Of those 79, 34 had findings or family histories that could be attributed to the variant (28 variants in 18 genes), 2 had indeterminate findings (2 variants in 2 genes), and 43 had no findings or a negative family history for the trait (34 variants in 28 genes). The presence of a phenotype was correlated with two mutation attributes: prior report of pathogenicity for the variant (p ¼ 0.0001) and prior report of other mutations in the same exon (p ¼ 0.0001). We conclude that 1/30 unselected individuals harbor a pLOF mutation associated with a phenotype either in themselves or their family. This is more common than has been assumed and has implications for the setting of prior probabilities of affection status for predictive medicine.

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Section: Iterative Phenotypingmentioning

confidence: 99%

Individualized Iterative Phenotyping for Genome-wide Analysis of Loss-of-Function Mutations

Johnston

Lewis

et al. 2015

The American Journal of Human Genetics

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“…A positive family history is frequent, but apparently sporadic cases due to de novo mutations or maternal imprinting have also been reported 22–24…”

Section: Clinical Spectrum Of M‐d Syndromementioning

confidence: 99%

“…De novo mutation in a patient with apparently sporadic M‐D has been reported, indicating that SGCE mutations should also be considered when the family history of M‐D is negative 23. In addition, the family history may be hidden by maternal imprinting in case of maternal transmission of the mutated allele over successive generations 22…”

Section: Genetic Basis Of M‐dmentioning

confidence: 99%

Myoclonus‐dystonia: An update

et al. 2009

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Our knowledge of the clinical, neurophysiological, and genetic aspects of myoclonus-dystonia (M-D) has improved markedly in the recent years. Basic research has provided new insights into the complex dysfunctions involved in the pathogenesis of M-D. On the basis of a comprehensive literature search, this review summarizes current knowledge on M-D, with a focus on recent findings. We also propose modified diagnostic criteria and recommendations for clinical management.

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“…However, both sensitivity and specificity of these sets of criteria in predicting SGCE mutated patients are expected to fall below 100%. On one hand, SGCE mutations have been associated with atypical phenotypes such as adult onset, predominant lower body involvement, or prominent dystonia without much myoclonus . Moreover, additional features including neurological signs are common in patients with large genomic deletions, due to haploinsufficiency of adjacent genes .…”

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confidence: 99%

Defining the Epsilon‐Sarcoglycan (SGCE) Gene Phenotypic Signature in Myoclonus‐Dystonia: A Reappraisal of Genetic Testing Criteria

et al. 2013

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Mutations or exon deletions of the epsilon-sarcoglycan (SGCE) gene cause myoclonus-dystonia (M-D), but a subset of M-D patients are mutation-negative and the sensitivity and specificity of current genetic testing criteria are unknown. We screened 46 newly enrolled M-D patients for SGCE mutations and deletions; moreover, 24 subjects previously testing negative for SGCE mutations underwent gene dosage analysis. In our combined cohorts, we calculated sensitivity, specificity, positive and negative predictive values, and area under the curve of 2 published sets of M-D diagnostic criteria. A stepwise logistic regression was used to assess which patients' characteristics best discriminated mutation carriers and to calculate a new mutation predictive score ("new score"), which we validated in previously published cohorts. Nine of 46 (19.5%) patients of the new cohort carried SCGE mutations, including 5 novel point mutations and 1 whole-gene deletion; in the old cohort, 1 patient with a complex phenotype carried a 5.9-Mb deletion encompassing SGCE. Current diagnostic criteria had a poor ability to discriminate SGCE-positive from SGCE-negative patients in our cohort; conversely, age of onset, especially if associated with psychiatric features (as included in the new score), showed the best discriminatory power to individuate SGCE mutation carriers, both in our cohort and in the validation cohort. Our results suggest that young age at onset of motor symptoms, especially in association with psychiatric disturbance, are strongly predictive for SGCE positivity. We suggest performing gene dosage analysis by multiple ligation-dependent probe amplification (MLPA) to individuate large SGCE deletions that can be responsible for complex phenotypes.

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Pediatric writer's cramp in myoclonus-dystonia: Maternal imprinting hides positive family history

Cited by 11 publications

References 24 publications

Individualized Iterative Phenotyping for Genome-wide Analysis of Loss-of-Function Mutations

Individualized Iterative Phenotyping for Genome-wide Analysis of Loss-of-Function Mutations

Myoclonus‐dystonia: An update

Defining the Epsilon‐Sarcoglycan (SGCE) Gene Phenotypic Signature in Myoclonus‐Dystonia: A Reappraisal of Genetic Testing Criteria

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