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Genotype-Phenotype Correlations and Characterization of Medication Use in Inherited Myotonic Disorders.

ABSTRACT: Introduction: Inherited myotonic disorders are genetically heterogeneous and associated with overlapping clinical features of muscle stiffness, weakness, and pain. Data on genotype-phenotype correlations are limited. In this study, clinical features and treatment patterns in genetically characterized myotonic disorders were compared. Methods: A retrospective chart review was completed in patients with genetic variants in CLCN1, SCN4A, DMPK, and CNBP to document clinical signs and symptoms, clinical testing, and antimyotonia medication use. Results: A total of 142 patients (27 CLCN1, 15 SCN4A, 89 DMPK, and 11 CNBP) were reviewed. The frequency of reported symptoms (stiffness, weakness, and pain) and electromyographic spontaneous activity were remarkably similar across genotypes. Most patients were not treated with antimyotonia agents, but those with non-dystrophic disorders were more likely to be on a treatment. Discussion: Among the features reviewed, we did not identify clinical or electrophysiological differences to distinguish CLCN1- and SCN4A-related myotonia. Weakness and pain were more prevalent in non-dystrophic disorders than previously identified. In addition, our results suggest that medical treatments in myotonic disorders may be under-utilized.

SUBMITTER: Meyer AP

PROVIDER: S-EPMC7332828 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Genotype-Phenotype Correlations and Characterization of Medication Use in Inherited Myotonic Disorders.

Meyer Alayne P AP Roggenbuck Jennifer J LoRusso Samantha S Kissel John J Smith Rachel M RM Kline David D Arnold W David WD

Frontiers in neurology 20200626

Introduction: Inherited myotonic disorders are genetically heterogeneous and associated with overlapping clinical features of muscle stiffness, weakness, and pain. Data on genotype-phenotype correlations are limited. In this study, clinical features and treatment patterns in genetically characterized myotonic disorders were compared. Methods: A retrospective chart review was completed in patients with genetic variants in CLCN1, SCN4A, DMPK, and CNBP to document clinic ...[more]

PMID: 32670189

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Project description:IMPORTANCE:The leukodystrophies comprise a clinically and genetically heterogeneous group of progressive hereditary neurological disorders mainly affecting the myelin in the central nervous system. Their onset is variable from childhood to adulthood and presentation can be with a variety of clinical features that include mainly for adult-onset cases cognitive decline, seizures, parkinsonism, muscle weakness, neuropathy, spastic paraplegia, personality/behavioral problems, and dystonia. Recently, Rademakers and colleagues identified mutations in the CSF1R gene as the cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS), offering the possibility for an in-life diagnosis. The detection of mutations in this gene in cases diagnosed with different clinical entities further demonstrated the difficulties in the clinical diagnosis of HDLS. OBJECTIVE:To better understand the genetic role of mutations in this gene, we sequenced a large cohort of adult-onset leukodystrophy cases. DESIGN:Whole-exome sequencing and follow up-screening by Sanger sequencing. SETTING:Collaborative study between the Institute of Neurology, University College London and the Inserm, Paris, France. PARTICIPANTS:A total of 114 probands, mostly European patients, with a diagnosis of adult-onset leukodystrophy or atypical cases that could fit within a picture of leukodystrophy. These included 3 extended families within the spectrum of leukodystrophy phenotype. INTERVENTIONS:Whole-exome sequencing in a family and Sanger sequencing of CSF1R. MAIN OUTCOMES AND MEASURES:Mutations in CSF1R. RESULTS:We identified 12 probands with mutations in CSF1R. The clinical diagnoses given to these patients included dementia with spastic paraplegia, corticobasal degeneration syndrome, and stroke disorders. Our study shows that CSF1R mutations are responsible for a significant proportion of clinically and pathologically proven HDLS. CONCLUSIONS AND RELEVANCE:These results give an indication of the frequency of CSF1R mutations in a European leukodystrophy series and expand the phenotypic spectrum of disorders that should be screened for this gene.

Project description:Less than 50 patients with FPD/AML (OMIM 601309) have been reported as of today and there may an underestimation. The purpose of this study was to describe the natural history, the haematological features and the genotype-phenotype correlations of this entity in order to, first, screen it better and earlier, before leukaemia occurrence and secondly to optimize appropriate monitoring and treatment, in particular when familial stem cell transplantation is considered.We have investigated 41 carriers of RUNX1 alteration belonging to nine unrelated French families with FPD/AML and two syndromic patients, registered in the French network on rare platelet disorders from 2005 to 2015.Five missense, one non-sense, three frameshift mutations and two large deletions involving several genes including RUNX1 were evidenced. The history of familial leukaemia was suggestive of FPD/AML in seven pedigrees, whereas an autosomal dominant pattern of lifelong thrombocytopenia was the clinical presentation of two. Additional syndromic features characterized two large sporadic deletions. Bleeding tendency was mild and thrombocytopenia moderate (>50 x10(9)/L), with normal platelet volume. A functional platelet defect consistent with a ?-granule release defect was found in ten patients regardless of the type of RUNX1 alteration. The incidence of haematological malignancies was higher when the mutated RUNX1 allele was likely to cause a dominant negative effect (19/34) in comparison with loss of function alleles (3/9). A normal platelet count does not rule out the diagnosis of FPD/AML, since the platelet count was found normal for three mutated subjects, a feature that has a direct impact in the search for a related donor in case of allogeneic haematopoietic stem cell transplantation.Platelet dysfunction suggestive of defective ?-granule release could be of values for the diagnosis of FPD/AML particularly when the clinical presentation is an autosomal dominant thrombocytopenia with normal platelet size in the absence of familial malignancies. The genotype-phenotype correlations might be helpful in genetic counselling and appropriate optimal therapeutic management.

Project description:Background Inherited retinal diseases (IRD) represent a prominent etiology of visual impairment on a global scale. The lack of a clear definition of the etiology and genotypic spectrum of IRD is attributed to the significant genetic variability seen. Additionally, there is a scarcity of available data about the correlations between genotypes and phenotypes in this context. This study aimed to clarify the range of mutations and the associations between genotypes and phenotypes in IRD. Methods This cohort consists of 223 patients who have been diagnosed with a range of retinal illnesses, such as retinitis pigmentosa (RP), Stargardt (STGD)/STGD-like disease, Usher syndrome, and Leber congenital amaurosis (LCA). The validation of each mutation and its pathogenicity was conducted by bioinformatics analysis, Sanger sequencing-based co-segregation testing, and computational assessment. The link between genotype and phenotype was analyzed in all patients who possessed mutations as described in the recommendations established by the American College of Medical Genetics. Results A total of 223 cases, comprising Turkish and Syrian families, were examined, revealing the presence of 175 distinct mutations in the IRD gene. Among these mutations, 58 were identified as unique, indicating that they had not been previously reported. A total of 119 mutations were identified to be likely pathogenic, while 104 mutations were classified as pathogenic. The study identified patterns of heredity, namely autosomal recessive, dominant, and X-linked inheritance. Conclusions The findings of this study broaden the clinical and molecular aspects of IRD and further enhance our understanding of its complex nature. The discovery of previously unknown relationships between genetic variations and observable traits, as well as the wide range of genetic variants associated with IRD, significantly contributes to our existing understanding of the diverse phenotypic and genotypic characteristics of IRD. This new information will prove invaluable in facilitating accurate clinical diagnoses as well as personalized therapeutic interventions for individuals affected by IRD.

Dataset Information

Genotype-Phenotype Correlations and Characterization of Medication Use in Inherited Myotonic Disorders.

Publications

Genotype-Phenotype Correlations and Characterization of Medication Use in Inherited Myotonic Disorders.

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