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SCN4A as modifier gene in patients with myotonic dystrophy type 2.

ABSTRACT: A patient with an early severe myotonia diagnosed for Myotonic Dystrophy type 2 (DM2) was found bearing the combined effects of DM2 mutation and Nav1.4 S906T substitution. To investigate the mechanism underlying his atypical phenotype,whole-cell patch-clamp in voltage- and current-clamp mode was performed in myoblasts and myotubes obtained from his muscle biopsy. Results characterizing the properties of the sodium current and of the action potentials have been compared to those obtained in muscle cells derived from his mother, also affected by DM2, but without the S906T polymorphism. A faster inactivation kinetics and a?+5?mV shift in the availability curve were found in the sodium current recorded in patient's myoblasts compared to his mother. 27% of his myotubes displayed spontaneous activity. Patient's myotubes showing a stable resting membrane potential had a lower rheobase current respect to the mother's while the overshoot and the maximum slope of the depolarizing phase of action potential were higher. These findings suggest that SCN4A polymorphisms may be responsible for a higher excitability of DM2 patients sarcolemma, supporting the severe myotonic phenotype observed. We suggest SCN4A as a modifier factor and that its screening should be performed in DM2 patients with uncommon clinical features.

SUBMITTER: Binda A

PROVIDER: S-EPMC6056531 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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SCN4A as modifier gene in patients with myotonic dystrophy type 2.

Binda Anna A Renna Laura V LV Bosè Francesca F Brigonzi Elisa E Botta Annalisa A Valaperta Rea R Fossati Barbara B Rivolta Ilaria I Meola Giovanni G Cardani Rosanna R

Scientific reports 20180723 1

A patient with an early severe myotonia diagnosed for Myotonic Dystrophy type 2 (DM2) was found bearing the combined effects of DM2 mutation and Nav1.4 S906T substitution. To investigate the mechanism underlying his atypical phenotype,whole-cell patch-clamp in voltage- and current-clamp mode was performed in myoblasts and myotubes obtained from his muscle biopsy. Results characterizing the properties of the sodium current and of the action potentials have been compared to those obtained in muscl ...[more]

PMID: 30038349

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Project description:Sleep disturbances such as excessive daytime sleepiness, central and obstructive sleep apneas, restless legs syndrome, and rapid eye movement sleep dysregulation are prominent in patients with myotonic dystrophy type 1 (DM1). Mild intellectual deficits presented in many patients with DM1. In addition, psychosocial issues caused by neuropsychiatric symptoms are a clinical problem. We herein present the cases of four DM1 patients with sleep disturbances and neuropsychiatric symptoms in the preceding stage of clinically significant muscle symptoms. One of the cases exhibited a sleep disorder and neuropsychiatric symptoms before electromyography showed myotonic discharge, suggesting that careful follow-up is also important. Patients 1 and 2 were first referred to our department due to daytime sleepiness. Patients 3 and 4 were objectively suffering from daytime sleepiness of which they were not subjectively aware of. Patients 1, 3, and 4 obtained high apnea-hypopnea index (AHI) scores, which reflected central and/or obstructive apnea, whereas patient 2 had an AHI score of zero. The daytime cerebrospinal fluid (CSF) orexin levels of all patients ranged from the normal lower limit to low, although they were not as low as those observed in narcolepsy with typical cataplexy. Neuropsychological tests of patients 1 and 2 showed frontal lobe dysfunction. Patients 3 and 4 were diagnosed with mild intellectual disability and autism spectrum disorder, respectively. All patients exhibited indifference toward their own symptoms, which may have resulted from the cognitive decline caused by DM1. Based on family history and/or neurological findings such as myotonia, we suspected DM1 as the cause of their sleep disturbances. Molecular analysis using the triplet repeat-primed polymerase chain reaction (TP PCR) method and Southern blotting, which provided a genetic confirmation of the diagnosis of DM1, were performed. These clinical features of sleep disturbances were unrelated to the length of CTG repeats and are caused by unknown molecular mechanisms. Clinicians should take into account that multisystem involvement in DM1 is hugely variable, and thus, a disabling sleep disorder could overshadow muscle impairment in DM1 patients.

Dataset Information

SCN4A as modifier gene in patients with myotonic dystrophy type 2.

Publications

SCN4A as modifier gene in patients with myotonic dystrophy type 2.

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