Dataset Information

Aberrant Myokine Signaling in Congenital Myotonic Dystrophy.

ABSTRACT: Myotonic dystrophy types 1 (DM1) and 2 (DM2) are dominantly inherited neuromuscular disorders caused by a toxic gain of function of expanded CUG and CCUG repeats, respectively. Although both disorders are clinically similar, congenital myotonic dystrophy (CDM), a severe DM form, is found only in DM1. CDM is also characterized by muscle fiber immaturity not observed in adult DM, suggesting specific pathological mechanisms. Here, we revealed upregulation of the interleukin-6 (IL-6) myokine signaling pathway in CDM muscles. We also found a correlation between muscle immaturity and not only IL-6 expression but also expanded CTG repeat length and CpG methylation status upstream of the repeats. Aberrant CpG methylation was associated with transcriptional dysregulation at the repeat locus, increasing the toxic RNA burden that upregulates IL-6. Because the IL-6 pathway is involved in myocyte maturation and muscle atrophy, our results indicate that enhanced RNA toxicity contributes to severe CDM phenotypes through aberrant IL-6 signaling.

SUBMITTER: Nakamori M

PROVIDER: S-EPMC5689469 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Aberrant Myokine Signaling in Congenital Myotonic Dystrophy.

Nakamori Masayuki M Hamanaka Kohei K Thomas James D JD Wang Eric T ET Hayashi Yukiko K YK Takahashi Masanori P MP Swanson Maurice S MS Nishino Ichizo I Mochizuki Hideki H

Cell reports 20171001 5

Myotonic dystrophy types 1 (DM1) and 2 (DM2) are dominantly inherited neuromuscular disorders caused by a toxic gain of function of expanded CUG and CCUG repeats, respectively. Although both disorders are clinically similar, congenital myotonic dystrophy (CDM), a severe DM form, is found only in DM1. CDM is also characterized by muscle fiber immaturity not observed in adult DM, suggesting specific pathological mechanisms. Here, we revealed upregulation of the interleukin-6 (IL-6) myokine signali ...[more]

PMID: 29091763

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Project description:Abstract BACKGROUND: Congenital Myotonic Dystrophy (CDM) is the harshest form of Myotonic Dystrophy type 1 (DM1,OMIM #160900). The mode of inheritance is autosomal dominant, and results from a microsatellite expansion in DMPK with an incidence of 2.1:1000,000 live births in Canada. The principal clinical signs during the neonatal period are myopathic facies, hypotonia and weakness resulting in such features as talipes equinovarus, nutritional, cardiac and respiratory problems. OBJECTIVES: To describe the main findings of CDM in the perinatal period. DESIGN/METHODS: A five year prospective cohort study from 2005 to 2010 of eligible incident cases of CDM was performed via the Canadian Pediatric Surveillance Program (CPSP). Reporting physicians completed a questionnaire with the medical history at birth and during the perinatal period. Our patients met the CDM criteria proposed by Campbell et al. (2013): 1) CDM symptoms with hospitalization greater of 72 hours; and 2) CTGrs above 200. RESULTS: We obtained 43 questionnaires, 22 female and 21 male (F:M ratio of 1.04:1). Average CTG repeat size (CGTrs) was 795.67 (250-2300). The main complication during the prenatal period was polyhydramnios (n=20). The majority of the patients (n=27) had full term pregnancy and with normal birth weight (n=25). Average Apgar was 4 at 1 (range 1-9), and 6 for 5 and 10. Intubation was required in 29/43 of the cases, with an average hospital stay of 43.5 days. Nutritional support (ie ng feeds) was required in 34/43, and it was longer than 14 days in 21 patients. Nine patients died, 6 of them due to respiratory failure. Four deaths were withdrawal of life support. CONCLUSION: The respiratory difficulties are well described as the principal complication in CDM (Ho et al. [2015]), but we found that the necessity of multiple nutritional interventions was the most frequent neonatal complication (79%), respiratory complications remains as the principal cause of death (66.6%). Zaki et al. (2010) describes a cohort with a 100% frequency of polyhydramnios, differing on ours where it is 46.5%. We conclude that CDM is not always evident prenatally by polyhydramnios, IUGR or preterm delivery. Nutritional and respiratory assessments should be prioritized, and nutritional interventions may extend for long periods of time. Despite high respiratory and feeding support needs, the majority of patients improved over time. Hence the importance of prenatal counseling and preparation for the complications in the neonatal period.

Dataset Information

Aberrant Myokine Signaling in Congenital Myotonic Dystrophy.

Publications

Aberrant Myokine Signaling in Congenital Myotonic Dystrophy.

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