Myotonic Dystrophy

“Myotonic dystrophy is part of a group of inherited disorders called muscular dystrophies. It is the most common form of muscular dystrophy that begins in adulthood. Myotonic dystrophy is characterized by progressive muscle wasting and weakness.

People with this disorder often have prolonged muscle contractions (myotonia) and are not able to relax certain muscles after use. For example, a person may have difficulty releasing their grip on a doorknob or handle. Also, affected people may have slurred speech or temporary locking of their jaw. Other signs and symptoms of myotonic dystrophy include clouding of the lens of the eye (cataracts) and abnormalities of the electrical signals that control the heartbeat (cardiac conduction defects).

In affected men, hormonal changes may lead to early balding and an inability to father a child (infertility).

The features of this disorder often develop during a person’s twenties or thirties, although they can occur at any age. The severity of the condition varies widely among affected people, even among members of the same family.

There are two major types of myotonic dystrophy: type 1 and type 2. Their signs and symptoms overlap, although type 2 tends to be milder than type 1. The muscle weakness associated with type 1 particularly affects the lower legs, hands, neck, and face. Muscle weakness in type 2 primarily involves the muscles of the neck, shoulders, elbows, and hips. The two types of myotonic dystrophy are caused by mutations in different genes. A variation of type 1 myotonic dystrophy, called congenital myotonic dystrophy, is apparent at birth. Characteristic features include weak muscle tone (hypotonia), an inward- and upward-turning foot (clubfoot), breathing problems, delayed development, and intellectual disability. Some of these health problems can be life-threatening.”

Myotonic Dystrophy Support Group

Muscular Dystrophy UK

“Myotonic dystrophy About 9,500 people in the UK have a form of myotonic dystrophy. It is a group of inherited conditions that show muscle weakness and myotonia. We at Muscular Dystrophy UK want you to know you’re not alone. If you’d like to meet other families living with myotonic dystrophy, just to talk, share experience or get some advice, we can put you in touch. Our helpline team is also here for you to offer support and advice. Read more:”

DM1Research (@DM1research) 08/03/2019, 03:12 Doing the math, this study indicates there are over 100,000 people with myotonic dystrophy type 1 in the U.S. Over 300,000 in the U.S. and EU combined. Yet there is only one drug in the clinic for DM1.

Disease burden of myotonic dystrophy type 1 Published: 24 February 2019

Disease burden in myotonic dystrophy type 1 (DM1) covers multiple domains and correlates with CTG repeat length, the DM1 genetic defect. Read our new paper by @drnicolenko and Erik Landfeldt, which used INQoL to assess burden on affected adults.

Nikoletta Nikolenko and Erik Landfeldt have published a new study on the impact of myotonic dystrophy type 1 (DM1) in the Journal of Neurology. They use a questionnaire-based method, the Individualized Neuromuscular Quality of Life Questionnaire (INQoL), to assess the burden of this condition on affected adults. The study provides further evidence of the wide range of domains affected in this multisystem disease. They are also able to show that INQoL scores correlate with the severity of the underlying genetic defect, linking CTG expansion with burden of illness.

The study provides important baseline data for healthcare and for clinical research in myotonic dystrophy. The full publication is available to read at the journal’s website here (open access) Disease burden of myotonic dystrophy type 1 Landfeldt, E., Nikolenko, N., Jimenez-Moreno, C. Cumming, S., Monckton, D.G., Gorman, G., Turner, C.,Lochmüller, H. J Neurol (2019).

Abstract Objective The objective of this cross-sectional, observational study was to investigate the disease burden of myotonic dystrophy type 1 (DM1), a disabling muscle disorder.

Methods Adults with DM1 were recruited as part of the PhenoDM1 study from Newcastle University (Newcastle upon Tyne, UK). Disease burden data were recorded through the Individualized Neuromuscular Quality of Life (INQoL) questionnaire. Results were examined by sex and clinical variables [e.g. the six-minute walk test (6MWT), the Mini Mental State Examination, and estimated progenitor and modal allele CTG repeat length].

Results Our sample consisted of 60 patients with DM1 (mean age: 45 years; 45% female). Muscle weakness and fatigue constituted the two most common disease manifestations, reported by 93% and 90% of patients, respectively, followed by muscle locking (73%). Most patients (> 55%) reported feeling anxious/worried, depressed, frustrated, and/or having low confidence/self-esteem, 23% and 33% indicated substantial impairment of daily and leisure activities, respectively, and 47% did not work as a consequence of the disease. Estimated progenitor CTG length corrected by age correlated surprisingly well with INQoL scores. Differences by sex were generally minor.

Conclusion We show that DM1 is associated with a substantial disease burden resulting in impairment across many different domains of patients’ lives, emphasizing the need for a holistic approach to medical management. Our results also show that the INQoL records relevant information about patients with DM1, but that further investigation of the psychometric properties of the scale is needed for meaningful interpretation of instrument scores.

DM1 Guidelines

DM1Research‏ @DM1research · Jan 28 2019  MDF’s consensus care recommendations published a few months ago, now the Spaniards publish their guidelines: Clinical guide for the diagnosis and follow-up of myotonic dystrophy type 1, MD1 or Steinert’s disease

Exercise in DM1 patients

Chronic exercise mitigates disease mechanisms and improves muscle function in myotonic dystrophy type 1 mice Alexander Manta , Derek W. Stouth , Donald Xhuti , Leon Chi , Irena A. Rebalka , Jayne M. Kalmar , Thomas J. Hawke , Vladimir Ljubicic First published: 10 January 2019|| Cited by: 1 Edited by: Scott Powers & Troy Hornberger

Abstract Key points Myotonic dystrophy type 1 (DM1), the second most common muscular dystrophy and most prevalent adult form of muscular dystrophy, is characterized by muscle weakness, wasting and myotonia. A microsatellite repeat expansion mutation results in RNA toxicity and dysregulation of mRNA processing, which are the primary downstream causes of the disorder. Recent studies with DM1 participants demonstrate that exercise is safe, enjoyable and elicits benefits in muscle strength and function; however, the molecular mechanisms of exercise adaptation in DM1 are undefined. Our results demonstrate that 7 weeks of volitional running wheel exercise in a pre‐clinical DM1 mouse model resulted in significantly improved motor performance, muscle strength and endurance, as well as reduced myotonia. At the cellular level, chronic physical activity attenuated RNA toxicity, liberated Muscleblind‐like 1 protein from myonuclear foci and improved mRNA alternative splicing.

Abstract Myotonic dystrophy type 1 (DM1) is a trinucleotide repeat expansion neuromuscular disorder that is most prominently characterized by skeletal muscle weakness, wasting and myotonia. Chronic physical activity is safe and satisfying, and can elicit functional benefits such as improved strength and endurance in DM1 patients, but the underlying cellular basis of exercise adaptation is undefined. Our purpose was to examine the mechanisms of exercise biology in DM1. Healthy, sedentary wild‐type (SED‐WT) mice, as well as sedentary human skeletal actin‐long repeat animals, a murine model of DM1 myopathy (SED‐DM1), and DM1 mice with volitional access to a running wheel for 7 weeks (EX‐DM1), were utilized. Chronic exercise augmented strength and endurance in vivo and in situ in DM1 mice. These alterations coincided with normalized measures of myopathy, as well as increased mitochondrial content. Electromyography revealed a 70–85% decrease in the duration of myotonic discharges in muscles from EX‐DM1 compared to SED‐DM1 animals. The exercise‐induced enhancements in muscle function corresponded at the molecular level with mitigated spliceopathy, specifically the processing of bridging integrator 1 and muscle‐specific chloride channel (CLC‐1) transcripts. CLC‐1 protein content and sarcolemmal expression were lower in SED‐DM1 versus SED‐WT animals, but they were similar between SED‐WT and EX‐DM1 groups. Chronic exercise also attenuated RNA toxicity, as indicated by reduced (CUG)n foci‐positive myonuclei and sequestered Muscleblind‐like 1 (MBNL1). Our data indicate that chronic exercise‐induced physiological improvements in DM1 occur in concert with mitigated primary downstream disease mechanisms, including RNA toxicity, MBNL1 loss‐of‐function, and alternative mRNA splicing.

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