What Is Myotonic Dystrophy?

Introduction

Myotonic dystrophy is a hereditary disorder characterized by increasing muscular weakness and atrophy.¹ Myotonic dystrophy can damage movement muscles as well as the electrical conduction system of the heart, breathing and swallowing muscles, the colon, the lens of the eye, and the brain. Diabetes and hormonal abnormalities, such as thyroid issues, can also occur. Myotonic dystrophy can damage both male and female reproductive systems, with some people showing personality and behavioural issues.

Recognizing the symptoms and signs of myotonic dystrophy early can lead to quicker diagnosis and intervention, potentially slowing down its progression and managing complications more effectively.¹

Understanding myotonic dystrophy

Myotonic Dystrophy (DM) is divided into two types :

• Type 1 Dystrophy (DM1), also known as Steinert disease, is caused by an abnormally enlarged part of the DMPK gene on chromosome 19, which is near the control region of another gene, SIX5.²
• Type 2 Dystrophy (DM2), identified in 1994 as a milder form of DM1, is caused by an abnormally enlarged region of the ZNF9 gene on chromosome 3. PROMM, or proximal myotonic myopathy, was the initial name for DM2, and it is still used today, albeit it is less common than DM2.²

Both DM1 and DM2 are inherited in an autosomal dominant form, which means that it only takes one faulty allele, one copy with the aberrant expansion, to generate illness symptoms. If one parent has the condition, each kid has a 50% chance of inheriting the faulty gene that causes it.^[3]

Clinical symptoms¹

• Muscle weakness and atrophy
• Myotonia (prolonged muscle contractions)
• Cardiac issues e.g., cardiac arrhythmia
• Muscle stiffness (myotonia)
• Clouding of the eye lens (cataracts)
• Slurred speech
• Dysphagia (problems with swallowing)
• Bowel problems like diarrhoea, constipation and incontinence
• Behavioural and personality problems
• Excessive sleepiness or tiredness

Diagnosis

1. The expansion of a CTG trinucleotide repeat in the noncoding region of DMPK causes DM1. Individuals with typical muscle weakness are suspected of having DM1, which is validated by DMPK molecular genetic testing. A CTG repeat duration of more than 34 repetitions is considered abnormal. Pathogenic variations are detected in approximately 100% of affected individuals using molecular genetic testing.

Other Test:

Electromyography (EMG): A needle electrode inserted into a muscle of an affected adult records myotonic discharges and myopathic-appearing motor units, primarily in the distal muscles. Electrical myotonic discharges are uncommon throughout infancy, but quick runs of single-fibre discharges resembling myotonic discharges are suggestive.

Serum CK concentration: Serum CK concentrations may be slightly higher in DM1 patients with weakness but are normal in asymptomatic patients.

Muscle biopsy: Rows of internal nuclei (with a boxcar appearance), ring fibres, sarcoplasmic masses, type I fibre predominance and atrophy, fibrosis and fatty infiltration, and a significantly increased number of intrafusal muscle fibres were all identified on muscle biopsy.⁴

• The presence of a heterozygous pathogenic expansion of a CCTG repeat within a complex repeat motif, (TG)n(TCTG)n(CCTG)n in CNBP confirms the diagnosis of DM2. A pathogenic expansion can have anywhere from 75 to more than 11,000 CCTG repeats, with a mean of around 5,000 repetitions. The detection rate of a CNBP CCTG expansion is greater than 99% when regular PCR, Southern blot analysis, and the PCR repeat-primed test are used together.

Other Test:

Molecular Gene Testing: This can include looking for a higher number (i.e., an expansion) of the CCTG nucleotide repeat. If routine PCR analysis detects only one allele, which occurs in 15% of unaffected homozygous individuals and in all affected individuals, both Southern blot analysis and the PCR repeat-primed assay are required to determine if the individual is homozygous for the normal-sized allele or has both a normal-sized allele and an expanded allele that fails to amplify by PCR due to its large size.

Muscle biopsy: Although molecular genetic testing is the preferred diagnosis method, muscle biopsy is still an effective diagnostic technique. Muscle pathology comprises atrophic fibres, scattered severely atrophic fibres with pyknotic myonuclei, and significant proliferation of fibres with central nuclei, all of which occur in both DM2 and myotonic dystrophy type 1 (DM1). Preferential type 2 fibre atrophy has been observed in individuals with DM2.⁵

Treatment and management

There is currently no cure for myotonic dystrophy. Thus, the purpose of supportive management is to maximize health and functional independence. This is intended to monitor and treat all of the medical concerns related with myotonic dystrophy.

Medical treatment

• Cardiovascular: Cardiac monitoring with a 12-lead ECG should be conducted in all individuals who have been diagnosed with myotonic dystrophy and should be done on a yearly basis to check cardiac conduction abnormalities. Baseline cardiac imaging should be conducted, followed by serial imaging every 1 to 5 years.
• Pulmonary: Obtain a baseline and do serial pulmonary function tests to check for neuromuscular respiratory failure.
• Daytime somnolence and obstructive sleep apnea: Examine for sleep apnea and, if necessary, prescribe continuous positive airway pressure (CPAP). Excessive drowsiness can be treated with neurostimulants such as methylphenidate.
• Ocular involvement: An annual eye exam, including a slit-lamp examination, is suggested. Cataract surgery is used to remove cataracts that affect vision and function.  
• Obstetrics and gynaecology care: Due to the risk of miscarriage, premature delivery, and respiratory issues during pregnancy, patients who are pregnant or considering pregnancy should have a high-risk obstetrics evaluation.
• Endocrine issues: Because these patients are at a higher risk of developing diabetes due to insulin resistance, baseline and annual fasting blood glucose and haemoglobin A1C measurements are indicated. A thyroid function test is also required. Because primary hypogonadism and erectile dysfunction are common in men with DM1, erectile dysfunction should be investigated and treated if low testosterone is confirmed on further testing.
• Myotonia: Prolonged myotonia is treated with sodium channel blockers such as mexiletine, tricyclic antidepressants, benzodiazepines, and calcium antagonists.

Therapy

Physical and occupational therapy is indicated for muscle strengthening, orthotics evaluation, and long-term medical equipment needs. SLP is essential for dysphagia and swallowing investigations, as well as dysarthria when suggested. SLP is also used to treat intellectual disorders and to teach learning skills.^[6]

Recent advances and future directions

Recent advances in myotonic dystrophy research have shown promising insights into the underlying genetic and molecular mechanisms of the disease. CRISPR-Cas9 gene editing techniques have been explored as potential tools to target and correct the genetic mutations responsible for myotonic dystrophy.

Additionally, advancements in understanding RNA toxicity and its role in the disease have led to the development of potential therapeutic strategies aimed at reducing the toxic effects of mutant RNA.

In terms of future directions, personalized medicine approaches are being explored to tailor treatments to the specific genetic and molecular characteristics of individual patients. This includes the development of small molecules and RNA-targeting therapies that could potentially modify the disease progression.

Collaborative efforts among researchers, clinicians, and patient advocacy groups will continue to drive research forward, with the ultimate goal of finding effective treatments or even a cure for myotonic dystrophy.

Summary

Myotonic dystrophy is a complex genetic disorder with variable symptoms affecting multiple body systems. In conclusion, the condition presents challenges in diagnosis, management, and treatment due to its diverse manifestations. Continued research and medical advancements are crucial to improving the quality of life for individuals living with myotonic dystrophy.

FAQ  

Is myotonic dystrophy hereditary?

Ans: Yes, myotonic dystrophy is an inherited disorder caused by mutations in specific genes. It can be passed down from affected parents to their children.³

How is myotonic dystrophy diagnosed?

Ans: Diagnosis involves a combination of clinical evaluation, genetic testing, and sometimes electromyography (EMG) to assess muscle function.^4,5

Is there a cure for myotonic dystrophy?

Ans: Currently there is no cure for myotonic dystrophy. Treatment focuses on managing symptoms and improving quality of life.⁶