Myotonic dystrophy

Introduction

Myotonic dystrophy is a hereditary neuromuscular disorder characterized by progressive muscle weakness and myotonia. It is the most common adult-onset muscular dystrophy and affects multiple organ systems beyond skeletal muscles. Understanding its genetic basis, clinical presentation, and management strategies is essential for effective patient care.

Definition and Classification

Definition

Myotonic dystrophy is a multisystemic disorder defined by delayed muscle relaxation following contraction, progressive muscle wasting, and involvement of cardiac, endocrine, ocular, and central nervous system structures.

Types

• DM1 (Steinert disease): Classic form, usually presenting with distal muscle weakness and early onset cataracts
• DM2 (Proximal myotonic myopathy): Milder form, often with proximal muscle weakness and later onset

Genetic Basis and Inheritance

Both DM1 and DM2 are inherited in an autosomal dominant pattern, meaning a single copy of the mutated gene is sufficient to cause the disorder. There is a phenomenon of anticipation in DM1, where symptoms may present at an earlier age and with increased severity in successive generations.

Etiology and Genetics

Genetic Mutations

Myotonic dystrophy results from unstable nucleotide repeat expansions in specific genes, leading to abnormal RNA processing and multi-systemic effects.

• DM1: Caused by CTG trinucleotide repeat expansion in the DMPK (dystrophia myotonica protein kinase) gene on chromosome 19
• DM2: Caused by CCTG tetranucleotide repeat expansion in the CNBP (ZNF9) gene on chromosome 3

Pathophysiology

The abnormal nucleotide repeats produce toxic RNA transcripts that interfere with normal splicing of multiple genes, resulting in widespread dysfunction.

• RNA toxicity and spliceopathy lead to impaired protein production
• Protein dysfunction affects muscle contraction, ion channel regulation, and other cellular processes
• Multi-systemic involvement occurs due to disrupted expression in cardiac, endocrine, ocular, and central nervous system tissues

Clinical Features

Muscular Manifestations

Muscular involvement is the hallmark of myotonic dystrophy and typically presents with both myotonia and muscle weakness.

• Myotonia: Delayed relaxation of muscles following voluntary contraction, often observed in handgrip and jaw muscles
• Muscle weakness: Progressive weakness affecting distal muscles in DM1 and proximal muscles in DM2
• Facial and neck muscles: Weakness leading to characteristic facial appearance, ptosis, and difficulty swallowing

Systemic Manifestations

Myotonic dystrophy affects multiple organ systems beyond skeletal muscles, contributing to morbidity and mortality.

• Cardiac: Conduction defects, arrhythmias, and risk of sudden cardiac death
• Endocrine: Insulin resistance, diabetes mellitus, and thyroid dysfunction
• Ocular: Early-onset cataracts and ptosis
• Respiratory: Restrictive lung disease, hypoventilation, and sleep apnea
• Central nervous system: Cognitive impairment, executive dysfunction, and personality changes

Diagnosis

Clinical Evaluation

Diagnosis of myotonic dystrophy begins with a detailed patient history and physical examination.

• History: Family history of similar symptoms, age of onset, and pattern of progression
• Physical examination: Observation of myotonia, distal or proximal muscle weakness, facial and neck muscle involvement, and grip tests

Laboratory and Electrophysiology

Laboratory and electrophysiological studies provide supportive evidence for diagnosis.

• Serum creatine kinase (CK) levels: Mildly elevated in most patients
• Electromyography (EMG): Detects myotonic discharges and abnormal muscle activity

Genetic Testing

Genetic testing confirms the diagnosis by identifying nucleotide repeat expansions in the DMPK or CNBP genes.

• Detection of CTG repeat expansion for DM1
• Detection of CCTG repeat expansion for DM2
• Prenatal and preimplantation genetic diagnosis available for at-risk families

Management and Treatment

Symptomatic Management

Treatment of myotonic dystrophy focuses on alleviating symptoms and improving quality of life, as there is currently no cure for the disorder.

• Medications for myotonia: Mexiletine may reduce delayed muscle relaxation
• Physical therapy: Strengthening exercises to maintain muscle function and prevent contractures
• Occupational therapy: Adaptations and exercises to improve daily activities and hand function

Cardiac and Respiratory Care

Cardiac and respiratory complications are common and require close monitoring and intervention.

• Cardiac monitoring: Regular ECGs to detect conduction defects and arrhythmias; pacemaker implantation if necessary
• Respiratory support: Management of restrictive lung disease, nocturnal hypoventilation, and sleep apnea using noninvasive ventilation or CPAP

Genetic Counseling

Genetic counseling is essential for affected individuals and their families to understand inheritance, risk, and reproductive options.

• Explanation of autosomal dominant inheritance and risk of passing the mutation to offspring
• Discussion of prenatal testing and preimplantation genetic diagnosis
• Support for family planning decisions and psychological counseling

Prognosis

The prognosis of myotonic dystrophy varies depending on the type, age of onset, severity, and extent of multi-system involvement. Early diagnosis and proper management can improve quality of life and reduce complications.

• Factors affecting disease progression: Severity of muscle weakness, cardiac involvement, respiratory function, and endocrine abnormalities
• Life expectancy: Typically reduced in DM1, especially in congenital or severe forms; DM2 generally has a milder course with near-normal life expectancy
• Impact of multi-system involvement: Cardiac arrhythmias and respiratory complications are major determinants of morbidity and mortality

References

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