Myotonic Dystrophy

Overview

Autosomal dominant disease characterised by trinucleotide repeat of CTG. Also known as Dystrophica Myotoncia the disease is causes an increase in muscle tone (Myotonia) with associated degeneration and shrinkage of muscle fibres (Dystrophy).

Classification

Myotonic dystrophy is divided into two primary genetic subtypes, with DM1 further subdivided by age of onset.

1. Myotonic Dystrophy Type 1 (DM1 / Steinert Disease)

• Prevalence: Accounts for ~98% of all myotonic dystrophy cases.
• Genetics: CTG repeat expansion in the 3′ untranslated region (UTR) of the DMPK gene on chromosome 19.

2. Myotonic Dystrophy Type 2 (DM2 / Proximal Myotonic Myopathy – PROMM)

• Genetics: CCTG repeat expansion in intron 1 of the CNBP gene on chromosome 3.
• Features: Proximal muscle weakness (rather than distal), milder clinical course, no congenital form, and minimal genetic anticipation.

Aetiology & Risk Factors

1. Aetiology & Genetics

• DM1: Autosomal dominant inheritance of unstable CTG repeats in DMPK.
  • Normal: 5–37 repeats.
  • Premutation: 38–49 repeats.
  • Symptomatic Disease: > 50 repeats (can expand to thousands).
• DM2: Autosomal dominant inheritance of unstable CCTG repeats in CNBP.
  • Normal: < 30 repeats.
  • Symptomatic Disease: 75 to > 11,000 repeats.

2. Risk Factors & Transmission Dynamics

• Family History: Positive family history of neuromuscular disease, unexplained early-onset cataracts, or early cardiac pacemakers.
• Maternal Transmission Risk: Congenital DM1 occurs almost exclusively when the expanded allele is inherited from the mother, due to massive intergenerational CTG expansion during maternal oogenesis.

Pathophysiology

• Genetic mutations -> abnormal mRNA
  • abnormal mRNA like these do not leave the nucleus
• The abnormal mRNA can cause these hairpin structures which disrupt existing proteins in the nucleus
• The abnormal mRNA causes existing proteins to lose function or gain function:
  • Loss of function of the MBNL proteins
  • Gain of function of CUGBP proteins
  • These proteins are normally involved in splicing, mRNA transport, stability and decay
  • These protein dysfunction are thought to be the pathological hallmark of Myotonic Dystrophy resulting in:
    • Disruption of alternative splicing 
    • Disruption mRNA transport
    • Disruption of mRNA decay
    • Abnormal protein production and function causing complications of Myotonic dystrophy.

Clinical Manifestation

Myotonia is defines as continued contraction of the muscle after voluntary contraction ceases.

• Delayed relaxation after contraction – hand shake slow to release
• Myotonic facies (expressionless, mouth open with a lean face)
  • Facial muscle weakness
  • Sternocledoid muscle weakness
• Difficulty opening eyes after firm closure
• Ptosis (often bilateral)
• Cataracts
• Balding
• Distal muscle wasting and weakness – hands
• Reduce reflexes
• Foot drop

Complications

• Diabetes – polyuria, polydipsia
• Cardiomyopathy – features of heart failure
• Conduction abnormality – pacemaker
  • Supraventriular tachycardia (most common)
  • 1st degree heart block (40%)
• Hypogonadism – gynacomastia and testicular atrophy
• Goitre

Diagnosis

Diagnosis is by Molecular Genetic Testing (Gold Standard)

• Targeted Mutation Analysis: PCR and Southern Blot analysis of peripheral blood leukocytes to measure CTG (DM1) or CCTG (DM2) repeat numbers. Confirms diagnosis without needing a muscle biopsy.
• Electromyography (EMG)
  • Myotonic Discharges: High-frequency repetitive muscle fiber action potentials that wax and wane in amplitude and frequency.
  • Auditory Finding: Produces a pathognomonic “dive-bomber” sound on the loudspeaker.

Other investigations are mainly to look for complications of Myotonic Dystrophy

• Ophthalmology review
• Electrocardiogram
• 24 holter monitor
• Echocardiogram
• Sleep study
• Pulmonary function test
• HbA1c
• TFT

Treatment

• Medications that reduce sustained myotonia
  • sodium channel blockers such as mexiletine
  • tricyclic antidepressants
  • benzodiazepines
  • calcium antagonists

Treatment again targets complications of Myotonic Dystrophy

• Pacemaker, ICD
• CPAP machine
• Incentive spirometry
• Insulin
• Thyroxine
• Speech pathology for dysphagia
• Physical and occupational therapy is recommended for strengthening weakened muscles, evaluation for orthotics, and durable medical equipment needs.

Complications

Endocrine complications

• Type II diabetes melitius
• Hypogonadism
• Nodular thyroid enlargement

Cardiovascular complications

• Resting ECG changes – everything prolonged (PR, QRS, QT)
• Arrhythmia
  • Supraventricular tachycardia (most common)
  • VT
• Conduction blocks
  • 1st (common)
  • 2nd
  • complete
• Mitral valve prolapse
• Cardiomyopathy

Gastrointestinal complications

• Dysphagia
• Reflux
• Delayed gastric emptying
• Malabsorption
• Bacterial overgrowth
• Megacolon

Respiratory complications

• Hypoventilation – poor sleep
• Respiratory failure follow anaesthesia
• Recurrent pneumonia

References

1. Thornton CA. Myotonic dystrophy. Neurol Clin. 2014;32(3):705-719. doi:10.1016/j.ncl.2014.04.011
2. Meola G, Cardani R. Myotonic dystrophies: An update on clinical aspects, genetic, pathology, and molecular pathogenesis. Acta Myol. 2015;34(1):6-20.
3. Heatwole C, Bode R, Johnson NE, et al. Patient-reported impact of myotonic dystrophy type 1: establish the DM1-HI. Muscle Nerve. 2012;46(3):324-333. doi:10.1002/mus.23301