Myotonic dystrophy

From Ganfyd

Myotonic dystrophy (dystrophia myotonica) is an autosomal dominant muscular dystrophy.

Presentation

• Muscle stiffness (myotonia)(38%).^[1]
• Myopathy
• Frontal balding
• Weakness of neck flexors
• A family history may aid the diagnosis
• Incidental - Haggard appearance, genetic screening

Common Features

• Myotonia (90%)^[1]
  • Tongue, forearm, and hand.
• Muscular dystrophy^[2]
• Fatigue (44%)^[1]
• Frontal balding
• Cataracts - a specific but not very sensitive sign i.e. many do not have it but if present with common features above diagnostic^[2]
• Infertility/Hypogonadism^[2]
• Muscle pain (20%)^[1]
• Cardiac arrhythmias
• Hypogammaglobulinemia

Cause

Genetics as below causing failure of switch from embryonic to adult alternative splicing pattern of certain genes. CUG-binding protein 1 (CUG-BP1) and muscleblind-like 1 (MBNL1), the antagonistic regulators of alternative splicing of messenger RNA are disrupted.In the case of myotonia the muscle-specific chloride channel (CIC-1) remains embryonic^[3]. In the case of insulin resistance, the insulin receptor has an embryonic gene splicing pattern.

Prevalence

• 2.2–5.5/100,000 in Europeans
• Less frequent in South-East Asians, rare in Polynesians, extremely rare in Central and Southern Africans. ^[1]

Types

Myotonic dystrophy-1 (DM1)

Presentation

Typically presents from 20 years onwards clinically, but there is a severe congenital form.

• Muscle dystrophy with onset distal muscles and only later proximal muscles (unlike other muscle dystrophies)
• Cardiac abnormalities
  • Conduction deficits eg complete heart block
  • Mitral valve prolapse
  • Ventricular wall motion abnormality
  • Exercise induced arrhythmias
• Cognitive deficits correlated with degree of CTG repeats over 1000.
• Sometimes hypersomnia, deafness, gastrointestinal hypermotility, ptosis and respiratory weakness.
• Often motor/sensory nerve involvement

Investigation

• EMG- most have myotonia
• Muscle biopsy non specific
• IgG levels low
• Blood glucose (5% diabetes)
• Gamma-glutamyltransferase (γGT) and creatine kinase (CK/CPK) may be increased.^[4]
• Genetics - diagnostic
  • Anticipation, mild through male line, much worse through female line
  • Expanded CTG repeats (200-2000 plus) in 3-prime untranslated region of dystrophia myotonica protein kinase(DMPK) gene at 19q13.2-q13.3.
    • Normal 5 to 30 CTG repeats
    • ≥38 repeats usual cut off for disease
    • Mild 50 to 80 CTG repeats
    • Severe 2,000 or more CTG repeats

Prognosis

• Adults are at high risk of arrhythmia and sudden death
  • Predictors of sudden death areNeeds citation:
    • Severe ECG abnormalities
      • Rhythm other than sinus
      • PR interval ≥ 240msec
      • QRS duration ≥ 120msec
      • second or third degree heart block
    • Atrial tachyarrhthmias

Myotonic dystrophy-2 (DM2)

• Myotonia onset usually third and fourth decade of life
• Muscular dystrophy usually mild proximal weakness fifth to seventh decade

No cognitive deficits, dysphagia, hypersomnia, deafness, gastrointestinal hypermotility, ptosis or respiratory weakness. Cataracts are rare.

• Genetics - diagnostic
  • Expanded CCTG repeats in intron 1 of the zinc finger protein-9(ZNF9) gene with no good clinical correlation between number of repeats (75 to 11,000 ) and phenotype.

Treatment

Myotonia theoretically by increasing expression of MBNL1 Likely to be improved by systematic approach once diagnosis made as complex multi-system disease with potentially fatal or disabling complications open to intervention ^[1]

References