Muscular dystrophies - myotonic dystrophy
Description
- Multisystem AD disorder: myotonia + distal weakness + cataracts + conduction disease + endocrine failure
- Myotonia = involuntary contraction continuing after voluntary effort ceases -> impaired relaxation
- Grip myotonia (delayed handshake release); percussion myotonia (thenar eminence)
- Warms up with repetition - opposite of paramyotonia congenita (worsens with repetition + cold)
DM1 vs DM2
| DM1 (Steinert) | DM2 (PROMM) | |
|---|---|---|
| Gene / repeat | DMPK 19q13, CTG | CNBP (ZNF9) 3q21, CCTG |
| Weakness | Distal > proximal; face, neck | Proximal (hip girdle); myalgia prominent |
| Anticipation | Marked | Minimal |
| Congenital form | Yes - almost always maternal | No |
| Course | Earlier, more severe | Milder, near-normal lifespan |
- One of the few myopathies with distal-predominant weakness
Epidemiology
- Commonest inherited adult neuromuscular disease
- DM1 ~1:8,000; M=F
- Classic adult onset 2nd-4th decade; congenital, childhood and late-onset forms exist
- Founder effect in Saguenay-Lac-St-Jean, Quebec (~1:500)
- DM2 probably under-diagnosed - milder, presents as proximal weakness + pain in later life
Aetiopathogenesis
Genetics
- AD; CTG repeat expansion in the 3'UTR of DMPK (chr 19)
| Repeat number | |
|---|---|
| 5-34 | Normal |
| 35-49 | Premutation - unaffected, unstable in transmission |
| >=50 | Affected |
| >1000 | Congenital |
- Repeat length: inversely correlates with age of onset, directly with severity
- Anticipation - repeat expands through meiosis, worse each generation
- Congenital DM1 is almost always maternally transmitted (the mother is often undiagnosed - examine and test her)
Mechanism - toxic RNA gain of function
- Expanded CUG transcript retained in nucleus -> ribonuclear foci
- Sequesters MBNL1 splicing regulator + upregulates CELF1
- -> widespread mis-splicing of unrelated genes
- CLCN1 chloride channel -> dec sarcolemmal Cl- conductance -> myotonia
- Insulin receptor -> insulin resistance
- Cardiac troponin T, RyR, others -> conduction disease
- Explains a multisystem disease from a single non-coding mutation - it is not a structural dystrophin-type defect
Diagnosis
Clinical pattern
- Distal weakness + wasting - intrinsic hands, forearm extensors, tibialis anterior -> foot drop
- Face: temporalis + masseter wasting -> long "hatchet" facies; bilateral non-fatigable ptosis (vs MG); nasal monotonous voice; slack expressionless face
- Sternomastoid weakness - early, characteristic
- Frontal balding - in both sexes
- Reflexes depressed; sensation intact
- Grip + percussion myotonia
- Myotonia fades as weakness advances - its absence late does not exclude the diagnosis
Confirming the diagnosis
- Genetic testing is diagnostic - PCR + triplet-primed PCR / Southern blot to size the repeat
- Sanger sequencing cannot size a large expansion
- EMG - waxing-and-waning myotonic discharges ("dive-bomber")
- Slit lamp - posterior subcapsular stellate / "Christmas tree" cataract
- May be the only finding in a mildly affected parent
- CK normal or only mildly raised (unlike other dystrophies)
- Biopsy rarely needed
Baseline multisystem workup
- ECG (PR, QRS), Holter, TTE
- Spirometry incl. supine FVC + MIP/SNIP (erect FVC misses diaphragm weakness); ABG for hypercapnia; sleep study
- HbA1c; LH/FSH/testosterone
- Swallow assessment; cognitive screen
Mimics
- MG - fatigable ptosis, no myotonia, no wasting
- Myotonia congenita (CLCN1) - myotonia + hypertrophy, no systemic features
- Paramyotonia congenita (SCN4A) - cold-induced, paradoxical worsening with exercise
- OPMD, IBM, distal myopathies
Management
No disease-modifying therapy. Management = anticipatory surveillance for the complications that kill, plus symptom control.
A. Cardiac - the leading preventable cause of death
- Annual ECG + at least annual Holter, lifelong, even if asymptomatic
- PR >240 ms or QRS >120 ms -> EP referral for invasive assessment
- Permanent pacemaker for high-grade AV block - low threshold
- ICD if sustained VT or LV dysfunction
- *Sudden death occurs with a normal ejection fraction* - conduction disease, not cardiomyopathy, is the problem
B. Respiratory
- Annual spirometry (supine FVC, MIP/SNIP)
- NIV for nocturnal hypoventilation or symptomatic hypercapnia
- Cough assist, aspiration precautions, influenza/pneumococcal/COVID vaccination
C. Myotonia - treat only if disabling
- Mexiletine - most effective
- *Check ECG first - avoid if conduction disease*
- Alternatives: carbamazepine, acetazolamide, phenytoin
- Most patients are more disabled by weakness and fatigue than by myotonia
D. Daytime somnolence
- Central hypersomnolence is intrinsic to the disease, independent of OSA
- Treat OSA/hypoventilation first; modafinil for residual
E. Endocrine, GI, eyes
- Annual HbA1c; testosterone if symptomatic hypogonadism
- Cataract extraction
- Dysphagia, constipation, pseudo-obstruction, gallstones - low threshold for cholecystectomy
F. Anaesthetic risk - flag on every chart
- Extreme sensitivity to opioids, benzodiazepines, propofol, thiopentone -> apnoea, delayed recovery
- Suxamethonium -> generalised myotonic contracture (masseter spasm, impossible intubation) - avoid
- Neostigmine may precipitate myotonia
- Post-op HDU monitoring; regional/local anaesthesia preferred
G. Function and genetics
- AFOs for foot drop, physiotherapy, avoid prolonged immobilisation
- Genetic counselling, cascade testing, prenatal/preimplantation options
- Test the mother of any congenital case
Associations
- Cardiac - conduction disease (bradycardia, prolonged PR, AV block) >> cardiomyopathy; mitral valve prolapse; AF/flutter
- Endocrine - insulin resistance and T2DM; hypogonadism with testicular atrophy, gynaecomastia, male infertility
- Respiratory - hypoventilation, OSA (crowded oropharynx) + central apnoea, restrictive defect, recurrent aspiration, bronchiectasis
- Eyes - posterior subcapsular cataract; external ophthalmoplegia
- CNS - hypersomnolence, apathetic/avoidant personality, executive dysfunction, intellectual impairment (marked in congenital form)
- GI - dysphagia, gastroparesis, constipation, pseudo-obstruction, gallstones (gallbladder sphincter dysfunction)
- Obstetric - polyhydramnios, preterm labour, prolonged labour, PPH
- Malignancy - modest inc risk of thyroid, ovarian and skin tumours
Natural history & complications
- Slowly progressive over decades; distal -> proximal spread
- Median survival ~55-60 yr in classic adult DM1; congenital form much worse
- Causes of death: respiratory failure (~1/3-1/2) and cardiac sudden death/arrhythmia
- Both are surveillable - this is the argument for lifelong annual review
- Congenital DM1 - hypotonia, talipes, respiratory failure at birth, intellectual disability in survivors
- DM2 - near-normal lifespan, less cardiac and no congenital form
Monitor
- Annual: ECG + Holter, spirometry (supine), HbA1c, swallow, function
- Periodic: echo, sleep study, slit lamp
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