Genetic Neuromuscular Disorders
5 sections · 30 min
Classification and Clinical Approach to Neuromuscular Disease
Neuromuscular disorders are divided by the anatomical level of involvement: anterior horn cell (lower motor neuron), peripheral nerve (motor/sensory), neuromuscular junction (NMJ), or muscle. The clinical pattern — proximal vs. distal weakness, presence of sensory involvement, reflexes, cardiac involvement, family history — guides localization and genetic differential. Electromyography (EMG) and nerve conduction studies (NCS) are essential for localization before genetic testing.
Key Points
- Proximal > distal weakness without sensory loss: suggests myopathy or anterior horn disease (SMA); elevated CK points to myopathy
- Distal > proximal weakness with sensory loss: peripheral neuropathy (CMT); decreased/absent reflexes; nerve conduction shows demyelinating or axonal pattern
- NMJ disorder (myasthenia gravis, congenital myasthenic syndrome): fatigable weakness, ptosis, diplopia; EMG shows decremental response on repetitive nerve stimulation
- CK level: massively elevated (>10× ULN) in muscular dystrophies (DMD, LGMD); mildly elevated in congenital myopathies; normal in neuropathies and anterior horn cell disease
- Muscle biopsy: essential in many congenital myopathies (nemaline rods, central cores, fiber type disproportion); immunohistochemistry for dystrophin, sarcoglycans, caveolin guides genetic testing. For an overview of testing strategies and expected yields, see the [[diagnostic-yields|Diagnostic Yields]] module
✦ Check Your Understanding
A 9-month-old infant presents with progressive hypotonia, feeding difficulty, macroglossia, and hypertrophic cardiomyopathy. CK is mildly elevated. Acid alpha-glucosidase (GAA) enzyme activity is markedly reduced on dried blood spot. The most likely diagnosis and initial management are:
Select an answer to reveal the explanation
Duchenne and Becker Muscular Dystrophy
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic X-linked recessive disorders caused by variants in the DMD gene (Xp21.2), encoding dystrophin — the largest gene in the human genome. Dystrophin links the intracellular actin cytoskeleton to the extracellular matrix via the dystrophin-associated protein complex (DAPC). Loss of dystrophin leads to membrane fragility, calcium influx, oxidative stress, and progressive muscle fiber necrosis and replacement by fat and connective tissue.
Key Points
- Reading-frame rule: DMD variants that disrupt the translational reading frame (frameshift deletions, nonsense variants) → no functional dystrophin → DMD phenotype; in-frame deletions allow production of truncated but partially functional dystrophin → BMD (milder)
- Deletions (65–70% of cases): multi-exon deletions detected by MLPA or aCGH; reading frame predicts DMD vs. BMD with ~90% accuracy — exons 51, 45, and 53 skipping are therapeutic targets
- DMD natural history: onset age 3–5 with proximal weakness, Gowers sign, calf pseudohypertrophy; loss of ambulation ~12 years; cardiomyopathy universal by age 18; respiratory failure without intervention
- Approved therapies: exon 51 skipping (eteplirsen — FDA 2016, AO-mediated, small benefit), exon 53 skipping (golodirsen — FDA 2019; viltolarsen — FDA 2020), exon 45 skipping (casimersen — FDA 2021), stop codon readthrough (ataluren for nonsense variants — EU approved), gene therapy (delandistrogene moxeparvovec/Elevidys — approved FDA 2023 for 4–5 year olds)
- Carrier females: CK often elevated; cardiomyopathy risk in ~10%; cardiac screening recommended; manifesting carriers with significant weakness possible due to skewed X-inactivation
✦ Check Your Understanding
A 4-year-old boy has difficulty rising from the floor (Gowers sign), pseudohypertrophy of calves, and CK of 25,000 U/L. MLPA shows deletion of DMD exons 48–50. Applying the reading-frame rule, the predicted phenotype is:
Select an answer to reveal the explanation
Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) has historically been the second most common fatal autosomal recessive disorder in children (after cystic fibrosis), though mortality has decreased dramatically with the advent of disease-modifying therapies (nusinersen, risdiplam, onasemnogene abeparvovec). It is caused by loss of survival motor neuron protein (SMN) due to homozygous deletion of the SMN1 gene on 5q13. SMN is essential for snRNP biogenesis and pre-mRNA splicing in motor neurons. The SMN2 gene, a nearly identical paralog on the same chromosome, produces only ~10–15% full-length SMN due to alternative splicing at exon 7 — the copy number of SMN2 is the major modifier of phenotype severity.
Key Points
- SMN1 deletion (exon 7+8): detected by MLPA or quantitative PCR; ~95% of patients have homozygous SMN1 exon 7 deletion; ~5% are compound heterozygous with a deletion on one allele and a point variant on the other
- SMA types: Type 0 (prenatal onset, severe congenital hypotonia, death <6mo); Type 1 (Werdnig-Hoffmann, onset <6mo, never sits, death <2yr without treatment); Type 2 (onset 6–18mo, sits but never stands); Type 3 (Kugelberg-Welander, onset >18mo, achieves walking); Type 4 (adult onset, mild)
- SMN2 copy number as modifier: 1–2 copies → Type 1; 3 copies → Type 2/3; 4+ copies → Type 3/4; higher SMN2 copy number associated with milder phenotype
- Nusinersen (Spinraza): antisense oligonucleotide administered intrathecally; modifies SMN2 splicing to include exon 7, increasing full-length SMN; approved 2016; first disease-modifying SMA therapy
- Risdiplam (Evrysdi): oral small-molecule SMN2 splicing modifier; promotes exon 7 inclusion in SMN2 mRNA, increasing full-length SMN protein; approved FDA 2020 for patients ≥2 months; advantage of oral administration and CNS + peripheral tissue distribution
- Onasemnogene abeparvovec (Zolgensma): AAV9-SMN1 gene replacement; single IV infusion; approved 2019 for children <2 years (US); most effective when given presymptomatically via newborn screening; also approved intrathecally for older/heavier patients in some countries. For detailed coverage of gene therapy and ASO mechanisms, see the [[therapies|Gene and Molecular Therapies]] module
✦ Check Your Understanding
A newborn is identified on expanded NBS with absent SMN1 exon 7 copy number. She is currently asymptomatic. The parents ask about prognosis and treatment. The most accurate statement is:
Select an answer to reveal the explanation
Congenital Myopathies and Muscular Dystrophies
Congenital myopathies are a heterogeneous group of genetic muscle disorders defined primarily by structural abnormalities on muscle biopsy rather than by dystrophic changes. They typically present at birth or in infancy with hypotonia, weakness, and respiratory insufficiency. The major genetic muscular dystrophies beyond DMD/BMD include the limb-girdle muscular dystrophies (LGMD), Emery-Dreifuss MD, and facioscapulohumeral MD (FSHD).
Key Points
- Nemaline myopathy (NEB, ACTA1, TPM2/3, TNNT1): nemaline rods on Gomori trichrome biopsy; NEB-related forms often severe; ACTA1 point variants more variable; respiratory and feeding difficulties predominate
- Central core disease (RYR1, dominant or recessive): central cores on oxidative stain; associated with malignant hyperthermia susceptibility (RYR1); myopathy relatively static; cores spare periphery of fiber
- FSHD (facioscapulohumeral MD): facial, scapular, and distal leg weakness; contraction of D4Z4 repeats on 4q35 (FSHD1) or SMCHD1 methylation defect (FSHD2) → aberrant DUX4 expression; AD, reduced penetrance
- Emery-Dreifuss MD (LMNA, EMD/emerin): early joint contractures (elbows, ankles, spine) + slowly progressive humeroperoneal weakness + cardiac conduction disease → sudden death risk; LMNA also causes dilated cardiomyopathy with minimal muscle disease — annual cardiac screening/ICD
- LGMD classification (2018 ENMC): >30 recognized subtypes including AD (LGMD-D) and AR (LGMD-R) forms; most common: LGMD-R1 (calpain-3/CAPN3), LGMD-R2 (dysferlin/DYSF, elevated CK), LGMD-R3-6 (sarcoglycanopathies), LGMD-R9 (anoctamin-5/ANO5)
✦ Check Your Understanding
A patient with Emery-Dreifuss muscular dystrophy (LMNA mutation) has developed early elbow and ankle contractures but has only mild limb weakness. The most important surveillance recommendation is:
Select an answer to reveal the explanation
Hereditary Neuropathies and Channelopathies
Charcot-Marie-Tooth disease (CMT) is the most common hereditary neuromuscular disorder, with a prevalence of ~1/2,500. It is genetically heterogeneous, with over 100 causative genes. The hereditary channelopathies (periodic paralysis, myotonia, paramyotonia) are autosomal dominant ion channel disorders causing episodic muscle weakness or stiffness. Together with congenital myasthenic syndromes, they round out the spectrum of hereditary neuromuscular disease.
Key Points
- CMT1A: PMP22 duplication on 17p12 (detected by MLPA) — most common CMT (~40%); demyelinating; uniform slowing of NCVs (MCV <38 m/s in median nerve); onset in childhood with high arches, hammertoes, distal weakness
- CMT1X: GJB1 (connexin-32) mutations; X-linked dominant; males more severely affected; intermediate NCV pattern; CNS involvement (T2 white matter changes) in some males
- CMT2A: MFN2 mutations; axonal CMT; onset in first two decades; severe disability common; length-dependent axonal degeneration; MFN2 encodes mitofusin 2 essential for mitochondrial dynamics
- Myotonic dystrophy type 1 (DMPK CTG repeat): most common adult MD; multisystem: myotonia, progressive weakness (facial, distal, respiratory), cataracts, cardiac conduction, endocrine, cognitive; anticipation; DMPK CUG repeats sequester MBNL1 → RNA splicing dysregulation
- Periodic paralysis: hypokalemic (CACNA1S or SCN4A — AD; attacks triggered by carbohydrate/rest after exercise; treat: acetazolamide, avoid triggers), hyperkalemic/normokalemic (SCN4A — AD; treat: mexiletine, thiazide diuretics); myotonia congenita (CLCN1 — muscle chloride channel; Thomsen AD, Becker AR; improves with exercise — 'warm-up' phenomenon). For pharmacogenomic considerations in neuromuscular disease (e.g., malignant hyperthermia with RYR1), see the [[pharmacogenetics|Pharmacogenetics]] module
✦ Check Your Understanding
A 30-year-old woman with myotonic dystrophy type 1 (DM1) is pregnant. She asks about risks to the baby. Her CTG repeat size in DMPK is 800 repeats. The most important genetic counseling point is:
Select an answer to reveal the explanation
0 of 5 sections read
Scroll through all sections to track your progress.