A genetics-focused guide to hereditary neuromuscular disorders — spanning the muscular dystrophies, spinal muscular atrophy, congenital myopathies, inherited neuropathies, and channelopathies. Emphasizes molecular diagnosis, genotype-phenotype correlations, and the rapidly evolving therapeutic landscape.
Tags: Neurogenetics · Advanced
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
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
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
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
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
1. 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:
This presentation — infantile-onset hypotonia, macroglossia, hypertrophic cardiomyopathy, and markedly reduced acid alpha-glucosidase (GAA) activity — is classic for infantile-onset Pompe disease (glycogen storage disease type II). Pompe disease is caused by biallelic pathogenic variants in the GAA gene, leading to lysosomal glycogen accumulation in cardiac and skeletal muscle. Enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme) or avalglucosidase alfa (Nexviazyme) should be initiated as early as possible, as cardiac and motor outcomes are significantly better with early treatment. Cross-reactive immunologic material (CRIM) status should be assessed to guide immunomodulation.
2. 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:
The reading-frame rule predicts that deletions disrupting the translational reading frame cause DMD (no functional dystrophin), while in-frame deletions cause BMD (truncated but partially functional dystrophin). Deletion of exons 48–50 shifts the reading frame, predicting a DMD phenotype. This patient's presentation (Gowers sign, pseudohypertrophy, CK 25,000) is entirely consistent. Notably, exon 51 skipping therapy would convert this to an in-frame deletion (removing exon 51 makes the exon 47–52 junction in-frame), potentially converting to BMD-like disease.
3. 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:
Multiple clinical trials demonstrate that presymptomatic treatment of SMA — initiated before motor neuron loss occurs — yields dramatically better outcomes than post-symptomatic treatment. Children treated presymptomatically with onasemnogene abeparvovec or nusinersen often achieve nearly normal motor milestones. This is the primary rationale for newborn screening for SMA. All children with biallelic SMN1 deletion, regardless of SMN2 copy number, should be offered treatment promptly.
4. 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:
The most serious complication of Emery-Dreifuss MD (especially LMNA-related) is cardiac involvement — progressive conduction disease, complete heart block, and dilated cardiomyopathy — which can cause sudden death even when muscular weakness is mild. Annual cardiac surveillance with ECG, Holter monitoring, and echocardiography is essential. Pacemaker implantation is often required for conduction disease, and ICD for those with reduced ejection fraction. This cardiac risk applies even to female carriers of LMNA variants.
5. 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:
Myotonic dystrophy type 1 follows autosomal dominant inheritance (50% transmission risk). A critical counseling point is that large CTG expansions (>800 repeats) transmitted maternally carry a high risk of congenital myotonic dystrophy (CDM) — a severe neonatal form characterized by profound hypotonia, respiratory failure requiring ventilation, feeding difficulty, and later intellectual disability. Anticipation is prominent: repeat size tends to increase across generations, particularly with maternal transmission of large expansions. The mother's repeat size of 800 places her offspring at substantial risk for CDM. Prenatal or preimplantation genetic testing can be offered.
6. A 6-year-old boy with SMA type 2 (3 copies of SMN2) has been on nusinersen for 2 years with stabilization of motor function. His parents ask about switching to oral risdiplam. Which statement best describes the mechanism and practical difference between these two therapies?
Both nusinersen and risdiplam promote exon 7 inclusion in SMN2 mRNA, increasing production of full-length SMN protein. Nusinersen is an antisense oligonucleotide (ASO) that binds a specific intronic splicing silencer (ISS-N1) in the SMN2 pre-mRNA and requires intrathecal administration (every 4 months after loading doses), limiting distribution to the CNS. Risdiplam is an oral small molecule that modifies SMN2 splicing systemically, reaching both CNS and peripheral tissues. The practical advantages of risdiplam include oral dosing and systemic distribution; however, direct comparison trial data are limited, and switching decisions should consider individual patient response and clinical context.