Spinal Muscular Atrophy (SMA)

Definition and Epidemiology

• Bradley and Daroff's Neurology in Clinical Practice

Genetics and Molecular Basis

• 95% of cases are due to homozygous deletion (or small mutations) of the SMN1 gene on chromosome 5q11.2-13.3
• SMN1 and SMN2 are nearly identical genes within an inverted gene duplication, but SMN2 produces only ~10% functional full-length protein due to a C-to-T transition in exon 7 that causes exon skipping
• The remaining 90% of SMN2 transcripts lack exon 7 and are unstable/rapidly degraded
• Motor neuron health requires at least 23% full-length SMN protein
• SMN2 copy number is the primary modifier of disease severity: infants with only 2 copies (producing ~9% functional transcript) have severe Type 1 disease, while 3-5 copies produce milder phenotypes
• Only 1-2% of childhood-onset SMA is unrelated to the chromosome 5 SMN locus
• Bradley and Daroff's Neurology in Clinical Practice

Classification

• Bradley and Daroff's Neurology in Clinical Practice

Clinical Features

Type 1 (Werdnig-Hoffmann Disease)

• Severe hypotonia, weak cry, respiratory distress within first months of life
• "Frog-leg" posture at rest (thighs externally rotated and abducted, knees flexed)
• Never able to sit unsupported; abdominal breathing due to relative diaphragm preservation
• Tongue fasciculations and areflexia
• EMG shows acute and chronic denervation; distinguishes from myopathies
• CK may be mildly elevated (rarely >1000 U/L)
• Natural history without treatment: median survival ~8 months, death from respiratory failure

Type 2 (Intermediate)

• Proximal lower limb weakness, hypotonia
• Achieves sitting but never standing/walking
• Progressive scoliosis is a major complication
• Respiratory insufficiency develops over time

Type 3 (Kugelberg-Welander)

• Proximal weakness, may resemble a limb-girdle muscular dystrophy
• Achieves walking; may lose ambulation later
• Mild respiratory involvement
• Progressive scoliosis common

Type 4 (Adult-onset)

• Proximal or distal weakness with slow progression
• Most (~70%) are AR allelic with types 1-3; remaining cases can be AD (e.g., VAPB mutation in Brazilian families)
• True adult-onset accounts for <10% of all SMA cases; estimated prevalence 0.32/100,000

Diagnosis

• Genetic testing (SMN1/SMN2 dosage analysis) is the primary confirmatory test
• Most without homozygous deletion are compound heterozygotes (deletion + point mutation)
• ~2% de novo mutation rate
• EMG/NCS: evidence of denervation (spontaneous activity, large motor unit potentials), with normal sensory studies
• Muscle biopsy (less commonly used now): grouped atrophy of type 1 and 2 fibers
• Newborn screening is now recommended to enable pre-symptomatic treatment

Treatment

• Benefit is greatest when treatment starts pre-symptomatically - magnitude decreases with time, making newborn screening essential
• Zolgensma: In the first trial, 15 infants treated - all survived to 20 months without respiratory support; 11 could sit unsupported, 2 walked independently
• Hepatotoxicity monitoring is required with Zolgensma; pre-existing anti-AAV antibodies can affect efficacy; most require prednisolone prophylaxis
• Nusinersen and risdiplam can also be used in older/symptomatic patients
• Thompson & Thompson Genetics and Genomics in Medicine; Bradley and Daroff's Neurology in Clinical Practice; Goldman-Cecil Medicine

Supportive Management

• Respiratory: Noninvasive ventilation (BiPAP), cough-assist devices; may require tracheostomy in severe cases
• Nutrition: Nasogastric or gastrostomy feeding in severe cases
• Orthopedic: Scoliosis bracing (controversial - may impair respiratory function); surgical spinal fusion usually when growth ceases, though may be needed earlier in severe non-ambulators
• Physical/occupational therapy: Maintaining upright posture delays scoliosis progression; specialized wheelchair assessment

Genetic Counseling

• Carrier detection uses SMN1/SMN2 gene dosage analysis
• Carrier parents each have one normal and one deleted SMN gene
• SMN2 copy number at prenatal diagnosis has prognostic value - more copies = milder expected phenotype
• Prenatal diagnosis is available

Other SMA Variants (Non-5q)

• Kennedy disease (X-linked bulbospinal neuropathy) - CAG trinucleotide repeat expansion in the androgen receptor gene; features progressive proximal weakness, bulbar dysfunction, gynecomastia (60-90%), sensory involvement (markedly abnormal SNAPs), elevated CK, and diabetes mellitus
• VAPB-related SMA - rare adult-onset AR form with vesicle trafficking protein mutation; can overlap with ALS phenotype