Spinal Muscular Atrophy
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- Spinal muscular atrophy (SMA) is a progressive disorder of motor neurons in the spinal cord and brainstem.
- Major symptom is proximal weakness.
- 3 forms are described based on clinical features:
- Type I, also known as Werdnig-Hoffman disease, typically presents by 6 months of age; these children never sit.
- Type II typically presents between 6 and 18 months of age; these children sit independently but never walk.
- Type III, also known as Kugelberg-Welander disease, may be diagnosed later; these children stand and walk at some point.
- There appears to be a spectrum of severity within and between each type.
The most common genetic cause of infant mortality
Incidence estimated at 1 in 6,000–10,000 live births; carrier frequency 1 in 40–50, although some variation between populations seems to exist.
- Genetic testing is recommended in all cases, even when the diagnosis appears clear.
- Genetic counseling is critical for all families with children affected by SMA, as the chance of recurrence is 25%.
- SMN2 copy number varies among the general population and is loosely correlated with SMA type (type I likely to have fewer copies); however, all copies of SMN2 are not equal (some make more SMN protein than others), and an individual patient’s SMN2 copy number should not be used for prognostic purposes.
- Universal newborn screening is strongly recommended by some but is controversial; a pilot study has been approved in limited states.
- All 3 types of proximal SMA follow an autosomal recessive inheritance and are caused by mutations in the survival motor neuron (SMN) gene on 5q11.2 to 13.3.
- 2 copies of SMN on each chromosome. SMN1 (SMNt), the telomeric copy, produces stable SMN protein. SMN2 (SMNc), the centromeric copy, is an inverted duplication of SMN1 with a single nucleotide change in an exonic splice enhancer, which produces mostly an unstable, truncated protein product and a smaller percentage of stable, full-length SMN protein.
- Individuals with SMA harbor homozygous deletions of exon 7 in the SMN1 gene, which renders it nonfunctional. The presence of SMN2 essentially “rescues” individuals with SMN1 deletions because complete absence of SMN protein appears to be embryonically lethal. The level of SMN protein roughly correlates with the severity of disease, making this a target of therapeutics development.
- The SMN protein plays a role in RNA processing; it is unclear why motor neurons (anterior horn cells) are selectively vulnerable to this defect, although a role in axonal mRNA trafficking and splicing is being explored.
- SMA appears to affect other organ systems, especially in those with the most severe form; cardiovascular, autonomic, and metabolic abnormalities are reported.
Commonly Associated Conditions
Other anterior horn cell diseases:
- SMA with respiratory distress (SMARD) or diaphragmatic SMA due to mutations in the IGHMBP2 gene on chromosome 11q
- Distal SMAs, a group of disorders with distal weakness, genetically heterogeneous
- Other variants are associated with arthrogryposis, pontocerebellar hypoplasia, congenital fractures, and congenital heart disease. Few such cases have been shown to have SMN mutations.
- Fazio-Londe disease: rare degeneration of anterior horn cells in the brainstem, childhood onset
- Kennedy disease, or X-linked spinal and bulbar muscular atrophy: anterior horn cell disease with adult onset; affected men have gynecomastia, bulbar weakness, and reduced fertility.