Basics
Description
- 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.
Epidemiology
The most common genetic cause of infant mortality
Incidence
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.
Risk Factors
Genetics
- 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.
Etiology
- 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.
Diagnosis
History
- Hypotonia and weakness are the primary features. Infants with SMA I will be floppy and less active and have delayed motor milestones, with preserved language/social interaction (a bright, alert demeanor is often remarked upon).
- Some babies with type I present with feeding problems and failure to thrive.
- History of reduced vigor of prenatal movements
Physical Exam
- Weakness and absent or reduced reflexes suggest a neuromuscular rather than central etiology for hypotonia. A proximal pattern of weakness is consistent with SMA, myopathies, and muscular dystrophies; a distal pattern usually suggests polyneuropathies.
- Weakness is almost universally symmetric, but occasional cases of asymmetric weakness have been reported in SMA III.
- Extraocular movements remain intact in SMA.
- Facial strength diminishes in children with type I over time, and jaw contractures may be present in type II.
- Dysmorphic features, or involvement of other organs, may point to alternative diagnoses. Occasionally, SMA presents with contractures (spectrum of arthrogryposis multiplex congenita).
- Tongue fasciculations strongly suggest SMA, but their absence does not exclude the diagnosis.
- Tremor of a specific type, polyminimyoclonus, is often present in type II.
Diagnostic Tests & Interpretation
Lab
- Initial screening tests: Serum creatinine kinase may be mildly elevated.
- Genetic testing
- Genetic testing of DNA extracted from blood (SMN deletions): now the gold standard in diagnosis, may be done prenatally, >95% sensitive
- Genetic testing for Prader-Willi syndrome (fluorescence in situ hybridization and methylation) may be indicated if there is no SMN gene deletion and electromyography (EMG) is normal in an infant who appears to have SMA.
- Other testing
- EMG may be helpful if the clinical presentation is atypical for SMA or if genetic testing is negative. EMG shows high-amplitude, long-duration motor units with a reduced recruitment pattern.
- With the advent of molecular testing, muscle biopsy is rarely performed. Use when genetic testing is unrevealing. The characteristic findings are fiber-type grouping with generalized atrophy of muscle fibers.
- If the entire evaluation is negative, MRI of the spine may be indicated to evaluate for an anomaly or mass lesion.
Differential Diagnosis
- Other genetic neuromuscular disorders include congenital muscular dystrophy, congenital myopathy, glycogen storage disorders (Pompe disease), myotonic dystrophy, mitochondrial disease, congenital myasthenia gravis, and Prader-Willi syndrome.
- More acute course may suggest infant botulism or Guillain-Barre syndrome, although the latter is rare in this age group.
- Systemic disorders: sepsis, meningitis, acute bowel syndromes
- SMA II differential: congenital muscular dystrophy, congenital myopathy, and congenital myasthenia gravis
- SMA III differential includes Duchenne, Becker, and the limb girdle muscular dystrophies; Lambert-Eaton myasthenic syndrome; and limb girdle congenital myasthenic syndromes.
- Spinal cord mass lesions may rarely resemble SMA.
Treatment
Alert
An apparently minor respiratory infection may carry a higher risk of respiratory failure in SMA I and later stages of SMA II and III. Depending on family/patient wishes regarding respiratory support, consider admitting such a patient to the hospital for observation. Infants with SMA may be exquisitely sensitive to postural shifts " watch for hypoventilation, for example, with forward truncal flexion associated with some seating arrangements.
Additional Treatment
General Measures
- A multidisciplinary approach to care is recommended, with early and proactive involvement of orthopedics, nutrition, pulmonary, and physical and occupational therapy as well as social work and psychological support for families and patients.
- Physical therapy is appropriate for all 3 types; although it may not affect the course in SMA I, it can lessen discomfort and make care easier by improving range of motion and preventing contractures.
- A wheelchair provides mobility in SMA II. Children as young as age 2 years may be considered for a motorized wheelchair, depending on developmental level. Adults with SMA III may require the use of a wheelchair later in their course.
- Bracing of ankles, wrists, and back can help reduce contractures and slow progression of scoliosis.
- Spinal fusion surgery may preserve respiratory function.
- Low threshold for empiric antibiotics for respiratory infection is appropriate.
- Chest physiotherapy and early implementation of cough-assist device can help prevent pneumonia and atelectasis.
- Be wary of symptoms of hypoventilation (disturbed sleep, daytime fatigue, moodiness, morning headaches), which may occur prior to other symptoms of respiratory insufficiency.
- Low threshold to order a sleep study if hypoventilation is suspected
- In acute respiratory illness, supplemental oxygen is appropriate as long as the patient is also evaluated and treated for hypercarbia.
- Noninvasive positive pressure ventilation (bilevel positive airway pressure [BiPAP] and other regimens) may improve quality of life and life expectancy in patients with decreased respiratory function. More aggressive respiratory management is becoming more common and accepted among families and physicians, but the extent of interventions varies widely. Start discussions about family/patient preferences early, as respiratory decompensation can occur very quickly.
- Avoid catabolic state with proactive nutritional support, including tube feeding.
- However, note that type II patients may have increased adiposity, and overweight is also a risk.
- Monitor for osteopenia, which is almost universal in types I and II, and ensure adequate calcium and vitamin D intake.
- Social and psychological support for caregivers and patients
Ongoing Care
Patient Education
- Families of SMA: http://www.curesma.org
- Fight SMA: http://www.fightsma.org
- Muscular Dystrophy Association: http://www.mdausa.org
- Spinal Muscular Atrophy Foundation: http://www.smafoundation.org
Prognosis
- Survival in all 3 forms has been increasing with improved supportive care and, in type I, ventilatory support.
- Most children with SMA type I die by 2 years without major pulmonary interventions. With ventilatory support, patients may survive several years longer; survival as long as 2 decades has been observed with tracheostomy and full mechanical ventilation.
- Children with SMA type II typically survive into late adolescence or early adulthood; this life expectancy is increasing with more aggressive pulmonary management.
- Individuals with SMA type III survive well into adulthood and often have a normal life expectancy. In 1 study of patients with SMA type III with onset <3 years, 50% could not walk 20 years later; for those with onset >3 years, 30% could not walk 20 years later.
- Intelligence is generally preserved.
- Death typically ensues from respiratory complications. Discuss the level of respiratory interventions, including resuscitation, early in SMA I and in the advanced stages of SMA II and III.
Complications
- Recurrent pneumonias, hypoventilation
- Swallowing difficulties may require tube feeding.
- Scoliosis may require surgery.
Additional Reading
- Arnold WD, Burghes AH. Spinal muscular atrophy: development and implementation of potential treatments. Ann Neurol. 2013;74(3):348 " 362. [View Abstract]
- Chung BH, Wong VC, Ip P. Spinal muscular atrophy: survival pattern and functional status. Pediatrics. 2004;114(5):e548 " e553. [View Abstract]
- Hardart MK, Truog RD. Spinal muscular atrophy " type I. Arch Dis Child. 2003;88(10):848 " 850. [View Abstract]
- Iannaccone ST, Burghes A. Spinal muscular atrophies. Adv Neurol. 2002;88:83 " 98. [View Abstract]
- Khirani S, Colella M, Caldarelli V, et al. Longitudinal course of lung function and respiratory muscle strength in spinal muscular atrophy type 2 and 3. Eur J Paediatr Neurol 2013;17(6):552 " 560. [View Abstract]
- Kolb SJ, Kissel JT. Spinal muscular atrophy: a timely review. Arch Neurol. 2011;68(8):979 " 984. [View Abstract]
- Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008;371(9630):2120 " 2133. [View Abstract]
- Messina S, Pane M, De Rose P, et al. Feeding problems and malnutrition in spinal muscular atrophy type II. Neuromuscul Disord. 2008;18(5):389 " 393. [View Abstract]
- Ogino S, Leonard DG, Rennert H, et al. Genetic risk assessment in carrier testing for spinal muscular atrophy. Am J Med Genet. 2002;110(4):301 " 307. [View Abstract]
- Petit F, Cuisset JM, Rouaix-Emery N, et al. Insights into genotype-phenotype correlations in spinal muscular atrophy: a retrospective study of 103 patients. Muscle Nerve. 2011;43(1):26 " 30. [View Abstract]
- Prasad AN, Prasad C. The floppy infant: contribution of genetic and metabolic disorders. Brain Dev. 2003;25(7):457 " 476. [View Abstract]
- Prior TW, Snyder PJ, Rink BD, et al. Newborn and carrier screening for spinal muscular atrophy. Am J Med Genet Part A. 2010;152A(7):1608 " 1616. [View Abstract]
- Shababi M, Lorson CL, Rudnik-Schoneborn SS. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J Anat. 2013;224(1):15 " 28. [View Abstract]
- Wang CH, Finkel RS, Bertini ES, et al. Participants of the International Conference on SMA Standard of Care. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007;22(8):1027 " 1049. [View Abstract]
- Zerres K, Rudnik-Schoneborn S. Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol. 1995;52(5):518 " 523. [View Abstract]
Codes
ICD09
- 335.10 Spinal muscular atrophy, unspecified
- 335.0 Werdnig-Hoffmann disease
- 335.11 Kugelberg-Welander disease
- 335.19 Other spinal muscular atrophy
ICD10
- G12.9 Spinal muscular atrophy, unspecified
- G12.0 Infantile spinal muscular atrophy, type I [Werdnig-Hoffman]
- G12.1 Other inherited spinal muscular atrophy
SNOMED
- 5262007 Spinal muscular atrophy
- 64383006 Werdnig-Hoffmann disease
- 54280009 Kugelberg-Welander disease
- 128212001 Spinal muscular atrophy, type II
FAQ
- Q: Can routine vaccinations be given to children with SMA?
- A: Yes. In addition to routine vaccinations, yearly influenza and respiratory syncytial virus (RSV) vaccinations are recommended.
- Q: How much respiratory support should a child with SMA receive?
- A: Standards of care are evolving rapidly, and a consensus remains elusive. Noninvasive respiratory interventions are becoming more widely accepted. Noninvasive respiratory options should be offered to all patients with SMA I and those in the later stages of SMA II. Tracheostomy is more controversial.
- Q: Are more effective therapies for SMA being developed?
- A: There are ongoing studies in animal models and on humans, involving both pharmacologic and gene-based therapies. Patients and families should be informed about clinical trials that may be available to them. Families of SMA, the Muscular Dystrophy Association, and other groups, as well as Clinicaltrials.gov, are sources of information on such research.