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Spinal muscular atrophy is characterised by slowly progressive muscle weakness and atrophy of the limb muscles associated with motor neurone loss in the spinal cord. Bulbar muscular atrophy affects the bulbar and facial muscles with motor neurone loss in the brainstem.
The spinal muscular atrophies (SMAs) are a spectrum of genetically inherited disorders. They all result in progressive lower motor neurone weakness. The gene defect is on chromosome 5q and the implicated gene is called survival motor neurone gene 1 (SMN1).
SMAs can be classified according to the age of symptom onset using the International Spinal Muscular Atrophy Consortium Classification System:
- SMA type I (acute infantile, Werdnig-Hoffmann disease)
- SMA type II (chronic infantile)
- SMA type III (chronic juvenile, Kugelberg-Welander syndrome)
- SMA type IV (adult onset)
However, there are 'long-term' survivors who do not comply with these classification criteria by age of onset or age of death. There are also a number of other SMAs not linked with the SMN gene.
Spinal muscular atrophy (SMA) types I-III
- Inheritance is autosomal recessive.
- Affected individuals have two copies of the altered gene.
- Those who carry one copy are usually unaffected carriers. Hence, there is often no family history.
- Loss of this gene results in loss of function of specific proteins required for RNA processing.
- This abnormal RNA processing seems to have a toxic effect on the lower motor neurones and results in their progressive degeneration in the spinal cord and also in the brainstem motor nuclei of cranial nerves V, VII, IX and XII.
- The body has an almost identical copy of the SMN1 gene - the SMN2 gene.
- About 95% of those with SMA have the SMN1 gene defect. About 50% of those more severely affected show a deletion in the second gene as well.
SMA type IV
- Has a number of different inheritance patterns.
- It can be autosomal recessive or autosomal dominant (ie only one parent needs to pass it on).
- It may also be non-hereditary and due to mutations in the SMN gene.
- There is an X-linked recessive form known as bulbo-SMA, or Kennedy's syndrome (daughters who inherit the gene become carriers and sons who inherit it show the symptoms).
SMA with respiratory distress (SMARD1)
- Inheritance is autosomal recessive due to mutations in the IGHMBP2 gene on chromosome 11q13.
- The estimated incidence is between 1 in 6,000 and 1 in 10,000 live births and the carrier frequency is between 1 in 40 and 1 in 60.
- SMA type II is the most common form.
- Spinal muscular atrophy (SMA) generally presents with muscle weakness and wasting. The limbs, respiratory and bulbar muscles and brainstem can be affected.
- Intellect is preserved and people with SMA often have above-average IQ.
- General clinical signs are that of lower motor neurone weakness:
- Flaccid weakness (muscles soft and floppy)
- Reduced or absent tendon reflexes
- Normal or absent plantar reflexes
- Muscle fasciculation
- Muscle atrophy
SMA type I
- Age of onset: <6 months.
- Features: the most severe form. Severe muscle weakness, hypotonia (no support of head when pulled up from lying to sitting; floppy when held in ventral suspension), poor suck and swallow reflexes, respiratory failure. Ocular and facial muscles and cerebral function are preserved. There may be deformities of limbs/joints at birth from in utero hypotonia. There may be a history of reduced fetal movements in utero.
- Mortality/morbidity: median survival is 7 months - 95% die before 18 months.
SMA type II
- Age of onset: 6-18 months.
- Features: developmental motor delay (delay in sitting, standing). Can usually eventually sit unsupported. Some can crawl or stand but these abilities may reduce as body weight increases. There may be finger tremor. Musculoskeletal deformities, respiratory failure. Pseudohypertrophy of gastrocnemius muscle.
- Mortality/morbidity: although remains a severe condition that may shorten life expectancy, improving care standards mean longer, more productive lives are possible for the majority of people.
SMA type III
- Age of onset: >18 months.
- Features: a milder disorder. Slowly progressive proximal weakness. Difficulty with more complex motor skills - eg, climbing stairs. May have gastrocnemius pseudohypertrophy. Chewing and swallowing may be affected later.
- Mortality/morbidity: can have a normal lifespan.
SMA type IV
- Age of onset: usually mid-30s.
- Features: similar to type III but tends to be less severe.
- Mortality/morbidity: can have a normal lifespan.
SMA with respiratory distress type 1(SMARD1)
- Age of onset: 1-6 months.
- Features: similar to SMA types I-IV but the predominant symptom is severe respiratory distress due to involvement of the diaphragm muscles. Respiratory problems are generally the first symptoms. Distal muscle weakness. Sensory and autonomic nervous systems may also be involved.
Bulbo-SMA, or Kennedy's syndrome
- Age of onset: 20-40 years.
- Features: bulbar and lower motor neurone weakness. Muscle cramps, facial fasciculations, hand tremor. Associated with type 2 diabetes and infertility.
- Motor neurone disease
- Primary lateral sclerosis
- Muscular dystrophy
- Congenital myopathies
- Disorders of carbohydrate metabolism (glycogen storage diseases)
- Myasthenia gravis
- Creatine kinase: usually normal in SMA type I; normal or slightly raised in other types.
- Can be carried out prenatally or postnatally.
- Shows diminished nerve signals.
- Helps to differentiate from other neuromuscular disorders.
- Sensory nerve conduction is usually normal.
- Other more complex testing involving motor action potentials can also be performed.
- Histology shows muscle fibre atrophy and can help to differentiate from other neuromuscular disorders.
There is currently no effective curative treatment.There is no proven effective drug treatment for SMA.[12, 13]However, scientific and clinical advances are currently heading towards developing effective treatment(s) for people with SMA.Gene therapy is under clinical trial. Drugs including valproate and phenylbutyrate have been shown to stimulate SMN2 gene activity and help to improve symptoms but further clinical trials are needed.
A multidisciplinary approach to supportive and palliative treatment is needed. The focus should be on the quality of life:
- In one study, >70% of type I and type II patients needed assistance in mobility and self-care.
- Splints and braces may be needed for limbs.
- Physiotherapy and special seats and wheelchairs can help to minimise joint contractures and scoliosis. Physiotherapy can also allow respiratory exercises.
- Respiratory support may be needed as the respiratory muscles become involved.
- Gastrostomy feeding may be needed as swallowing becomes affected.
- Spinal deformity
- Joint contractures
- Respiratory infection
- Respiratory failure
Although SMA involves a wide range of disease severity and a high mortality and morbidity rate, recent advances in multidisciplinary supportive care have enhanced quality of life and life expectancy.
- There is a 25% risk that each offspring of two carrier parents will be affected with the autosomal recessive inherited forms of SMA.
- Genetic testing can be done prenatally by amniocentesis and chorionic villus sampling to look for SMN gene deletions (prenatal genetic diagnosis). Parents can then decide to abort an affected fetus.
- IVF and pre-implantation genetic diagnosis can also be carried out if families have had a previous child affected by SMA. Embryos are tested to see if they are affected by SMA and unaffected embryos can be transferred to the uterus. Chorionic villus sampling may then be used later in the pregnancy to confirm that the growing fetus is unaffected.
- Research has shown that non-invasive analysis through testing of circulating fetal cells in the mother's blood may also be possible in the future.
Further reading and references
Tanaka F, Katsuno M, Banno H, et al; Current status of treatment of spinal and bulbar muscular atrophy. Neural Plast. 20122012:369284. doi: 10.1155/2012/369284. Epub 2012 Jun 7.
D'Amico A, Mercuri E, Tiziano FD, et al; Spinal muscular atrophy. Orphanet J Rare Dis. 2011 Nov 26:71. doi: 10.1186/1750-1172-6-71.
Spinal Muscular Atrophy, Type 1, SMA1; Online Mendelian Inheritance in Man (OMIM)
Spinal Muscular Atrophy Type II (Chronic Infantile); Online Mendelian Inheritance in Man (OMIM)
Spinal Muscular Atrophy, Type III, SMA3; Online Mendelian Inheritance in Man (OMIM)
Spinal Muscular Atrophy Type IV (Adult-onset); Online Mendelian Inheritance in Man (OMIM)
Chung BH, Wong VC, Ip P; Spinal muscular atrophy: survival pattern and functional status. Pediatrics. 2004 Nov114(5):e548-53. Epub 2004 Oct 18.
Jedrzejowska M, Madej-Pilarczyk A, Fidzianska A, et al; Severe phenotypes of SMARD1 associated with novel mutations of the IGHMBP2 gene and nuclear degeneration of muscle and Schwann cells. Eur J Paediatr Neurol. 2013 Dec 15. pii: S1090-3798(13)00183-9. doi: 10.1016/j.ejpn.2013.11.006.
Markowitz JA, Singh P, Darras BT; Spinal muscular atrophy: a clinical and research update. Pediatr Neurol. 2012 Jan46(1):1-12. doi: 10.1016/j.pediatrneurol.2011.09.001.
Wadman RI, Bosboom WM, van der Pol WL, et al; Drug treatment for spinal muscular atrophy type I. Cochrane Database Syst Rev. 2012 Apr 184:CD006281. doi: 10.1002/14651858.CD006281.pub4.
Wadman RI, Bosboom WM, van der Pol WL, et al; Drug treatment for spinal muscular atrophy types II and III. Cochrane Database Syst Rev. 2012 Apr 184:CD006282. doi: 10.1002/14651858.CD006282.pub4.
Lewelt A, Newcomb TM, Swoboda KJ; New therapeutic approaches to spinal muscular atrophy. Curr Neurol Neurosci Rep. 2012 Feb12(1):42-53. doi: 10.1007/s11910-011-0240-9.
Wirth B, Brichta L, Hahnen E; Spinal muscular atrophy: from gene to therapy. Semin Pediatr Neurol. 2006 Jun13(2):121-31.
Haaker G, Fujak A; Proximal spinal muscular atrophy: current orthopedic perspective. Appl Clin Genet. 2013 Nov 146(11):113-120. eCollection 2013.
Beroud C, Karliova M, Bonnefont JP, et al; Prenatal diagnosis of spinal muscular atrophy by genetic analysis of circulating fetal cells. Lancet. 2003 Mar 22361(9362):1013-4.
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