Spinal muscular atrophy

Editors-in-Chief: C. Michael Gibson, M.S., M.D.; Priyamvada Singh, MBBS

• Incidence of SMA – 1 in 6,000 – 10,000 live births or 7.8-10 per 100,000 live births .

• Carrier frequency for SMN 1 gene mutation is 1:38 to 1:50. ^[1], ^[2], ^[3], ^[4]

• 7.5 million Americans are carriers.

• A 2005 study in Cuba found a reduced incidence of Type I SMA amongst the Cuban population overall, (3.53 per 100,000 live births) and especially amongst those of African ancestry (0.89 to 0.93 per 100,000 live births) ^[5].

• Template:NINDS
• SMA Support
• Spinal Muscular Atrophy – Fight SMA – An international nonprofit dedicated to finding a treatment or cure for spinal muscular atrophy. Visit Fight SMA’s website and also the Spinal Muscular Atrophy Blog for the latest news and research information about the leading genetic killer of children under two.
• Families of Spinal Muscular Atrophy – An international nonprofit dedicated to advancing research and supporting individuals and families with sma. FSMA has a web site with news, information and message boards for individuals to post questions. FSMA is one of the largest US private funders of SMA research and has more than 30 chapters worldwide.FSMA
• SMA Trust – a UK registered charity working to fund medical research into Spinal Muscular Atrophy
• Jennifer Trust for Spinal Muscular Atrophy – A national charity in the UK dedicated both to supporting people affected by SMA, and investing in essential research into causes, treatments and eventually a cure for the condition

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da:Spinal muskulær atrofi de:Spinale Muskelatrophie el:Νωτιαία μυϊκή ατροφία nl:Spinale Musculaire Atrofieën fi:Spinaaliset lihasatrofiat sv:Spinal muskelatrofi

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Editors-in-Chief: C. Michael Gibson, M.S., M.D.; Priyamvada Singh, MBBS

• ~98% of parents of an affected child are carriers. Whereas, the rest of 2% that are not carriers have denovo mutation.

• The pattern of inheritance is autosomal recessive in SMA. The risk of occurrence/recurrence if both the parents are carriers is 25%, while the risk of having an unaffected carrier child is 50%.

This means that in every pregnancy there is

• 1 chance in 4 (25% chance) that they will have a child who inherits both copies of the mutated gene. So, there will be no working gene product in the child and he/she will be affected by the condition.
• 1 chance in 4 (25% chance) that their child will inherit both copies of the working gene and will be unaffected by the condition
• 1 chance in 2 (i.e. 2 chances in 4; 50% chance) that their child will inherit the mutated gene and the working copy of the gene from each parent and he/she will be an unaffected carrier of the faulty gene, just like the parents i.e. carrier for the condition

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Editors-in-Chief: C. Michael Gibson, M.S., M.D.; Priyamvada Singh, MBBS

Carrier testing^[1], ^[2], ^[3] – Carrier testing helps to identify carriers of the mutated genes (SMN, survival motor neuron gene). This can help to predict the risk of SMA in future pregnancies in the carriers.

• PCR-based dosage assay – Detect carriers with homozygous deletions or compound heterozygosity.

• Sequencing of the SMN gene – Detect point mutations.

• Other methods – family linkage analysis to identify the Parents genotype.

New Born screening^[3] may help to identify pre-symptomatic individuals and institution of early treatment (once it becomes available). This can prevent the occurrence of severe disease forms in future.

• Template:NINDS
• SMA Support
• Spinal Muscular Atrophy – Fight SMA – An international nonprofit dedicated to finding a treatment or cure for spinal muscular atrophy. Visit Fight SMA’s website and also the Spinal Muscular Atrophy Blog for the latest news and research information about the leading genetic killer of children under two.
• Families of Spinal Muscular Atrophy – An international nonprofit dedicated to advancing research and supporting individuals and families with sma. FSMA has a web site with news, information and message boards for individuals to post questions. FSMA is one of the largest US private funders of SMA research and has more than 30 chapters worldwide.FSMA
• SMA Trust – a UK registered charity working to fund medical research into Spinal Muscular Atrophy
• Jennifer Trust for Spinal Muscular Atrophy – A national charity in the UK dedicated both to supporting people affected by SMA, and investing in essential research into causes, treatments and eventually a cure for the condition

Template:Diseases of the nervous system

da:Spinal muskulær atrofi de:Spinale Muskelatrophie el:Νωτιαία μυϊκή ατροφία nl:Spinale Musculaire Atrofieën fi:Spinaaliset lihasatrofiat sv:Spinal muskelatrofi

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Editors-in-Chief: C. Michael Gibson, M.S., M.D.; Priyamvada Singh, MBBS

Spinal muscular atrophy (SMA) is a collection of different muscle diseases. Grouped together, it is the second leading cause of neuromuscular disease. The autosomal recessive SMA is the commonest type (>95%) and is caused by the mutation in the chromosome 5q13. The non-5q13 associated spinal muscular atrophies, are a heterogeneous group of motor neuron diseases associated with mutations in a variety of different known genes and others not yet defined (e.g. X linked, autosomal dominant, mutations in IGHMBP2 gene on chromosome 11q). Patients with these disorders generally have some clinical characteristics that can help differentiate them from those with 5q13-associated or “proximal” SMA. All forms of SMA have in common weakness caused by denervation, that is, the muscle atrophies because it has lost the signal to contract due to loss of the innervating nerve. Spinal muscular atrophy only affects motor nerves. Heritable disorders that cause both weakness due to motor denervation along with sensory impairment due to sensory denervation are known by the inclusive label Charcot-Marie-Tooth or Hereditary Motor Sensory Neuropathy. The term spinal muscular atrophy thus refers to atrophy of muscles due to loss of motor neurons within the spinal cord.

• Hereditary Bulbo-Spinal SMA Kennedy’s disease (X linked, Androgen receptor)
• Spinal Muscular Atrophy with Respiratory Distress (SMARD 1) (chromsome 11, IGHMBP2 gene)
• Distal SMA with upper limb predominance (chromosome 7, glycyl tRNA synthase)
• X-Linked infantile SMA (gene UBE1)^[1][2]

• Template:NINDS
• SMA Support
• Spinal Muscular Atrophy – Fight SMA – An international nonprofit dedicated to finding a treatment or cure for spinal muscular atrophy. Visit Fight SMA’s website and also the Spinal Muscular Atrophy Blog for the latest news and research information about the leading genetic killer of children under two.
• Families of Spinal Muscular Atrophy – An international nonprofit dedicated to advancing research and supporting individuals and families with sma. FSMA has a web site with news, information and message boards for individuals to post questions. FSMA is one of the largest US private funders of SMA research and has more than 30 chapters worldwide.FSMA
• SMA Trust – a UK registered charity working to fund medical research into Spinal Muscular Atrophy
• Jennifer Trust for Spinal Muscular Atrophy – A national charity in the UK dedicated both to supporting people affected by SMA, and investing in essential research into causes, treatments and eventually a cure for the condition

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da:Spinal muskulær atrofi de:Spinale Muskelatrophie el:Νωτιαία μυϊκή ατροφία nl:Spinale Musculaire Atrofieën fi:Spinaaliset lihasatrofiat sv:Spinal muskelatrofi

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Editors-in-Chief: C. Michael Gibson, M.S., M.D.; Priyamvada Singh, MBBS

Spinal muscular atrophy is caused by the mutation in SMN1 (survival motor neuron 1)gene. SMN 1 gene produces SMN protein. This protein is ubiquitously found in all cells (located in both the cytoplasm and in the nucleus). The main function that is found to be associated with them are-

• Components of spliceosome, involved in pre-m-RNA splicing (transcription) ^[1]
• Involved in actin cytoskeletal dynamics (motor axon pathfinding)^[2]
• Involved in maintaining structural and physiological integrity of neuromuscular junction ^[3]

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Editors-in-Chief: C. Michael Gibson, M.S., M.D.; Priyamvada Singh, MBBS

Spinal muscular atrophy is caused by mutation in SMN (survival motor neuron) gene present on chromosome 5q 13 in 98.6% of patients. The chromosome 5 contains an inverted duplication that contains the SMN1 gene (this is mutated in patients with SMA) and the SMN2 gene (a duplication of SMN1 that differs from it by only five nucleotides) ^[1]. Due to this difference in nucleotide in SMN2 gene, a truncated (Survival motor neuron) SMN protein is produced, much of which is non-functional and thus degraded. However, some of the SMN2 gene skips this and are able to produce some functional protein (^[2]). The number of copies of SMN2 per chromosome 5 and the amount of SMN protein are inversely correlated with the severity of disease (^[3], ^[4]). 95% of patients of SMA with SMA have deletions of the SMN1 gene whereas others have intragenic, denovo mutation or gene conversion (^[5], ^[6]).

• Template:NINDS
• SMA Support
• Spinal Muscular Atrophy – Fight SMA – An international nonprofit dedicated to finding a treatment or cure for spinal muscular atrophy. Visit Fight SMA’s website and also the Spinal Muscular Atrophy Blog for the latest news and research information about the leading genetic killer of children under two.
• Families of Spinal Muscular Atrophy – An international nonprofit dedicated to advancing research and supporting individuals and families with sma. FSMA has a web site with news, information and message boards for individuals to post questions. FSMA is one of the largest US private funders of SMA research and has more than 30 chapters worldwide.FSMA
• SMA Trust – a UK registered charity working to fund medical research into Spinal Muscular Atrophy
• Jennifer Trust for Spinal Muscular Atrophy – A national charity in the UK dedicated both to supporting people affected by SMA, and investing in essential research into causes, treatments and eventually a cure for the condition

da:Spinal muskulær atrofi de:Spinale Muskelatrophie el:Νωτιαία μυϊκή ατροφία nl:Spinale Musculaire Atrofieën fi:Spinaaliset lihasatrofiat sv:Spinal muskelatrofi

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Editors-in-Chief: C. Michael Gibson, M.S., M.D.; Priyamvada Singh, MBBS

The autosomal recessive SMA caused by mutation of SMN gene present on chromosome 5q13 comprises 95% of all SMA. SMA is mainly classified into three broad types (Type I – Type III) based on the clinical severity and prognosis. Two more type of SMA, Type 0 and Type IV have been recently defined. The different types of SMA have a clinical continuum.

Type I SMA, Werdnig-Hoffman disease

1. Present from birth to 6 months of age
2. Survival mostly up to 2 years of age.
3. Never able to sit
4. Hypotonic (predominately proximal weakness, lower limb more than upper)
5. Poor head control
6. Risk of aspiration, failure to thrive
7. Normal cognition,
8. Respiratory failure common.

Type II SMA, Intermediate SMA

1. Presents mostly at 6-12 months of age
2. 70% survive beyond 25 years of age
3. Sitter but never able to walk
4. Clinical features similar to type I (hypotonic with predominance proximal weakness) but of less severity than Type I SMA.
5. Cognition normal or even more than normal.

Type III SMA, Kugelberg-Welander disease

1. Walkers
2. Onset of disease more than 12 months of age
3. Life span normal
4. Milder symptoms (less hypotonic, little or no respiratory failure) compared to type I and II.

Outliers There are two more types of SMA recently defined as Type ‘0’ and Type ‘IV’. Type 0 is the most severe of all the types of SMA with onset as early as prenatal period. Life expectancy is reduced and mostly the child is unable to survive beyond 6 months of age. Mostly they don’t attain any motor milestones can present with facial diplegia, opthalmoplegia and arthrogryposis and respiratory failure. Type IV SMA is the mildest variety.

Other: Non-5q13 associated SMA –

SMA in this category include X linked, autosomal dominant spinal muscular atrophies, distal spinal muscular atrophies, distal hereditary motor neuropathies, SMA with respiratory distress and pontocerebellar hypoplasia with infantile SMA. Infantile X-Linked SMA is similar to but distinguishable from Werdnig Hoffmann disease, manifested at or before birth in boys. Boys who inherit the gene usually die before age 2. Girls who inherit the gene are carriers, but are otherwise unaffected.It is caused by mutation of the UBE1 gene on X Chromosome

• Template:NINDS
• SMA Support
• Spinal Muscular Atrophy – Fight SMA – An international nonprofit dedicated to finding a treatment or cure for spinal muscular atrophy. Visit Fight SMA’s website and also the Spinal Muscular Atrophy Blog for the latest news and research information about the leading genetic killer of children under two.
• Families of Spinal Muscular Atrophy – An international nonprofit dedicated to advancing research and supporting individuals and families with sma. FSMA has a web site with news, information and message boards for individuals to post questions. FSMA is one of the largest US private funders of SMA research and has more than 30 chapters worldwide.FSMA
• SMA Trust – a UK registered charity working to fund medical research into Spinal Muscular Atrophy
• Jennifer Trust for Spinal Muscular Atrophy – A national charity in the UK dedicated both to supporting people affected by SMA, and investing in essential research into causes, treatments and eventually a cure for the condition

Template:Diseases of the nervous system

da:Spinal muskulær atrofi de:Spinale Muskelatrophie el:Νωτιαία μυϊκή ατροφία nl:Spinale Musculaire Atrofieën fi:Spinaaliset lihasatrofiat sv:Spinal muskelatrofi

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Editors-in-Chief: C. Michael Gibson, M.S., M.D.; Priyamvada Singh, MBBS

The diagnosis of SMA is done by a combination of different methods. The commonly used methods are – Genetic testing, blood tests (Enzyme levels), Nerve conduction study, Needle EMG, muscle biopsy. In order to be diagnosed with Spinal muscular atrophy, symptoms need to be present. In most cases a diagnosis can be made by the SMN gene test, which determines whether there is at least one copy of the SMN1 gene by looking for its unique sequences (that distinguish it from the almost identical SMN2) in exons 7 and 8. In some cases, when the SMN gene test is not possible or does not show any abnormality, other tests such as an electromyography (EMG) or muscle biopsy may be indicated.

Genetic testing– It is currently performed with PCR-based targeted mutation analysis using a restriction enzyme that digests exon 7 (the specific area of chromosome 5 that is affected in the disease). This test can diagnose SMA patients who are homozygous deleted (both allele deleted), compound heterozygotes (deletion in one SMN1 allele and an intragenic point mutation in the other) ^[1].

Creatine Kinase (CK) – SMA patients may have 2-4 fold serum CK elevation.

Nerve conduction studies – May show decreased compound motor action potential (CMAP) amplitudes ^[2].

Needle EMG– In needle EMG a thin needle electrode is inserted into the muscle. The electrode on the needle picks up the electrical activity of the muscles. This electrical activity is displayed on a monitor called an oscilloscope or heard through a speaker. The presence, size, and shape of the action potential provides information about muscle’s ability to respond when the nerves are stimulated. It Shows denervation in SMA I patients without evidence of reinnervation changes ^[3].

Muscle biopsy– shows atrophy of muscle groups.^[4].

• Template:NINDS
• SMA Support
• Spinal Muscular Atrophy – Fight SMA – An international nonprofit dedicated to finding a treatment or cure for spinal muscular atrophy. Visit Fight SMA’s website and also the Spinal Muscular Atrophy Blog for the latest news and research information about the leading genetic killer of children under two.
• Families of Spinal Muscular Atrophy – An international nonprofit dedicated to advancing research and supporting individuals and families with sma. FSMA has a web site with news, information and message boards for individuals to post questions. FSMA is one of the largest US private funders of SMA research and has more than 30 chapters worldwide.FSMA
• SMA Trust – a UK registered charity working to fund medical research into Spinal Muscular Atrophy
• Jennifer Trust for Spinal Muscular Atrophy – A national charity in the UK dedicated both to supporting people affected by SMA, and investing in essential research into causes, treatments and eventually a cure for the condition

Template:Diseases of the nervous system

da:Spinal muskulær atrofi de:Spinale Muskelatrophie el:Νωτιαία μυϊκή ατροφία nl:Spinale Musculaire Atrofieën fi:Spinaaliset lihasatrofiat sv:Spinal muskelatrofi

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Editors-in-Chief: C. Michael Gibson, M.S., M.D.; Priyamvada Singh, MBBS

Differential diagnosisof Spinal Muscular Atrophy are as follow –

• Floppy child
• Arthrogryposis multiplex congenita
• X-linked infantile spinal muscular atrophy
• Spinal muscular atrophy with respiratory distress type 1
• Congenital myasthenic syndromes
• Congenital myopathies
• Pompe’s disease
• Congenital myotonic dystrophy
• Hypoxic-ischemic myelopathy
• Lysosomal acid maltase deficiency
• Prader-Willi syndrome
• Traumatic myelopathy
• Zellweger syndrome

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Editors-in-Chief: C. Michael Gibson, M.S., M.D.; Priyamvada Singh, MBBS

Infantile SMA is the most severe form. Some of the symptoms include:

• muscle weakness
• poor muscle tone
• weak cry
• limpness or a tendency to flop
• difficulty sucking or swallowing
• accumulation of secretions in the lungs or throat
• legs that tend to be weaker than the arms
• hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells
• feeding difficulties
• increased susceptibility to respiratory tract infections
• developmental milestones, such as lifting the head or sitting up, can’t be reached.

In general, the earlier the symptoms appear, the shorter the life span. The onset is sudden and dramatic. Once symptoms appear the motor neuron cells quickly deteriorate shortly after. The disease can be fatal and there is no cure for SMA yet known. The major management issue in Type 1 SMA is the prevention and early treatment of respiratory infections; pneumonia is the cause of death in the majority of the cases. Infants with Type 1 SMA have a life expectancy of less than two years, however, some grow to be adults. Intellectual and later, sexual functions, are unaffected by SMA.

• Template:NINDS
• SMA Support
• Spinal Muscular Atrophy – Fight SMA – An international nonprofit dedicated to finding a treatment or cure for spinal muscular atrophy. Visit Fight SMA’s website and also the Spinal Muscular Atrophy Blog for the latest news and research information about the leading genetic killer of children under two.
• Families of Spinal Muscular Atrophy – An international nonprofit dedicated to advancing research and supporting individuals and families with sma. FSMA has a web site with news, information and message boards for individuals to post questions. FSMA is one of the largest US private funders of SMA research and has more than 30 chapters worldwide.FSMA
• SMA Trust – a UK registered charity working to fund medical research into Spinal Muscular Atrophy
• Jennifer Trust for Spinal Muscular Atrophy – A national charity in the UK dedicated both to supporting people affected by SMA, and investing in essential research into causes, treatments and eventually a cure for the condition

Template:Diseases of the nervous system

da:Spinal muskulær atrofi de:Spinale Muskelatrophie el:Νωτιαία μυϊκή ατροφία nl:Spinale Musculaire Atrofieën fi:Spinaaliset lihasatrofiat sv:Spinal muskelatrofi

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Editors-in-Chief: C. Michael Gibson, M.S., M.D.; Priyamvada Singh, MBBS

The course of SMA is directly related to the severity of weakness. Infants with the severe form of SMA frequently succumb to respiratory disease due to weakness of the muscles that support breathing. Children with milder forms of SMA naturally live much longer although they may need extensive medical support, especially those at the more severe end of the spectrum. Although gene replacement strategies are being tested in animals, current treatment for SMA consists of prevention and management of the secondary effect of chronic motor unit loss. It is likely that gene replacement for SMA will require many more years of investigation before it can be applied to humans. Due to molecular biology, there is a better understanding of SMA. The disease is caused by deficiency of SMN (survival motor neuron) protein, and therefore approaches to developing treatment include searching for drugs that increase SMN levels, enhance residual SMN function, or compensate for its loss. Much can be done for SMA patients in terms of medical and in particular respiratory, nutritional and rehabilitation care. However, there is currently no drug known to alter the course of SMA. Significant progress has been made in preclincial research towards an effective treatment. Several drugs have been identified in laboratory experiments that hold promise for patients. To evaluate if these drugs benefit SMA patients, clinical trials are needed. In a clinical trial a new medication is tested while the patients are carefully monitored for their safety and for any possible drug effects, positive or negative.

Some drugs under clinical investigation for the treatment of SMA:

• Butyrates
• Valproic acid
• Hydroxyurea
• Riluzole

Editors-in-Chief: C. Michael Gibson, M.S., M.D.; Priyamvada Singh, MBBS

In 1978 Pearn published a series of papers on SMA. He reported that childhood onset SMA is not an uncommon disease and has an incidence in the Northern UK in range of 4 per 100,000 births. At that time the association between the severe infantile form of SMA and the milder forms was not understood. With the advantage of knowledge about the causative gene, it is now known that SMA1, SMA2 and SMA3 are all caused by mutations in the same gene. The overall incidence of SMA, of all types, is in the range of 1 per 6,000 individual. It affects individuals of all races, unlike other well known autosomal recessive disorders like sickle cell disease, and cystic fibrosis, that have significant differences in occurrence rate between races. Overall, SMA1 is the most common genetic cause of death in infants.

The autosomal recessive versions of SMA are caused by inheritance of a mutated gene from each parent, who would not know that they have the abnormal gene because having only one mutated copy produces no symptoms. Once a child is affected, each subsequent baby has a 25% chance of having the illness. If a sibling does not inherit the disorder, he or she has a 2/3 chance of being a carrier.

On the other hand, X-linked infantile SMA is passed from mothers only to sons. Sons have a 50% chance of inheriting the defective gene from a mother who is a carrier and suffering the disease, while daughters have a 50% chance of becoming carriers without symptoms themselves. Couples may want to have genetic counseling before deciding to have more children. Counseling is available to these families through the community.

In 1990 mapping of the gene for SMA to chromosome 5q11.2-13.3 was reported and culminated in a 3 year research funded in part by the Muscular Dystrophy Association. The findings were also confirmed by French researchers. The identification of the gene for autosomal recessive SMA on chromosome 5q has allowed for prenatal diagnosis. Families who are at risk, or who have had a child with the diagnosis can have an amniocentesis done during pregnancy for DNA testing.

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