Survival motor neuron spinal muscular atrophy: Wikis

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Survival motor neuron spinal muscular atrophy
Classification and external resources
ICD-10 G12.0-G12.1
ICD-9 335.0-335.1
DiseasesDB 14093 12315
MedlinePlus 000996
eMedicine orthoped/304 pmr/62
MeSH D014897

Survival motor neuron spinal muscular atrophy (Spinal muscular atrophies of childhood) is a term used used to describe certain forms of spinal muscular atrophy that are associated with survival of motor neuron. These include Werdnig-Hoffmann disease and Kugelberg-Welander disease.

It can involve SMN1 and SMN2.[1]

Sometimes the term "spinal muscular atrophy" is used to imply an association with survival motor neuron, but the phrase "spinal muscular atrophy" is also used to refer to unrelated conditions such as Kennedy disease.

The term dates back to at least 1973.[2]

Contents

Types

The most common form of SMA is caused by mutation of the SMN gene, and manifests over a wide range of severity affecting infants through adults. This spectrum has been divided into groups, depending on the age of onset, and are as followed:

Group OMIM Eponym General age of onset Description
Type 1: "Infantile" 253300 Werdnig-Hoffmann disease 0-6 months SMA type I, also known as severe infantile SMA or Werdnig Hoffmann disease, is the most severe, and manifests in the first year of life. This type generally onsets quickly and unexpectedly after birth; babies diagnosed with Type I SMA do not generally live past one year of age. Pneumonia is considered the ultimate cause of death due to deterioration of survival motor neurons; motor neuron death causes insufficient functioning of the major bodily organ systems, particularly respiratory (e.g. breathing, ridding of pooled secretions inside lungs).
Type 2: "Intermediate" or "infantile chronic" 253550 7-18 months Type II SMA, or intermediate SMA, describes those children who are never able to stand and walk, but who are able to maintain a sitting position at least some time in their life. The onset of weakness is usually recognized some time between 6 and 18 months. It is known to vary, some patients gradually grow weaker over time, while others through careful maintenance avoid any progression. Major causes for concern include the Respiratory System, as once weakened it never fully recovers.
Type 3: "Juvenile" or "mild childhood and adolescent" 253400 Kugelberg-Welander disease >18 months SMA type 3 describes those who are able to walk at some time. Many may later lose this ability, but the designation at type III remains based upon their history.
Type 4: "Adult" 271150

Causes

It has been linked to an abnormal survival motor neuron (SMN) gene.

In humans and chimps, the region of chromosome 5 that contains the SMN (survival motor neuron) gene has a large duplication. A large sequence that contains several genes occurs twice -- i.e. once in each of the adjacent segments. A second change that is found only in humans is that the two copies of the gene -- known as SMN1 and SMN2 -- differ by only a few base pairs. The important change in the SMN2 gene, for the purposes of SMA, is a silent mutation that occurs at the splice junction of intron 6 to exon 7. This affects splicing of the SMN2 pre-RNA, resulting in about 90% of the transcripts being inappropriately spliced into a form that excludes exon 7. This shorter mRNA transcript codes for a shorter SMN protein, which is rapidly degraded. About 10% of the mRNA transcript from SMN2 is spliced into the full length transcript that codes for the fully functional SMN protein.

SMA is caused by loss of the SMN1 gene from both chromosomes. The severity of SMA, ranging from SMA 1 to SMA 3, is partly related to how well the remaining SMN 2 genes can make up for the loss of SMN 1. In part this is related to how many copies of the SMN2 gene are present. The mutations that cause the loss of SMN 1 are of two types. One is a deletion mutation, decreasing the copy number of SMN1 by one. The other is a conversion mutation (rare in animals), that changes the SMN 1 sequence to that of SMN2. By this and other means, additional copies of SMN 2 may arise. Two copies is most often associated with SMA type 1. There is a lot of overlap between the type of SMA and the number of copies, however, such that copy number is not useful to determine the type of SMA any one individual has. It should be thought of as a research tool, rather than as a test with individual significance.

All forms of SMN-associated SMA have a combined incidence of about 1 in 6,000. SMA is the most common cause of genetically determined neonatal death. The gene frequency is thus around 1:80, and thus approximately one in 40 persons are carriers. There are no known health consequences of being a carrier, and presently the only way one may know to consider the possibility is if a relative is affected.

Eponyms

Werdnig-Hoffman disease is named for Johann Hoffmann and Guido Werdnig.[3][4][5]

Kugelberg-Welander disease is named for Erik Kugelberg and Lisa Welander.[6][7]

Symptoms

It is evident before birth or within the first few months of life. There may be a reduction in fetal movement in the final months of pregnancy. Affected children never sit or stand unassisted and will require respiratory support to survive beyond the age of 2. Other symptoms include:

Diagnosis

Key clinical point is hypotonia associated with absent reflexes in early infancy

Genetics

Werdnig-Hoffman disease has an autosomal recessive pattern of inheritance.

Werdnig-Hoffman disease is inherited in an autosomal recessive pattern, which means the defective gene is located on an autosome, and two copies of the gene - one from each parent - are required to inherit the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but do not have the disorder.

Treatment

Treatment is symptomatic and supportive and includes treating pneumonia, curvature of the spine and respiratory infections, if present. Also, physical therapy, orthotic supports, and rehabilitation are useful. For individuals who survive early childhood, assistive technology can be vital to providing access to work and entertainment. Genetic counseling is imperative.

Tracheostomy is often (but not always) a part of the treatment plan.[8]

Prognosis

Children with Werdnig-Hoffmann disease / SMA Type 1 face a difficult battle. The patient's condition tends to deteriorate over time, depending on the severity of the symptoms.

The child is constantly at risk of respiratory infection and pneumonia.

Poor chewing and swallowing may lead to malnutrition; supplemental tube feedings may be required through the nose or directly into the stomach.

Recurrent respiratory problems (the primary cause of morbidity in this condition)[9] mean that mechanical support for breathing—usually initially in the form of BiPAP and later often tracheostomy and ventilation—are necessary for the baby to have any chance of long-term survival.

Affected children never sit or stand and usually die before the age of 2 without breathing support.

However, some individuals have survived to become adults.[10]

Research

In 1978 Pearn published a series of papers on SMA.[11][12][13] 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.

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.

References

  1. ^ Prior TW (August 2007). "Spinal muscular atrophy diagnostics". J. Child Neurol. 22 (8): 952–6. doi:10.1177/0883073807305668. http://jcn.sagepub.com/cgi/pmidlookup?view=long&pmid=17761649.  
  2. ^ Moosa A, Dubowitz V (May 1973). "Spinal muscular atrophy in childhood. Two clues to clinical diagnosis". Arch. Dis. Child. 48 (5): 386–8. PMID 4703068.  
  3. ^ synd/1825 at Who Named It?
  4. ^ J. Hoffmann. Weitere Beiträge zur Lehre von der progressiven neurotischen Muskeldystrophie. Deutsche Zeitschrift für Nervenheilkunde, Berlin, 1891, 1: 95-120.
  5. ^ G. Werdnig. Zwei frühinfantile hereditäre Fälle von progressiver Muskelatrophie unter dem Bilde der Dystrophie, aber auf neurotischer Grundlage. Archiv für Psychiatrie und Nervenkrankheiten, Berlin, 1891, 22: 437-481
  6. ^ synd/1234 at Who Named It?
  7. ^ Kugelberg E, Welander L (May 1956). "Heredofamilial juvenile muscular atrophy simulating muscular dystrophy". AMA Arch Neurol Psychiatry 75 (5): 500–9. PMID 13312732.  
  8. ^ Bach JR, Niranjan V, Weaver B (April 2000). "Spinal muscular atrophy type 1: A noninvasive respiratory management approach". Chest 117 (4): 1100–5. doi:10.1378/chest.117.4.1100. PMID 10767247. http://www.chestjournal.org/cgi/pmidlookup?view=long&pmid=10767247.  
  9. ^ Yuan N, Wang CH, Trela A, Albanese CT (June 2007). "Laparoscopic Nissen fundoplication during gastrostomy tube placement and noninvasive ventilation may improve survival in type I and severe type II spinal muscular atrophy". J. Child Neurol. 22 (6): 727–31. doi:10.1177/0883073807304009. PMID 17641258. http://jcn.sagepub.com/cgi/pmidlookup?view=long&pmid=17641258.  
  10. ^ Bach JR (May 2007). "Medical considerations of long-term survival of Werdnig-Hoffmann disease". Am J Phys Med Rehabil 86 (5): 349–55. doi:10.1097/PHM.0b013e31804b1d66. PMID 17449979. http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?an=00002060-200705000-00004.  
  11. ^ Pearn JH, Hudgson P, Walton JN (December 1978). "A clinical and genetic study of spinal muscular atrophy of adult onset: the autosomal recessive form as a discrete disease entity". Brain 101 (4): 591–606. PMID 737522. http://brain.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=737522.  
  12. ^ Pearn J (September 1978). "Autosomal dominant spinal muscular atrophy: a clinical and genetic study". J. Neurol. Sci. 38 (2): 263–75. PMID 712386.  
  13. ^ Pearn J, Bundley S, Carter CO, Wilson J, Gardner-Medwin D, Walton JN (July 1978). "A genetic study of subacute and chronic spinal muscular atrophy in childhood. A nosological analysis of 124 index patients". J. Neurol. Sci. 37 (3): 227–48. PMID 681978.  
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