Survival motor neuron spinal muscular atrophy
Encyclopedia
Survival motor neuron spinal muscular atrophy (Spinal muscular atrophies of childhood) is a term used used to describe certain forms of spinal muscular atrophy
(SMA) that are associated with the Survival of Motor Neuron
(SMN) protein. These include Werdnig-Hoffmann disease and Kugelberg-Welander disease.
It can involve SMN1
and SMN2
.
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.
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 chromosome
s. 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.
.
Kugelberg-Welander disease is named for Erik Klas Hendrik Kugelberg (1913, Stockholm, Sweden - 1983) and Lisa Welander (1909-2001).
Key clinical point is hypotonia associated with absent reflexes in early infancy
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.
Tracheostomy is often (but not always) a part of the treatment plan.
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) 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 sometimes die before the age of 2 without breathing support.
However, some individuals have survived to become adults.
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 5
q11.2-13.3 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.
Spinal muscular atrophy
Spinal Muscular Atrophy is a neuromuscular disease characterized by degeneration of motor neurons, resulting in progressive muscular atrophy and weakness. The clinical spectrum of SMA ranges from early infant death to normal adult life with only mild weakness...
(SMA) that are associated with the Survival of Motor Neuron
Survival of motor neuron
The Survival of Motor Neuron is a protein involved in the assembly of snRNPs, the essential components of spliceosomal machinery. A lack of SMN due to SMN1 deletion results in widespread splicing defects, especially in spinal motor neurons, and is one cause of spinal muscular atrophy.SMN also...
(SMN) protein. These include Werdnig-Hoffmann disease and Kugelberg-Welander disease.
It can involve SMN1
SMN1
Survival motor neuron protein is a protein that in humans is encoded by the SMN1 gene.-Interactions:SMN1 has been shown to interact with Gem-associated protein 7, GEMIN4, KPNB1, Survival of motor neuron protein-interacting protein 1, DDX20, Coilin, Small nuclear ribonucleoprotein D1, Fibrillarin,...
and SMN2
SMN2
Survival of motor neuron 2, centromeric also known as SMN2 is a protein which in humans is encoded by the SMN2 gene.- Gene :This gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to...
.
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
Kennedy disease
Kennedy's disease or X-linked Spinal and Bulbar Muscular Atrophy or Spinobulbar Muscular Atrophy or X-Linked Bulbo-Spinal Atrophy is an X-linked recessive, slow progressing, neurodegenerative disease associated with mutation of the androgen receptor...
.
The term dates back to at least 1973.
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 Eponym An eponym is the name of a person or thing, whether real or fictitious, after which a particular place, tribe, era, discovery, or other item is named or thought to be named... |
General age of onset | Description |
|---|---|---|---|---|
| Type 1: "Infantile" | 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 without intensive respiratory support. 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" | 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" | 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" |
Causes
It has been linked to an abnormal survival motor neuron (SMN) gene.In humans and chimps, the region of chromosome 5
Chromosome 5 (human)
Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 181 million base pairs and represents almost 6% of the total DNA in cells. Chromosome 5 is one of the largest human chromosomes, yet has one of the lowest gene...
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
Silent mutation
Silent mutations are DNA mutations that do not result in a change to the amino acid sequence of a protein. They may occur in a non-coding region , or they may occur within an exon in a manner that does not alter the final amino acid sequence...
that occurs at the splice junction of intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
6 to exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
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 chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
s. 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 WerdnigGuido Werdnig
Guido Werdnig was an Austrian neurologist.Werdnig-Hoffmann disease is named for him: it was first described in the...
.
Kugelberg-Welander disease is named for Erik Klas Hendrik Kugelberg (1913, Stockholm, Sweden - 1983) and Lisa Welander (1909-2001).
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:- Fasciculations (quivering) of the tongue
- Marked HypotoniaHypotoniaHypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
in legs, arms, rib, chest & bulbar muscles - Patient lies in a frog-leg position, i.e. hips abducted & knees flexed
- Flaccid quadriplegiaQuadriplegiaTetraplegia, also known as quadriplegia, is paralysis caused by illness or injury to a human that results in the partial or total loss of use of all their limbs and torso; paraplegia is similar but does not affect the arms...
- Difficulty breathing
- Poor feeding
- Weak cry
- Areflexive extremities
Diagnosis
- Electromyogram (EMG) will show fibrillationFibrillationFibrillation is the rapid, irregular, and unsynchronized contraction of muscle fibers. An important occurrence is with regards to the heart.-Cardiology:There are two major classes of cardiac fibrillation: atrial fibrillation and ventricular fibrillation....
& muscle denervation - Serum creatine kinaseCreatine kinaseCreatine kinase , also known as creatine phosphokinase or phospho-creatine kinase , is an enzyme expressed by various tissues and cell types. CK catalyses the conversion of creatine and consumes adenosine triphosphate to create phosphocreatine and adenosine diphosphate...
may be normal or increased
Key clinical point is hypotonia associated with absent reflexes in early infancy
Genetics
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
, 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.
Prognosis
Werdnig-Hoffmann disease / SMA Type 1 is the most severe form of SMA. The conditions of children diagnosed with it tend 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) 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 sometimes die before the age of 2 without breathing support.
However, some individuals have survived to become adults.
Research
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.
In 1990 mapping of the gene for SMA to chromosome 5
Chromosome 5 (human)
Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 181 million base pairs and represents almost 6% of the total DNA in cells. Chromosome 5 is one of the largest human chromosomes, yet has one of the lowest gene...
q11.2-13.3 was reported and culminated in a 3 year research funded in part by the Muscular Dystrophy Association
Muscular Dystrophy Association
The Muscular Dystrophy Association is an American organization which combats muscular dystrophy and diseases of the nervous system and muscular system in general by funding research, providing medical and community services, and educating health professionals and the general public...
. 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
Amniocentesis
Amniocentesis is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections, in which a small amount of amniotic fluid, which contains fetal tissues, is sampled from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for...
done during pregnancy for DNA testing.