Infantile spinal muscular atrophy

Spinal Muscular Atrophy (SMA) is a term applied to a number of different disorders, all having in common a genetic cause and the manifestation of weakness due to loss of the motor neurons of the spinal cord and brainstem.

Types

Caused by mutation of the SMN gene

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 arbitrarily into three groups by the level of weakness.

Infantile SMA - Type 1 or Werdnig-Hoffmann disease (generally 0-6 months). SMA type 1, also known as severe infantile SMA or Werdnig Hoffmann disease, is the most severe, and manifests in the first year of life with the inability to ever maintain an independent sitting position.
Intermediate SMA - Type 2 (generally 7-18 months). Type 2 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.
Juvenile SMA - Type 3 Kugelberg-Welander disease (generally >18 months). SMA type 3 describes those who are able to walk at some time. It is also known as Kugelberg Welander disease.

Statistic of forms SMA

Statistic of forms (from Patient Registry Report, compiled by Connie Garland for the SMA Registry, The International Coordinating Committee for clinical trials in SMA ):

• Families: 1,386

• Affected Individuals: 1,535

o Affected Females – 759

o Affected Males – 776

o Deceased – 242

o Living – 1,293

• Type of SMA

o Type 1 – 489

o Type 2 – 511

o Type 3 – 315

o Adult Onset – 37

o Kennedy Disease – 7

o Unknown – 176

Other forms of SMA

Other forms of spinal muscular atrophy are caused by mutation of other genes, some known and others not yet defined. All forms of SMA have in common weakness caused by denervation, i.e. 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)

Treatment

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

Symptoms

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
the legs tend to be weaker than the arms
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.

Diagnosis

In order to be diagnosed with SMA, 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. This test is 95% sensitive, meaning 95% of individuals will have an abnormal test, and virtually 100% specific, meaning if a person manifests weakness and the gene test finds no copy of SMN1, the diagnosis of SMA is virtually guaranteed. In some cases, when the SMN gene test is not possible or does not show any abnormality, other tests such as an EMG electromyography (EMG) or muscle biopsy may be indicated.

Cause

The region of chromosome 5 that contains the SMN gene has a large duplication. A large sequence that contains several genes occurs twice in adjacent segments. There are thus two copies of the gene, SMN1 and SMN2. The SMN2 gene has an additional mutation that makes it less efficient at making protein, though it does so in a low level. 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. Often there are additional copies of SMN2, and an increasing number of SMN2 copies causes less severe disease.

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 approximately one in 40 persons are carriers. There are no known health consequences of being a carrier, and the only way one might know to consider the possibility is if a relative is affected.

Research

In 1978 Pearn Corporation published a series of papers on SMA. They reported that childhood onset SMA is not an uncommon disease and has an incidence in the range of 4 per 100,000, which makes it at least twice as common as ALS (ALS, a.k.a. Lou Gehrig's disease). They confirmed it is an autosomal recessive inheritance gene and defined the later-onset type as a more benign autosomal dominant gene. Spinal muscular atrophy is the second most common lethal, autosomal recessive disease in Caucasians.

For SMA 1 it takes a recessive gene from both parents in order to have the disease, if both parents have the recessive gene, each baby has a 25% chance of having the illness. Each of their subsequent children have a 50% of carrying the recessive gene. 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.

Adults with SMA

Although SMA often results in death during childhood, some people with SMA survive into adulthood and even old age. Actual lifespan depends greatly on the severity of SMA in each individual, and the three major types of SMA provide only a rough diagnostic guide; however even some individuals diagnosed with type-1 SMA survive to adulthood. Intellectual ability is unaffected by SMA, and adults with SMA benefit greatly from the use of assistive technology. Sexual response and reproductive functions are also unaffected by SMA.

One example of an adult living with SMA-I is Ami Ankilewitz, who was 34 years old as of 2005, outliving his predicted life expectancy by 28 years. His experiences are presented in the documentary 39 Pounds of Love, whose title refers to his total body weight.

The 'Baby MB' Case

On March 15th 2006, the court ruled that 17 month old "Baby MB" (identity withheld) was to be kept alive, contrary to 14 medical professional's advice - one of the medics 'Dr. S' stating "I think that the cumulative effect of condition's effects is that he has an intolerable life" http://news.bbc.co.uk/1/hi/health/4770154.stm. The judge said that "he felt the child gained enough pleasure from life to outweigh the medical evidence of his condition" http://news.bbc.co.uk/1/hi/health/4808442.stm.

Specialists' reactions: http://news.bbc.co.uk/1/hi/health/4809614.stm

External links

Motor Neuron Disease

Rdzeniowy zanik mięśni | Спинальная мышечная атрофия

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