Spinal muscular atrophy

Spinal muscular atrophy
Classification and external resources
ICD-10	G12
ICD-9	335.0-335.1
OMIM	253300 253550 253400 271150
DiseasesDB	14093 32911 12315
MeSH	D009134
GeneReviews	Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA) is a neuromuscular disease characterized by degeneration of motor neurons,^[1][2] resulting in progressive muscular atrophy (wasting away) and weakness. The clinical spectrum of SMA ranges from early infant death to normal adult life with only mild weakness. These patients often require comprehensive medical care involving multiple disciplines, including pediatric pulmonology, pediatric neurology, pediatric orthopedic surgery, Lower Extremity & Spinal Orthosis, pediatric critical care, and physical medicine and rehabilitation; and physical therapy, occupational therapy, respiratory therapy, and clinical nutrition. Genetic counseling is also helpful for the parents and family members. Sensation and the ability to feel are not affected. Intellectual activity is normal and it is often observed that patients with SMA are unusually bright and sociable.[1]

The term "juvenile spinal muscular atrophy" refers to Kugelberg-Welander syndrome.^[3]

Symptoms

In all of its forms, the primary feature of SMA is muscle weakness, accompanied by atrophy of muscle. This is the result of denervation, or loss of the signal to contract, that is transmitted from the spinal cord. This is normally transmitted from motor neurons in the spinal cord to muscle via the motor neuron's axon, but either the motor neuron with its axon, or the axon itself, is lost in all forms of SMA.

The features of SMA are strongly related to its severity and age of onset. SMA caused by mutation of the SMN gene has a wide range, from infancy to adult, fatal to trivial, with different affected individuals manifesting every shade of impairment between these two extremes. Many of the symptoms of SMA relate to secondary complications of muscle weakness, and as such can be at least partially remediated by prospective therapy.

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

• muscle weakness
• poor muscle tone
• weak cry
• weak cough
• limpness or a tendency to flop
• difficulty sucking or swallowing
• accumulation of secretions in the lungs or throat
• bell-shaped torso, caused by breathing using muscles around the abdominal area
• clenched fists with sweaty hands
• flickering/vibrating of the tongue
• head often tilted to one side, even when lying down
• legs that tend to be weaker than the arms
• legs lying in the "frogs leg" position
• hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells
• feeding difficulties
• increased susceptibility to respiratory tract infections
• bowel/bladder weakness
• lower-than-normal weight
• developmental milestones, such as lifting the head or sitting up, can't be reached

Diagnosis

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 EMG electromyography (EMG) or muscle biopsy may be indicated.

Types

Caused by mutation of the SMN1 gene

Main article: Survival motor neuron spinal muscular atrophy

The most common form of SMA is caused by mutations of the SMN gene, and manifests over a wide range of severity affecting infants through adults. The SMN gene is found on chromosome 5, and the affected SMN gene is called SMN1.

SMA Caused by mutation of other genes

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, that is, muscle weakens because muscle fibers lose the connection from the spinal cord that communicates when to contract.

Name	OMIM	Gene	Locus
Hereditary Bulbo-Spinal SMA Kennedy's disease, "SMAX1"	313200	Androgen receptor	Xq11-q12
X-linked spinal muscular atrophy 2, "SMAX2"	301830	UBE1[4]	Xp11.23
Spinal Muscular Atrophy with Respiratory Distress (SMARD 1) or Autosomal recessive distal spinal muscular atrophy 1 "DSMA1"	604320	IGHMBP2	11q13.3
Distal SMA with upper limb predominance or "HMN5"	600794	glycyl tRNA synthase	7p15

Related conditions

Spinal muscular atrophy only affects motor nerves. The term spinal muscular atrophy thus refers to atrophy of muscles due to loss of motor neurons within the spinal cord.

By contrast, 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 and sensory neuropathy (HMSN).

Treatment

Individuals with SMA are living longer and fuller lives with the help of assistive technology such as ventilators, power wheelchairs, and modified access to computers. These mitigate the effects of SMA upon the individuals' daily lives, allowing them to participate in the community like everyone else.

Ventilation is especially important. 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. Scoliosis is a common secondary complication and occurs due to contractures. This can create respiratory problems due to intercostal muscle involvement. Individuals may benefit from manual or mechanical percussion techniques (done over the lobes of the lungs) and postural drainage which can help facilitate airway clearance.^[5] 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.

Due to molecular biology, there is a better understanding of SMA. Many experimental treatments are being tested, including gene replacement, stem-cell replacement of motor neurons, and most promising therapies intended to increase the expression of the SMN 2 gene or increase the percentage of mRNA transcript from SMN 2 that is spliced to the full length form. Other potential therapies are directed to drugs that might enhance residual SMN function, or compensate for its loss. 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
• Quinazoline495^[6]

Other compounds have been identified that increase SMN gene expression or the percentage of full length SMN transcript spliced from SMN2. These compounds are undergoing further pre-clinical development prior to beginning clinical trials.

Presently, treatment for SMA consists of prevention and management of the secondary effect of chronic motor unit loss. Given that much of the mortality is caused by treatable complications, this is important and may be, even in the long run, as important to maintaining overall function as specific treatment of SMN levels.

Adults with SMA

Although SMA can result in death during childhood, many 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. The slowing of the rate of degeneration has a major influence on survival overall, and even some individuals diagnosed with type-1 SMA can survive to adulthood. Intellectual ability is unaffected by SMA. Many children and adults with SMA benefit greatly from the use of assistive technology, such as speech recognition or Switch Access software. Upper limb function may be improved by use of a gravity balanced upper limb exoskeleton.^[7] Such devices allow people with even very limited mobility to use a computer to read, write, communicate, play video games, and access environmental controls. Sexual response and reproductive functions are also unaffected by SMA; individuals with SMA can enjoy active sex lives and have given birth to children.

'Baby MB' Case

On March 15, 2006, the High Court of Justice of England and Wales ruled that 17 month old "Baby MB" (identity withheld) was to be kept alive, contrary to 14 medical professionals' advice - one of the medics 'Dr. S' stating "I think that the cumulative effect of the condition's effects is that he has an intolerable life".^[8] The judge said that "he felt the child gained enough pleasure from life to outweigh the medical evidence of his condition".^[9][10] Baby MB died nine months later, in December 2006.^[11]

SMA Treatment Acceleration Act

In 2007, the SMA Treatment Acceleration Act was introduced in the United States Congress "to authorize the Secretary of Health and Human Services to conduct activities to rapidly advance treatments for spinal muscular atrophy, neuromuscular disease, and other pediatric diseases, and for other purposes." It is currently in committee in the 111th Congress.

See also

• Polyneuropathy in dogs and cats
• 3'-Cluster
• Gideon Dreyfuss
• This American Life, Season II Episode I List of This American Life (TV series) episodes#Season two (2008)

References

1. ^ "spinal muscular atrophy" at Dorland's Medical Dictionary
2. ^ Kostova FV, Williams VC, Heemskerk J, et al. (August 2007). "Spinal muscular atrophy: classification, diagnosis, management, pathogenesis, and future research directions". J. Child Neurol. 22 (8): 926–45. doi:10.1177/0883073807305662. PMID 17761647. http://jcn.sagepub.com/cgi/pmidlookup?view=long&pmid=17761647. 
3. ^ "juvenile spinal muscular atrophy" at Dorland's Medical Dictionary
4. ^ Years-Long Search Unlocks Deadly Genetic Disease
5. ^ Goodman, C.C; Glanzman, A. & Miedaner J. (2003). "22". In Goodman, Fuller & Boissonnault. Pathology: Implications for the Physical therapist (2nd ed.). Philedelphia: Saunders. pp. 829–867. ISBN 978-0-7216-9233-3. 
6. ^ Families of Spinal Muscular Atrophy Receives FDA Orphan Drug Designation For Quinazoline495 For The Treatment of Spinal Muscular Atrophy.
7. ^ http://www.rehab.research.va.gov/jour/06/43/5/pdf/rahman.pdf
8. ^ "Life of sick baby 'intolerable'". BBC News. March 7, 2006. http://news.bbc.co.uk/1/hi/health/4770154.stm. Retrieved May 23, 2010. 
9. ^ BBC News: Sick baby's family thanks judge
10. ^ BBC News: Specialists' reactions
11. ^ BBC News: 'I'm glad we prolonged our sick son's life'

External links

• Spinal muscular atrophy at the Open Directory Project
• SMA Foundation