Spinal muscular atrophy
Encyclopedia
Spinal Muscular Atrophy (SMA) is a neuromuscular disease characterized by degeneration of motor neuron
s, 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.http://www.fsma.org
The term "juvenile spinal muscular atrophy" refers to Kugelberg-Welander syndrome.
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:
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.
.
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).
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. 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:
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.
, such as speech recognition
or Switch Access
software. Upper limb function may be improved by use of a gravity balanced upper limb exoskeleton. 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.
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". The judge said that "he felt the child gained enough pleasure from life to outweigh the medical evidence of his condition". Baby MB died nine months later, in December 2006.
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.
Motor neuron
In vertebrates, the term motor neuron classically applies to neurons located in the central nervous system that project their axons outside the CNS and directly or indirectly control muscles...
s, 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.http://www.fsma.org
The term "juvenile spinal muscular atrophy" refers to Kugelberg-Welander syndrome.
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 weaknessMuscle weaknessMuscle weakness or myasthenia is a lack of muscle strength. The causes are many and can be divided into conditions that have true or perceived muscle weakness...
- poor muscle tone
- weak cry
- weak cough
- limpness or a tendency to flop
- difficulty sucking or swallowingSwallowingSwallowing, known scientifically as deglutition, is the process in the human or animal body that makes something pass from the mouth, to the pharynx, and into the esophagus, while shutting the epiglottis. If this fails and the object goes through the trachea, then choking or pulmonary aspiration...
- accumulation of secretionSecretionSecretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...
s 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 (arthrogryposisArthrogryposisArthrogryposis, also known as Arthrogryposis Multiplex Congenita, is a rare congenital disorder that is characterized by multiple joint contractures and can include muscle weakness and fibrosis. It is a non-progressive disease...
) associated with loss of anterior horn cells - feeding difficulties
- increased susceptibility to respiratory tract infectionRespiratory tract infectionRespiratory tract infection refers to any of a number of infectious diseases involving the respiratory tract. An infection of this type is normally further classified as an upper respiratory tract infection or a lower respiratory tract infection...
s - 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 SMN1SMN1
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,...
gene by looking for its unique sequences (that distinguish it from the almost identical 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...
) 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.
Caused by mutation of the SMN1 gene
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 SMN1SMN1
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,...
.
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 Locus (genetics) In the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map... |
|---|---|---|---|
| Hereditary Bulbo-Spinal SMA Kennedy's disease, "SMAX1" | Androgen receptor Androgen receptor The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus... |
Xq11-q12 X chromosome The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system... |
|
| X-linked spinal muscular atrophy 2 X-linked spinal muscular atrophy 2 X-linked spinal muscular atrophy 2 is a form of spinal muscular atrophy.It is similar to but distinguishable from Werdnig-Hoffmann disease. Typically it manifests at or before birth, which is unusual for SMN-SMA, and it only affects boys, where SMN-SMA affects both sexes equally.The "2" is used to... , "SMAX2" |
UBE1 UBE1 Ubiquitin-like modifier activating enzyme 1, also known as UBA1, is an enzyme which in humans is encoded by the UBA1 gene.- Function :... |
Xp11.23 X chromosome The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system... |
|
| Spinal Muscular Atrophy with Respiratory Distress (SMARD 1) or Autosomal recessive distal spinal muscular atrophy 1 Autosomal recessive distal spinal muscular atrophy 1 Autosomal recessive distal spinal muscular atrophy 1 is a form of spinal muscular atrophy.... "DSMA1" |
IGHMBP2 IGHMBP2 DNA-binding protein SMUBP-2 is a protein that in humans is encoded by the IGHMBP2 gene.-Further reading:... |
11q13.3 | |
| Distal SMA with upper limb predominance or "HMN5" | glycyl tRNA synthase | 7p15 Chromosome 7 (human) Chromosome 7 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 7 spans more than 158 million base pairs and represents between 5 and 5.5 percent of the total DNA in cells.Identifying genes on each chromosome is an active area of genetic... |
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
Hereditary motor and sensory neuropathy
Hereditary motor and sensory neuropathies are a group of neuropathies which are characterized by their impact upon both afferent and efferent neural communication.They are more common than hereditary sensory and autonomic neuropathies.-Types:...
(HMSN).
Treatment
Individuals with SMA are living longer and fuller lives with the help of assistive technologyAssistive technology
Assistive technology or adaptive technology is an umbrella term that includes assistive, adaptive, and rehabilitative devices for people with disabilities and also includes the process used in selecting, locating, and using them...
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
Scoliosis
Scoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...
is a common secondary complication and occurs due to contractures. This can create respiratory problems due to intercostal muscle
Intercostal muscle
Intercostal muscles are several groups of muscles that run between the ribs, and help form and move the chest wall. The intercostal muscles are mainly involved in the mechanical aspect of breathing...
involvement. Individuals may benefit from manual or mechanical percussion techniques (done over the lobes of the lungs) and postural drainage
Postural drainage
Drainage used in bronchiectasis and lung abscess. The patient's body is positioned so that the trachea is inclined downward and below the affected chest area . Postural drainage is essential in treating bronchiectasis and patients must receive physiotherapy to learn to tip themselves into a...
which can help facilitate airway clearance. 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
Molecular biology
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
, 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 acidValproic acidValproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
- HydroxyureaHydroxyureaHydroxycarbamide or hydroxyurea is an antineoplastic drug, first synthesized in 1869, used in myeloproliferative disorders, specifically polycythemia vera and essential thrombocythemia...
- RiluzoleRiluzoleRiluzole is a drug used to treat amyotrophic lateral sclerosis. It delays the onset of ventilator-dependence or tracheostomy in selected patients and may increase survival by approximately 3–5 months....
- Quinazoline495
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 technologyAssistive technology
Assistive technology or adaptive technology is an umbrella term that includes assistive, adaptive, and rehabilitative devices for people with disabilities and also includes the process used in selecting, locating, and using them...
, such as speech recognition
Speech recognition
Speech recognition converts spoken words to text. The term "voice recognition" is sometimes used to refer to recognition systems that must be trained to a particular speaker—as is the case for most desktop recognition software...
or Switch Access
Switch Access
Many people with severe physical or cognitive impairment use one or more switches to access computers. A switch is an assistive technology device that replaces the need to use a computer keyboard or a mouse.-Types of switch:...
software. Upper limb function may be improved by use of a gravity balanced upper limb exoskeleton. 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 JusticeHigh Court of Justice
The High Court of Justice is, together with the Court of Appeal and the Crown Court, one of the Senior Courts of England and Wales...
of England
England
England is a country that is part of the United Kingdom. It shares land borders with Scotland to the north and Wales to the west; the Irish Sea is to the north west, the Celtic Sea to the south west, with the North Sea to the east and the English Channel to the south separating it from continental...
and Wales
Wales
Wales is a country that is part of the United Kingdom and the island of Great Britain, bordered by England to its east and the Atlantic Ocean and Irish Sea to its west. It has a population of three million, and a total area of 20,779 km²...
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". The judge said that "he felt the child gained enough pleasure from life to outweigh the medical evidence of his condition". Baby MB died nine months later, in December 2006.
SMA Treatment Acceleration Act
In 2007, the SMA Treatment Acceleration ActSMA Treatment Acceleration Act
The SMA Treatment Acceleration Act is a bill originally introduced in 2007 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...
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 catsPolyneuropathy in dogs and catsPolyneuropathy in dogs and cats is a collection of peripheral nerve disorders that often are breed-related in these animals. Polyneuropathy indicates that multiple nerves are involved, unlike mononeuropathy. Polyneuropathy usually involves motor nerve dysfunction, also known as lower motor neuron...
- 3'-Cluster3'-ClusterA 3'-Cluster is a negative DNA sequence discovered by Singh and coworkers, using a technique known as in vivo selection of an entire exon.The presence of 3'-Clusters prohibit the SMN2 gene from producing its normal proteins which can lead to Spinal muscular atrophy...
- Gideon DreyfussGideon DreyfussDr. Gideon Dreyfuss is the Isaac Norris Professor Biochemistry and Biophysics at the University of Pennsylvania School of Medicine and a investigator of the Howard Hughes Medical Institute....
- This American Life, Season II Episode I List of This American Life (TV series) episodes#Season two (2008)