| Spinal muscular atrophies | |
|---|---|
| Classification and external resources | |
Location of neurons affected in spinal muscular atrophies |
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| ICD-10 | G12 |
| MeSH | D009134 |
Spinal Muscular Atrophies are a genetically and clinically heterogeneous group of disorders characterized by degeneration and loss of anterior horn cells in the spinal cord, leading to degeneration of motor neurons,[1] [2] resulting in muscle weakness and atrophy. The clinical spectrum of spinal muscular atrophies ranges from early infant death to normal adult life with only mild weakness.
Patients often require comprehensive medical care involving multiple disciplines, including pediatric pulmonology, pediatric neurology, pediatric orthopedic surgery, lower extremity and spinal orthoses, pediatric critical care, and physical therapy, occupational therapy, respiratory therapy, and clinical nutrition.
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The most common among muscular atrophies, spinal muscular atrophy (SMA), is responsible for around 95% of cases and is caused by a mutation of the SMN1 gene on chromosome 5. Other muscular atrophies are caused by mutation of other genes, some known and others not yet defined. The following table gives an overview of the different muscular atrophies identified so far:
| Name | OMIM | Gene | Locus | Inheritance | Remarks |
|---|---|---|---|---|---|
| Spinal muscular atrophy (SMA) | (multiple) | SMN1 | 5q13 | Autosomal recessive | Affects primarily proximal muscles in people of all ages |
| Spinal muscular atrophy with respiratory distress type 1 (SMARD1) | 604320 | IGHMBP2 | 11q13.3 | Autosomal recessive | Affects primarily distal muscles in newborn boys |
| Spinal and bulbar muscular atrophy (SBMA, SMAX1, KD) | 313200 | NR3C4 | Xq11-q12 | X-linked recessive | "Kennedy's disease"; affects primarily boys |
| X-linked spinal muscular atrophy type 2 (SMAX2, XLSMA) | 301830 | UBE1 | Xp11.23 | X-linked recessive | Affects newborn boys |
| X-linked spinal muscular atrophy type 3 (SMAX3, DSMAX) | 300489 | ATP7A | Xq21.1 | X-linked recessive | Affects distal muscles of all extremities in children, slowly progressive |
| Autosomal dominant proximal spinal muscular atrophy (ADSMA) | 182980 | VAPB | 20q13.32 | Autosomal dominant | "Finkel-type spinal muscular atrophy"; affects proximal muscles in adults |
| Spinal muscular atrophy with lower extremity predominance (SMA-LED) | 158600 | Unknown | 14q32 | Autosomal dominant | Affects proximal muscles in infants, rare |
| Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH) | VRK1 | 14q32 | Unknown | Affects infants, very rare | |
| Spinal muscular atrophy with congenital bone fractures (SMA-CBF) | 271225 | Unknown | Unknown | Autosomal recessive (?) | Affects infants, extremely rare |
| Segmental spinal muscular atrophy | 183020 | (multiple) | 18q21.3 | Unknown | Affects primarily hands, non-progressive, rare |
| Scapuloperoneal spinal muscular atrophy (SPSMA) | 181405 | TRPV4 | 12q24.11 | Autosomal dominant or X-linked dominant |
"Scapuloperoneal hereditary motor neuropathy"; very rare |
The common feature of all forms of muscular atrophy is muscle wasting (atrophy) caused by their lack of movement, which in turn is caused by the death of motor neurons in the anterior horn of spinal cord. Only motor neurons are affected; sensory neurons, which are located at the posterior horn of spinal cord, are not affected. By contrast, hereditary disorders that cause both weakness due to motor denervation along with sensory impairment due to sensory denervation are known as hereditary motor and sensory neuropathies (HMSN).
Hereditary motor neuropathies (HMN) are a class of HMSN which involve death of motor neurons and consequent motor impairment. Several conditions affecting distal muscles are variously classified either as distal spinal muscular atrophies or distal hereditary motor neuropathies.
In all of its forms, the primary feature 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 spinal muscular atrophies.
The symptoms are strongly related to the age of onset and the exact disease (see above). Spinal muscular atrophies caused by mutation of the SMN1 gene have a wide range, from infancy to adult, fatal to trivial, with different affected individuals manifesting every shade of impairment between these two extremes. Other muscular atrophies have a different and often very severe course. However, in all cases the majority of symptoms are a consequence of muscle weakness.
The most common symptoms - which may or may not be characteristic of all the variations of muscular atrophies - include:
While the presence of several symptoms may point towards a genetic disorder of the spinal muscular atrophy group, the actual disease type can only be established by genetic testing which detects the underlying genetic mutation.
Although some forms of muscular atrophy can result in childhood death, many patients survive into adulthood and even old age. Actual lifespan depends greatly on the severity of the disease in each individual. The slowing of the rate of degeneration has a major influence on survival overall. Intellectual ability is unaffected by muscular atrophies. Many children and adults with muscular atrophies 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.[3] Such devices allow people with even very limited mobility to use a computer to read, write, communicate, play video games, and access environmental controls.
Ventilation is especially important. The course of muscular atrophy is directly related to the severity of weakness. Infants with the severe form of spinal muscular atrophy 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.[4] Children with milder forms of muscular atrophy naturally live much longer, although they may need extensive medical support, especially those at the more severe end of the spectrum.
Sexual response and reproductive functions are unaffected by muscular atrophy; patients can enjoy active sex lives and have given birth to children.
For emerging therapies, see articles on individual diseases.
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".[5] The judge said that "he felt the child gained enough pleasure from life to outweigh the medical evidence of his condition".[6][7] Baby MB died nine months later, in December 2006.[8]
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.
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