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 orthopaedic surgery, 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.

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 tummy area
• clenched fists with sweaty hands
• flickering/vibrating of the tongue
• head often tilted to one side, even when laying 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
• 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 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.

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.

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).

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

  • Females : Males

  759 : 776

  • Deceased : Living

  242 : 1,293

• Type of SMA (SMN-related)
  • Type 1: 489
  • Type 2: 511
  • Type 3: 315
  • Adult Onset: 35

• Kennedy Disease: 7
• Unknown : 176

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 anyone 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. 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^[5]

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. 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" ^[6]. The judge said that "he felt the child gained enough pleasure from life to outweigh the medical evidence of his condition" ^[7][8]. Baby MB died nine months later, in December 2006^[9].

See also

• Polyneuropathy in dogs and cats
• 3'-Cluster
• Gideon Dreyfuss

References

External links

The Ally Cadence Trust for Spinal Muscular Atrophy - http://www.actsma.co.uk - The Ally Cadence Trust is a non profit organisation in the UK, which provides both emotional and financial support to families affected by Spinal Muscular Atrophy. ACT for SMA also donate money to reseach into finding a cure for Spinal Muscular Atrophy.

Families of Spinal Muscular Atrophy, http://curesma.org, is dedicated to creating a treatment and cure by: Funding and advancing a comprehensive research program; Supporting SMA families through networking, information and services; Improving care for all SMA patients; Educating health professionals and the public about SMA; Enlisting government support for SMA; Embracing all touched by SMA in a caring community. Our vision is a world where Spinal Muscular Atrophy is treatable and curable. Families of SMA has created hope for the community that did not exist in 1984. FSMA has raised and funded over $50 million for SMA research. Support comes from generous individual donations and numerous fundraising events held by volunteer families and Chapters. Families of SMA funds and directs the leading SMA research programs. The successful results and progress from basic research to drug discovery programs to clinical trials provides real hope for families and patients FSMA is a non-profit, 501(c)3 tax exempt organization, with 27 Chapters throughout the United States and over 65,000 members and supporters. FSMA is a collaborative organization where families and friends and researchers are all working together towards the same goal.

Fight SMA, http://www.fightsma.org, is an international nonprofit organization dedicated to finding a treatment or cure for spinal muscular atrophy. Their website includes the web's leading SMA blog, the Spinal Muscular Atrophy Guidebook, and Fighting Back Podcast. Founded in 1991 by the parents of a child with SMA, the organization is made up of 19 chapters across the U.S. and Canada, and sponsors an annual conference in Washington D.C. that allows SMA families to receive updates on the disease and meet leading researchers.

Bipap for SMA, http://www.bipapforsma.com, is a resource for Parents and Carers trying to find Bipap and Cpap masks to fit small infants and children with Spinal Muscular Atrophy (type 1) and other conditions where Bipap is deemed appropriate. Very few masks are available for infants and this site aims to build a knowledge resource and has some other tips and tricks for the care of SMA infants.

• Spinal muscular atrophy at the Open Directory Project