GAD antibody-spectrum disorders
Dec. 15, 2021
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What is spinal muscular atrophy?
Spinal muscular atrophy (SMA) is a group of hereditary diseases that progressively destroys motor neurons—nerve cells in the brain stem and spinal cord that control essential skeletal muscle activity such as speaking, walking, breathing, and swallowing, leading to muscle weakness and atrophy. Motor neurons control movement in the arms, legs, chest, face, throat, and tongue. When there are disruptions in the signals between motor neurons and muscles, the muscles gradually weaken, begin wasting away and develop twitching (called fasciculations).
What causes spinal muscular atrophy?
The most common form of SMA is caused by defects in both copies of the survival motor neuron 1 gene (SMN1) on chromosome 5q. This gene produces the survival motor neuron (SMN) protein which maintains the health and normal function of motor neurons. Individuals with SMA have insufficient levels of the SMN protein, which leads to loss of motor neurons in the spinal cord, producing weakness and wasting of the skeletal muscles. This weakness is often more severe in the trunk and upper leg and arm muscles than in muscles of the hands and feet.
There are many types of spinal muscular atrophy that are caused by changes in the same genes. Less common forms of SMA are caused by mutations in other genes including the VAPB gene located on chromosome 20, the DYNC1H1 gene on chromosome 14, the BICD2 gene on chromosome 9, and the UBA1 gene on the X chromosome. The types differ in age of onset and severity of muscle weakness; however, there is overlap between the types.
How is it inherited?
Except in the rare cases caused by mutations in the UBA1 gene, SMA is inherited in an autosomal recessive manner, meaning that the affected individual has two mutated genes, often inheriting one from each parent. Those who carry only one mutated gene are carriers of the disease without having any symptoms. Autosomal recessive diseases may affect more than one person in the same generation (siblings or cousins).
What are the types of SMA?
There is a wide range of impairment seen in SMA caused by defects in the SMN1 gene, from onset before birth with breathing difficulties at birth to mild weakness in adults. Accordingly, this most common form of SMA can be classified into four types, based on highest motor milestone achieved.
How is SMA diagnosed?
A blood test is available to look for deletions or mutations of the SMN1 gene. This test identifies at least 95 percent of SMA Types I, II, and III and may also reveal if a person is a carrier of a defective gene that could be passed on to children. If the SMN1 gene is not found to be abnormal or the individual’s history and examination are not typical of SMA, other diagnostic tests may include electromyography (which records the electrical activity of the muscles during contraction and at rest), nerve conduction velocity studies (which measure the nerve’s ability to send an electrical signal), muscle biopsy (used to diagnose many neuromuscular disorders), and other blood tests.
Are there treatments for SMA?
There is no complete cure for SMA. Treatment consists of managing the symptoms and preventing complications.
In December 2016 the U.S. Food and Drug Administration approved nusinersen (Spinraza™) as the first drug approved to treat children and adults with SMA. The drug is administered by injection into the fluid surrounding the spinal cord. It is designed to increase production of the full-length SMN protein, which is critical for the maintenance of motor neurons. The benefit is best documented in infants and children, particularly when started early. Several other therapies are in late stages of development and may become available to affected individuals in the near future.
In May 2019, the FDA approved onasemnogene abeparovec-xioi (Zolgensma ™) gene therapy for children less than 2 years old who have infantile-onset SMA. A safe virus delivers a fully functional human SMN gene to the targeted motor neurons, which in turn improves muscle movement and function, and also improves survival.
Physical therapy, occupational therapy, and rehabilitation may help to improve posture, prevent joint immobility, and slow muscle weakness and atrophy. Stretching and strengthening exercises may help reduce contractures, increase range of motion, and keeps circulation flowing. Some individuals require additional therapy for speech and swallowing difficulties. Assistive devices such as supports or braces, orthotics, speech synthesizers, and wheelchairs may be helpful to improve functional independence.
Proper nutrition and calories are essential to maintaining weight and strength, while avoiding prolonged fasting. People who cannot chew or swallow may require insertion of a feeding tube. Non-invasive ventilation at night can improve breathing during sleep, and some individuals also may require assisted ventilation during the day due to muscle weakness in the neck, throat, and chest.
What is the prognosis?
Prognosis varies depending on the type of SMA. Some forms of SMA are fatal without treatment.
People with SMA may appear to be stable for long periods, but improvement should not be expected without treatment.
What research is being done?
The National Institute of Neurological Disorders and Stroke (NINDS), a component of the National Institutes of Health (NIH), conducts basic, translational, and clinical research on SMA in laboratories at the NIH and also supports research through grants to major medical institutions across the country.
Cellular and molecular studies seek to understand the mechanisms that trigger motor neurons to degenerate.
Scientists have analyzed human tissue and developed a broad range of model systems in animals and cells to investigate disease processes and expedite the testing of potential therapies. Among these efforts:
NIH-supported scientists have collected longitudinal data on pre-symptomatic or recently diagnosed children with SMA types 1, 2, or 3 and their healthy siblings. The goal of this study is to provide counselling and education to the parents about possible clinical trial opportunities.
NINDS established the NeuroNext (NINDS Network for Excellence in Neuroscience Clinical Trials) clinical trials network to promote the rapid development and implementation of trials for neurological disorders that affect adults and/or children. Among its goals, the network is designed to develop early-phase trials aimed at identifying biomarkers—usually a physical trait or substance in the blood or other bodily fluids that can be measured to determine the presence and severity of a disease—and testing promising, emerging therapies. One project was to identify biomarkers for SMA and to understand the cause and mechanisms underlying the disease. The natural history data obtained through this study led to the approval decision for nusinersen. Knowledge gained from this study has enhanced the design of additional clinical trials in SMA.
Where can I get more information?
For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute's Brain Resources and Information Network (BRAIN) at:
P.O. Box 5801
Bethesda, MD 20824
Information also is available from the following organizations:
925 Busse Road
Elk Grove Village, IL 60007
Spinal Muscular Atrophy Foundation
126 East 56th Street
New York, NY 10022
Muscular Dystrophy Association
161 N. Clarke,
Chicago, IL 60601
"Spinal Muscular Atrophy Fact Sheet", NINDS, Publication date May 2019. NIH Publication No. 19-NS-5597.
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National Institute of Neurological Disorders and Stroke
National Institutes of Health
Bethesda, MD 20892
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