Quote: "The different subtypes, SMA 0-4, are based on the age of onset of symptoms and the course and progression of the disease."
Spinal muscular atrophies (SMA's) are characterized by degeneration of nerve cells or, 'motor nuclei,' within the lowest region of a person's brain and certain motor neurons in the person's spinal cord leading to muscle weakness of the truncal and extremity muscles initially. What follows are difficulties with chewing, swallowing and breathing. Motor neurons are nerve cells that transmit nerve impulses from a person's spinal cord or brain to muscle and glandular tissue.
Spinal muscular atrophies (SMAs) are defined as a genetically and clinically heterogeneous group of rare debilitating disorders characterized by the degeneration of lower motor neurons (neuronal cells situated in the anterior horn of spinal cord) and subsequent atrophy (wasting) of various muscle groups in the body. While some SMAs lead to early infant death, other types permit normal adult life with only mild weakness.
Around 80% of people with SMA fall into the severe category with Werdnig-Hoffman disease or SMA1. Infants with SMA1 experience severe weakness before they reach the age of 6 months and never gain the ability to sit independently. Muscle weakness, poor muscle tone and lack of motor development are the major clinical manifestations of SMA1. Infants with the gravest prognosis have issues with sucking or swallowing. Some infants show abdominal breathing in the first few months of their lives.
Abdominal breathing is noted when the abdomen protrudes during inspiration. Usually, the chest expands during inspiration as the intercostal muscles expand during inspiration. Unusual breathing happens when the intercostal muscles are weak and the diaphragm muscle is responsible for inspiration. Movement of the person's diaphragm expands causing the abdomen to move during the inspiration cycle. Twitching of the tongue is often seen. Cognitive development is average. Most children with SMA1 die before the age of 2, yet survival might be dependent on the degree of respiratory function and respiratory support.
The different subtypes, SMA 0-4, are based on the age of onset of symptoms and the course and progression of the disease. SMA represents a spectrum or continuum of disease with a mild end and a severe end. People with SMA0 are very weak at the time they are born and need immediate artificial ventilation; they will never breathe independently. Werdnig-Hoffman disease, also known as, 'spinal muscular atrophy type 1,' or, 'SMA1,' or, 'acute spinal muscular atrophy,' refers to people who have symptoms before the age of 6 months. People with SMA2 show symptoms before the age of 1 and will sit but never walk. People with SMA3 show symptoms after 1 year of age and will walk for a period of time prior to losing motor abilities. People with SMA4 will not develop symptoms before the age of 10.
All of the SMA's are inherited as an autosomal recessive trait. Molecular genetic testing has shown that all types of autosomal recessive SMA's are caused by errors or disruptions in the SMN1 gene on chromosome 5.
The symptoms and progression of Werdnig-Hoffman disease or SMA1 vary among people who are affected. Infants who are affected are weak before the age of 6 months. The early signs include:
The muscles in an affected person's face are not initially affected. Mental development is usually average. Typically, an affected child does not gain head control, is unable to sit or stand and cannot turn over. Children with SMA might develop difficulties with sucking, swallowing and breathing. They have an increased susceptibility to respiratory infections, or develop complications that may lead to potentially life-threatening abnormalities within the first months or years of life.
For infants who seem to have average development for several months before the onset of muscle weakness, the disorder might tend to have a more slowly progressive course. Muscles of the lower extremities seem to be disproportionately affected. As the disease progresses, diminished muscle tone and weakness might gradually spread to affect nearly all voluntary muscles, with the exception of certain muscles controlling eye movement.
The rate of progression of Werdnig-Hoffman disease varies. Within a few months, breathing and bowel difficulties might develop. An affected infant might not be able to swallow. Respiratory failure may happen, or food inhaled into their lungs may cause choking. The majority of affected children die prior to the age of 2, yet survival may be dependent on the degree of their respiratory function.
All forms of spinal muscular atrophy (SMA) are caused by mutations in the SMN1 gene at chromosomal locus 5q11-q13. A second gene known as the SMN2 gene plays a role in the development of SMA. The SMN2 gene is next to the SMN1 gene on chromosome 5. While the mutations of the SMN1 cause SMA, evidence has been developed that SMN2 influences severity of the disease. People with more copies of the SMN2 gene tend to experience a milder form of SMA.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each person. Human body cells usually have 46 chromosomes. Pairs of human chromosomes are numbered from 1 to 22 and the gender chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated, 'p,' and a long arm designated as, 'q.' Chromosomes are further sub-divided into a number of bands that are numbered. For example; 'chromosomal locus 5q11-q13,' refers to band 11-13 on the long arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the person's mother and father. All SMA's are inherited in an autosomal recessive manner. Recessive genetic disorders happen when a person inherits the same abnormal gene for the same trait from each of their parents. If a person receives one average gene and one gene for the disease, they will be a carrier of the disease but usually do not present with symptoms. The risk for two carrier parents to both pass the defective gene and have a child who is affected is 25% for each pregnancy. The chance for a child to receive average genes from both parents and be genetically average for that particular trait is also 25%. The risk is the same for both females and males.
Parents of a number of people with Werdnig-Hoffman disease have been closely related by blood. All people carry 4-5 abnormal genes. Parents who are consanguineous have a greater chance than unrelated parents to both carry the same abnormal gene, which increases the risk of having children with a recessive genetic disorder.
The specific underlying cause of Werdnig-Hoffman disease remains unknown. With SMA, it appears that the SMN1 and SMN2 genes produce a protein that is essential for the appropriate function of motor neurons. Mutation of the SMN1 causes the gene to produce a defective protein that is unable to perform its intended function. It is believed that SMN2 gene produces a partially-effective protein required by motor neurons to function; this is the reason why people with more copies of SMN2 have a milder form of SMA.
More genes might influence the development of SMA. Deletion of the NAIP (neuronal apoptosis inhibitory protein) gene that is close to the SMN gene might also be associated with SMA. More people with Werdnig-Hoffman than other types of SMA have NAIP deletions. Some researchers suggest a loss of the NAIP gene and/or different mutations of the SMN gene might have a role in affecting the severity of the disorder. Some investigators also indicate that additional genetic factors might contribute to the variable clinical expression of the disorder.
A diagnosis of SMA might be suspected based on a detailed history of the person, a thorough clinical examination and identification of characteristic findings. A diagnosis may be confirmed through molecular genetic testing, something that may determine whether a mutation is present in the SMN gene. SMA is caused by a complete or partial loss of the SMN gene and around 95% of people affected will show a deletion of, 'exon 7, in one copy of the SMN gene and a different mutation in the other copy of the SMN gene.
Before the availability of molecular testing, electromyogram testing and microscopic study of samples of affected muscle tissue were used to achieve a diagnosis. The tests are no longer needed unless SMN gene testing presents as average. Carrier testing for SMA is a molecular genetic test in which the number of copies of the SMN gene in which exons 7 and 8 are present is determined.
There is no cure for infants with Werdnig-Hoffman disease. Treatment is aimed at the particular symptoms that are present in each person. Treatment might require a team of medical specialists.
Feeding Difficulties: Difficulties with feeding might cause nutritional concerns and may require a, 'gastrostomy,' which is a procedure in which a feeding tube is inserted directly into the person's stomach through a surgical opening.
Breathing Function: Breathing function declines in people with Werdnig-Hoffman disease. Treatment options range from offering no respiratory support to using non-invasive procedures or long-term invasive ones such as a tracheotomy. A tracheotomy is a procedure in which a tube is inserted through a surgical opening in the person's trachea. A non-invasive option is intermittent positive pressure ventilation (NIPPV), in which the person's breathing is mechanically assisted without the creation of an artificial airway. The specific treatment for the life-threatening respiratory complications of Werdnig-Hoffman disease (SMA1) remains controversial. Any decisions for treatment need to be made following consultation between the person's parents and the entire medical team. Treatment decisions need to be made on an individual basis.
Occupational and Physical Therapy: Occupational and physical therapy is helpful in minimizing contractures and helps the person or their caretakers to develop compensatory strategies. Muscle strengthening is not a reason for therapy. Orthopedic devices such as braces, as well as surgery to correct scoliosis, might be necessary. Genetic counseling might be beneficial for those affected and their family members. Other treatment is symptomatic as well as supportive.
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