SMA is an autosomal recessive genetic disease. About 1 out of every 40 people are genetic carriers of the disease (meaning that they carry the mutated gene but do not have SMA). In order for a child to be affected by SMA, usually both parents are carriers of the abnormal gene and pass this gene on to their child. Thus the child has 2 abnormal copies of the gene, one from each parent, and this is termed a recessive genetic disease. When both parents are carriers, the possibility of a child inheriting the disorder is 1 in 4, or 25%, with each pregnancy.
SMA is caused by a missing or abnormal (mutated) gene known as survival motor neuron gene 1 (SMN1). In a healthy person, this gene produces a protein in the body called survival motor neuron (SMN) protein. In a person with mutated genes, this protein is absent or significantly decreased, and causes severe problems for motor neurons. Motor neurons are nerve cells in the spinal cord which send out nerve fibers to muscles throughout the body. Since SMN protein is critical to the survival and health of motor neurons, nerve cells may shrink and eventually die without this protein, resulting in muscle weakness. As a child with SMA grows, it is difficult for his/her weakened muscles to keep up with the demands of daily activities. The resulting weakness can also lead to bone and spine changes that may cause breathing problems and further loss of function.
There are four types of SMA: Type I, II, III, and IV. The determination of the type of SMA is based upon the physical milestones achieved. It is important to note that the course of the disease may be different for each affected individual. Although SMA is not generally regarded as a progressive disease, people affected with SMA typically lose function over time as muscles continue to weaken. Loss of function may occur gradually or more rapidly in the context of a growth spurt or illness. The reasons why muscle weakness and subsequent loss of function occur at different rates in different individuals remain poorly understood. It has been observed that individuals with SMA may be very stable in terms of their abilities for prolonged periods of time, often years, although the almost universal tendency is for continued loss of body function as they grow older.
SMA Type I is also called Werdnig-Hoffmann Disease. The diagnosis of children with this type is usually made before 6 months of age, depending on the severity of their disease. Usually children with SMA Type I have poor head control and are not able to accomplish developmentally-expected motor skills. The hallmark feature of SMA Type I is that children are unable to sit or stand without help. They will require equipment such as strollers or wheelchairs for mobility. Swallowing and feeding will become difficult for children with this type of SMA and they will eventually lose the ability to swallow safely without aspirating (choking or inhaling secretions and food particles into the lungs). Children may eventually require a feeding tube to supplement their nutrition which permits the administration of liquid food into their stomachs. Families have different opinions and can make personal decisions about whether to place a feeding tube or not. If families chose to have a feeding tube placed, they may choose to do so before swallowing becomes difficult, however the timing for this procedure is also an individual preference. Please see the booklet entitled Caring Choices for Families of Infants Newly Diagnosed with SMA Type I for more information on individual decision making. Children with SMA Type I will experience weakness of the muscles used for breathing, those that help expand the chest and fill the lungs with air. The chest is smaller than usual in these children and they begin to breathe using primarily their stomach muscles (belly breathing). The lungs do not fully develop due to this type of breathing, and coughing becomes very weak. It may be difficult for children to get enough air into their lungs while sleeping, and eventually throughout the day. Many of these children will require equipment to help them breathe; again this is based on what each family chooses. Weakness also leads to problems with the spine (scoliosis) and hips (displacement) that may lead to further loss of ability/function. Severe curvature of the spine can be treated with a brace and in some instances surgery. Bones become weak and may break easily, and several different therapeutic supports are available to help position children with SMA Type I comfortably.
The diagnosis of SMA Type II is almost always made before 2 years of age. Children with this type have delayed motor milestones and display a range of physical abilities. The hallmark feature of SMA Type II is the ability to maintain a seated position unsupported, however, some children may initially require assistance getting into that seated position. With assistance and bracing these children may be able to stand, but are unable to walk and require a wheelchair to get around. Children with SMA Type II usually do not have swallowing problems, but this can vary from child to child. Some children may have difficulty eating enough food by mouth to maintain their weight and grow, and a feeding tube may become necessary if the family decides this is best. Children with SMA Type II may also develop weakness of the muscles used for breathing and experience difficulty coughing. Some of these children may require equipment to help them breathe easier at night. Weakness also leads to problems with the spine (scoliosis) and hips (displacement) that may lead to further loss of function. Severe curvature of the spine can be treated with a brace and in many instances surgery. Bones become weak and may break easily, and a variety of therapeutic supports are available to help position children with SMA Type II comfortably.
SMA Type III is also known as Kugelberg-Welander Disease, or Juvenile Spinal Muscular Atrophy. It is typically diagnosed by 3 years of age, but can be diagnosed as late as the teenage years. The hallmark feature of SMA Type III is the ability to stand and walk independently. Affected individuals may have difficulty walking, running, and climbing stairs as they get older; some will lose the ability to walk independently in childhood, while others may remain ambulatory into adolescence or adulthood. Problems with the spine (scoliosis) may develop at various rates and ages. Swallowing and coughing difficulties, along with breathing difficulty at night, may occur but do so less commonly and later in the disease course than in SMA Type II. Children and adults with SMA Type III are at risk of becoming overweight, as they are not usually able to be extremely physically active. Fine shaking of the fingers and hands (tremors) can be seen in this type of SMA, and symptoms of joint aches and overuse frequently occur. Curvature of the spine may occur and can be treated with a brace and in some instances surgery. As in SMA Type II, bones become weak and may break easily, and a variety of therapeutic supports are available to help position individuals with SMA Type III comfortably and maintain mobility.
Type IV (Adult Onset)
In the adult form of SMA, mild to moderate symptoms usually begin in the second or third decade of life, typically after the age of 35, although they may occur as early as 18 in some cases. Adult onset SMA is much less common than the other forms. It is typically characterized by mild motor impairment such as muscle weakness, tremor, and twitching, with or without respiratory problems. Weakness is gradual and the muscles used for swallowing and breathing are rarely affected in Type IV. Life expectancy is normal and therapeutic supports are available to help maintain optimal function for individuals with SMA Type IV.
Other Rare Forms of SMA with Different Genetic Causes
SMARD is very rare and has been identified as a variant of SMA Type I. Children with this type of SMA present similarly to infants with SMA Type I and the diagnosis is usually made very early on in life, if at all. Infants with SMARD experience symptoms of severe respiratory distress due to extreme weakness in the muscles used for breathing; the arms and nearby muscles are affected more than other muscles. SMARD differs from SMA Type I in that the upper spinal cord is affected more than the lower spinal cord. The specific location of the genetic mutation for SMARD has been identified on gene IGHMBP2 and thus it can be determined through genetic testing when infants/children show signs of SMARD.
Spinal Muscular Atrophy Type V/Distal Hereditary Motor Neuropathy
SMA Type V is very rare and only a few cases have been reported. It is an autosomal dominant genetic disease, meaning that only one copy of the abnormal gene needs to be present (from one parent) for the disease to occur, and it is caused by mutations in the BSCL2 and GARS genes. Type V affects nerve cells in the spinal cord, and muscle weakness occurs in the hands and feet only. The defining characteristic, which usually occurs first and may be brought on by exposure to cold temperatures, is cramps or weakness and wasting of the muscles of the hand, specifically on the thumb side of the index finger and in the palm at the base of the thumb. A high arch of the foot (pes cavus) is also common and some individuals may develop trouble walking (gait abnormalities). Symptoms usually begin during adolescence, but may occur from infancy through the mid-thirties. People with this disorder have normal life expectancies.
Kennedy’s Disease is a rare form of SMA that affects only males. It is an X-linked autosomal recessive disease (the mother carries the defective gene on one of her X chromosomes); each male child born to a mother with the defective gene has a 50% chance of having the disease, and daughters born have a 50% chance of being a carrier of the disease. Early symptoms include slight shaking (tremor) of the outstretched hands, muscle cramps with exertion, and muscle twitching visible under the skin (fasiculations). Limb weakness usually begins in the shoulder or pelvic region, and may eventually spread to the facial and tongue muscles leading to difficulty swallowing (dysphagia), difficulty speaking (dysarthria), and aspiration pneumonia. Individuals with Kennedy’s Disease may require a wheelchair during later stages of the disease. Some males may experience breast enlargement (gynecomastia), low sperm count/infertility, and/or non-insulin-dependent diabetes mellitus. Disease onset usually occurs between the ages of 20 and 40, although it has been diagnosed from adolescence up to age 70. People with this disorder have normal life expectancies.
Individuals have two genes called Survival Motor Neuron (SMN) 1 and 2. Researchers have identified the SMN1 gene as the primary producer of the SMN protein. In approximately 95% of patients with SMA, the SMN1 gene is missing, and in some cases, the SMN1 gene may be present but is altered, abnormal, or somehow damaged. The SMN2 gene is similar to SMN1, but does not produce as much SMN protein, or the right kind of protein, as the SMN1 gene. The presence of SMN2 is necessary for survival (as individuals cannot live without either SMN1 or SMN2) and is sometimes referred to as the “rescue gene.” Genetic testing looks at genetic material in a patient’s blood sample to determine if the SMN1 gene is missing or damaged, thereby confirming the diagnosis of SMA. Currently, more specific genetic testing can also be done to identify the number of copies of the SMN2 gene present, although this is not done routinely. Samples must be sent out to a specific diagnostic genetic laboratory for this kind of testing, if the neurologist thinks it is necessary. The numbers of copies of SMN2 an individual has is somewhat related to how severely that individual will be affected by SMA. Because the SMN1 gene is missing, the greater the number of SMN2 copies present, the more SMN protein is produced and the greater likelihood that more motor neurons will remain healthy and productive. Individuals with only 1 or 2 copies of the SMN2 gene will typically have the most severe expressions of the disease, whereas three or more copies of the SMN2 gene will typically mean a less severe expression. It must be noted, however, that the number of copies of SMN2 does not reliably predict what type of SMA an individual will have or how weak their muscles will become. Therefore, even after genetic testing results are reviewed by the SMA team, it is nearly impossible for any clinician to predict exactly how SMA will affect a given individual.
Please see the booklet entitled The Genetics of SMA for more information on genetics.
This figure illustrates the three types of SMN1 mutations: deletions, gene conversion of SMN1 to SMN2, and single nucleotide point mutations. (a) Xs indicate a deletion. A deletion removes part or all of the SMN1 gene. (b) In the case of gene conversion, the SMN1 gene has been converted to an SMN2-like gene (indicated by the nucleotide change to T). These two types of mutations (deletions and gene conversion events) are the most frequent types found in SMN1. About 95% of 5q-SMA patients have these two types of mutation, and these mutations are easily detected by the current diagnostic test for SMA as they both result in the loss of SMN1 exon 7. (c) Point mutations can also be found in the SMN1 gene, but at a much lower frequency than the other two types of mutations. Shown here are the locations of point mutations that have been found in the SMN1 gene. They are labeled A through T. About 5% of 5q-SMA patients have a deletion or gene conversion mutation on one chromosome and a point mutation on the other chromosome. An individual with this combination of mutations (point mutation with either a deletion or conversion mutation) will not be diagnosed as having SMA using the SMA diagnostic test as only one copy of the SMN1 gene is gone. Rather, this person will look like a carrier using the quantitative carrier test, even though they are symptomic for SMA.
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