What is SMA?

Spinal Muscular Atrophy (SMA) is a motor neuron disease. The motor neurons affect the voluntary muscles that are used for activities such as crawling, walking, head and neck control, and swallowing. It is a relatively common "rare disorder": approximately 1 in 6000 babies born are affected, and about 1 in 40 people are genetic carriers.

SMA affects muscles throughout the body, although the proximal muscles (those closest to the trunk of one’s body - i.e. shoulders, hips, and back) are often most severely affected. Weakness in the legs is generally greater than in the arms. Sometimes feeding and swallowing can be affected. Involvement of respiratory muscles (muscles involved in breathing and coughing) can lead to an increased tendency for pneumonia and other lung problems. Sensation and the ability to feel are not affected. Intellectual activity is normal and it is often observed that patients with SMA are unusually bright and sociable. Patients are generally grouped into one of four categories, based on certain key motor function milestones.

 What Causes SMA?

 SMA is an autosomal recessive genetic disease. In order for a child to be affected by SMA, both parents must be carriers of the abnormal gene and both must pass this gene on to their child. Although both parents are carriers the likelihood of a child inheriting the disorder is 25%, or 1 in 4.

An individual with SMA has a missing or mutated gene (SMN1, or survival motor neuron 1) that produces a protein in the body called Survival Motor Neuron (SMN) protein. This protein deficiency has its most severe affect on 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, without this protein nerve cells may atrophy, shrink and eventually die, resulting in muscle weakness.

As a child with SMA grows their bodies are doubly stressed, first by the decrease in motor neurons and then by the increased demands on the nerve and muscle cells as their bodies grow larger. The resulting muscle atrophy can cause weakness and bone and spinal deformities that may lead to further loss of function, as well as additional compromise of the respiratory (breathing) system.

Types of SMA

Type I (Non-Sitters)

Werdnig-Hoffmann Disease

Type I SMA is also called Werdnig-Hoffmann Disease. The diagnosis of children with this type is usually made before 6 months of age and in the majority of cases the diagnosis is made before 3 months of age. Some mothers even note decreased movement in of the final months of their pregnancy.

Usually a child with Type I is never able to lift his/her head or accomplish the normal motor skills expected early on in infancy. They generally have poor head control, and may not kick their legs as vigorously as they should, or bear weight on their legs. They do not achieve the ability to sit up unsupported. Swallowing and feeding may be difficult and are usually affected at some point, and the child may show some difficulties managing their own secretions. The tongue may show atrophy, and rippling movements or fine tremors, also called fasciculations. There is weakness of the intercostal muscles (the muscles between the ribs) that help expand the chest, and the chest is often smaller than usual. The strongest breathing muscle in an SMA patient is the diaphragm. As a result, the patient appears to breath with their stomach muscles. The chest may appear concave (sunken in) due to the diaphragmatic (tummy) breathing. Also due to this type of breathing, the lungs may not fully develop, the cough is very weak, and it may be difficult to take deep enough breaths while sleeping to maintain normal oxygen and carbon dioxide levels.

Type II (Sitters)

The Diagnosis of Type II SMA is almost always made before 2 years of age, with the majority of cases diagnosed by 15 months. Children with this type may sit unsupported when placed in a seated position, although they are often unable to come to a sitting position without assistance. At some point they may be able to stand. This is accomplished with the aid of assistance or bracing and/or a parapodium/standing frame. Swallowing problems are not usually characteristic of Type II, but vary from child to child. Some patients may have difficulty eating enough food by mouth to maintain their weight and grow, and a feeding tube may become necessary. Children with Type II SMA frequently have tongue fasciculations and manifest a fine tremor in the outstretched fingers. Children with Type II also have weak intercostals muscles and are diaphragmatic breathers. They have difficulty coughing and may have difficulty taking deep enough breaths while they sleep to maintain normal oxygen levels and carbon dioxide levels. Scoliosis is almost uniformly present as these children grow, resulting in need for spinal surgery or bracing at some point in their clinical course. Decreased bone density can result in an increased susceptibility to fractures.

Type III (Walkers)

Kugelberg-Welander Disease

The diagnosis of Type III, often referred to as Kugelberg-Welander or Juvenile Spinal Muscular Atrophy, is much more variable in age of onset, and children can present from around a year of age or even as late as adolescence, although diagnosis prior to age 3 years is typical. The patient with Type III can stand alone and walk, but may show difficulty with walking at some point in their clinical course. Early motor milestones are often normal. However, once they begin walking, they may fall more frequently, have difficulty in getting up from sitting on the floor or a bent over position, and may be unable to run. With Type III, a fine tremor can be seen in the outstretched fingers but tongue fasciculations are seldom seen. Feeding or swallowing difficulties in childhood are very uncommon. Type III individuals can sometimes lose the ability to walk later in childhood, adolescence, or even adulthood, often in association with growth spurts or illness.

Type IV (Adult Onset)

In the adult form, symptoms typically begin after age 35. It is rare for Spinal Muscular Atrophy to begin between the ages of 18 and 30. Adult onset SMA is much less common than the other forms. It is defined as onset of weakness after 18 years of age, and most cases reported as type IV have occurred after age 35. It is typically characterized by insidious onset and very slow progression. The bulbar muscles, those muscles used for swallowing and respiratory function, are rarely affected in Type IV.

Patients with SMA typically lose function over time. Loss of function can occur rapidly in the context of a growth spurt or illness, or much more gradually. The explanation for this loss is unclear based on recent research. It has been observed that patients with SMA may often be very stable in terms of their functional abilities for prolonged periods of time, often years, although the almost universal tendency is for continued loss of function as they age.

Other Rare Forms of SMA with Different Genetic Causes

Spinal Muscular Atrophy Respiratory Distress (SMARD)

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.

SMA Carrier Illustration

Both parents are carriers

One parent is a carrier, the other does not have SMA and is a non-carrier

One parent has SMA, the other does not have SMA and is a non-carrier

One parent has SMA, the other is a carrier

Both parents have SMA

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

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.

For information on Kennedy's Disease, please see www.KennedysDisease.org.

A Closer Look at the Genetics of SMA

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.