Spinal muscular atrophy types 0, I, II, III and IV – SMN1 and SMN2 genes

Spinal muscular atrophy (SMA) is a genetic disease that affects voluntary musculature due to the loss of motor neurons in the spinal cord and medulla oblongata. Loss of motor neurons causes weakness and atrophy of the muscles involved in movements. In severe cases it can affect the respiratory musculature and swallowing. There are many types of SMA, differentiated according to the age of onset of muscle disorders and the intensity of muscle weakness.

• Spinal muscular atrophy type 0 (also called prenatal onset SMA) affects baby before birth and is the rarest and most serious form of SMA. Affected newborns present contractures, hypotonia and congenital heart defects. Frequently, they don’t survive after childhood due to respiratory failure associated to the weakness of the respiratory muscles.

• Spinal muscular atrophy type I or SMA1 (also called Werding-Hoffman disease)is a type of disorder that manifests at birth or in the first months of life. Affected children suffer from delays, most of them are unable to keep their head up or sit alone, and have breathing and swallowing difficulties, which can lead to choking.

• Spinal muscular atrophy type II or SMA2 (also called Dubowitz disease)manifests as a muscle weakness that develops in children between 6 and 12 months of age. These children may sit by themselves, although they may need help to maintain the position, and are unable to walk or stand up alone. Other common signs may include involuntary trembling of the fingers, scoliosis and respiratory muscle weakness.

• Spinal muscular atrophy type III or SMA3 (also called Kugelberg-Welander disease) is characterized by milder features that develop between childhood and adolescence. Affected individuals can stand and walk without help, although they have difficulty making some more complex movements, such as climbing stairs, and many of them will require a wheelchair later in life.

• Spinal atrophy type IV (SMA4) often arises after age 30. This atrophy affects the proximal musculature. Affected individuals usually have weakness of the muscles, tremors and mild respiratory difficulties.

All types of spinal muscular atrophy described above are due to mutations in the SMN1 gene (survival of motor neuron 1, telomeric), located on the long arm of chromosome 5 (5q13.2). Moreover, additional copies of the SMN2 gene (survival of motor neuron 2, centromeric), located on the long arm of chromosome 5 (5q13.2), modify the severity of SMA and determine the type of disease that is develops. Both genes, SMN1 and SMN2, are involved in the synthesis of SMN proteins in motor neurons. The most relevant part of SMN proteins is encoded by the SMN1 gene and, to a lesser extent, by the SMN2 gene. This last gene encodes several different versions of the SMN protein, but only one version is functional, while the other versions are smaller and decompose rapidly. This SMN protein is found throughout the body, its concentration in the spinal cord is high, and is particularly important for the maintenance of motor neurons in the spinal cord and the medulla oblongata. The SMN protein participates in synthesis of mRNA (specifically, pre-mRNA), which is involved in protein synthesis. On the other hand, this protein is also important for the development of axons and dendritic endings, components of neurons responsible for the transmission of nerve impulse between nerves and between nerves and musculature.

Many mutations in the SMN1 gene associated to spinal muscular atrophy have been described. Approximately 95% of individuals with SMA have mutations that suppress exon 7 in both copies of the SMN1 gene in each cell, so little SMN protein is produced. On the other hand, about 5% of the affected people manifest a deletion in exon 7 in one of the copies of the SMN1 gene in each cell, and the other copy of the gene has a different mutation that alters the coding or function of SMN protein. It is considered that a deficiency of SMN protein results in the death of motor neurons and, as a consequence, the signals are not transmitted between the brain and muscles. Therefore, muscles cannot contract without receiving signals from the brain, so many skeletal muscles weaken, leading to the signs and symptoms of SMA.

Usually, people have two copies of the SMN1 gene and one or two copies of the SMN2 gene in each cell. However, the number of copies of the SMN2 gene may vary even more depending on the individual, and some people have up to eight copies of this gene. In this way, people with spinal muscular atrophy type 0 generally have one or no copy of the SMN2 gene in each cell; those affected by type I usually have one or two copies; those with type II have three copies; those with type III have three or four copies; and in those with type IV four or more copies can be found. Multiple copies of the SMN2 gene are often associated with less serious features of SMA and develop at a later stage of life. Maybe the small amount of SMN protein produced by the SMN2 gene can compensate for protein deficiency due to mutations of the SMN1 gene. Other factors, many of them unknown, also contribute to the varying severity of the disease.

Spinal muscular atrophy is inherited with an autosomal recessive pattern, which means that both copies of the SMN1 gene in each cell have mutations. In most cases, the parents of an individual with an autosomal recessive disease carry a copy of the mutated gene, but usually don’t show signs and symptoms of the disease. There are rare cases in which a person with SMA inherits a mutation of the SMN1 gene from one progenitor, and acquires a new mutation in the other copy of the gene during the formation of reproductive cells or at the beginning of embryonic development. In these cases, only one of the parents is a carrier of the mutation of the SMN1 gene. People with more than usually two copies of the SMN2 gene generally do not inherit the additional copies of a parent, but arise from a random error when new copies of DNA are made in the reproductive cells or just after fertilization.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with spinal muscular atrophy types 0, I, II, III and IV, by means of the complete PCR amplification of the exons of the SMN1 and SMN2 genes, respectively, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).