SNP Shot: Genomic Insights

Spinal muscular atrophy (SMA) is a genetic disease causing muscle weakness and wasting (atrophy), primarily affecting skeletal muscles used for movement. This occurs because motor neurons, specialized nerve cells that control muscle movement, are lost. Typically, muscles closer to the body's center (proximal) are more severely affected than those further away (distal). The muscle weakness usually progresses over time. Different types of SMA exist, all stemming from alterations in the same genes, and are classified by the age of onset and severity of muscle weakness. However, there can be overlap in symptoms between types. Rarer forms of SMA and similar motor neuron disorders, like spinal muscular atrophy with progressive myoclonic epilepsy, spinal muscular atrophy with lower extremity predominance, X-linked infantile spinal muscular atrophy, and spinal muscular atrophy with respiratory distress type 1, are caused by mutations in different genes.

SMA type 0, the rarest and most severe form, is apparent before birth. Babies with this condition move less in the womb, leading to joint deformities (contractures) at birth. They exhibit extremely weak muscle tone (hypotonia). Their respiratory muscles are severely compromised, often leading to respiratory failure and death in infancy. Some infants with SMA type 0 may also have congenital heart defects.

SMA type I, also known as Werdnig-Hoffmann disease, is the most common type. It's a severe form where muscle weakness is noticeable at birth or within the first few months of life. Affected children often struggle to control their head movements or sit without support. Swallowing difficulties can lead to feeding problems and poor growth. Respiratory problems arise due to weak respiratory muscles and an abnormally bell-shaped chest, hindering full lung expansion. Most children with SMA type I don't survive past early childhood due to respiratory failure.

SMA type II, also called Dubowitz disease, is characterized by muscle weakness that appears between 6 and 12 months of age. Children with this type can sit without support, although they may need assistance getting into that position. As the muscle weakness progresses, they may require support even to sit. Individuals with SMA type II cannot stand or walk independently. They frequently experience involuntary tremors in their fingers, a curved spine (scoliosis), and respiratory muscle weakness that can be life-threatening. The lifespan of individuals with SMA type II varies, but many live into their twenties or thirties.

SMA type III, also known as Kugelberg-Welander disease, typically causes muscle weakness after early childhood. Individuals with this type can stand and walk without assistance, but walking and climbing stairs may become increasingly difficult over time. Many require wheelchair assistance later in life. People with SMA type III generally have a normal life expectancy.

SMA type IV is rare and usually begins in early adulthood. Affected individuals typically experience mild to moderate muscle weakness, tremors, and mild breathing difficulties. People with SMA type IV have a normal life expectancy.

Inheritance:

SMA is inherited in an autosomal recessive manner. This means that both copies of the SMN1 gene in each cell must have mutations for the condition to develop. Usually, both parents of an individual with SMA carry one copy of the mutated gene but do not show signs or symptoms of the condition. Rarely, an individual with SMA inherits an SMN1 gene mutation from one parent and develops a new mutation in the other copy of the gene during the formation of reproductive cells (eggs or sperm) or early embryonic development. In these cases, only one parent is a carrier. Individuals with more than the usual two copies of the SMN2 gene usually do not inherit the extra copies from a parent. They typically arise during a random error when making new copies of DNA (replication) in an egg or sperm cell or just after fertilization.