Spinal muscular atrophy with lower extremity predominance (SMA-LED) is a rare type of spinal muscular atrophy (SMA), a group of neuromuscular disorders that causes the loss of motor neurons (nerve cells that control muscles). SMA-LED leads to muscle weakness, muscle atrophy (muscle wasting), and other symptoms affecting the lower limbs.
SMA-LED is a type of SMA that primarily affects the lower limbs, usually without affecting other parts of the body. SMA-LED is a progressive disease that develops slowly. It is usually diagnosed in infants and children, but it can also develop in adulthood.
The symptoms of SMA-LED vary in severity between people, but they always include muscle weakness and muscle atrophy in the lower extremities, most frequently in the thigh muscles (quadriceps). SMA-LED is an inherited disease and tends to run in families. Because it is such a rare disease, the prevalence of SMA-LED is unknown.
There are two types of SMA-LED. Each type is caused by mutations in a different gene: Type 1 SMA-LED (SMALED1) is caused by DYNC1H1 gene mutations, and type 2 SMA-LED (SMALED2) is caused by BICD2 gene mutations.
SMALED2 has two subtypes, SMALED2A (childhood onset) and SMALED2B (prenatal onset). SMALED2B is more severe.
Like other types of SMA, the main symptom of SMA-LED is muscle weakness. SMA-LED mostly affects the upper part of the legs (thighs), causing weakness and loss of muscle mass in the quadriceps (thigh muscles). Quadricep weakness can affect a person’s ability to raise their upper leg and extend their leg (hip flexion and knee extension). This weakness and muscle atrophy leads to difficulty walking and running. In severe cases, people with SMA-LED lose the ability to walk.
People with SMA-LED typically develop an unsteady or “waddling” gait. They also have difficulty walking up stairs and standing up from a sitting position. These symptoms typically appear in early childhood, but in about 25 percent of cases, symptoms do not develop until adulthood. People with SMA-LED usually have a normal life span.
Other symptoms include:
Diagnosis of SMA-LED requires a family medical history, physical exam, and genetic testing. A detailed family medical history is important to identify any family members or relatives who have been diagnosed with SMA-LED or other muscular dystrophies. A thorough physical exam is needed to identify which muscle groups are affected and to test for abnormal reflexes.
Genetic testing, using a blood sample, is the primary way to diagnose SMA-LED. Genetic testing looks for specific gene mutations. Before genetic testing was available, a muscle biopsy (taking a sample of muscle tissue) and electromyogram (EMG) were used for diagnosis. Muscle biopsy and EMG may still be used if genetic testing is inconclusive.
No treatment can currently reverse or cure SMA-LED; unlike the most common types of SMA, there are no disease-modifying gene therapies available for this rare condition. Treatments to maintain or improve mobility include physical therapy and leg braces. People with severe SMA-LED may require a wheelchair for mobility.
As with other types of SMA, it is important to maintain range of motion and improve muscle strength when possible. Physical therapy to maintain range of motion is especially important to prevent contractures that can permanently prevent joint movement and lead to joint deformity. Foot orthotics and knee or ankle braces can help some people with SMA walk more easily.
SMA-LED is different from other types of SMA because it predominantly affects the lower limbs. It is also caused by different genetic mutations and is inherited differently than most types of SMA.
SMA-LED symptoms affect the lower limbs and rarely involve the upper limbs (arms), while the most common types of SMA affect muscles throughout the body. SMA-LED is a type of proximal spinal muscular atrophy, meaning that it affects the proximal (upper) muscles of the leg. Another rare type of SMA, distal SMA, primarily affects the hands and feet.
The most common types of SMA are caused by a mutation in a single gene, the survival motor neuron protein 1 (SMN1) gene. This gene encodes SMN protein. SMA-LED, however, is caused by mutations in one of two other genes.
SMALED1 is caused by a mutation in the DYNC1H1 gene on chromosome 14. Mutations of this gene are also seen in some cases of Charcot-Marie-Tooth disease, a neurological disorder that affects both motor and sensory neurons. SMALED2 is caused by a mutation in the BICD2 gene on chromosome 9. Both the DYNC1H1 and BICD2 genes make proteins that work to transport “cargoes” along microtubules inside of cells, like a train moving cargo on a railroad track. Intracellular transport is important in all cells in the body, but especially so in the nervous system, because it allows us to move and breathe.
The motor neurons that are affected by SMA start in the spinal cord and extend to muscles throughout the body. Motor neurons affected by SMA-LED, however, only extend from the lower spinal cord to the thigh muscles. When intracellular transport along these nerves is impaired (i.e., due to a genetic mutation), the nerve cannot signal to the muscle to move. Eventually, both the nerve and muscle die. It is not understood why SMA-LED affects the upper muscles of the leg and not the lower muscles, which have longer nerves.
Most types of SMA are autosomal recessive, meaning that the mutated genes that cause the disease must be inherited from both parents for the disease to occur (homozygous genotype). But SMA-LED is autosomal dominant, meaning that a defective gene only needs to be inherited from one parent for the disease to occur (heterozygous genotype). This also means that people with SMA-LED have a 50 percent chance of passing the gene to their children. Because SMA-LED is autosomal dominant, it is usually found in clusters affecting multiple family members and extended relatives.
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