Spinal Muscular Atrophy
Spinal Muscular Atrophy (SMA) is a hereditary neuromuscular disorder characterized by degeneration and progressive loss of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem, resulting in muscle weakness and atrophy. The disease is most commonly caused by homozygous deletions or mutations in the survival motor neuron 1 (SMN1) gene located on chromosome 5q13, which leads to insufficient production of the survival motor neuron (SMN) protein. This deficiency disrupts the maintenance and function of motor neurons, ultimately causing their degeneration. The reduction in SMN protein impairs the ability of motor neurons to transmit signals to skeletal muscles, resulting in progressive muscle weakness, respiratory compromise, and, in severe cases, early mortality. SMA primarily affects proximal muscles, with varying severity depending on the residual SMN protein level, and can have profound impacts on mobility, respiratory function, swallowing, and overall quality of life.
Type 0 is the most severe and rarest form of spinal muscular atrophy, with onset occurring in utero. Affected fetuses exhibit decreased fetal movements, severe hypotonia, joint contractures, and profound muscle weakness at birth. Respiratory failure is typically present at birth or develops within hours, and affected infants usually do not survive beyond the neonatal period.
Type 1 is the most common and severe form presenting in infancy, usually before six months of age. Infants display profound hypotonia, generalized muscle weakness, poor head control, and difficulty swallowing and sucking. Respiratory muscle weakness leads to progressive respiratory insufficiency, and without intervention, most affected infants do not survive past two years of age.
Type 2 typically presents between 6 and 18 months of age. Children may achieve the ability to sit without support but are generally unable to stand or walk unaided. Progressive proximal muscle weakness, particularly affecting the lower limbs, is characteristic. Complications include scoliosis, joint contractures, and respiratory compromise. Life expectancy is variable and often reduced due to respiratory complications.
Type 3 presents after 18 months of age, often in childhood or adolescence. Patients achieve independent ambulation, but develop progressive proximal muscle weakness, especially in the legs. Many lose the ability to walk in adulthood. Bulbar and respiratory involvement is less common, and life expectancy is typically near normal, though quality of life may be affected by mobility limitations.
Type 4 is the mildest form, with onset in the second or third decade of life. It is characterized by slowly progressive muscle weakness and atrophy, predominantly affecting proximal muscles. Respiratory and bulbar muscles are usually spared, and life expectancy is not significantly reduced.
Spinal Muscular Atrophy is one of the most common autosomal recessive disorders, with an estimated incidence of approximately 1 in 6,000 to 1 in 10,000 live births worldwide. The carrier frequency is about 1 in 40 to 1 in 60 in most populations. All ethnic groups are affected, though some variation in prevalence exists across different regions. SMA accounts for a significant proportion of genetic causes of infant mortality. Type 1 SMA constitutes approximately 60% of cases, with Types 2 and 3 comprising most of the remainder. The introduction of newborn screening programs in several countries has improved early identification and intervention, potentially altering the epidemiological landscape.
Diagnosis of spinal muscular atrophy is based on clinical presentation, family history, and confirmatory genetic testing. Initial suspicion is raised in infants and children with hypotonia, symmetrical proximal muscle weakness, and delayed motor milestones. Electromyography (EMG) and nerve conduction studies may reveal evidence of denervation and reduced compound muscle action potentials, but are often performed to rule out other neuromuscular disorders. The definitive diagnosis is established by molecular genetic testing for homozygous deletion or mutation of the SMN1 gene. Quantification of SMN2 gene copy number is also routinely performed, as it correlates with disease severity and prognosis. Ancillary evaluations, including pulmonary function tests, swallowing assessments, and musculoskeletal imaging, are utilized to assess disease complications and guide multidisciplinary management. Prenatal diagnosis is available for at-risk pregnancies via chorionic villus sampling or amniocentesis.
Risdiplam is an orally administered small molecule designed to increase the production of functional SMN protein by modifying SMN2 pre-mRNA splicing, thereby compensating for the loss of SMN1 gene function in patients with spinal muscular atrophy. Onasemnogene abeparvovec is a gene therapy administered as a single intravenous infusion, delivering a functional copy of the SMN1 gene to motor neuron cells through an adeno-associated viral vector, with the goal of restoring sustained SMN protein expression. Nusinersen is an antisense oligonucleotide administered intrathecally, which modulates the splicing of SMN2 pre-mRNA to enhance the production of full-length SMN protein, thereby addressing the underlying molecular deficiency in spinal muscular atrophy.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
 | risdiplam (Rec INN; USAN) | 1825352-65-5 | C22 H23 N7 O | 401.464 |
| onasemnogene abeparvovec (Prop INN; Rec INN; USAN); onasemnogene abeparvovec-xioi | 1922968-73-7 | |||
| nusinersen (Rec INN; USAN) | 1258984-36-9 |
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