Proximal spinal muscular atrophy

Proximal spinal muscular atrophy (SMA) is a group of inherited neuromuscular disorders characterized by the degeneration of motor neurons in the anterior horn of the spinal cord, leading to progressive proximal muscle weakness and atrophy. Also known as 5q spinal muscular atrophy, it is caused by homozygous deletions or mutations in the SMN1 (survival motor neuron 1) gene on chromosome 5q13. The disease severity is largely influenced by the copy number of a modifying gene, SMN2, which produces a small amount of functional SMN protein. SMA is classified into several types based on age of onset and maximum motor function achieved: Type I (Werdnig-Hoffmann disease, severe infantile form), Type II (intermediate form), Type III (Kugelberg-Welander disease, mild juvenile form), and Type IV (adult-onset form). The hallmark clinical features include symmetric proximal muscle weakness that is more pronounced in the lower limbs than the upper limbs, hypotonia, reduced or absent deep tendon reflexes, and in severe forms, respiratory insufficiency and feeding difficulties. In SMA Type I, the most severe form, onset occurs before six months of age, and affected infants never achieve the ability to sit independently. Type II presents between 6 and 18 months, with children able to sit but unable to walk independently. Type III has onset after 18 months, and patients achieve independent walking but may lose this ability over time. Type IV presents in adulthood with mild proximal weakness. Tongue fasciculations and fine tremor of the hands may also be observed. The treatment landscape for SMA has been transformed in recent years with the approval of disease-modifying therapies. Nusinersen (Spinraza) is an antisense oligonucleotide administered intrathecally that modifies SMN2 pre-mRNA splicing to increase production of functional SMN protein. Onasemnogene abeparvovec (Zolgensma) is a gene replacement therapy delivered intravenously that provides a functional copy of the SMN1 gene. Risdiplam (Evrysdi) is an oral small molecule SMN2 splicing modifier. These therapies have significantly improved outcomes, particularly when initiated early, which has driven the implementation of newborn screening programs in many countries. Supportive care including respiratory management, nutritional support, orthopedic interventions, and physical therapy remains essential for comprehensive disease management.

Common questions about Proximal spinal muscular atrophy