Spinal muscular atrophies include several types of hereditary disorders characterized by skeletal muscle wasting due to progressive degeneration of anterior horn cells in the spinal cord and of motor nuclei in the brain stem. Manifestations may begin in infancy or childhood. They vary by the specific type and may include hypotonia; hyporeflexia; difficulty sucking, swallowing, and breathing; unmet developmental milestones; and, in more severe types, very early death. Diagnosis is by genetic testing. Treatment is supportive.
Spinal muscular atrophies usually result from autosomal recessive mutations that affect the survival motor neuron 1 (SMN1) gene on the long arm of chromosome 5, most often causing a homozygous deletion of exon 7. Spinal muscular atrophies may involve the central nervous system and thus are not purely peripheral nervous system disorders. SMN2 is a modifier gene; it is 99% identical to the SMN1 gene and is located on 5q; if present in multiple copies, SMN2 may modify the severity of the disease and explain phenotypic differences between children with SMA. Also, there are rare forms of SMA that are not due to 5q mutations.
There are 5 main types of spinal muscular atrophy.
In spinal muscular atrophy type 0, onset is prenatal; it manifests as decreased fetal movement in late pregnancy and severe weakness and hypotonia at birth. Affected neonates have facial diplegia, areflexia, cardiac defects, and sometimes arthrogryposis. Death due to respiratory failure occurs within the first 6 months.
Spinal muscular atrophy type 1 (infantile spinal muscular atrophy, or Werdnig-Hoffmann disease) is also present in utero and becomes symptomatic by about age 6 months. Affected infants have hypotonia (often notable at birth), hyporeflexia, tongue fasciculations, and pronounced difficulty sucking, swallowing, and eventually breathing. Death, usually due to respiratory failure, occurs within the first year in 95% and by age 4 years in all.
In spinal muscular atrophy type 2 (intermediate form, or Dubowitz disease), symptoms usually manifest between 3 and 15 months of age; < 25% of affected children learn to sit, and none walk or crawl. Children have flaccid muscle weakness and fasciculations, which may be hard to see in young children. Deep tendon reflexes are absent. Dysphagia may be present. Most children are confined to a wheelchair by age 2 to 3 years. The disorder is often fatal in early life, frequently resulting from respiratory complications. However, progression can stop spontaneously, leaving children with permanent, nonprogressive weakness and a high risk of severe scoliosis and its complications.
Spinal muscular atrophy type 3 (juvenile form, or Wohlfart-Kugelberg-Welander disease) usually manifests between age 15 months and 19 years. Findings are similar to those of type I, but progression is slower and life expectancy is longer; some patients have a normal life span. Some familial cases are secondary to specific enzyme defects (eg, hexosaminidase deficiency). Symmetric weakness and wasting progress from proximal to distal areas and are most evident in the legs, beginning in the quadriceps and hip flexors. Later, arms are affected. Life expectancy depends on whether respiratory complications develop.
Spinal muscular atrophy type 4 (late-onset) can be recessive, dominant, or X-linked, with adult onset (age 30 to 60 years) and slow progression of primarily proximal muscle weakness and wasting. Differentiating this disorder from amyotrophic lateral sclerosis that involves predominantly lower motor neurons may be difficult.
Diagnosis of SMAs
Electrodiagnostic testing
Genetic testing
A diagnosis of spinal muscular atrophy should be suspected in patients with unexplained muscle wasting and flaccid weakness, particularly in infants and children.
Electromyography (EMG) and nerve conduction studies should be done; muscles innervated by cranial nerves should be included. Conduction is normal, but affected muscles, which are often clinically unaffected, are denervated.
Definitive diagnosis is by genetic testing, which detects the causative mutation in about 95% of patients (1).
Muscle biopsy is done occasionally to exclude treatable causes and to determine whether the cause is fatal. Serum enzymes (eg, creatine kinase, aldolase) may be slightly increased.
Amniocentesis, done if family history is positive, is often diagnostic.
Diagnosis reference
1. Ogino S, Wilson RB: Genetic testing and risk assessment for spinal muscular atrophy (SMA). Hum Genet 111 (6):477–500, 2002. doi: 10.1007/s00439-002-0828-x
Treatment of SMAs
Supportive care
There is no cure. Treatment of spinal muscular atrophies includes supportive measures.
Physical therapy, braces, and special appliances can benefit patients with static or slowly progressive disease by preventing scoliosis and contractures. Adaptive devices available through physical and occupational therapists may improve children’s independence and self-care by enabling them to feed themselves, write, or use a computer.
SMN21). It must be given intrathecally.
SMN gene to motor neuron cells. A one-time, single dose of the medication is given over 1 hour by IV infusion. In a study involving 15 children, some achieved motor milestones, including sitting unassisted, feeding orally, rolling over, and walking independently (2). Serious liver injury is a potential risk.
3). Fever, diarrhea, and rash were the most common adverse effects.
Treatment references
1. Pechmann A, Behrens M, Dörnbrack K, et alBrain 146 (2):668–677, 2023. doi: 10.1093/brain/awac252
2. Mendell JR,, Al-Zaidy S, Shell R, et al: Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 377 (18):1713–1722, 2017. doi: 10.1056/NEJMoa1706198
3. Baranello G, Servais L, Day J, et alNeuromuscul Disord 29 (supplement 1):S184, 2019, doi: https://doi.org/10.1016/j.nmd.2019.06.515
Key Points
If infants and children have unexplained muscle wasting and flaccid weakness, evaluate them for spinal muscular atrophies.
EMG shows muscle denervation.
Use genetic testing to confirm the presence and type of spinal muscular atrophy.
Refer patients to physical and occupational therapists, who may help patients learn to function more independently.
