Spinal Muscular Atrophy

CHAPTER 65

Spinal Muscular Atrophy

Introduction/Etiology/Epidemiology

• Spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality.

• It is characterized by degeneration of the α-motor neurons in the anterior horn of the spinal cord and lower bulbar nuclei.

• Generally transmitted in an autosomal-recessive manner, it affects all ethnic groups. Incidence is 1 per 11,000 live births with a healthy carrier frequency of 1:40 to 1:60. De novo mutations occur in 2% of patients.

• The most common type of SMA is caused by mutations in the survival motor neuron (SMN) 1 gene, SMN1, in chromosome 5 resulting in SMN protein deficiency. A similar SMN2 gene produces small amounts of functional SMN protein, which influences the SMA phenotype. The most severe (SMA type 0) typically has 1 copy of SMN2 gene, whereas the least severe (type 4) has 4 or more copies.

Signs and Symptoms

• Varying degrees of diffuse, symmetric, proximal trunk and limb weakness, greater in lower versus upper extremities. Bulbar and respiratory weakness is associated with more severe limb weakness.

• Deep tendon reflexes are markedly decreased or absent.

• Sensation and intelligence are typically normal; cases of severe SMA with brain, cardiovascular, and autonomic and sensory nervous system involvement have been reported.

• Varying degrees of restrictive respiratory insufficiency can occur.

• Classified into 5 subtypes based on maximum attainable physical function and associated SMN2 gene copy number (Box 65-1).

Box 65-1. Classification of Spinal Muscle Atrophy

Type 0

• Age of onset, fetal; age of diagnosis, birth

• Congenital joint contractures

• Severe hypotonia with an inability to sit or roll

• Muscle atrophy and areflexia

• Respiratory insufficiency at birth

• Death by a few weeks after birth

Type 1 (Werdnig-Hoffman/infantile onset disease)

• Most common variety (45% of cases), and most severe variety

• Age of onset, fetal or infancy; age of diagnosis, younger than 2 weeks–6 months

• Severe generalized hypotonia; proximal muscle weakness and absent DTR

• Never roll or sit independently

• Weakness of the lower bulbar muscles results in a poor suck-swallow reflex, weak cry, tongue fasciculation, and greater susceptibility to aspiration pneumonia

• Weak intercostal muscles and relative sparing of the diaphragm lead to a bell-shaped chest and paradoxical breathing with respiratory insufficiency

• Infant has alert expression, furrowed brow, and normal eye movements because upper cranial nerves are spared

• Most have normal sensation, but in severe cases, sensory nerve involvement has been reported

• Mean life expectancy is 2–4 years of age

Type 2 (intermediate or juvenile spinal muscular atrophy)

• About 20% of cases

• Age of onset, infancy; age of diagnosis, 6–18 months

• Mild to moderate hypotonia

• Progressive muscle weakness (proximal to distal, lower limbs to upper limbs to trunk) with or without areflexia

• Tongue atrophy with fasciculation; finger polymyoclonus tremor

• Can sit without support by 9 months; some can stand but cannot walk independently; verbal intelligence may be above average

• Difficulty chewing, swallowing, and coughing; prone to respiratory insufficiency

• Joint contractures are common. Progressive kyphoscoliosis can prevent comfortable sitting and can further compromise lung function with age.

• Greater risk of becoming overweight

• Ninety-three percent live to 25 years of age.

Type 3 (Kugelberg-Welander syndrome)

• About 30% of cases

• Age of onset, early to late childhood; age of diagnosis, 6–36 months

• Progressive proximal muscle weakness; DTR reduced or absent; finger polymyoclonus tremor

• Standing and walking are typical, but jumping or running are less likely; many lose all these abilities over time

• Ambulatory patients may have a foot deformity. Those who lose ambulation often develop obesity, scoliosis, and osteoporosis.

• There is little to no respiratory muscle weakness

• Most have a normal life expectancy

Type 4

• Less than 5% of cases

• Age of onset, adult; age of diagnosis, 35 years or older

• Onset of proximal muscle weakness with gross motor function difficulty

• Mildest clinical course; normal motor milestones until early adulthood

• No respiratory or nutritional problems

• Normal life expectancy

Abbreviation: DTR, deep tendon reflexes.

MUSCULOSKELETAL COMPLICATIONS

• Scoliosis is primarily noted in patients with SMA types 2 and 3. It is caused by severe truncal weakness and is associated with gastrointestinal reflux, respiratory dysfunction, and postural discomfort.

— Prevalence of scoliosis is 60% to 95% (SMA type 2 is toward the higher end of the range), with a progression of approximately 7 degrees per year.

— Scoliosis varies from the characteristic long C-shaped curves (up to 88% of patients) beginning in the mid to upper thorax with pelvic tilt, to the less common S-shaped curves with thoracic and compensatory lumbar curves.

• Kyphosis often occurs with SMA types 2 and 3 and is associated with scoliosis.

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