Spinal Muscular Atrophy Type I (Werdnig-Hoffmann Disease)

In the healthy newborn infant, purposeless extremity movements have a well-defined muscular tone, despite the lack of coordinated motor function. Concomitantly, full-term newborns have well-developed suck and swallow function. At birth, many SMA type I infants appear normal; however, within a few weeks to months, generalized hypotonia and neuromuscular weakness develop. A classic hypotonic posture characterized by abducted hips, internal rotation of the forearms, and frog-legged and jug-handle habitus is typical. Their respiratory pattern is characterized by paradoxic chest and abdomen movement resulting from selective intercostal muscle weakness with preserved diaphragm function. Without supportive treatment, such infants subsequently develop characteristic bell-shaped deformities of the thorax. Progressive bulbar and respiratory insufficiency results in a vulnerability to both aspiration and infectious pneumonias.

Extraocular and facial movements are preserved; these infants typically have a bright, attentive countenance. Careful evaluation of the tongue reveals tongue fasciculations. In contrast to adult motor neuron disorders, fasciculations in limbs are difficult to appreciate due to excessive subcutaneous infantile fat. Abnormal motor milestones with poor head control, inability to roll and to achieve independent sitting, as expected during the first few months, leads to investigation and eventual diagnosis of SMA type I. In a most severe subset, reduced fetal movements occurs prenatally; these infants are born with generalized hypotonia, weakness, respiratory insufficiency, bulbar dysfunction, and proximal joint contractures.

Spinal muscular atrophy with respiratory distress (SMARD) is distinguished by early respiratory failure due to diaphragm involvement, especially in association with more distal presentation of limb weakness. X-linked SMA manifests as a severe infantile SMA variant predominantly affecting males.

SMA II infants initially can sit but never become able to walk and are diagnosed at ages 6 to 24 months. Kugelberg-Welander disease, SMA III, typically occurs between ages 2 and 14 years with symptoms of proximal weakness. These children may have mild elevations of creatinine kinase (CK, <1000 IU/L).

More than 95% of SMA I infants have a homozygous deletion/mutation of exon 7 of the survival motor neuron 1 gene (SMN1 gene) on chromosome 5q11-13. Infants who do not have this deletion identified may have a non–chromosome 5 SMA or a mutation(s) in the survival motor neuron gene not detectable with the currently used polymerase chain reaction (PCR)-based methods. Both SMA II and SMA III have exactly the same genetic defects as those with type I. When a child with proximal muscle weakness, shown by electromyography (EMG), demonstrates neurogenic changes, deoxyribonucleic acid (DNA) testing for SMN1 gene is the diagnostic tool of choice.

Electromyography is a very sensitive primary diagnostic tool; however, it has been largely supplanted by DNA analysis. However, when DNA testing is normal and significant weakness is manifest, the EMG findings are distinct in type I SMA, demonstrating diffuse fibrillations in virtually all muscles in association with markedly reduced recruitment of small motor units in the absence of the typical large complex motor units characteristic of reinnervation in milder, more chronic forms of the disorder. Muscle biopsy demonstrates findings typical of neurogenic atrophy, although the reduced reinnervation capacity in SMA type I often results in a predominance of small rounded fibers within entirely denervated fascicles.

Other lesions in the motor unit can mimic Werdnig-Hoffmann disease (WHD), but, as a rule, can be differentiated by clinical and electromyographic findings and examination of muscle biopsy specimens if genetic and/or neurophysiologic testing are not definitive. Differential diagnosis includes the very rare recessive inherited peripheral neuropathy variants, such as congenital hypomyelinating neuropathy that may clinically mimic WHD, even to the point of tongue fasciculations. More distally within the motor unit, neuromuscular junction disorders, including transient neonatal myasthenia gravis and infantile botulism, as well as the various congenital myopathies and dystrophies, may present as a floppy baby.

Treatment for Werdnig-Hoffmann disease remains largely supportive. The prognosis is generally poor, with onset is in the neonatal period. Many of these infants do not survive until their first birthday. However, even in the absence of extensive supportive care, historically, up to 30% of infants with SMA type I survive beyond 2 years of age, some into adolescence or beyond.

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