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ABSTRACT

Spinal muscular atrophies (SMA) are characterized by degeneration of lower motor neurons and occasionally bulbar motor neurons leading to progressive limb and trunk paralysis associated with muscular atrophy. Childhood SMA is a frequent recessive autosomal disorder and represents a common genetic cause of death in childhood. A positional cloning strategy allowed the localization and the identification of the survival of motor neuron gene (SMN). These developments have greatly improved the clinical management and family planning options of SMA patients and their parents. Furthermore, the presence or the absence of a SMN gene defect contributed to a better nosology of SMA-related diseases. The last 10 years saw major advances in the field of SMA. The function of the SMN gene product has been, at least partly, elucidated, and mouse models of SMA have been created. These advances represent starting points for designing therapeutic strategies of this devastating neurodegenerative disease for which no curative treatment is known so far.

CLINICAL PHENOTYPES

The various types of SMA can be distinguished clinically by the distribution of weakness, by the pattern of inheritance, and by the age of onset.

Infantile SMA

There are two different forms of infantile SMA: an acute form or type I (MIM 253300) and a more chronic form or type II (MIM 253550). Both are inherited as autosomal recessive traits.

The acute or type I SMA, first described by Werdnig1,2 and by Hoffmann,3 is characterized by its severe generalized muscle involvement and fatal outcome. In about one-third of cases, the disease manifests before birth by diminished fetal movements in utero or by mild contractures. In the other cases, the onset occurs at birth or within the first 6 months of life. Generalized weakness associated with areflexia is the most common clinical features. Active movements are usually confined to the fingers and toes. Fasciculations can be detected in the tongue. The face is usually spared and the infant usually has a bright, normal expression. Intercostal paralysis with severe collapse of the chest is the rule. Breathing is almost entirely diaphragmatic, the diaphragmatic muscle being spared. The extraocular movements are normal. Feeding and breathing difficulties are usually responsible for death within 2 years of age. Some studies have presented survival statistics on type I SMA indicating that all patients with an age of onset in the first 6 months of life are deceased by 2 years of age.4,5 Another study showed a bad prognosis for patients with onset within the first 3 months of life; 50 percent died by 7 to 8 months and all were deceased before 5 years of age.6 However, life span of many patients with early SMA onset is often better than expected.

Type II SMA is a more slowly progressive generalized disease with a variable prognosis. Infants are able to sit unsupported but none are able ...

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