Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Estimated incidence is 1 in 6,000 to 1 in 10,000 live births and carrier frequency of 1/40-1/60. This disease is characterized by generalized muscle weakness and atrophy predominating in proximal limb muscles, and phenotype is classified into four grades of severity (SMA I, SMAII, SMAIII, SMA IV) based on age of onset and motor function achieved. This disease is caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene, and the diagnostic test demonstrates in most patients the homozygous deletion of the SMN1 gene, generally showing the absence of SMN1 exon 7. The test achieves up to 95% sensitivity and nearly 100% specificity. Differential diagnosis should be considered with other neuromuscular disorders which are not associated with increased CK manifesting as infantile hypotonia or as limb girdle weakness starting later in life.Considering the high carrier frequency, carrier testing is requested by siblings of patients or of parents of SMA children and are aimed at gaining information that may help with reproductive planning. Individuals at risk should be tested first and, in case of testing positive, the partner should be then analyzed. It is recommended that in case of a request on carrier testing on siblings of an affected SMA infant, a detailed neurological examination should be done and consideration given doing the direct test to exclude SMA. Prenatal diagnosis should be offered to couples who have previously had a child affected with SMA (recurrence risk 25%). The role of follow-up coordination has to be managed by an expert in neuromuscular disorders and in SMA who is able to plan a multidisciplinary intervention that includes pulmonary, gastroenterology/nutrition, and orthopedic care. Prognosis depends on the phenotypic severity going from high mortality within the first year for SMA type 1 to no mortality for the chronic and later onset forms.
Highlights
Definition Spinal muscular atrophy (SMA) is a severe neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis
The genetic defect was localized to 5q11.2-q13.3 a century later [3] with the identification of the survival motor neuron gene (SMN) gene as the disease-causing gene in 1995 [4]
Clinical description and Classification SMA is clinical classified into four phenotypes on the basis of age of onset and motor function achieved [7] (See table 1)
Summary
Muskelatrophie unter dem Bilde der Dystrophie, aber auf neurotischer Grundlage [Two early infantile hereditary cases of progressive muscular atrophy simulating dystrophy, but on a neural basis; in German]. 2. Hoffmann J: U” ber chronische spinale Muskelatrophie im Kindesalter, auf familiärer Basis [On chronic spinal muscular atrophy in childhood, with a familial basis; in German]. 3. Brzustowicz LM, Lehner T, Castilla LH, Penchaszadeh GK, Wilhelmsen KC, Daniels R, Davies KE, Leppert M, Ziter F, Wood D, Dubowitz V, Zerres K, Hausmanowa-Petrusewicz I, Ott J, Munsat TL, Gilliam TC: Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. 5. Ogino S, Leonard DG, Rennert H, Ewens WJ, Wilson RB: Genetic risk assessment in carrier testing for spinal muscular atrophy. 6. Prior TW, Snyder PJ, Rink BD, Pearl DK, Pyatt RE, Mihal DC, Conlan T, Schmalz B, Montgomery L, Ziegler K, Noonan C, Hashimoto S, Garner S: Newborn and carrier screening for spinal muscular atrophy.
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