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22:1328–47 2. Acsadi G, Lee I, Li X, Khaidakov M, Pecinova A, et al. 2009. Mitochondrial dysfunction in a neural cell model of spinal muscular atrophy. J. Neurosci. Res. 87:2748–56 3. Akten B, Kye MJ, Hao LT, Wertz MH, Singh S, et al. 2011. Interaction of survival of motor neuron (SMN) and HuD proteins with mRNA cpg15 rescues motor neuron axonal deficits. PNAS 108:10337– 42 4. Al-Zaidy SA, Kolb SJ, Lowes L, Alfano LN, Shell R, et al. 2019. AVXS-101 (onasemnogene abeparvovec) for SMA1: comparative study with a prospective natural history cohort. J. Neuromuscul. Dis. 6:307–17 5. Al-Zaidy SA, Pickard AS, Kotha K, Alfano LN, Lowes L, et al. 2019. Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy. Pediatr. Pulmonol. 54:179–85 6. Alias L, Bernal S, Fuentes-Prior P, Barcelo MJ, Also E, et al. 2009. Mutation update of spinal muscular atrophy in Spain: molecular characterization of 745 unrelated patients and identification of four novel mutations in the SMN1 gene. Hum. Genet. 125:29–39 252 Wirth et al. Annu. Rev. Genom. Hum. Genet. 2020.21:231-261. Downloaded from www.annualreviews.org Access provided by 2600:1700:3c30:a3d0:89dc:b3d1:ac73:5085 on 01/23/22. For personal use only. 7. Andrews JA, Miller TM, Vijayakumar V, S Spinal muscular atrophy Adele D’Amico1 , Eugenio Mercuri2*, Francesco D Tiziano3 and Enrico Bertini1 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. Keywords: Proximal spinal muscular atrophy, SMN1, SMN2, motor neurons Disease names and synonyms: Spinal muscular atrophy 5q linked, Proximal SMA 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 disease was first described in the 1890s by Werdnig [1] and by Hoffmann [2]. 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]. Epidemiology SMA is the second most common fatal autosomal recessive disorder after cystic fibrosis,
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