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major motor milestones, as well as independent walking. However during infancy they develop proximal muscular weakness. Some might need wheelchair assistance in childhood, whereas others might continue to walk and live productive adult lives with minor muscular weakness. Patients who lose ambulation often develop scoliosis and other medical problems related to poor mobility such obesity and osteoporosis [16-18]. Concerning natural history data on 329 SMA type III patients, 2 subgroups of severity have been suggested on the probability of being able to walk by 10 years and on increased probability to lose walking by the age of 40 years. Significant differences loosing ability to walk were observed in relation to those with an onset of weakness before (SMA III a) and after age 3 years of age (SMA IIIb) [19]. SMA type IV has been added to this classification to describe those patients with adult onset (> 18 ys) and mild course. This group includes patients who are able to walk in adulthood and without respiratory and nutritional problems. Since all SMA types belong to a single spectrum and share the same etiology, patient selection for clinical trials is actually independent of the historical classification, and is essentially determined by the intervention characteristics and the choice of endpoints. Molecular genetics and Etiology Two almost identical SMN genes are present on chromosome 5q13: the telomeric or SMN1 gene, which is the spinal muscular atrophy- determining gene, and the centromeric or SMN2 gene. The coding sequence of SMN2 differs from that of SMN1 by a single nucleotide (840C > T), which does not alter the aminoacidic sequence but results in Table 1 Clinical classification criteria for spinal muscular atrophy Age of onset Highest function achieved Type I (Werdnig-Hoffmann disease) 0-6 months Never sit Type II (intermediate) 7-18 months Sit never stand Type III (mild, Kugelberg-Welander disease) in adulthood > 18 months Stand and Walk during aldulthood Type IV (adult) 2°-3° decade Walk unaided D’Amico et al. Orphanet Journal of Rare Diseases 2011, 6:71 http://www.ojrd.com/content/6/1/71 Page 2 of 10 alternative splicing of exon 7. Due to the alternative splicing of exon 7, SMN2 genes produce a reduced amount of full length transcripts (SMN-fl) and protein, and a variable amount of mRNA lacking exon 7 (10% to 50%, SMN-del7) which give raise to a truncated and unstable protein [20]. About 95% of patients have a homozygous disruption of SMN1 due to deletion or gene conversion of SMN1 to SMN2 [21]. About 3% of affected individuals are compound heterozygotes for deletion of one SMN1 allele and subtle intragenic mutations. All patients, however, retain at least one copy of SMN2, generally 2-4. Loss of SMN1 is essential to the pathogenesis of SMA, while the severity of the disease is primarily related to the number of copies of SMN2. Most SMA type I patients have two copies of SMN2 [22], three SMN2 copies are common in SMA type II, while type III and IV generally have three or four [23,24]. SMN genes encode for SMN protein which is ubiquitously expressed and localized in the cytoplasm and in the nucleus, and is particularly abundant in motor neurons of the spinal cord [25]. Within the nucleus, SMN protein is concentrated in dot-like structures associated with coiled (Cajal) bodies, named “gems” (gemini of coiled bodies) [26]. Although the exact cellular function of SMN protein responsible for the pathogenesis of SMA remains unknown, cells from patients with spinal muscular atrophy contain fewer gems compared controls and carriers [26]. Animal models by disruption of SMN has been obtained in yeast, nematode, fly, zebrafish, and mouse. These models of spinal muscular atrophy have not only been fundamental for increasing knowledge about the molecular and cellular pathways of SMN, but also to better understand the mechanism(s) of disease, and to provide a platform from which highthroughput genetic and drug screens can be performed [27]. However Spinal muscular atrophy mutant mice that die soon after birth (low copy SMN2+/+; Smn -/-) preclude detailed analysis of pathogenic mechanisms and preclinical drug testing [28] However, this
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