Alternative titles; symbols
SNOMEDCT: 128212001; ORPHA: 70, 83418; DO: 0050530;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q13.2 | Spinal muscular atrophy-2 | 253550 | Autosomal recessive | 3 | SMN1 | 600354 |
A number sign (#) is used with this entry because spinal muscular atrophy type II (SMA2) is caused by homozygous or compound heterozygous mutation in the SMN1 gene (600354) on chromosome 5q13.
The SMN1 gene is also involved in the more severe SMA type I (253300) and the less severe SMA type III (253400) and SMA type IV (271150).
Spinal muscular atrophy refers to a group of autosomal recessive neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetric muscle weakness and atrophy (summary by Wirth, 2000).
Fried and Emery (1971) suggested the existence of a distinct form of spinal muscular atrophy intermediate in severity between the infantile form SMA type I and juvenile form SMA III. The intermediate form, which they designated SMA II, is characterized by onset usually between 3 and 15 months and survival beyond 4 years and usually until adolescence or later. Proximal muscle weakness is the cardinal feature as in other forms of spinal muscular atrophy. They presented 14 cases, of whom 2 were sibs. The parents were all unaffected and nonconsanguineous.
Imai et al. (1995) demonstrated peripheral but not central conduction abnormalities in patients with SMA II.
Pearn et al. (1973) used a method of sib-sib correlation introduced by Haldane (1941) to support the existence of separate 'acute' and 'chronic' forms of spinal muscular atrophy.
Hanson and Bundey (1974) described 2 brothers in a sibship of 4. They suggested that SMA I and SMA III may be due to homozygosity of allelic genes, and SMA II could represent the genetic compound.
Hausmanowa-Petrusewicz et al. (1985) referred to this as the infantile chronic form of SMA.
Imai et al. (1995) demonstrated peripheral but not central conduction abnormalities in patients with SMA II.
On the basis of 13 clinically heterogeneous SMA families, Brzustowicz et al. (1990) concluded that 'chronic' childhood-onset SMA (including intermediate SMA, or SMA type II, and Kugelberg-Welander syndrome, or SMA type III) is genetically homogeneous, mapping to chromosomal region 5q11.2-q13.3. Their data indicated that the acute childhood SMA (type I or Werdnig-Hoffmann disease) maps to the same or a closely linked locus on 5q. The findings suggested that all 3 forms of SMA, types I, II, and III, are allelic.
In 24 multiplex families of distinct ethnic origin with chronic forms of proximal SMA, i.e., types II and III, Melki et al. (1990) demonstrated linkage to the DNA marker D5S39, thus mapping the locus to 5q12-q14. No evidence for genetic heterogeneity for types II and III was found.
To confirm the localization of the chronic forms of SMA, types II and III, to 5q12-q14 and to test for genetic homogeneity in the French-Canadian population, Simard et al. (1992) studied 8 families. They showed tight linkage to marker locus D5S39 and loose linkage to D5S6. They also presented a family that appeared to be discordant for the localization on chromosome 5; however, the family contained an apparently asymptomatic individual who was shown to be homozygous for the mutant SMA alleles.
Genetic Heterogeneity
In a linkage study of 161 families in which individuals suffered from the intermediate or mild form of SMA, Merette et al. (1994) found support for the hypothesis of linkage heterogeneity, with 5% of the families unlinked to the region 5q11.2-q13.3.
Nevo et al. (1998) presented evidence that there may be a form of type II SMA (intermediate SMA with onset between 3 and 18 months) that is unrelated to the SMN1 region on 5q13.
The transmission pattern of SMA II in the families reported by Matthijs et al. (1996) was consistent with autosomal recessive inheritance.
Matthijs et al. (1996) used an SSCP assay for the molecular diagnosis of 58 patients with SMA, including 12 patients (7 Belgian and 5 Turkish) with SMA II. This assay discriminates between the SMN gene (600354) and the almost identical centromeric BCD541 repeating unit. In 11 of the 12 patients, homozygous deletion of exon 7 of the SMN gene was detected. Of these 11, the deletion was associated with homozygous deletion of exon 8 in 10 and with heterozygous deletion of exon 8 in 1. Deletion of the SMN gene was not found in 1 Turkish patient with atypical manifestations of SMA II.
Samilchuk et al. (1996) carried out deletion analysis of the SMN gene and the neighboring NAIP (600355) gene in 11 cases of type I SMA and in 4 type II SMA cases. The patients were of Kuwaiti origin. They also analyzed samples from 41 healthy relatives of these patients and 44 control individuals of Arab origin. Samilchuk et al. (1996) found homozygous deletions of exons 7 and 8 of the SMN gene in all SMA patients studied. Exon 5 of the NAIP gene was homozygously absent in all type I SMA patients but was retained in the type II patients. They noted that there findings were consistent with the previously reported observations that the incidence of NAIP deletion is much higher in the clinically more severe cases (type I SMA) than in the milder forms, and all of the type II SMA patients in their study had at least one copy of the intact NAIP gene.
Modifying Factors
Jedrzejowska et al. (2008) reported 3 unrelated families with asymptomatic carriers of the biallelic deletion of the SMN1 gene. In the first family, the biallelic deletion was found in 3 sibs: 2 affected brothers with SMA3 and a 25-year-old asymptomatic sister. All of them had 4 copies of the SMN2 gene (601627). In the second family, 4 sibs were affected, 3 with SMA2 and 1 with SMA3, and each had 3 copies of SMN2. The clinically asymptomatic 47-year-old father had the biallelic deletion and 4 copies of SMN2. In the third family, the biallelic SMN1 deletion was found in a girl affected with SMA1 and in her healthy 53-year-old father who had 5 copies of SMN2. The findings again confirmed that an increased number of SMN2 copies in healthy carriers of the biallelic SMN1 deletion is an important SMA phenotype modifier, but also suggested that other factors play a role in disease modification.
Stratigopoulos et al. (2010) evaluated blood levels of PLS3 (300131) mRNA transcripts in 88 patients with SMA, including 29 males under age 11 years, 12 males over age 11, 29 prepubertal girls, and 18 postpubertal girls in an attempt to examine whether PLS3 was a modifier of the phenotype. PLS3 expression was decreased in the older patients of both sexes. However, expression correlated with phenotype only in postpubertal girls: expression was greatest in those with SMA type III, intermediate in those with SMA type II, and lowest in those with SMA type I, and correlated with residual motor function as well as SMN2 copy number. Stratigopoulos et al. (2010) concluded that the PLS3 gene may be an age- and/or puberty-specific and sex-specific modifier of SMA.
In fibroblast cultures from patients with SMA1, SMA2, or SMA3, Andreassi et al. (2004) found a significant increase in SMN2 gene (601627) expression (increase in SMN2 transcripts of 50 to 160% in SMA1, and of 80 to 400% in SMA2 and SMA3) and a more moderate increase in SMN protein expression in response to treatment with 4-phenylbutyrate (PBA). PBA treatment also resulted in an increase in the number of SMN-containing nuclear structures (GEMS). The authors suggested a potential use for PBA in treatment of various types of SMA.
Grzeschik et al. (2005) reported that cultured lymphocytes from patients with SMA showed increased production of the full-length SMN mRNA and protein in response to treatment with hydroxyurea. The findings suggested that hydroxyurea promoted inclusion of exon 7 during SMN2 transcription.
In a study of valproic acid (VPA) treatment in 10 SMA carriers and 20 patients with SMA1, SMA2, or SMA3, Brichta et al. (2006) found that VPA increased peripheral blood full-length SMN mRNA and protein levels in 7 carriers, increased full-length SMN2 mRNA in 7 patients, and left full-length SMN2 mRNA levels unchanged or decreased in 13 patients. The effect on protein levels in carriers was more pronounced than on mRNA levels, and the variability in augmentation among carriers and patients suggested to the authors that VPA interferes with transcription of genes encoding translation factors or regulates translation or SMN protein stability.
Brzustowicz et al. (1990) noted that HEXB (606873) maps to the same region and that deficiency of the product of this gene (as well as of the product of the HEXA gene) has been found in association with chronic cases of SMA.
Andreassi, C., Angelozzi, C., Tiziano, F. D., Vitali, T., De Vincenzi, E., Boninsegna, A., Villanova, M., Bertini, E., Pini, A., Neri, G., Brahe, C. Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy. Europ. J. Hum. Genet. 12: 59-65, 2004. [PubMed: 14560316] [Full Text: https://doi.org/10.1038/sj.ejhg.5201102]
Brichta, L., Holker, I., Haug, K., Klockgether, T., Wirth, B. In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valproate. Ann. Neurol. 59: 970-975, 2006. [PubMed: 16607616] [Full Text: https://doi.org/10.1002/ana.20836]
Brzustowicz, L. M., Lehner, T., Castilla, L. H., Penchaszadeh, G. K., Wilhelmsen, K. C., Daniels, R., Davies, K. E., Leppert, M., Ziter, F., Wood, D., Dubowitz, V., Zerres, K., Hausmanowa-Petrusewicz, I., Ott, J., Munsat, T. L., Gilliam, T. C. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3. Nature 344: 540-541, 1990. [PubMed: 2320125] [Full Text: https://doi.org/10.1038/344540a0]
Fried, K., Emery, A. E. H. Spinal muscular atrophy type II. A separate genetic and clinical entity from type I (Werdnig-Hoffmann disease) and type III (Kugelberg-Welander disease). Clin. Genet. 2: 203-209, 1971. [PubMed: 5146579]
Grzeschik, S. M., Ganta, M., Prior, T. W., Heavlin, W. D., Wang, C. H. Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells. Ann. Neurol. 58: 194-202, 2005. [PubMed: 16049920] [Full Text: https://doi.org/10.1002/ana.20548]
Haldane, J. B. S. The relative importance of principal and modifying genes in determining some human diseases. J. Genet. 41: 149-157, 1941.
Hanson, J. E., Bundey, S. E. Spinal muscular atrophy: an unusual variant with infantile onset and prolonged survival. Birth Defects Orig. Art. Ser. X(4): 339-340, 1974.
Hausmanowa-Petrusewicz, I., Zaremba, J., Borkowska, J. Chronic proximal spinal muscular atrophy of childhood and adolescence: problems of classification and genetic counselling. J. Med. Genet. 22: 350-353, 1985. [PubMed: 2370051] [Full Text: https://doi.org/10.1007/BF00193198]
Imai, T., Matsuya, M., Matsumoto, H., Ishikawa, Y., Minami, R. Preservation of central motor conduction in patients with spinal muscular atrophy type II. Brain Dev. 17: 432-435, 1995. [PubMed: 8747423] [Full Text: https://doi.org/10.1016/0387-7604(95)00087-9]
Jedrzejowska, M., Borkowska, J., Zimowski, J., Kostera-Pruszczyk, A., Milewski, M., Jurek, M., Sielska, D., Kostyk, E., Nyka, W., Zaremba, J., Hausmanowa-Petrusewicz, I. Unaffected patients with a homozygous absence of the SMN1 gene. Europ. J. Hum. Genet. 16: 930-934, 2008. [PubMed: 18337729] [Full Text: https://doi.org/10.1038/ejhg.2008.41]
Matthijs, G., Schollen, E., Legius, E., Devriendt, K., Goemans, N., Kayserili, H., Apak, M. Y., Cassiman, J.-J. Unusual molecular findings in autosomal recessive spinal muscular atrophy. J. Med. Genet. 33: 469-474, 1996. [PubMed: 8782046] [Full Text: https://doi.org/10.1136/jmg.33.6.469]
Melki, J., Abdelhak, S., Sheth, P., Bachelot, M. F., Burlet, P., Marcadet, A., Aicardi, J., Barois, A., Carriere, J. P., Fardeau, M., Fontan, D., Ponsot, G., Billette, T., Angelini, C., Barbosa, C., Ferriere, G., Lanzi, G., Ottolini, A., Babron, M. C., Cohen, D., Hanauer, A., Clerget-Darpoux, F., Lathrop, M., Munnich, A., Frezal, J. Gene for chronic proximal spinal muscular atrophies maps to chromosome 5q. Nature 344: 767-768, 1990. [PubMed: 1970420] [Full Text: https://doi.org/10.1038/344767a0]
Merette, C., Brzustowicz, L. M., Daniels, R. J., Davies, K. E., Gilliam, T. C., Melki, J., Munnich, A., Pericak-Vance, M. A., Siddique, T., Voosen, B., Wirth, B., Ott, J. An investigation of genetic heterogeneity and linkage disequilibrium in 161 families with spinal muscular atrophy. Genomics 21: 27-33, 1994. [PubMed: 8088801] [Full Text: https://doi.org/10.1006/geno.1994.1220]
Nevo, Y., Kramer, U., Legum, C., Shomrat, R., Fatal, A., Soffer, D., Harel, S., Shapira, Y. SMA type 2 unrelated to chromosome 5q13. Am. J. Med. Genet. 75: 193-195, 1998. [PubMed: 9450884]
Pearn, J. H., Carter, C. O., Wilson, J. The genetic identity of acute infantile spinal muscular atrophy. Brain 96: 463-470, 1973. [PubMed: 4743929] [Full Text: https://doi.org/10.1093/brain/96.3.463]
Samilchuk, E., D'Souza, B., Bastaki, L. Deletion analysis of the SMN and NAIP genes in Kuwaiti patients with spinal muscular atrophy. Hum. Genet. 98: 524-527, 1996. [PubMed: 8882869] [Full Text: https://doi.org/10.1007/s004390050253]
Simard, L. R., Vanasse, M., Rochette, C., Morgan, K., Lemieux, B., Melancon, S. B., Labuda, D. Linkage study of chronic childhood-onset spinal muscular atrophy (SMA): confirmation of close linkage to D5S39 in French Canadian families. Genomics 14: 188-190, 1992. [PubMed: 1427826] [Full Text: https://doi.org/10.1016/s0888-7543(05)80305-2]
Stratigopoulos, G., Lanzano, P., Deng, L., Guo, J., Kaufmann, P., Darras, B., Finkel, R., Tawil, R., McDermott, M. P., Martens, W., Devivo, D. C., Chung, W. K. Association of plastin 3 expression with disease severity in spinal muscular atrophy only in postpubertal females. Arch. Neurol. 67: 1252-1256, 2010. [PubMed: 20937953] [Full Text: https://doi.org/10.1001/archneurol.2010.239]
Wirth, B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum. Mutat. 15: 228-237, 2000. [PubMed: 10679938] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(200003)15:3<228::AID-HUMU3>3.0.CO;2-9]