Alternative titles; symbols
ICD10CM: G12.1; ORPHA: 70, 83420; DO: 0050529;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q13.2 | Spinal muscular atrophy-4 | 271150 | Autosomal recessive | 3 | SMN1 | 600354 |
A number sign (#) is used with this entry because autosomal recessive adult-onset spinal muscular atrophy type IV (SMA4) is caused by mutation or deletion in the SMN1 gene (600354) on chromosome 5q13.
Allelic disorders with overlapping phenotypes of differing severity and age at onset include SMA type I (253300), SMA type II (253550), and SMA type III (253400).
Pearn et al. (1978) described 9 patients from 6 families with adult-onset spinal muscular atrophy. The median age at onset was 35 years, and the mean age at initial medical presentation was 37 years. The condition was relatively benign, with symmetrical proximal muscle involvement and preservation of the distal musculature. Family studies suggested autosomal recessive inheritance.
Brahe et al. (1995) reported 6 patients from 4 families with autosomal recessive adult-onset SMA. Age at onset ranged from 20 to 32 years, and symptoms included tongue fasciculations, hand tremor, symmetrical weakness of the proximal muscles that was more severe in the lower limbs, and atrophy of the quadriceps muscle. Three patients had bilateral hypertrophy of the calves. One patient was very mildly affected; 3 patients had done military service, apparently without problems. In a letter, Zerres et al. (1995) noted that they defined SMA type IV as onset after age 30; patients with onset before age 30 years who retained the ability to walk were defined as having SMA type III.
Clermont et al. (1995) reported a 73-year-old woman who developed type IV SMA at age 47, with proximal muscle weakness, muscular atrophy, and patellar areflexia. Three of her 5 children had SMA type II, and all died before age 15 years. Molecular analysis showed that the mother had deletion of SMN exons 7 and 8 on both chromosomes, but no DNA from the children was available. Clermont et al. (1995) concluded that adult and childhood SMA are allelic disorders, emphasizing the continuum of clinical phenotypes caused by SMN gene mutations and deletions.
Habets et al. (2022) evaluated the bioenergetic and structural characteristics of the biceps and triceps muscles in 14 patients with SMA type III and 1 patient with SMA type IV. MRIs demonstrated fatty infiltration in both triceps and biceps, which was greater in the triceps, and atrophy of the triceps muscles. Maximal voluntary contraction of force was reduced in both triceps and biceps muscles, and blood lactate increases after exercise were lower in patients compared to controls. 31P magnetic resonance spectroscopy studies identified white-to-red shift of muscle fiber types and slow metabolic recovery after exercise in white myofibers due to ATP synthetic dysfunction. Habets et al. (2022) concluded that these findings demonstrated the disproportionate vulnerability of white myofibers to SMN protein depletion.
Weihl et al. (2006) reported increased quantitative muscle strength and subjective function in 7 adult patients with SMA3/SMA4 who were treated with oral valproate for a mean duration of 8 months. Most patients reported improvement within a few months of beginning treatment. The authors noted that previous studies (see Brichta et al., 2003) had suggested that inhibitors of histone deacetylase, such as valproate, may increase SMN2 (601627) gene transcription and result in increased production of full-length SMN protein.
In 6 patients with SMA4, Brahe et al. (1995) identified deletion of exons 7 and 8 of the SMN1 gene, indicating that autosomal recessive adult SMA is allelic to the childhood forms of SMA.
Mazzei et al. (2004) found evidence for a gene conversion event in SMN1 in 3 patients with SMA4, supporting the notion that a gene conversion event is usually associated with a milder SMA phenotype and a later age at disease onset.
Modifying Factors
Wirth et al. (2006) analyzed SMN2 copy number in 115 patients with SMA3 or SMA4 who had confirmed homozygous absence of SMN1 and found that 62% of SMA3 patients with age of onset less than 3 years had 2 or 3 SMN2 copies, whereas 65% of SMA3 patients with age of onset greater than 3 years had 4 to 5 SMN2 copies. Of the 4 adult-onset (SMA4) patients, 3 had 4 SMN2 copies and 1 had 6 copies. Wirth et al. (2006) concluded that SMN2 may have a disease-modifying role in SMA, with a greater SMN2 copy number associated with later onset and better prognosis.
Heterogeneity
Hahnen et al. (1995) reported 4 patients with onset of SMA after age 30 who showed no homozygous deletion of exons 7 and 8 of the SMN1 gene, suggesting genetic heterogeneity. However, the 4 patients with presumed SMA IV had no family history, and spontaneous autosomal dominant mutation at a different locus could not be excluded.
Although human SMN1 and SMN2 both encode the SMN protein, the SMN2 gene is unable to compensate for the loss of SMN1 protein in SMA patients. A translationally silent T at nucleotide +6 of SMN2 exon 7 instead of SMN1's C causes the final RNA product to be improperly regulated, with the majority of SMN2 pre-mRNA transcripts lacking exon 7. While humans have both SMN1 and SMN2 genes, mice and other mammals have only a single Smn gene. Using mouse and human SMN minigenes and homologous recombination, Gladman et al. (2010) created a mouse model of SMA by inserting the SMN2 C-to-T nucleotide alteration into the endogenous mouse Smn gene. The C-to-T mutation was sufficient to induce exon 7 skipping in the mouse minigene as in the human SMN2. When the mouse Smn gene was humanized to carry the C-to-T mutation, keeping it under the control of the endogenous promoter, and in the natural genomic context, the resulting mice exhibited exon 7 skipping and mild adult-onset SMA characterized by muscle weakness, decreased activity, and an alteration of muscle fiber size. Gladman et al. (2010) proposed that the Smn C-to-T mouse is a model for the adult-onset form of SMA (type III/IV) known as Kugelberg-Welander disease.
Brahe, C., Servidei, S., Zappata, S., Ricci, E., Tonali, P., Neri, G. Genetic homogeneity between childhood-onset and adult-onset autosomal recessive spinal muscular atrophy. Lancet 346: 741-742, 1995. [PubMed: 7658877] [Full Text: https://doi.org/10.1016/s0140-6736(95)91507-9]
Brichta, L., Hofmann, Y., Hahnen, E., Siebzehnrubl, F. A., Raschke, H., Blumcke, I., Eyupoglu, I. Y., Wirth, B. Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy. Hum. Molec. Genet. 12: 2481-2489, 2003. [PubMed: 12915451] [Full Text: https://doi.org/10.1093/hmg/ddg256]
Clermont, O., Burlet, P., Lefebvre, S., Burglen, L., Munnich, A., Melki, J. SMN gene deletions in adult-onset spinal muscular atrophy. (Letter) Lancet 346: 1712-1713, 1995. [PubMed: 8551862] [Full Text: https://doi.org/10.1016/s0140-6736(95)92881-2]
Gladman, J. T., Bebee, T. W., Edwards, C., Wang, X., Sahenk, Z., Rich, M. M., Chandler, D. S. A humanized Smn gene containing the SMN2 nucleotide alteration in exon 7 mimics SMN2 splicing and the SMA disease phenotype. Hum. Molec. Genet. 19: 4239-4252, 2010. [PubMed: 20705738] [Full Text: https://doi.org/10.1093/hmg/ddq343]
Habets, L. E., Bartels, B., Asselman, F.-L., Hooijmans, M. T., van den Berg, S., Nederveen, A. J., van der Pol, W. L., Jeneson, J. A. L. Magnetic resonance reveals mitochondrial dysfunction and muscle remodelling in spinal muscular atrophy. Brain 145: 1422-1435, 2022. [PubMed: 34788410] [Full Text: https://doi.org/10.1093/brain/awab411]
Hahnen, E., Forkert, R., Marke, C., Rudnik-Schoneborn, S., Schonling, J., Zerres, K., Wirth, B. Molecular analysis of candidate genes on chromosome 5q13 in autosomal recessive spinal muscular atrophy: evidence of homozygous deletions of the SMN gene in unaffected individuals. Hum. Molec. Genet. 4: 1927-1933, 1995. [PubMed: 8595417] [Full Text: https://doi.org/10.1093/hmg/4.10.1927]
Mapelli, G., Ramelli, E. Familial progressive spinal amyotrophy with limb root distribution and onset in adult life (neurogenic pseudomyopathy of Wohlfart-Kugelberg-Welander). In: Waston, J. N.; Canal, N.; Scorlato, G. (eds.): Muscle Diseases. Amsterdam: Excerpta Medica (pub.) 1970.
Mazzei, R., Gambardella, A., Conforti, F. L., Magariello, A., Patitucci, A., Gabriele, A. L., Sprovieri, T., Labate, A., Valentino, P., Bono, F., Bonavita, S., Zappia, M., Muglia, M., Quattrone, A. Gene conversion events in adult-onset spinal muscular atrophy. Acta Neurol. Scand. 109: 151-154, 2004. [PubMed: 14705979] [Full Text: https://doi.org/10.1034/j.1600-0404.2003.00181.x]
Pearn, J. H., Hudgson, P., Walton, J. N. A clinical and genetic study of spinal muscular atrophy of adult onset. Brain 101: 591-606, 1978. [PubMed: 737522] [Full Text: https://doi.org/10.1093/brain/101.4.591]
Tsukagoshi, H., Nakanishi, T., Kondo, K., Tsubaki, T. Hereditary proximal neurogenic muscular atrophy in adults. Arch. Neurol. 12: 597-603, 1965. [PubMed: 14295959] [Full Text: https://doi.org/10.1001/archneur.1965.00460300045005]
Weihl, C. C., Connolly, A. M., Pestronk, A. Valproate may improve strength and function in patients with type III/IV spinal muscle atrophy. Neurology 67: 500-501, 2006. [PubMed: 16775228] [Full Text: https://doi.org/10.1212/01.wnl.0000231139.26253.d0]
Wirth, B., Brichta, L., Schrank, B., Lochmuller, H., Blick, S., Baasner, A., Heller, R. Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number. Hum. Genet. 119: 422-428, 2006. [PubMed: 16508748] [Full Text: https://doi.org/10.1007/s00439-006-0156-7]
Zerres, K., Rudnik-Schoneborn, S., Forkert, R., Wirth, B. Genetic basis of adult-onset spinal muscular atrophy. (Letter) Lancet 346: 1162 only, 1995. [PubMed: 7475624] [Full Text: https://doi.org/10.1016/s0140-6736(95)91835-3]