Özge’s background is in research; she holds a MSc. in Molecular Genetics from the University of Leicester and a PhD. in Developmental Biology from the University of London. Özge worked as a bench scientist for six years in the field of neuroscience before embarking on a career in science communication. She worked as the research communication officer at MDUK, a UK-based charity that supports people living with muscle-wasting conditions, and then a research columnist and the managing editor of resource pages at BioNews Services before joining Rare Disease Advisor.
Spinal muscular atrophy (SMA) is a rare genetic disease characterized by the loss of lower motor neurons. This results in muscle weakness and wasting, especially in the lower and upper extremities.
SMA types 0 through 4 are caused by mutations in the SMN1 gene, which is located on chromosome 5.1 These are known as 5q SMA. SMA type 0 is the most severe form of the disease, with symptoms appearing before birth. In SMA type 4, the least severe form, symptoms do not appear until after the third decade of life.
Learn more about SMA classifications.
Other, rarer types of SMA are caused by mutations in genes that include IGHMBP2 (SMA with respiratory distress), UBA1, DYNC1H1, TRPV4, PLEKHG5, GARS, FBXO38 (distal SMA), and UBA1 (X-linked SMA).
Genetics of 5q SMA
SMA types 0 through 4 are caused by homozygous deletion of the SMN1 gene or heterozygous deletion and a point mutation on the existing SMN1 allele.2 SMN1 codes for survival motor neuron (SMN) protein, which is essential for the health of motor neurons. In the case of a deletion or point mutation, cells cannot make SMN protein from the SMN1 gene. In most cases (95%), SMA is caused by deletion of both alleles of the SMN1 gene. Other cases may have a point mutation on one allele and a deletion on the other.
A second gene, SMN2, which is similar to SMN1, also codes for SMN protein. However, SMN1 and SMN2 differ by a single base.3 Consequently, exon 7 is excluded from most of the mature SMN2 mRNA as a consequence of alternative splicing,4 so that most of the SMN protein made from SMN2 is shorter than normal and nonfunctional. It is estimated that only 10% to 15% of the SMN protein made from the SMN2 gene is of full length and functional.3
Because of gene duplication or conversion, the number of copies of the SMN2 gene varies among individuals from 1 or 2 copies to 8 copies. A higher SMN2 copy number is associated with a less severe SMA phenotype. Thus, people with SMA type 0 usually have 1 copy of the SMN2 gene, those with SMA type 1 have 2 copies, those with SMA type 2 have 3 copies, those with SMA type 3 have 3 or 4 copies, and those with SMA type 4 usually have 4 or more copies.5
However, it is not possible to predict accurately the type of SMA a patient will have based on the SMN2 copy number alone because other genetic factors may be affecting the severity of the symptoms.3 For example, research has shown that the severity of SMA correlates with the length of the deletion in the telomeric copy of the 5q13 locus. This locus can include both the SMN1 gene and another gene, called NAIP, which codes for NLR family apoptosis inhibitory protein. Deletions in the fifth exon of the NAIP gene are observed significantly more often in patients with relatively severe SMA.6
Genetics of Other Types of SMA
Spinal muscular atrophy with respiratory distress (SMARD) is caused by mutations in the IGHMBP2 gene.7 More than 60 different mutations have been identified in this gene. The protein encoded by the IGHMBP2 gene plays a role in DNA replication, transcription. and translation. When IGHMBP2 protein is defective, motor neurons are damaged and die through an unknown mechanism.
Distal SMA can be caused by mutations in 6 different genes: UBA1, DYNC1H1, TRPV4, PLEKHG5, GARS, and FBXO38. Some forms of distal SMA overlap with Charcot-Marie-Tooth disease.8 SMA caused by mutations in DYNC1H1, TRPV4, GARS, and FBXO38 is inherited in an autosomal dominant manner, in contrast to SMA types 0 to 4.9
X-linked SMA is caused by mutations in the UBA1 gene, located on the X chromosome.10 The UBA1 gene codes for the ubiquitin-activating enzyme E1, which is necessary for the degradation of damaged or unneeded protein within cells. Mutations in UBA1, therefore, result in protein accumulation and the disruption of protein homeostasis within cells. Motor neurons are particularly vulnerable to protein accumulation, likely because of their large size.
Reviewed by Michael Sapko, MD on 7/1/2021
- Spinal muscular atrophy. Muscular Dystrophy Association. Accessed June 10, 2021.
- Spinal muscular atrophy fact sheet. National Institute of Neurological Disorders and Stroke. Published May 2019. Accessed June 10, 2021.
- The genetics of 5q spinal muscular atrophy. Spinal muscular atrophy UK. Accessed June 10, 2021.
- Khoo B, Krainer AR. Splicing therapeutics in SMN2 and APOB. Curr Opin Mol Ther. 2009;11(2):108-115.
- Spinal muscular atrophy. MedlinePlus. Updated August 18, 2020. Accessed June 10, 2021.
- Hryshchenko NV, Yurchenko AA, Karaman HS, Livshits LA. Genetic modifiers of the spinal muscular atrophy phenotype. Cytol Genet. 2020;54:130-136. doi:10.3103/S0095452720020073
- Spinal muscular atrophy with respiratory distress. National Organization for Rare Disorders. Published 2019. Accessed June 10, 2021.
- Types of SMA. Muscular Dystrophy Association. Accessed June 10, 2021.
- Farrar MA, Kiernan MC. The genetics of spinal muscular atrophy: progress and challenges. Neurotherapeutics. 2015;12(2):290-302. doi:10.1007/s13311-014-0314-x
- X-linked infantile spinal muscular atrophy. MedlinePlus. Updated August 18, 2020. Accessed June 10, 2021.