Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder that leads to progressive weakness and loss of movement. SMA results from the degeneration of alpha motor neurons in the anterior horn of the spinal cord.1,2 Common symptoms include symmetrical muscle weakness, hypotonia, and muscular atrophy, typically of the proximal muscles and the lower extremities.1
The classical form of SMA in infants was first clinically described in 1890.3 A year after its identification, several cases of infants with progressive muscle weakness were described and the term “spinal muscular atrophy” was introduced.4 Milder forms of SMA were described in the following years.5,6
Today, SMA is a common genetic cause of death in infants, affecting about 1 in 11,000 individuals and with a carrier frequency of 1:54.7
Pathophysiology and Diagnosis of SMA
SMA is caused by mutations and deletions in the survival motor neuron 1 (SMN1) gene on chromosome 5q.8,9 SMA diagnosis is based on a genetic testing that evidences the homozygous deletion of SMN1 gene.12 Full SMN1 sequencing might be also important in cases where the genetic test is negative.1
Abnormalities affecting the SMN1 gene lead to a poor expression of the survival motor neuron (SMN) protein, a critical player for proper muscle functioning. Motor neuron development is consequently impaired when SMN protein levels decrease. Muscle wasting and weakness paired with feeding and respiratory difficulties also set in.10
A similar gene, SMN2, encoding for the same SMN protein, is also present in the 5q chromosome.1 The protein level expressed by this SMN2 gene is, however, lower when compared to SMN expression resulting from SMN1. Patients with SMA carry at least 1 copy of the SMN2 gene.11 To a certain degree, the severity of the resulting SMA phenotype is inversely proportional to the number of copies of the SMN2 gene and the resulting functional SMN protein produced.9
Classification of SMA
The first classification of SMA was proposed in 1961.13 Three groups were identified, based on the onset of presentation. In 1992, SMA classification was updated to include the highest level of motor function that patients can achieve.14 Today, there are 5 clinical phenotypes of SMA described, including a congenital variant and an adult form of the disease.1,11
- SMA Type 0 – Typically presents in utero or at birth, and represents the most severe form of the disease.
- SMA Type I (Werdnig-Hoffmann disease) – Responsible for 50% to 60% of the incidence of SMA. Onset of symptoms starts a few months after birth and death typically occurs before the patient reaches 2 years of age. These patients are never able to sit.
- SMA Type II – Typically presents between 6 and12 months of age. Patients with this phenotype are unable to walk without aid.
- SMA Type III (Kugelberg-Welander disease) – Onset of symptoms usually starts after 18 months. This type is a milder form of the disease; patients are able to walk independently but can lose this ability over time.
- SMA Type IV – Adult presentation and a milder form of the disease.
Management and Treatment of SMA
Until very recently, management of SMA was focused on providing supportive care. Maintenance of normal respiratory and muscular functions is essential for SMA patients’ quality of life. The identification of SMN1 as the gene responsible for SMA development and the pinpointing of SMN2 as a disease modulator paved the way for gene expression intervention.
To date, there are few SMN-dependent therapeutic approaches available in the market for SMA treatment. The intrathecal administration of nusinersen (marketed as SpinrazaⓇ) was approved by the US Food and Drug Administration (FDA) in 2016.10 The use of this antisense oligonucleotide (ASO) increases the expression of SMN protein through modulation of the SMN2 splicing, consequently improving motor function and survival.3 Nusinersen is the only therapeutic approved by the FDA for the treatment of all types of SMA; more than 8000 patients have received it.1
A different therapeutic strategy, approved by the FDA in 2019, is being explored with the administration of onasemnogene abeparvovec-xioi (marketed as ZolgensmaⓇ). In this therapy, the focus is SMN1 gene replacement using adeno-associated virus (AAV) serotypes, allowing the transfer of the SMN1 gene into neural cells and the improvement of SMN protein production.1
Risdiplam (Evrysdi™), approved in 2020, is the most recent drug to receive FDA approval for the treatment of SMA. This small molecule was developed to stimulate SMN2 gene expression of SMN protein and is the first oral medication approved as an SMA treatment.15
- Wirth B, Karakaya M, Kye et al. Twenty-five years of spinal muscular atrophy research: from phenotype to genotype to therapy, and what comes next. Annu Rev Genomics Hum Genet. 2020;21:231-261. doi:10.1146/annurev-genom-102319-103602
- Darbà J. Orphanet. Management and current status of spinal muscular atrophy: a retrospective multicentre claims database analysis. Orphanet J Rare Dis. 2020;15:(8). doi:10.1186/s13023-019-1287-y
- Werdnig G. Zwei frühinfantile hereditäre Fülle von progressive Muskelatrophie unter dem Bilde der Dystrophie aber auf neurotischer Grundlage. Archiv f Psychiatrie. 1891;22:437-480. doi:10.1007/BF01776636
- Hoffman J. Ueber chronische spinale Muskelatrophie im Kindesalter auf familiärer Basis. Dtsch Z Nervenheilkd. 1892;3:427-470. doi:10.1007/BF01668496
- Wohlfart G, Fex J, Eliasson S. Hereditary proximal spinal muscle atrophy, a clinical entity simulating progressive muscular dystrophy. Acta Psychiatr Neurol Scand. 1955;30(1-2):395-406.
- Kugelberg E, Welander L. Heredofamilial juvenile muscular atrophy simulating muscular dystrophy. AMA Arch Neurol Psychiatry. 1956;75(5):500-509. doi:10.1001/a rchneurpsyc.1956.02330230050005
- Yeo CJJ, Darras BT. Overturning the paradigm of spinal muscular atrophy as just a motor neuron. Pediatr Neurol. 2020;109:2-19. doi:10.1016/j.pediatrneurol.2020.01.003
- Lin CW, Kalb SJ, Yeh WS. Delay in diagnosis of spinal muscular atrophy: a systematic literature review. Pediatr Neurol. 2015;53:293e300. doi: 10.1016/j.pediatrneurol.2015.06.002
- Chen TH. New and developing therapies in spinal muscular atrophy: from genotype to phenotype to treatment and where do we stand? Int J Mol Sci. 2020;21(9):3297. doi:10.3390/ijms21093297
- Mercuri E, Pera MC, Scoto MC, Finkel R, et al. Spinal muscular atrophy — insights and challenges in the treatment era. Nat Rev Neurol. 2020;16(12):706-715. doi:10.1038/s41582-020-00413-4
- Arnold WD, Simard LR, Rutkove SB et al. Development and testing of biomarkers in spinal muscular atrophy. 2017;383-97. doi:10.1016/B978-0-12-803685-3.00024-0
- Boido M, Vercelli A. Neuromuscular junctions as key contributors and therapeutic targets in spinal muscular atrophy. Front Neuroanat. 2016;10:6. doi: 10.3389/fnana.2016.00006
- Byers RK, Banker BQ. Infantile muscular atrophy. Arch Neurol. 1961;5(2):140-164. doi:10.1001/archneur.1961.00450140022003
- Munsat TL, Davies KE. International SMA consortium meeting. Neuromuscul Disord. 1992;2(5-6):423-428. doi:10.1016/s0960-8966(06)80015-5
- Dhillon, S. Risdiplam: first approval. Drugs. 2020;80(17):1853-1858. doi:10.1007/s40265-020-01410-z
Reviewed by Michael Sapko, MD, on 7/1/2021.