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), a rare genetic disease that affects the nervous system and muscles, is caused by mutations in the SMN1 gene. The SMN1 gene encodes for the SMN protein, which is essential for the survival of motor neurons, the nerve cells that control muscle movement. When there is a mutation in the SMN1 gene, cells cannot produce enough SMN protein, leading to motor neuron death and the inability to send nervous signals to muscles. Without the signals coming from motor neurons, muscle cells atrophy over time. The result is serious, widespread muscle weakness and wasting in spinal muscular atrophy patients.
For the purposes of spinal muscular atrophy diagnosis and treatment, the disease is classified into 5 broad types, depending on the severity of the disease and the age of onset of the symptoms. SMA type 0 is the most severe disease type, where symptoms appear even before birth, and SMA type 4 is the least severe, only affecting adults later in life.
An SMA diagnosis is typically determined by a neurologist through a range of diagnostic approaches as part of the disease’s standard workup.
Physical Examination And Family History
The first diagnostic approach consists of a physical examination to assess the patient’s muscle strength and identify whether the patient is lagging in meeting key developmental milestones. Signs and symptoms of SMA to assess during a physical examination include a history of motor difficulties, loss of motor skills, weakness in proximal muscles, hyporeflexia or areflexia, tongue fasciculations, and signs of lower motor neuron disease. In pediatric patients, early physical examinations are usually conducted by pediatricians, which may lead to subsequent referrals to other specialists, such as neurologists.
Additionally, doctors review the patient’s family history and ask whether any other family members have been diagnosed with SMA.
Creatine Kinase Levels in SMA Diagnosis
If the doctor sees any signs of muscle weakness or wasting, he or she may order a serum creatine kinase (CK) test.1 CK is a protein that leaks out of muscles into the bloodstream when there is muscle damage.
The CK test is not specific to SMA, however, and other neuromuscular conditions, such as muscular dystrophy (MD), can also lead to high levels of CK in the blood. Moreover, levels of CK in patients diagnosed with SMA type 1 are usually normal and slightly high in patients with SMA type 2 and type 3.2 So while CK levels are often ordered as part of a workup for muscle weakness and atrophy in children, they are not a standard part of the workup for SMA.
Nerve Conduction Studies and Electromyography in SMA Diagnosis
These tests usually show features of motor neuron and axon loss consistent with the loss of function of motor neurons in patients with SMA.3
Nerve conduction studies typically show features of chronic motor axonal loss. However, sensory nerve action potentials are preserved. The amplitude of compound muscle action potential is mainly affected while conduction velocities are usually preserved.
EMG shows active denervation and reinnervation to compensate as well as enlargement of motor unit action potential. Abnormal spontaneous activity is also usually seen.
SMA Genetic Testing in SMA Diagnosis
Genetic testing is by far the most accurate way to diagnose spinal muscular atrophy. In SMA genetic testing, the patient’s DNA is isolated from a small sample of blood and tested to see if there are any mutations in the SMN1 gene. Genetic testing can identify at least 95% of SMA cases.7
Most cases of SMA are caused by the homozygous deletion of the SMN1 gene or a gene conversion event. In very rare cases, it can be caused by intragenic mutations that inactivate the gene.5 Genetic testing first looks for SMN1 gene deletions. If there is no deletion, the gene is sequenced.6
Further, genetic testing of family members can identify other carriers.. This is usually coupled with genetic counseling. If it is revealed that a family member is a carrier of SMA, a genetic counselor can help them calculate their risk of having a child affected by the disease.
If 2 carriers have already conceived a baby, then there is a risk that the fetus might have inherited SMA. In such cases, there are genetic tests available before the baby is born.8 These tests include chorionic villus sampling (CVS) and amniocentesis. In CVS, doctors collect a sample of cells from the placenta and test it genetically for mutations in the SMN1 gene. In amniocentesis, a sample of amniotic fluid is collected and tested. Both methods carry a small risk of miscarriage.
According to the International SMA Consortium (ISMAC), CVS and amniocentesis can predict SMA prenatally with 88% to 99% accuracy.9
SMA Newborn Screening in SMA Diagnosis
Newborn screening is a method of diagnosing genetic diseases through heel stick testing at the time of birth, usually before symptoms of SMA appear. Diagnosing SMA at birth allows treatment to begin as early as possible, before irreversible damage occurs, potentially maximizing the effectiveness of treatment.
SMA atrophy is currently part of newborn screening programs in 34 states in the US.10 In Europe, the disease is not yet included in newborn screening programs.
Muscle Biopsy in SMA Diagnosis
Although muscle biopsy is no longer performed to diagnose SMA, there are certain histological features that could identify disease severity.3
Infants with SMA types 1 and 2 show large groups of atrophic type 1 and 2 fibers, which are round rather angular. These are interspersed with fascicles of hypertrophied and normal fibers.
In milder cases of SMA type 2 and 3, there are groups of uniformly atrophic fibers of varying size between groups of non-atrophic fibers arranged in large groups of 30 to 200 fibers.
The features of muscle biopsy in SMA type 4 are similar to those seen in SMA type 3.
Reviewed by Michael Sapko, MD on 7/1/2021
- Spinal muscular atrophy. Muscular Dystrophy Association. Accessed June 1, 2021.
- Zhang Y, Huang JJ, Wang ZQ, et al. Value of muscle enzyme measurement in evaluating different neuromuscular diseases. Clin Chim Acta. 2012;413(3-4):520-524. doi:10.1016/j.cca.2011.11.016
- Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve. 2015; 51(2):157-167. doi:10.1002/mus.24497
- Spinal muscular atrophy (SMA). UCSF Benioff Children’s Hospitals. Accessed May 28, 2021.
- Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum. Mutat. 2000;15(3):228-237. doi:10.1002/(SICI)1098-1004(200003)15:3<228::AID-HUMU3>3.0.CO;2-9
- Mercuri E, Bertini E, Iannaccone ST. Childhood spinal muscular atrophy: controversies and challenges. Lancet Neurol. 2012;11(5):443-452. doi:10.1016/S1474-4422(12)70061-3
- Spinal muscular atrophy fact sheet. National Institute of Neurological Disorders and Stroke. Accessed May 30, 2021.
- Diagnosis: spinal muscular atrophy. NHS. Accessed May 27, 2021.
- Milunsky JM, Cheney SM. Prenatal diagnosis of spinal muscular atrophy by direct molecular analysis: efficacy and potential pitfalls. Genet Test. 1999;3(3):255-258. doi:10.1089/109065799316554
- Newborn screening for SMA. Cure SMA. Accessed May 27, 2021.