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.
SMA type 4
Spinal muscular atrophy (SMA) type 4 is the least severe form of SMA.1 It usually only affects adults later in life and is characterized by muscle weakness, especially in the legs. Patients usually maintain mobility throughout their lives.2 The prevalence of SMA type 4 is estimated to be approximately 1/300,000.3
SMA Type 4 Causes
SMA type 4 is caused by mutations in the SMN1 gene, which encodes for the survival motor neuron (SMN) protein.4 The mutations prevent the SMN1 gene from making SMN protein.
A second, similar gene, SMN2,5 encodes for several different versions of the SMN protein due to alternative splicing of the mRNA. Only 10% to 15% of the SMN protein from the SMN2 gene is full-length and functional. The remaining protein is too short and quickly degraded by cells.
The copy number of the SMN2 gene differs from person to person and determines the severity of SMA in people who have a mutation in the SMN1 gene. Those with type 4 SMA have 4 to 8 copies of the SMN2 gene.2
The SMN protein is essential for the survival of lower motor neurons. As a result, when cells cannot produce enough SMN protein, lower motor neurons die. This causes muscles that do not receive any signals from them to atrophy, leading to muscle weakness and hypotonia.
SMA type 4 is inherited in an autosomal recessive manner; a person develops the disease only if they have inherited 2 faulty copies of the SMN1 gene from their parents.7
SMA Type 4 Symptoms
The symptoms of SMA type 4 usually appear after age 30. They include muscle weakness in the legs and hips which progresses to the shoulders and arms.3
Patients may have a waddling gait but maintain their ability to walk throughout their lives. Other symptoms include finger trembling and hypertrophy of the calf muscle. The disease does usually not affect the muscles used for breathing and swallowing and does not impact intelligence or life expectancy.
SMA Type 4 Diagnosis
It is difficult to diagnose SMA type 4, as symptoms resemble those of other neuromuscular conditions. The first step in diagnosis is taking the patient’s family history and performing a physical examination.
Studies to exclude other neuromuscular conditions such as amyotrophic lateral sclerosis, primary lateral sclerosis, myasthenia gravis, and carbohydrate metabolism disorders may be necessary.3
These tests include electromyography (EMG) to measure the electrical activity of the muscles, nerve conduction studies to assess the function of nerves, blood tests to check for creatine kinase levels and rule out muscular dystrophy, and in some cases, muscle biopsy to check the health of the muscle tissue.3 In SMA, muscle fibers are smaller in diameter, whereas in other muscular dystrophies, they vary in size.8
A definite diagnosis can be reached with genetic testing that shows a homozygous deletion in the SMN1 gene. If the SMN1 gene is present, sequencing it could reveal other mutations that could mean the gene is inactive. Genetic testing could eliminate the need for muscle biopsy and myography; however, physicians would need to consider SMA type 4 in the differential diagnosis alongside other more common causes of adult-onset motor neuron disease or movement disorders.
If a person is diagnosed with SMA type 4, genetic counseling should be provided to them and their family members.3 Genetically testing other family members could identify carriers and reduce their risk of passing the disease onto the next generation.
SMA Type 4 Treatment
There is currently no cure for any type of SMA. Treatment options focus on improving patients’ quality of life.3 Physiotherapy can help prevent contractures and relieve pain and fatigue. An occupational therapist can prescribe aids and adaptations to help patients maintain their independence and mobility for as long as possible.
Nusinersen (SpinrazaⓇ) is the first disease-modifying treatment approved by the US Food and Drug Administration (FDA) to treat SMA in all pediatric and adult patients.9 It is an antisense oligonucleotide that aims to increase the amount of functional SMN protein made from the SMN2 gene. Nusinersen has not been tested in clinical trials in patients with type 4 SMA and it is not known whether it benefits patients with this type.6,10
Another disease-modifying therapy approved by the FDA to treat all types of SMA is risdiplam (EvrysdiⓇ).11 It is a small molecule therapy that also aims to increase the production of functional SMN protein from the SMN2 gene. Again, it is not clear whether risdiplam would be beneficial for people with SMA type 4.
Reviewed by Michael Sapko, MD on 7/1/2021
- Types of SMA. Cure SMA. Accessed May 27, 2021.
- Butchbach MER. Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front Mol Biosci. 2016;3:7. doi:10.3389/fmolb.2016.00007
- Spinal muscular atrophy type 4. Genetic and Rare Disease Information Center. Accessed May 27, 2021.
- SMN1 gene. Medline Plus. Accessed May 27, 2021.
- SMN2 gene. Medline Plus. Accessed May 27, 2021.
- Spinal muscular atrophy type 4. Spinal Muscular Atrophy Support UK. Accessed May 27, 2021.
- About spinal muscular atrophy. National Human Genome Research Institute. Accessed May 27, 2021.
- Muscle biopsy. Neuromuscular Disease Center. Accessed May 27, 2021.
- FDA approves first drug for spinal muscular atrophy. News release. US Food and Drug Administration. December 23, 2016.
- Spinal muscular atrophy (SMA)|Diagnosis & treatment. Boston Children’s Hospital. Accessed May 27, 2021.
Evrysdi. Cure SMA. Accessed May 27, 2021.