DESCRIPTION
Spinal Muscular Atrophy Types
There are four different types of SMA.
They are classified by:
- When symptoms start for a child
- How much motor development the child can achieve
Types of SMA:
The most common form of SMA is Type 1:
- Type 1 affects 55-60% of SMA patients.
- Without treatment, most infants with SMA Type 1 die of breathing failure by age 2.
Genetic Basis of SMA
SMA is caused by a genetic difference. The survival motor neuron 1 gene (SMN1 gene) produces the survival motor neuron (SMN) protein. The SMN protein is important for motor neuron survival.
Most people have two copies of the SMN1 gene. In those with this disorder, the two SMN1 copies are absent or mutated. This leads to low levels of the SMN protein.
The SMN2 gene is a “backup” version of the SMN1 gene, but it only produces about 5% to 10% percent of the SMN protein SMN1 produces. All of us have zero, one, two, or more copies of SMN2. It does not matter how many SMN2 genes someone without SMA has. There is enough SMN protein produced from the two SMN1 genes. However, in people with SMA, the number of SMN2 genes matters a lot. The more SMN2 genes, the more SMN protein is produced, and the less severe the disease.
The number of SMN2 genes can impact what type of SMA a child has:
- Type 1 patients usually have 2 copies of SMN2.
- Type 2 patients usually have 3 copies of SMN2.
- Type 3 patients have 3 or 4 copies of SMN2.
- Type 4 patients have 4 or more copies of SMN2.
New Therapies and the SMN2 Gene
It is important to know about SMN2 because two new SMA drugs work on increasing SMN protein production from the existing “backup” SMN2 genes.
CAUSES
SMA is a genetic disease caused by problems with both SMN1 genes.
- 95% of patients are missing both copies
- 5% of patients are missing one copy, while the other is mutated
1 in 50 people worldwide of all ethnic backgrounds have only one copy of this gene. These individuals are called “carriers,” but they will not have SMA.
Here are some possible outcomes for children of SMA carriers:
One parent has one copy, the other parent has two copies
Both parents have only one copy
Those with zero SMN1 genes and only a few copies of SMN2 genes will experience drastically lowered SMN protein levels throughout the body. Tissues cannot function well without SMN protein. The most vulnerable cells, the motor neurons, will begin to die.
TREATMENT AND THERAPIES
There are three innovative therapies which replace SMN1 or act on SMN2 to increase its production of SMN protein. These FDA approved therapies are Nusinersen, Onasemnogene Abeparvovec-Xioi Gene Replacement Therapy, and Risdiplam.
While none of these therapies are cures, they significantly improve the lifespan, muscle function, breathing, and swallowing of most SMA patients. So far, the safety profiles of these drugs are good. However, there are some unknowns. Speak to your doctor about medication options and their side effects.
These three drugs are among the most expensive in the world. They may become a financial burden without appropriate insurance coverage. Coverage for the drugs and their procedures differs, based on policy providers. Policy provider restrictions can include age, type of SMA, and location of patient.
All three drug companies have co-pay assistance programs for those with commercial insurances and may be able to refer to charitable organizations for third-party assistance. Medicare and Medicaid also provide coverage on a case by case basis.
OUTLOOK
Improved Outlook for Children with SMA
Since these new treatments were FDA-approved after 2016, the prognosis for children with SMA is promising. This is particularly true for those treated earlier in life, before much motor neuron loss and weakness has occurred. Those diagnosed through newborn screening will have access to these early treatments.
Children who are treated can expect to have a longer lifespan and achieve motor milestones never before achieved for those with SMA. With treatment, some Type 1 patients can sit and sometimes even stand or walk. Some Type 2 patients can stand and walk. This is unprecedented in this disease. In babies treated very early before any symptoms arise, SMA can be essentially prevented.
Unknowns of Treatment
No clinical trials have been conducted to test which of the three treatments above is most effective or has the fewest risks.
FDA-approved dosages of nusinersen remain constant from infancy to adulthood. It is not known at this point whether such doses need to be optimized by age and weight as the child grows.
It is too early to tell how long the treatment effects of gene replacement therapy will last. We also need to watch out for side effects for these new treatments.
Limitations of Treatment
Treatment effects can differ from patient to patient. Treatment is not curative. There is likely to be residual weakness, which can require
- Physical and occupational therapy
- Mobility aids and wheelchairs
However, if a child is treated after a newborn screening, before symptoms occur, the disease may be prevented.
Educational Outlook
Memory and learning are generally unaffected by SMA. School performance is unlikely to be a concern. Many Type 2 and Type 3 children do very well in school. They can get advanced degrees. There is not enough data about this for Type 1 children, because in the past, most died by age 2.
So far, there have not been any reports of poor school performance in those who have been treated for SMA and survived to childhood.
Other Considerations
Diet and exercise are important for those with SMA and enhance the effect of the disease-modifying treatments.
Resources
ORGANIZATIONS/GROUPS
Cure SMA
Cure SMA leads the way to a world without spinal muscular atrophy, the number one genetic cause of death for infants. They fund and direct comprehensive research that drives breakthroughs in treatment and care. They also provide resources and support for families both locally and nationally through events and conferences. Cure SMA has 36 volunteer-led chapters in the U.S.
5-Part Series: Let’s Talk About Spinal Muscular Atrophy
Let’s Talk About Spinal Muscular Atrophy is an in-depth look at SMA. Child Neurology Foundation created this five-part video series in collaboration with Cure SMA.
Muscular Dystrophy Association
Families are at the heart of Muscular Dystrophy Association’s mission. A caring and concerned group of families started MDA in 1950, and they continue to relentlessly pursue their promise to free families from the life-threatening effects of muscular dystrophy and muscle-debilitating diseases today. MDA focuses on over 43 neuromuscular diseases in children and adults, including Spinal Muscular Atrophy.
MDA empowers families with support by providing: A Resource List, Outside Organization Programs & Information, Summer Camp, Community Education, Community Events, and Young Adult Programs. MDA’s research program awards grants to the world’s best scientists investigating promising theories and therapies that may accelerate treatments and cures for families living with muscular dystrophy, ALS and related neuromuscular diseases.
PUBLICATIONS
JCN: Spinal Muscular Atrophy
Podcast from SAGE Neuroscience and Neurology/Journal of Child Neurology (JCN). Dr. Alison Christy interviews Dr. Richard Finkel on his article “Spinal Muscular Atrophy Type I” and Dr. Adrian Kranier of Cold Springs Harbor about the development of nusinercin – a medication that may revolutionize how we treat SMA and other childhood diseases. Moira Flanigan also discusses our learning topic, the basics of SMA.
JCN: What Your Pediatric Neurologist Wants You to Know
Podcast from SAGE Neuroscience and Neurology/Journal of Child Neurology (JCN). JCN’s Residents and Fellows Board Director, Dr. Alison Christy, interviews Dr. Farida Abid, Assistant Professor in Pediatric Neurology at Texas Children’s Hospital about Neuromuscular disease.
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