Spinal Muscular Atrophy
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Spinal Muscular Atrophy
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Spinal Muscular Atrophy header

Authors:

Crystal Jing Jing Yeo, MD, PhD, MRCP(UK)
School of Medicine, Medical Sciences and Nutrition, University of Aberdeen; LKC School of Medicine-Imperial College London and NTU Singapore; Boston Children’s Hospital 

Professor Basil T. Darras, MD
Boston Children’s Hospital; Harvard Medical School 

Reviewed: July 2021 

SUMMARY

Spinal muscular atrophy (SMA) is a neurological disorder that affects about 1 in 10,000 births. It is caused by the death of motor neurons in the spinal cord. Spinal motor neurons are special nerve cells that carry signals from the spinal cord to the muscles. When thedie, the muscles they connect shrink and become weak. This makes moving, breathing, and swallowing difficult. 

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Disorder Overview

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: 

Type 1

Symptoms start by the age of 6 months. The child never sits.   

Type 2

Symptoms start between 6 to 18 months. The child can sit but not walk.  

Type 3

 Symptoms start between 18 months and older childhood. The child can walk but may lose this ability as the disease progresses.

Type 4

Symptoms start in adulthood. The adult experiences mild muscle weakness. 

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. 
Spinal Muscular Atrophy

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.  

SIGNS AND SYMPTOMS

When a baby is born “floppy” and very weak, doctors may suspect SMA. They may send blood for genetic testing. In most states in the US, SMA is part of newborn screening. If this screening shows that the baby is missing both SMN1 genes, the number of SMN2 genes is checked. Babies with 2, 3, or even 4 copies of SMN2 genes should receive SMA drugs urgently, before they develop symptoms of disease. Babies with only 1 SMN2 copy can be considered also. It is a medical emergency as death of motor neurons is irreversible. The earlier the babies are treated, the more motor neurons can be saved, and the better they fare.  

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

Children have a 50% chance of inheriting only one copy of the SMN1 gene. Children will not have SMA. 

Both parents have only one copy

Children have a 25% chance of receiving zero copies of the SMN1 gene and 25% chance of receiving 2 copies. Children have a 25% chance of having SMA, and a 50% chance of being a carrier with one SMN1 gene. 

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.   

Spinal Muscular Atrophy 1

LABORATORY INVESTIGATIONS 

Genetic tests can be used to diagnose SMA. They can look for: 

  • SMN1 gene copies  
  • SMN1 gene mutations 
  • SMN2 gene copies 

Testing determines which infants are eligible for new therapies. New therapies can: 

  • Replace SMN1 
  • Act on SMN2 to increase SMN protein 

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.  

Spinal Muscular Atrophy 3

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.  

Spinal Muscular Atrophy 2

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 ListOutside Organization Programs & InformationSummer Camp, Community EducationCommunity 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. 

Childhood Stroke 1

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. 

Child Neurology Foundation (CNF) solicits resources from the community to be included on this webpage through an application process. CNF reserves the right to remove entities at any time if information is deemed inappropriate or inconsistent with the mission, vision, and values of CNF. 

Research 

ClincalTrials.gov for Spinal Muscular Atrophy are clinical trials that are recruiting or will be recruiting. Updates are made daily, so you are encouraged to check back frequently.  

ClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted around the world. This is a resource provided by the U.S. National Library of Medicine (NLM), which is an institute within the National Institutes of Health (NIH). Listing a study does not mean it has been evaluated by the U.S. Federal Government. Please read the NLM disclaimer for details.  

Before participating in a study, you are encouraged to talk to your health care provider and learn about the risks and potential benefits. 

Family Stories

Cure SMA shares inspirational stories from the Spinal Muscular Atrophy community on their Community Spotlight page.

The information in the CNF Child Neurology Disorder Directory is not intended to provide diagnosis, treatment, or medical advice and should not be considered a substitute for advice from a healthcare professional. Content provided is for informational purposes only.  CNF is not responsible for actions taken based on the information included on this webpage. Please consult with a physician or other healthcare professional regarding any medical or health related diagnosis or treatment options. 

References

Yeo CJJ, Darras BT. Extraneuronal phenotypes of spinal muscular atrophy. Ann Neurol. 2021 Jan;89(1):24–6. PMID: 33051879; https://doi.org/10.1002/ana.25930 

Yeo CJJ, Darras BT. Overturning the paradigm of spinal muscular atrophy as just a motor neuron disease. Pediatric Neurology. 2020 Aug;109:12–9. https://doi.org/10.1016/j.pediatrneurol.2020.01.003  

Darras BT, Masson R, Mazurkiewicz-Bełdzińska M, Rose K, Xiong H, Zanoteli E, et al. Firefish part 2: 24-month efficacy and safety of risdiplam in infants with type 1 spinal muscular atrophy(Sma)(4126). Neurology [Internet]. 2021 Apr 13 [cited 2021 Jun 18];96(15 Supplement). Available from: https://n.neurology.org/content/96/15_Supplement/4126  

De Vivo DC, Bertini E, Swoboda KJ, Hwu W-L, Crawford TO, Finkel RS, et al. Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study. Neuromuscular Disorders. 2019 Nov;29(11):842–56. PMID: 31704158; https://doi.org/10.1016/j.nmd.2019.09.007  

Mendell JR, Al-Zaidy S, Shell R, Arnold WD, Rodino-Klapac LR, Prior TW, Lowes L, Alfano L, Berry K, Church K, Kissel JT, Nagendran S, L’Italien J, Sproule DM, Wells C, Cardenas JA, Heitzer MD, Kaspar A, Corcoran S, Braun L, Likhite S, Miranda C, Meyer K, Foust KD, Burghes AHM, Kaspar BK. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med. 2017 Nov 2;377(18):1713-1722. PMID: 29091557; https://doi.org/10.1056/nejmoa1706198  

Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC; ENDEAR Study Group. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017 Nov 2;377(18):1723-1732. PMID: 29091570; https://doi.org/10.1056/nejmoa1702752  

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