SMA Overview | SMA Screening | SMA for Patients | SMA Video Resources

Faculty

Melissa Gibbons, MS, CGC

Samone Masters, MS, CGC

Tamar Ailenberg, MS, CHC, CCG

Melissa Gibbons, a certified genetic counselor, is an associate professor in the Department of Pediatrics- Genetics at the University of Colorado School of Medicine and Children’s Hospital Colorado in Aurora, CO

Samone Masters is the Supervising Genetic Counselor in the Department of Obstetrics and Gynecology at Jacobi Medical Center in Bronx, NY

Tamar Ailenberg is a certified genetic counsellor with both the American Board of Genetic Counselors and the Canadian Association of Genetic Counsellors. She is a practicing genetic counselor in Ontario, Canada

SUMMARY:  

Both ACOG and ACMG recommend offering carrier screening for spinal muscular atrophy (SMA) to all individuals contemplating pregnancy regardless of race or ethnicity.  SMA has also been added to state newborn screening tests that are performed at birth.  SMA is a disorder characterized by progressive muscle weakness and atrophy due to degeneration of the anterior horn cells in the spinal cord with variable onset and clinical course.  The muscle weakness is diffuse, symmetric and greater in proximal than distal muscles.  Symptoms can include respiratory failure, scoliosis, failure to thrive, joint contractures, and fatigue.  More severe symptoms include inability to walk or sit, paralysis, and even death, particularly without treatment. Cognition and sensation are spared. Physical and occupational therapy, rehabilitation, pulmonary, and nutrition management are utilized to support the health of those affected with SMA.  Recently, the FDA approved several SMA-specific medical therapies.

How Common is SMA? 

• Incidence of SMA has been estimated at 1 in 10,000 live births  
• The gene deletion and other pathogenic variants have been identified across ethnicities  
  • The pan-ethnic carrier frequency is 1 in 54 
• SMA type I is the most common form of SMA, accounting for ~50% of SMA diagnoses 

Different Subtypes Different Prognoses 

SMA Has Traditionally Been Separated into The Following Subtypes, Based on Age of Onset and Maximum Motor Milestones Achieved if Untreated 

SMA type 0 (Prenatal) 

• Prenatal onset and death from respiratory failure within weeks of birth 
• Severe muscle weakness and hypotonia at birth and no motor milestones are achieved 
• Often a decrease in or loss of fetal movement in late pregnancy 

SMA type 1 (Infantile; Werdnig-Hoffman disease) 

• Onset at <6 months of age and majority die from respiratory failure by 2 years of age  
• Sitting unassisted is not achieved 

SMA type 2 (Dubowitz disease) 

• Onset at age 6 to 12 months and most are alive at 25 years 

• Sitting is achieved but sometimes lost in teenage years; cannot independently ambulate 

SMA type 3 (Kugelberg-Welander disease) 

• Onset can be from age 18 months to adulthood, normal lifespan 
• Independent ambulation is achieved but may regress | Falling and trouble climbing stairs 

SMA type 4 

• Adult onset (often age ≥30 years), normal lifespan 
• All motor milestones are achieved; ambulation is usually maintained 

Note: With the introduction of new medical interventions and their impact on clinical course, the medical community is increasingly classifying those affected by their motor milestone achieved: non-sitter, sitter, or walker 

Genetic Basics     

• The survival motor neuron 1 (SMN1) gene is located on chromosome 5q13.2 
• SMN1 codes for survival motor neuron (SMN) protein  
  • Key in lower motor (alpha) neuron cell survival 
• Without sufficient SMN protein, lower motor neurons do not function properly and do not send sufficient signals to skeletal muscle, which are therefore not used and atrophy over time 
• SMA is an autosomal recessive disease 
• The most common mutation in the SMN1 gene is a deletion in exon 7  
  • 95% of individuals with SMA are homozygotes for this deletion 
  • The remainder are mostly heterozygotes for an exon 7 SMN1 deletion and a point mutation in SMN1 
  • The SMN1 gene makes fully functional protein 
• There is a second gene called survival motor neuron 2 (SMN2)  
  • SMN2 is located on chromosome 5q13.2 
  • SMN2 has a SNP that differs from SMN1 in exon 7  
    • This change results in only ~10% of the SMN protein being a full-length and functioning product due to exon 7 being spliced out of most transcripts  
  • The number of copies of SMN2 varies from person to person, and may range from 0 to 5 in SMA 
  • The number of SMN2 gene copies a person carries has been shown to modify SMA disease severity 
  • For more information on carrier testing, please see SMA Screening: A Practical Approach 

What Tests are Used to Diagnose SMA? 

• Molecular genetic testing is required to determine the presence or absence of 2 functional copies of SMN1    
• Dosage studies can look for absence or presence of exon 7 
• Sequencing studies can be used to look for point mutations

Genotype-Phenotype: Is There a Relationship Between Genetics and Disease Severity? 

• There is a relationship between SMN2 copy number and disease severity 
• Although phenotype cannot be absolutely predicted from genotype, there is an inverse relationship between SMN2 copy number and disease severity 
• However, disease severity cannot always be predicted based on SMN2 gene copy number alone, as other modifying factors are still unknown  

Management  

• Currently, there is no cure for SMA 
• The available treatment options include  
  • Supportive therapy: Respiratory | Orthopedic | Nutritional 
  • Disease-modifying treatments that target underlying pathophysiology of SMA.
  • Individuals treated with disease-modifying medications were shown to have  
    • Longer lifespan | Improvement in motor milestone achievements | Less likely to require permanent ventilation compared to untreated individuals 

FDA-Approved Disease-Modifying Treatments for SMA 

• Nusinersen (Spinraza) 
  • Antisense oligonucleotide (ASO) 
  • The drug targets SMN2 and promotes inclusion of exon 7 resulting in more functional SMN protein 
  • Available for all subtypes of SMA and all ages 
  • Administered intrathecally 
  • After initial 4 loading doses, nusinersen is administered once every 4 months 
• Onasemnogene abeparvovec-xioi (Zolgensma)  
  • Gene therapy 
  • Uses a recombinant adeno-associated virus (AAV9) vector to deliver a functional SMN copy. 
  • Available for patients with SMA < 2 years old 
  • Administered by a single IV infusion  

• Risdiplam (Evrysdi) 
  • Small molecule SMN2 splicing modifier 
  • Binds to pre-messenger mRNA of SMN2 to correct its splicing defect and increase the level of full length SMN protein 
  • Liquid administered orally or through a feeding tube daily 

Note: Long-term data are still being collected | Experts predict that the expected course of disease will likely be altered by these drugs, therefore, the traditional SMA subtypes may no longer be useful to families and clinicians to estimate prognosis 

Timing of Medical Therapy 

• Regardless of what medical therapy is chosen, it is important to begin therapy as early as possible 
• Early therapy helps prevent irreversible loss of motor neurons, muscle atrophy, and therefore may halt or slow disease progression 

In The Pipeline 

• Different modalities of administering gene therapy 
• Therapies focused on motor neuron and muscle survival through mechanisms independent of SMN1 and SMN2 
• Combination therapy  

REFERENCES: 

Gene Reviews: Spinal Muscular Atrophy 

Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance (Keinath et al.  Appl Clin Genet, 2021) 

Correlation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. (Calucho M et al. Neuromuscul Disord, 2018) 

Spinal Muscular Atrophy (Kolb SJ, Kissel JT. Neurol Clin, 2015)  

Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care (Mercuri E, et al. Neuromuscul Disord, 2018) 

Diagnosis and management of spinal muscular atrophy: Part 2: Pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics (Finkel RS et al. Neuromuscul Disord, 2018) 

Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy (Finkel RS et al. N Engl J Med, 2017) 

Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy (Mercuri E et al. N Engl J Med, 2018) 

Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study (De Vivo DC et al. Neuromuscul Disord, 2019) 

Safety and efficacy of nusinersen in spinal muscular atrophy: The EMBRACE study (Acsadi G et al. Muscle Nerve, 2021) 

Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy (Mendell et al. N Engl J Med, 2017) 

Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy (Al-Zaidy S. et al. Pediatr Pulmonol, 2019) 

Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial (Day JW et al. Lancet Neurol, 2021) 

Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial (Strauss et al. Nature Medicine, 2022) 

Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes (Waldrop MA. et al. Pediatrics, 2020) 

Thrombotic Microangiopathy Following Onasemnogene Abeparvovec for Spinal Muscular Atrophy: A Case Series (Chand DH et al. J Pediatr, 2021) 

FIREFISH Working Group. Risdiplam in Type 1 Spinal Muscular Atrophy (Baranello G. et al. N Engl J Med, 2021) 

SUNFISH Study Group. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial (Mercuri E. et al. Lancet Neurol, 2022)  

FIREFISH, SUNFISH, JEWELFISH Working Groups. Risdiplam treatment has not led to retinal toxicity in patients with spinal muscular atrophy (Sergott RC et al. Ann Clin Transl Neurol, 2021) 

Intelligence and cognitive function in children and adolescents with spinal muscular atrophy (von Gontard et al. Neuromuscul Disord , 2002) 

FDA: Zolgensma  

FDA: Evrysdi 

FDA: Spinraza 

Faculty Disclosures 

Melissa Gibbons has participated in Taysha Gene Therapy Advisory Board 

Samone Masters has no relevant financial relationships to disclose 

Tamar Ailenberg has no relevant financial relationships to disclose  

Commercial Support 

11/2023 US-UNB-23-0023

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