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Spinal Muscular Atrophy (G12)

Spinal Muscular Atrophy (SMA) is a severe, progressive genetic neuromuscular disease characterized by the irreversible degeneration of lower motor neurons in the spinal cord. This loss interrupts nerve signaling to voluntary muscles, resulting in proximal muscle weakness, muscle wasting (atrophy), and subsequent paralysis. Inherited as an autosomal recessive trait, SMA is primarily caused by homozygous deletions or loss-of-function mutations in the survival motor neuron 1 (SMN1) gene on chromosome 5. This mutation leaves the body deficient in functional SMN protein, which is vital for motor neuron survival.

Causes

The etiology of spinal muscular atrophy (SMA) is most commonly linked to homozygous deletion or mutation of the SMN1 (survival motor neuron 1) gene located on chromosome 5q13, resulting in insufficient production of survival motor neuron (SMN) protein. SMN protein is essential for normal motor neuron maintenance, RNA processing, and neuromuscular function. The disorder is inherited in an autosomal recessive pattern, meaning affected individuals inherit defective SMN1 alleles from both parents. Disease severity is influenced by the number of copies of the related SMN2 gene, which produces only small amounts of fully functional SMN protein because of alternative splicing that excludes exon 7 in most transcripts. Individuals with more SMN2 copies generally develop milder disease phenotypes due to partial compensation for SMN1 deficiency. The resulting lack of adequate SMN protein leads to progressive degeneration of alpha motor neurons within the spinal cord and brainstem, ultimately causing muscle weakness, atrophy, and impaired motor function.

Pathophysiology

The pathophysiology of spinal muscular atrophy (SMA) centers on deficiency of the survival motor neuron (SMN) protein, which is essential for the maintenance and function of alpha motor neurons within the anterior horn of the spinal cord and motor nuclei of the brainstem. Loss or mutation of the SMN1 gene results in inadequate SMN protein production, impairing critical cellular processes such as RNA splicing, ribonucleoprotein assembly, axonal transport, and neuromuscular junction integrity. Although the related SMN2 gene produces limited amounts of functional SMN protein, most SMN2 transcripts exclude exon 7 and generate unstable, nonfunctional protein, leading to insufficient compensation. Motor neurons are particularly vulnerable to SMN deficiency, resulting in progressive neuronal degeneration, denervation of skeletal muscle fibers, and muscle atrophy. As neuromuscular signaling deteriorates, patients develop weakness that predominantly affects proximal, respiratory, bulbar, and postural muscles. Progressive respiratory muscle involvement may lead to impaired ventilation, recurrent infections, and respiratory failure in severe forms of the disease. The severity and progression of SMA correlate closely with the degree of residual SMN protein expression, which is influenced largely by SMN2 copy number.

Clinical features

The clinical features of spinal muscular atrophy (SMA) vary according to disease severity and age of onset but are characterized primarily by progressive symmetric muscle weakness and atrophy resulting from degeneration of lower motor neurons. Weakness typically affects proximal muscles more severely than distal muscles and commonly involves the shoulders, hips, trunk, and respiratory musculature. Infants with severe forms may present with hypotonia, poor head control, weak cry, feeding difficulties, diminished reflexes, respiratory distress, and delayed motor milestones, often appearing “floppy” on examination. Older children and adults with milder forms may experience difficulty walking, climbing stairs, rising from seated positions, or maintaining posture, with gradual loss of ambulation over time. Bulbar weakness can lead to dysphagia and impaired airway protection, while respiratory muscle involvement predisposes patients to hypoventilation, recurrent pulmonary infections, and respiratory failure. Sensory function and cognitive development are generally preserved because the disease primarily affects motor neurons rather than sensory or cortical pathways.

Diagnosis

The diagnosis of spinal muscular atrophy (SMA) is established primarily through genetic testing demonstrating homozygous deletion or pathogenic mutation of the SMN1 (survival motor neuron 1) gene. Patients are typically evaluated after presenting with progressive muscle weakness, hypotonia, delayed motor milestones, diminished or absent deep tendon reflexes, and evidence of lower motor neuron dysfunction. Molecular testing not only confirms the diagnosis but also determines SMN2 copy number, which helps predict disease severity and guide treatment planning. Electromyography may demonstrate denervation and chronic neurogenic changes consistent with motor neuron disease, while nerve conduction studies are generally normal because sensory nerves are preserved. Serum creatine kinase levels are often normal or only mildly elevated. In many regions, newborn screening programs now identify SMA before symptom onset, allowing early initiation of disease-modifying therapies such as Spinraza, Evrysdi, or Zolgensma, which can significantly improve neurologic and developmental outcomes.

Mechanism of action videos

Biological pathways

  • Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA
  • Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA
  • KSRP (KHSRP) binds and destabilizes mRNA
  • mRNA decay by 3' to 5' exoribonuclease
  • tRNA processing in the nucleus
  • Regulation of mRNA stability by proteins that bind AU-rich elements
  • Unfolded Protein Response (UPR)
  • ATF4 activates genes in response to endoplasmic reticulum stress
  • Nuclear RNA decay
  • PERK regulates gene expression
  • Defective HLCS causes multiple carboxylase deficiency
  • Metabolism of RNA
  • Defects in biotin (Btn) metabolism
  • COPI-independent Golgi-to-ER retrograde traffic
  • Deadenylation-dependent mRNA decay
  • Cellular responses to stimuli
  • Biotin transport and metabolism
  • Cellular responses to stress
  • tRNA processing
  • Major pathway of rRNA processing in the nucleolus and cytosol
  • Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy

Clinical trials

  • A Phase II, Open-label Study to Investigate the Pharmacokinetics and Safety of Risdiplam in Infants With Spinal Muscular Atrophy
  • An Open-Label Study of Risdiplam in Infants With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy
  • A Multicenter Single Arm Phase II Study With Bicalutamide in Combination With Abemaciclib in 4 Cohorts of Locoregionally Advanced Inoperable or Metastatic Androgen Receptor-positive Triple-negative Breast Cancer
  • Long-term Follow-up of Patients With Spinal Muscular Atrophy Treated With OAV101 IT or OAV101 IV in Clinical Trials
  • Patients With ALS and Other Motor Discorders Will be Treated With Mesenchymal Cell Exosome Solution
  • Study of AAV-hSMN1 (Vesemnogene Lantuparvovec) Gene Therapy in Subjects With Progressive Spinal Muscular Atrophy
  • Vasodilators and Exercise as Adjuvant Therapy for Duchenne Muscular Dystrophy (VASO-REx Study)
  • A Phase 3, Two-part, Randomized, Open-label, Adaptive Study Comparing BMS-986365 Versus Investigator's Choice of Therapy Comprising Either Docetaxel or Second Androgen Receptor Pathway Inhibitor (ARPI), in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) - rechARge
  • TulmiSTAR-02: A Two-part Phase I Dose Escalation Study of Tulmimetostat (DZR123) in Combination With Darolutamide or Abiraterone Followed by Open-label, Randomized, Phase II Dose Expansion Study to Assess the Safety and Efficacy of Tulmimetostat in Combination With Darolutamide Versus Darolutamide Alone in Patients With Metastatic Hormone-sensitive Prostate Cancer
  • A Phase IV Open-Label Study Evaluating the Effectiveness and Safety of Risdiplam Administered in Pediatric Patients With Spinal Muscular Atrophy Who Experienced a Plateau or Decline in Function After Gene Therapy
  • An Open-Label Study to Assess the Efficacy and Safety of Multiple Doses of Salanersen (BIIB115) Delivered Intrathecally to Treatment-Naïve, Presymptomatic Infants With Genetically Diagnosed Spinal Muscular Atrophy
  • A Phase IV Open-Label Study Evaluating the Effectiveness and Safety of Risdiplam Administered as an Early Intervention in Pediatric Patients With Spinal Muscular Atrophy After Gene Therapy
  • A Phase I/II, Modular, Open-Label, Multi-Centre Study to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of AZD9750 as Monotherapy and in Combination With Other Anticancer Agents in Participants With Metastatic Prostate Cancer (ANDROMEDA)
  • A Phase 2, Double-Blind Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Efficacy, and Safety of Apitegromab in Subjects <2 Years Old With Spinal Muscular Atrophy (SMA)
  • A Phase 2 Double-Blinded, Randomized, Placebo-Controlled Study to Assess the Safety, Tolerability, Efficacy, Pharmacokinetics, and Immunogenicity of Intravenous Administration of ARGX-119 in Pediatric Participants Aged 5 to Less Than 18 Years With Spinal Muscular Atrophy
  • An Open-Label, Phase 3 Study to Evaluate the Efficacy and Safety of Salanersen (BIIB115) in Participants Aged 15-60 Years With Spinal Muscular Atrophy Who Are Either Treatment-Naïve or Have Previously Been Treated With Risdiplam
  • Long-term Follow-up Study of Patients With Spinal Muscular Atrophy Receiving Risdiplam Treatment
  • A Phase 2, Randomised, Double-blind, Placebo-controlled, 2-way Crossover Study to Evaluate the Efficacy, Safety, and Tolerability of NMD670 in Ambulatory Adults With Type 3 Spinal Muscular Atrophy
  • Phase II Study of Darolutamide (ODM-201) in Patients With Androgen Receptor-positive Salivary Gland Carcinoma (Discovary Study)
  • Onasemnogene Abeparvovec: ASsessing The REAl-world Safety & Effectiveness of Spinal Muscular Atrophy Participants Treated With Intrathecal Onasemnogene Abeparvovec-brve (ITVISMA®): A U.S. Pragmatic Multicenter Study (STREAM)
  • An Open Label, Single Cohort Study to Assess the Pharmacokinetic Profile of Nusinersen (BIIB058) Administered Via the ThecaFlex DRx™ System (PIERRE-PK)
  • A Two-Part, Seamless, Multi-Center, Randomized, Placebo-Controlled, Double-Blind Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of RO7204239 in Combination With Risdiplam (RO7034067) in Patients With Spinal Muscular Atrophy
  • A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of NIDO-361 in Patients With Spinal and Bulbar Muscular Atrophy (SBMA)
  • A Phase 3, Randomized, Double-Blinded Study to Evaluate the Safety and Efficacy of Salanersen (BIIB115) After Onasemnogene Abeparvovec Treatment in Infants With Genetically Diagnosed Spinal Muscular Atrophy
  • A Phase 1-2, Open-Label, Multicenter Study to Assess the Safety, Tolerability and Efficacy of a Single Dose of GB221 Delivered Into the Cisterna Magna of Pediatric Participants From 2 Weeks to Younger Than 12 Months of Age With Spinal Muscular Atrophy Type 1
  • A Randomized, Blinded, Placebo-Controlled, Phase 1 Single Ascending Dose Study in Healthy Adult Male Volunteers and an Open-Label Multiple Ascending Dose Study With Long-Term Extension in Pediatric SMA Participants Previously Treated With Onasemnogene Abeparvovec (Zolgensma™) to Evaluate the Safety, Tolerability, and Pharmacokinetics of BIIB115
  • A Long-Term Extension Study of Nusinersen (BIIB058) Administered at Higher Doses in Participants With Spinal Muscular Atrophy Who Previously Participated in an Investigational Study With Nusinersen
  • A Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the Efficacy and Safety of Taldefgrobep Alfa in Ambulatory and Non-Ambulatory Participants With Spinal Muscular Atrophy With Open-Label Extension
  • Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy Clinical Trial for Patients With Spinal Muscular Atrophy Type 1 With One or Two SMN2 Copies Delivering AVXS-101 by Intravenous Infusion
  • Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy Clinical Trial for Patients With Spinal Muscular Atrophy Type 1 With One or Two SMN2 Copies Delivering AVXS-101 by Intravenous Infusion
  • A Global Study of a Single, One-Time Dose of AVXS-101 Delivered to Infants With Genetically Diagnosed and Pre-symptomatic Spinal Muscular Atrophy With Multiple Copies of SMN2
  • Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy Clinical Trial for Patients With Spinal Muscular Atrophy Type 1 With One or Two SMN2 Copies Delivering AVXS-101 by Intravenous Infusion
  • Phase 3, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Apitegromab (SRK-015) in Patients With Later-Onset Spinal Muscular Atrophy Receiving Background Nusinersen or Risdiplam Therapy
  • Phase II Trial of pTVG-HP DNA Vaccine With or Without pTVG-AR DNA Vaccine and Pembrolizumab in Patients With Castration-Resistant, Metastatic Prostate Cancer
  • Real World Clinical Effectiveness & Safety of Vesemnogene Lantuparvovec for Spinal Muscular Atrophy (SMA) in Low-middle Income Countries (LMIC).
  • Asian Multinational Phase 3, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study of Oral Enzalutamide in Chemotherapy Naïve Subjects With Progressive Metastatic Prostate Cancer Who Have Failed Androgen Deprivation Therapy
  • An Open-Label Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Multiple Doses of ISIS 396443 Delivered Intrathecally to Subjects With Genetically Diagnosed and Presymptomatic Spinal Muscular Atrophy
  • A Phase 4 Study of Nusinersen (BIIB058) Among Patients With Spinal Muscular Atrophy Who Received Onasemnogene Abeparvovec
  • An Open-Label Study to Investigate the Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of Risdiplam (RO7034067) in Adult and Pediatric Patients With Spinal Muscular Atrophy
  • Phase I/IIa Intrathecal Gene Delivery Clinical Trial for IGHMBP2-Related Diseases

Therapeutic area: Neurology