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Matthew Wong, DO
Fellow, Division of Pediatric Pulmonary Medicine, UPMC Children’s Hospital of Pittsburgh
A full-term boy presented at his 2-month-old well-child visit with significant weight loss (50th to 20th percentile) despite no feeding difficulties or intercurrent illness. On examination, he was noted to have poor head control and was referred to the neurology clinic for initial evaluation. His parents reported no developmental regression but did confirm delayed milestone acquisition.
Upon neurologic evaluation, the patient had significant generalized hypotonia with diaphragmatic respiration and absent reflexes. He was admitted to the hospital for further neurologic workup with suspected Spinal Muscular Atrophy (SMA). During this initial hospitalization, he was found to have significant aspiration and underwent a gastrostomy tube placement with Nissen fundoplication.
Genetic testing confirmed SMA with two gene copies of SMN2. He was started on Nusinersen (Spinraza®) within two weeks of diagnosis. Following initiation of Nusinersen, the parents reported that he was slowly acquiring new milestones with improved tone. He required no respiratory support at that time.
At 7 months of age, he developed acute respiratory failure secondary to pneumonia, and biphasic noninvasive ventilatory support (NIV) was initiated. He was discharged with the trilogy home ventilator to be used noninvasively during sleep. With intercurrent respiratory illnesses, he would require NIV continuously for a few days. No further hospitalizations occurred. He received gene therapy with Zolgensma® at 9 months of age and continued with his quarterly Nusinersen treatment.
The patient is now almost 3 years of age and has not been hospitalized since 7 months of age. He continues to display significant improvements in his overall motor function. He can independently propel his wheelchair and can stand using a stander. His bulbar muscle strength has improved to the point where he is now safely tolerating small oral feeds with gastrostomy tube supplementation. Furthermore, his most recent polysomnogram showed no evidence of sleep-disordered breathing or alveolar hypoventilation.
SMA is an autosomal recessive neurodegenerative disease caused by a homozygous mutation/deletion in the Survival Motor Neuron 1 (SMN1) gene on chromosome 5q. This gene deletion leads to decreased expression of Survival Motor Neuron (SMN) protein, which clinically manifests as muscular weakness and hypotonia. While the exact role of SMN protein within motor neurons is not completely understood, it is believed to play a role in motor neuron development, as SMA is characterized by degeneration of motor neurons in both the spinal cord and the brainstem. Currently, SMA is the leading genetic cause of infant mortality with an incidence of approximately 1 in 11,000 live births and an estimated carrier frequency of 1 in 54.1-3 Without any form of respiratory support, the historical median life expectancy for a child with SMA Type 1 is approximately 2 years.1-4 Due to the development of new therapies, the natural history of SMA continues to change rapidly.
SMA has classically been divided into five phenotypes based on the age of symptom onset and the patient's maximal motor function. Type 1 onset occurs by 6 months of age, and patients are unable to sit upright independently. Type 2 onset occurs between 6-18 months, and though patients can sit upright independently, they are unable to ambulate. Type 3 typically presents with mild symptoms after 18 months of age, while Type 4 presents in adulthood. Type 3 and Type 4 patients can generally ambulate independently into adulthood but may lose this ability over time. Type 0 is the rarest and most severe phenotype that begins in utero and results in early mortality. It is associated with congenital heart defects and vascular issues in the extremities affecting perfusion, along with diffuse hypotonia, joint contractures, and pulmonary hypoplasia with significant respiratory distress and chest wall deformities noted at birth.5,6
SMA Type 1 (also known as Werdnig-Hoffman Disease) is the most common form of SMA and affects an estimated 60% of all SMA cases. Prior to the advent of new therapies, natural history studies of SMA Type I showed that approximately 68% die within 2 years and 82% by 4 years of age without respiratory and nutritional support.2 Mortality has been reduced to about 30% by 2 years of age with the use of NIV and gastrostomy placement. The median age of symptom onset is approximately 1.2 months of age, with a median time to full ventilator dependence at approximately 13.5 months of age.2,7
Initially, SMA Type 1 patients present with a variety of symptoms including the inability to sit upright, poor head control, and overall muscular weakness. While the diaphragm is not affected, weak intercostal muscles result in a baseline paradoxical breathing pattern (inward motion of the chest during inspiration) and the development of a structurally bell-shaped upper torso and pectus excavatum. Bulbar denervation results in characteristic tongue fasciculations, in addition to a weak suck and swallow. Patients are at increased risk for nutritional growth failure, aspiration pneumonia, and frequent lower respiratory tract infections from insufficient airway clearance with a weak cough. Pulmonary compromise remains the primary cause of death in SMA.1,2
Historically, there were no effective therapeutic options for SMA, and management primarily consisted of supportive care. Treatment targets for SMA involve two genes, Survival Motor Neuron 1 (SMN1) and Survival Motor Neuron 2 (SMN2). SMN1 is the primary gene involved in the production of functional SMN protein. In humans, SMN2 is a similar gene that differs from SMN1 by approximately 11 nucleotides and codes for the same SMN protein. The difference between the two is located at an exon splice enhancer site that regulates the inclusion of Exon 7. While SMN2 produces some functional SMN protein, nearly 90% of the mRNA coded by SMN2 is nonfunctional due to splicing that excludes Exon 7. This produces a smaller protein that is quickly degraded by the body. Patients that possess a higher copy number of SMN2 produce more functional SMN protein and usually display a milder phenotype.1,2,5,8
In 2016, the U.S. Food and Drug Administration (FDA) approved Nusinersen, the first treatment for patients with SMA. Nusinersen is an antisense oligonucleotide drug that modifies the splicing of SMN2 to include Exon 7, thereby promoting increased production of the full-length functional SMN protein.3,4,8 It is administered by repeated intrathecal injections due to its inability to cross the blood-brain barrier, with four loading doses of 12 mg in the first two months of treatment, followed by routine doses approximately every three months. Nusinersen has been found to be well-tolerated in infants and children with SMA.
This therapy option has drastically changed the clinical landscape for SMA patients. A clinical trial examining Nusinersen versus a sham control showed a benefit-risk assessment in favor of Nusinersen4, which caused early termination of this trial and expedited FDA approval. All patients were then subsequently enrolled in an open-label extension study to receive Nusinersen. Overall, the risk of death or the use of chronic ventilation was approximately 47% lower in those treated with Nusinersen as compared to a sham control. Furthermore, postmortem studies demonstrated that Nusinersen caused an increase in the amount of full-length SMN2 mRNA, as well as SMN protein compared to untreated SMA infants.9 Nusinersen also demonstrated progressive improvement in overall motor function and survival in treated infants. While age-appropriate function was not achieved, many of the Nusinersen treated patients developed the ability to sit independently and exhibited improvements in other motor functions such as head control and the ability to roll over.
Although Nusinersen has significantly affected the natural history of SMA in a positive direction, it is not a cure for the disease. Patients with more advanced disease at the time of Nusinersen treatment displayed less dramatic functional improvement, suggesting that earlier initiation of treatment may maximize its efficacy. Patients who ultimately received permanent ventilator assistance while receiving Nusinersen did so within 13 weeks of receiving their first dose of Nusinersen. Meanwhile, there were several patients receiving Nusinersen who died, did not achieve any normal motor development, and required nutritional and ventilatory support during the trials.4 These outcomes highlighted the need for early initiation of therapy. Most states have worked to quickly include SMA in their newborn screening programs.
Research continued into other SMA therapies, and a gene replacement therapy was FDA approved in 2018 for the treatment for SMA. This gene therapy, AVXS-101 (Onasemnogene Abeparvovec, Zolgensma®), is an adeno-associated viral vector that carries SMN1 DNA encoding functional human SMN with a continuous promoter.10, 11 Inside the cell, it causes the expression of SMN1 mRNA, thereby increasing the amount of functional SMN protein. Children who were in the first gene replacement trial received a single intravenous infusion shortly after birth and have demonstrated longer event-free survival as compared to historical cohorts. Moreover, patients demonstrated improved motor function and achievement of milestones, including the ability to sit upright independently with improved feeding, swallowing, and ventilatory status.8 This August, another SMN2 modifier, risdiplam (EvrysdiTM), was approved by the FDA for patients 2 months of age and older.5,6 Risdiplam is a daily orally administered medication.
Recent treatment advances have drastically changed the clinical landscape of SMA and improved the mortality and morbidity previously associated with this disease. Children on treatment are showing improved motor function, achievement of milestones, and decreased reliance on nutritional and respiratory support.
However, as this new cohort of SMA patients ages, new challenges are occurring in this population with increased incidence of scoliosis and the need for adaptive equipment to continue to support and nurture their new independence. A strong multidisciplinary neuromuscular clinic is critical to continue to help these young pioneers thrive.
1. Lunn MR, Wang CH. Spinal Muscular Atrophy. Lancet. 2008; 371(9630): 2120-2133.
2. Finkel RS, McDermott MP, Kaufmann P, et al. Observational Study of Spinal Muscular Atrophy Type I and Implications for Clinical Trials. Neurology. 2014; 83(9): 810-817.
3. Mendell JR, Al-Zaidy S, Shell R, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. N Engl J Med. 2017; 377(18): 1713-1722.
4. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen Versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017; 377(18): 1723-1732.
5. Araujo Ap, Araujo M, Swoboda KJ. Vascular Perfusion Abnormalities in Infants With Spinal Muscular Atrophy. J Pediatr. 2009; 155(2): 292-294.
6. Shababi M, Lorson CL, Rudnik-Schöneborn SS. Spinal Muscular Atrophy: A Motor Neuron Disorder or a Multi-organ Disease. J Anat. 2014; 224(1): 15-28.
7. Rao VK, Kapp D, Schroth M. Gene Therapy for Spinal Muscular Atrophy: An Emerging Treatment Option for a Devastating Disease. J Manag Care Spec Pharm. 2018; 24(12-a Suppl): S3-S16.
8. Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen Versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med. 2018; 378(7): 625-635.
9. Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of Infantile-onset Spinal Muscular Atrophy With Nusinersen: A Phase 2, Open-label, Dose-escalation Study. Lancet. 2016; 388(10063): 3017-3026.
10. Al-Zaidy SA, Kolb SJ, Lowes L, et al. AVXS-101 (Onasemnogene Abeparvovec) for SMA1: Comparative Study With a Prospective Natural History Cohort. J Neuromuscul Dis. 2019; 6(3): 307-317.
11. Al-Zaidy SA, Mendell JR. From Clinical Trials to Clinical Practice: Practical Considerations for Gene Replacement Therapy in SMA Type 1. Pediatr Neurol. 2019; 100: 3-11.
12. Michelson D, Ciafaloni E, Ashwal S, et al. Evidence in Focus: Nusinersen Use in Spinal Muscular Atrophy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018; 91(20): 923-933.
13. Tisdale S, Pellizzoni L. Disease Mechanisms and Therapeutic Approaches in Spinal Muscular Atrophy. J Neurosci. 2015; 35(23): 8691-8700.
14. LoMauro A, Mastella C, Alberti K, Masson R, Aliverti A, Baranello G. Effect of Nusinersen on Respiratory Muscle Function in Different Subtypes of Type 1 Spinal Muscular Atrophy. Am J Respir Crit Care Med. 2019; 200(12): 1547-1550.