Spinal Muscular Atrophy Added to Recommended Uniform Screening Panel

Spinal muscular atrophy (SMA) is now among the disorders officially included in the Recommended Uniform Screening Panel (RUSP), which state public health departments use to screen newborns for genetic disorders.

Secretary of the Department of Health and Human Services (HHS) Alex M. Azar II formally added SMA to the panel on July 2 on the recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children.

“Adding SMA to the list will help ensure that babies born with SMA are identified, so that they have the opportunity to benefit from early treatment and intervention,” according to a statement from the Muscular Dystrophy Association about the decision. “This testing can also provide families with a genetic diagnosis—information that often is required to determine whether their child is eligible to participate in clinical trials.”

Adding SMA to the RUSP does not mean that states must screen newborns for the disorder. Each state’s public health apparatus decides independently whether to accept the recommendation and which disorders on the RUSP to screen for. Most states screen for most disorders on the RUSP. Evidence compiled by the advisory committee suggested a wide variation in resources, infrastructure, funding, and time to implementation among states.

Drug Approval Raised Ethical Questions

An estimated one in 11,000 newborns has SMA, a disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. SMA affects motor neurons in the brainstem and spinal cord, thus leading to motor weakness and atrophy. The only treatment for SMA had been palliative care until the FDA approved nusinersen for the disorder in December 2016. The drug’s approval has raised ethical questions.^1–3

After reviewing the evidence at its February 8 meeting, the advisory committee recommended adding SMA screening to the RUSP in a March 8 letter from committee chair Joseph A. Bocchini Jr, MD, Professor and Chair of Pediatrics at Louisiana State University Health in Shreveport.

Secretary Azar accepted the recommendation based on the evidence the committee provided; he also requested a follow-up report within two years “describing the status of implementing newborn screening for SMA and clinical outcomes of early treatment, including any potential harms, for infants diagnosed with SMA.”

The advisory committee makes its recommendations to HHS about which heritable disorders to include in the RUSP after it has assessed a systematic, evidence-based review conducted by an external, independent group. Alex R. Kemper, MD, MPH, Professor of Pediatrics at the Ohio State University and Division Chief of Ambulatory Pediatrics at Nationwide Children’s Hospital, both in Columbus, led the review group for SMA. Dr. Kemper is also deputy editor of Pediatrics and a member of the US Preventive Services Task Force.

 

According to Secretary Azar’s summary in his July 2 letter of acceptance, the evidence review suggested that “early screening and treatment can lead to decreased mortality for individuals with SMA and improved motor milestones.”

“SMA can be detected through newborn screening, and treatment is now available that can not only reduce the risk of death, but decrease the development of neurologic impairment,” he said in an interview. “As with adding any condition to newborn screening, public health laboratories will need to develop strategies to incorporate the screening test. The current FDA-approved treatment, nusinersen, is delivered by lumbar puncture into the spinal fluid. In addition, there are exciting advances in gene therapy leading to new treatment approaches.”

Symptom Onset Distinguishes the Types of SMA

Approximately 95% of SMA cases result from the deletion of exon 7 from both alleles of SMN1. Other, rarer cases are caused by mutations in different genes. Without the SMN protein produced by SMN1, a person gradually loses muscle function.

A similar gene, SMN2, also can produce the SMN protein, but in much lower amounts—typically less than 10% of what a person needs. People can, however, have multiple copies of SMN2, which can produce slightly more SMN protein and slow the disease process.

The five types of SMA are determined according to symptom onset, which directly correlates with disorder severity and prognosis. Approximately 54% of SMA cases are Type I, in which progressive weakness occurs over the first six months of life and results in early death. Only 18% of children with Type I live past age 4, and 68% die by age 2. Type 0 is rarer, but more severe, usually causing fetal loss or early infant death.

Type II represents 18% of SMA cases and causes progressive weakness by age 15 months. Most people with Type II survive to their 30s but later experience respiratory failure and rarely reach their 40s. Individuals with Types III and IV typically have a normal lifespan and only begin to see progressive muscle weakness after age 1 or in adulthood.

Dr. Kemper’s group focused on the three types diagnosed in infancy: Types I, II, and III. “It will be critical to make sure that infants diagnosed with SMA through newborn screening receive follow-up shortly afterward to determine whether they would benefit from nusinersen,” said Dr. Kemper. “More information is needed about the long-term outcomes of those infants who begin treatment following newborn screening, so we not only know about outcomes in later childhood and adolescence, but treatment approaches can be further refined and personalized.”

Long-Term Data on Nusinersen Are Lacking

Nusinersen alters the splicing of precursor messenger RNA in SMN2 so that the mRNA strands are longer, which increases the amount of SMN protein produced. Concerns about the medication, however, have included its cost—$750,000 in the first year and $375,000 every following year for life—and potential adverse events from repeated administration. Nusinersen is injected into the spinal canal four times in the first year and once annually thereafter, and the painful injections require patient immobilization. Potential adverse events include thrombocytopenia and nephrotoxicity, along with potential complications from repeated lumbar punctures over time.²

Other concerns about the drug include its limited evidence base, lack of long-term data, associated costs with administration (eg, travel costs), the potential for patients taking nusinersen to be excluded from future clinical trials on other treatments, and ensuring parents have enough information on the drug’s limitations and potential risks to provide adequate informed consent.²

 

Yet evidence to date is favorable in children with early onset SMA. Dr. Bocchini wrote in the letter to Secretary Azar that “limited data suggest that treatment effect is greater when the treatment is initiated before symptoms develop and when the individual has more copies of SMN2.”

Dr. Kemper’s group concluded that screening can detect SMA in newborns and that treatment can modify the disease course. “Grey literature suggests those with total disease duration less than or equal to 12 weeks before nusinersen treatment were more likely to have better outcomes than those with longer periods of disease duration.

“Presymptomatic treatment alters the natural history” of the disorder, the group found, although outcome data past age 1 are not yet available. Based on findings from a New York pilot program, they predicted that nationwide newborn screening would avert 33 deaths and 48 cases of children who were dependent on a ventilator among an annual cohort of four million births.

 

At the time of the evidence review, Massachusetts, Minnesota, Missouri, North Carolina, New York, Utah, and Wisconsin initiated pilot programs or whole-population mandated screening for SMA. Of the three states that reported costs, all reported costs of $1 or less per screen.

The research for the evidence review was funded by a Health Resources and Services Administration grant to Duke University in Durham, North Carolina. No disclosures were provided for evidence review group members.

—Tara Haelle

References

1. King NMP, Bishop CE. New treatments for serious conditions: ethical implications. Gene Ther. 2017;24(9):534-538.

2. Gerrity MS, Prasad V, Obley AJ. Concerns about the approval of nusinersen sodium by the US Food and Drug Administration. JAMA Intern Med. 2018;178(6):743-744.

3. Burgart AM, Magnus D, Tabor HK, et al. Ethical challenges confronted when providing nusinersen treatment for spinal muscular atrophy. JAMA Pediatr. 2018;172(2):188-192.

Spinal muscular atrophy (SMA) is now among the disorders officially included in the Recommended Uniform Screening Panel (RUSP), which state public health departments use to screen newborns for genetic disorders.

Secretary of the Department of Health and Human Services (HHS) Alex M. Azar II formally added SMA to the panel on July 2 on the recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children.

“Adding SMA to the list will help ensure that babies born with SMA are identified, so that they have the opportunity to benefit from early treatment and intervention,” according to a statement from the Muscular Dystrophy Association about the decision. “This testing can also provide families with a genetic diagnosis—information that often is required to determine whether their child is eligible to participate in clinical trials.”

Adding SMA to the RUSP does not mean that states must screen newborns for the disorder. Each state’s public health apparatus decides independently whether to accept the recommendation and which disorders on the RUSP to screen for. Most states screen for most disorders on the RUSP. Evidence compiled by the advisory committee suggested a wide variation in resources, infrastructure, funding, and time to implementation among states.

Drug Approval Raised Ethical Questions

An estimated one in 11,000 newborns has SMA, a disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. SMA affects motor neurons in the brainstem and spinal cord, thus leading to motor weakness and atrophy. The only treatment for SMA had been palliative care until the FDA approved nusinersen for the disorder in December 2016. The drug’s approval has raised ethical questions.^1–3

After reviewing the evidence at its February 8 meeting, the advisory committee recommended adding SMA screening to the RUSP in a March 8 letter from committee chair Joseph A. Bocchini Jr, MD, Professor and Chair of Pediatrics at Louisiana State University Health in Shreveport.

Secretary Azar accepted the recommendation based on the evidence the committee provided; he also requested a follow-up report within two years “describing the status of implementing newborn screening for SMA and clinical outcomes of early treatment, including any potential harms, for infants diagnosed with SMA.”

The advisory committee makes its recommendations to HHS about which heritable disorders to include in the RUSP after it has assessed a systematic, evidence-based review conducted by an external, independent group. Alex R. Kemper, MD, MPH, Professor of Pediatrics at the Ohio State University and Division Chief of Ambulatory Pediatrics at Nationwide Children’s Hospital, both in Columbus, led the review group for SMA. Dr. Kemper is also deputy editor of Pediatrics and a member of the US Preventive Services Task Force.

 

According to Secretary Azar’s summary in his July 2 letter of acceptance, the evidence review suggested that “early screening and treatment can lead to decreased mortality for individuals with SMA and improved motor milestones.”

“SMA can be detected through newborn screening, and treatment is now available that can not only reduce the risk of death, but decrease the development of neurologic impairment,” he said in an interview. “As with adding any condition to newborn screening, public health laboratories will need to develop strategies to incorporate the screening test. The current FDA-approved treatment, nusinersen, is delivered by lumbar puncture into the spinal fluid. In addition, there are exciting advances in gene therapy leading to new treatment approaches.”

Symptom Onset Distinguishes the Types of SMA

Approximately 95% of SMA cases result from the deletion of exon 7 from both alleles of SMN1. Other, rarer cases are caused by mutations in different genes. Without the SMN protein produced by SMN1, a person gradually loses muscle function.

A similar gene, SMN2, also can produce the SMN protein, but in much lower amounts—typically less than 10% of what a person needs. People can, however, have multiple copies of SMN2, which can produce slightly more SMN protein and slow the disease process.

The five types of SMA are determined according to symptom onset, which directly correlates with disorder severity and prognosis. Approximately 54% of SMA cases are Type I, in which progressive weakness occurs over the first six months of life and results in early death. Only 18% of children with Type I live past age 4, and 68% die by age 2. Type 0 is rarer, but more severe, usually causing fetal loss or early infant death.

Type II represents 18% of SMA cases and causes progressive weakness by age 15 months. Most people with Type II survive to their 30s but later experience respiratory failure and rarely reach their 40s. Individuals with Types III and IV typically have a normal lifespan and only begin to see progressive muscle weakness after age 1 or in adulthood.

Dr. Kemper’s group focused on the three types diagnosed in infancy: Types I, II, and III. “It will be critical to make sure that infants diagnosed with SMA through newborn screening receive follow-up shortly afterward to determine whether they would benefit from nusinersen,” said Dr. Kemper. “More information is needed about the long-term outcomes of those infants who begin treatment following newborn screening, so we not only know about outcomes in later childhood and adolescence, but treatment approaches can be further refined and personalized.”

Long-Term Data on Nusinersen Are Lacking

Nusinersen alters the splicing of precursor messenger RNA in SMN2 so that the mRNA strands are longer, which increases the amount of SMN protein produced. Concerns about the medication, however, have included its cost—$750,000 in the first year and $375,000 every following year for life—and potential adverse events from repeated administration. Nusinersen is injected into the spinal canal four times in the first year and once annually thereafter, and the painful injections require patient immobilization. Potential adverse events include thrombocytopenia and nephrotoxicity, along with potential complications from repeated lumbar punctures over time.²

Other concerns about the drug include its limited evidence base, lack of long-term data, associated costs with administration (eg, travel costs), the potential for patients taking nusinersen to be excluded from future clinical trials on other treatments, and ensuring parents have enough information on the drug’s limitations and potential risks to provide adequate informed consent.²

 

Yet evidence to date is favorable in children with early onset SMA. Dr. Bocchini wrote in the letter to Secretary Azar that “limited data suggest that treatment effect is greater when the treatment is initiated before symptoms develop and when the individual has more copies of SMN2.”

Dr. Kemper’s group concluded that screening can detect SMA in newborns and that treatment can modify the disease course. “Grey literature suggests those with total disease duration less than or equal to 12 weeks before nusinersen treatment were more likely to have better outcomes than those with longer periods of disease duration.

“Presymptomatic treatment alters the natural history” of the disorder, the group found, although outcome data past age 1 are not yet available. Based on findings from a New York pilot program, they predicted that nationwide newborn screening would avert 33 deaths and 48 cases of children who were dependent on a ventilator among an annual cohort of four million births.

 

At the time of the evidence review, Massachusetts, Minnesota, Missouri, North Carolina, New York, Utah, and Wisconsin initiated pilot programs or whole-population mandated screening for SMA. Of the three states that reported costs, all reported costs of $1 or less per screen.

The research for the evidence review was funded by a Health Resources and Services Administration grant to Duke University in Durham, North Carolina. No disclosures were provided for evidence review group members.

—Tara Haelle

References

1. King NMP, Bishop CE. New treatments for serious conditions: ethical implications. Gene Ther. 2017;24(9):534-538.

2. Gerrity MS, Prasad V, Obley AJ. Concerns about the approval of nusinersen sodium by the US Food and Drug Administration. JAMA Intern Med. 2018;178(6):743-744.

3. Burgart AM, Magnus D, Tabor HK, et al. Ethical challenges confronted when providing nusinersen treatment for spinal muscular atrophy. JAMA Pediatr. 2018;172(2):188-192.

Spinal muscular atrophy (SMA) is now among the disorders officially included in the Recommended Uniform Screening Panel (RUSP), which state public health departments use to screen newborns for genetic disorders.

Secretary of the Department of Health and Human Services (HHS) Alex M. Azar II formally added SMA to the panel on July 2 on the recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children.

“Adding SMA to the list will help ensure that babies born with SMA are identified, so that they have the opportunity to benefit from early treatment and intervention,” according to a statement from the Muscular Dystrophy Association about the decision. “This testing can also provide families with a genetic diagnosis—information that often is required to determine whether their child is eligible to participate in clinical trials.”

Adding SMA to the RUSP does not mean that states must screen newborns for the disorder. Each state’s public health apparatus decides independently whether to accept the recommendation and which disorders on the RUSP to screen for. Most states screen for most disorders on the RUSP. Evidence compiled by the advisory committee suggested a wide variation in resources, infrastructure, funding, and time to implementation among states.

Drug Approval Raised Ethical Questions

An estimated one in 11,000 newborns has SMA, a disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. SMA affects motor neurons in the brainstem and spinal cord, thus leading to motor weakness and atrophy. The only treatment for SMA had been palliative care until the FDA approved nusinersen for the disorder in December 2016. The drug’s approval has raised ethical questions.^1–3

After reviewing the evidence at its February 8 meeting, the advisory committee recommended adding SMA screening to the RUSP in a March 8 letter from committee chair Joseph A. Bocchini Jr, MD, Professor and Chair of Pediatrics at Louisiana State University Health in Shreveport.

Secretary Azar accepted the recommendation based on the evidence the committee provided; he also requested a follow-up report within two years “describing the status of implementing newborn screening for SMA and clinical outcomes of early treatment, including any potential harms, for infants diagnosed with SMA.”

The advisory committee makes its recommendations to HHS about which heritable disorders to include in the RUSP after it has assessed a systematic, evidence-based review conducted by an external, independent group. Alex R. Kemper, MD, MPH, Professor of Pediatrics at the Ohio State University and Division Chief of Ambulatory Pediatrics at Nationwide Children’s Hospital, both in Columbus, led the review group for SMA. Dr. Kemper is also deputy editor of Pediatrics and a member of the US Preventive Services Task Force.

 

According to Secretary Azar’s summary in his July 2 letter of acceptance, the evidence review suggested that “early screening and treatment can lead to decreased mortality for individuals with SMA and improved motor milestones.”

“SMA can be detected through newborn screening, and treatment is now available that can not only reduce the risk of death, but decrease the development of neurologic impairment,” he said in an interview. “As with adding any condition to newborn screening, public health laboratories will need to develop strategies to incorporate the screening test. The current FDA-approved treatment, nusinersen, is delivered by lumbar puncture into the spinal fluid. In addition, there are exciting advances in gene therapy leading to new treatment approaches.”

Symptom Onset Distinguishes the Types of SMA

Approximately 95% of SMA cases result from the deletion of exon 7 from both alleles of SMN1. Other, rarer cases are caused by mutations in different genes. Without the SMN protein produced by SMN1, a person gradually loses muscle function.

A similar gene, SMN2, also can produce the SMN protein, but in much lower amounts—typically less than 10% of what a person needs. People can, however, have multiple copies of SMN2, which can produce slightly more SMN protein and slow the disease process.

The five types of SMA are determined according to symptom onset, which directly correlates with disorder severity and prognosis. Approximately 54% of SMA cases are Type I, in which progressive weakness occurs over the first six months of life and results in early death. Only 18% of children with Type I live past age 4, and 68% die by age 2. Type 0 is rarer, but more severe, usually causing fetal loss or early infant death.

Type II represents 18% of SMA cases and causes progressive weakness by age 15 months. Most people with Type II survive to their 30s but later experience respiratory failure and rarely reach their 40s. Individuals with Types III and IV typically have a normal lifespan and only begin to see progressive muscle weakness after age 1 or in adulthood.

Dr. Kemper’s group focused on the three types diagnosed in infancy: Types I, II, and III. “It will be critical to make sure that infants diagnosed with SMA through newborn screening receive follow-up shortly afterward to determine whether they would benefit from nusinersen,” said Dr. Kemper. “More information is needed about the long-term outcomes of those infants who begin treatment following newborn screening, so we not only know about outcomes in later childhood and adolescence, but treatment approaches can be further refined and personalized.”

Long-Term Data on Nusinersen Are Lacking

Nusinersen alters the splicing of precursor messenger RNA in SMN2 so that the mRNA strands are longer, which increases the amount of SMN protein produced. Concerns about the medication, however, have included its cost—$750,000 in the first year and $375,000 every following year for life—and potential adverse events from repeated administration. Nusinersen is injected into the spinal canal four times in the first year and once annually thereafter, and the painful injections require patient immobilization. Potential adverse events include thrombocytopenia and nephrotoxicity, along with potential complications from repeated lumbar punctures over time.²

Other concerns about the drug include its limited evidence base, lack of long-term data, associated costs with administration (eg, travel costs), the potential for patients taking nusinersen to be excluded from future clinical trials on other treatments, and ensuring parents have enough information on the drug’s limitations and potential risks to provide adequate informed consent.²

 

Yet evidence to date is favorable in children with early onset SMA. Dr. Bocchini wrote in the letter to Secretary Azar that “limited data suggest that treatment effect is greater when the treatment is initiated before symptoms develop and when the individual has more copies of SMN2.”

Dr. Kemper’s group concluded that screening can detect SMA in newborns and that treatment can modify the disease course. “Grey literature suggests those with total disease duration less than or equal to 12 weeks before nusinersen treatment were more likely to have better outcomes than those with longer periods of disease duration.

“Presymptomatic treatment alters the natural history” of the disorder, the group found, although outcome data past age 1 are not yet available. Based on findings from a New York pilot program, they predicted that nationwide newborn screening would avert 33 deaths and 48 cases of children who were dependent on a ventilator among an annual cohort of four million births.

 

At the time of the evidence review, Massachusetts, Minnesota, Missouri, North Carolina, New York, Utah, and Wisconsin initiated pilot programs or whole-population mandated screening for SMA. Of the three states that reported costs, all reported costs of $1 or less per screen.

The research for the evidence review was funded by a Health Resources and Services Administration grant to Duke University in Durham, North Carolina. No disclosures were provided for evidence review group members.

—Tara Haelle

References

1. King NMP, Bishop CE. New treatments for serious conditions: ethical implications. Gene Ther. 2017;24(9):534-538.

2. Gerrity MS, Prasad V, Obley AJ. Concerns about the approval of nusinersen sodium by the US Food and Drug Administration. JAMA Intern Med. 2018;178(6):743-744.

3. Burgart AM, Magnus D, Tabor HK, et al. Ethical challenges confronted when providing nusinersen treatment for spinal muscular atrophy. JAMA Pediatr. 2018;172(2):188-192.