23 minute read
Spinal Muscular Atrophy: Early Diagnosis for Proactive Management
INFECTIOUS DISEASE: HERPES ZOSTER RZV is recommended for the prevention of HZ and related complications for immunocompetent adults previously administered ZVL.
in the US in 1995, more than 3.5 million cases of varicella, 9000 hospitalizations, and 100 deaths have been prevented each year by varicella vaccination.1 Children who have been vaccinated against varicella have a lower risk for HZ compared with children who became infected with the varicella virus.1,2
The most common complication of HZ is postherpetic neuralgia (PHN), which occurs in 10% to 18% of those affected. The chronic nerve pain lasts after the blisters have healed. The course of PHN can be severe and life-changing, lasting months to years.3 Early treatment of HZ can reduce the severity and incidence of PHN. Less common but severe complications of HZ include blindness caused by secondary bacterial infection, pneumonia, and hearing problems.1-3
Treatment of Shingles
Treatment of shingles includes antiviral medications, which reduce both the acute pain of herpes zoster and risk for PHN. Antiviral treatment should be started as soon as possible and is most effective when started within 72 hours of rash onset (Table).4
Shingles Prevention During COVID-19
According to the Centers for Disease Control and Prevention (CDC), HZ vaccination is an essential preventive care service for older adults that should not be delayed or discontinued during the COVID-19 pandemic unless a patient is suspected or confirmed to have COVID-19.5
Only 1 Food and Drug Administration (FDA)-approved vaccine for the prevention of HZ is available: recombinant zoster vaccine (RZV, Shingrix). According to the Advisory Committee on Immunization Practices (ACIP), RZV is recommended for the prevention of HZ and related complications for adults 50 years and older and is preferred over zoster vaccine live (ZVL, Zostavax), which was approved in 2006 and removed from the market in November 2020 because of the superior efficacy of RZV.6,7 RZV is recommended for the prevention of HZ and related complications for immunocompetent adults who previously received ZVL.6
The vaccination consists of 2 doses (0.5 mL each) administered intramuscularly 2 to 6 months apart.6,7 Two doses of RZV are more than 90% effective at preventing HZ and PHN. The vaccine’s effectiveness against HZ remains greater than 85% for at least the first 4 years after vaccination.2
The ACIP also recommended that people with a history of HZ should be vaccinated because HZ can recur. Individuals with a current outbreak of HZ should wait until the acute phase of the disease is over and all lesions have completely healed before getting vaccinated. It is not necessary to screen for a history of varicella before administering the shingles vaccine. However, an individual who presents with negative laboratory evidence of chickenpox probably would not benefit from the vaccine because it does not protect against chickenpox infection.7
Safety and Side Effects
Postlicensure surveillance data on RZV from October 2017 through June 2018 reaffirm that the vaccine is safe and highly effective. Serious adverse events were rare. However, as was seen in clinical trials, local and systemic reactions can occur including pain, swelling, and redness at the injection site as well as fever, chills, and body aches.7 Counseling patients about potential side effects is especially important during the COVID-19 pandemic because some side effects of shingles vaccination may be similar to symptoms of COVID-19.5 These reactions are self-limited and resolve in a few days.8
Because the shingles vaccine stimulates the immune system, patients can expect such reactions to occur. The immune system responses are not a sign of allergy to the vaccination, and patients should not omit the second dose if such reactions occur, especially because the effectiveness of a single dose of RZV has not been studied.7 Reactions to the first dose of the vaccine have not been shown to predict reactions to the second dose.
The only contraindication to RZV is a severe allergic reaction to components of the vaccine. Adults with chronic medical conditions including diabetes mellitus, chronic pulmonary disease, and chronic renal failure should receive RZV. The vaccine also is indicated for immunocompromised persons,
TABLE. Antiviral Therapies for Herpes Zoster in Adults4
Name Usual Dosage Length of Treatment
Acyclovir 800 mg 5 times a day 7-10 days
Famciclovir 500 mg 3 times a day 7 days
Valacyclovir 1000 mg 3 times a day 7 days
All dosages are for oral administration.
Shingles vaccination rates among adults 60 years and older remain low and increased from 6.7% in 2008 to only 34.5% in 2018.
including those taking immunosuppressive therapy or recovering from an immunocompromising illness. However, RZV’s e ectiveness in these individuals has not been studied.7
Vaccination Rates
The United States is falling short in immunizing older adults against HZ. Findings from the National Health Interview Survey revealed that shingles vaccination rates among adults 60 years and older increased from 6.7% in 2008 to 33.4% in 2016 and then remained relatively constant through 2018, reaching 34.5%.9 Shingles vaccination rates did not di er by sex in 2018. However, non-Hispanic White adults (38.6%) were approximately twice as likely as non-Hispanic Black (18.8%) and Hispanic (19.5%) adults to have ever received a shingles vaccination.9
Vaccination coverage was highest for those with higher incomes and those who had more than a high school education. For example, adults with incomes below the federal poverty level ($12,760 for an individual) were only half as likely to get immunized as adults with annual incomes of more than $25,000.9 These ndings are consistent with disparities seen with other adult vaccines.10
The cost of RZV can have a negative impact on vaccination rates, especially among patients of low socioeconomic status, many of whom do not have health insurance. Commercial health insurance plans generally cover RZV when it is given at a provider’s o ce. However, RZV is covered under Medicare Part D plans, unlike most other vaccinations, including in uenza and pneumococcal, which are covered under Part B. Part D vaccinations typically are administered at a retail site of care, such as a pharmacy, and the out-of-pocket cost to the patient can vary greatly because of di erent plan designs. Medicaid may or may not cover the vaccine.11
To improve shingles vaccination rates, the CDC encourages health care providers to increase awareness among patients of the severity of HZ and e cacy of the RZV as well as use of tools for implementing the Standards for Adult Immunization Practice. 10,12 To address racial and ethnic disparities in vaccination rates, providers should include regular assessment of adult vaccination needs and o er to administer vaccinations as part of routine clinical care. In addition, the CDC suggests that providers consider developing immunization quality improvement projects at their practices to increase adult immunization rates.10,12
Information for Providers
Health care providers who previously had used ZVL should be aware of the di erences in administration and storage for RZV. For example, RZV is supplied as 2 components: a single-dose vial of lyophilized varicella virus glycoprotein and a single-dose vial of adjuvant suspension. Both the antigen and adjuvant should be kept refrigerated between 2 ºC and 8 ºC (36 ºF and 46 ºF). If the components are frozen, they should be discarded.
The vaccine should be administered immediately after being reconstituted or refrigerated and used within 6 hours. If it is not used within 6 hours after reconstitution, it should be discarded. Recombinant zoster vaccine must be given by intramuscular injection, unlike ZVL, which was given by subcutaneous injection. Two doses of RZV are required with the second dose given 2 to 6 months after the rst dose.13 The vaccine series does not have to be restarted if more than 6 months have elapsed since the rst dose, but the e cacy of alternate dosing regimens has not been studied.7
More information about mRNA COVID-19 vaccine coadministration with other vaccines is available at: https://www. cdc.gov/vaccines/covid-19/clinical-considerations/index.html
Summary
Greater e orts are needed by all health care providers to increase shingles vaccination rates among older adults. The
POLL POSITION
As of 2018, what percentage of US adults aged ≥60 years were vaccinated against herpes zoster?
■ 22.8%
■ 34.5%
■ 43.8%
■ 53.3% 40.91% 7.58% 1%
50.51%
For more polls, visit ClinicalAdvisor.com/Polls
Continues on page 26
vaccine has been shown to reduce the risk for shingles and PHN by more than 90% in people 50 years and older. During patient counseling, providers should emphasize the painful disease process, complications, and possible long-term sequelae of HZ as well as the proven safety and efficacy of RZV. Targeted efforts are needed to increase vaccination rates among older adults of low socioeconomic status and racial/ ethnic minorities. ■
Mary Jane S. Hanson, PhD, CRNP, FNP-BC, FAANP, FAAN, is professor and director of the graduate nursing program at the University of Scranton and works at Lehigh Valley Physician Group – Family Medicine in Lehighton, Pennsylvania.
References
1. Centers for Disease Control and Prevention. Shingles (Herpes zoster). Accessed April 28, 2021. https://www.cdc.gov/shingles/ 2. Centers for Disease Control and Prevention. Shingles (Herpes zoster): clinical overview. Accessed June 17, 2021. https://www.cdc.gov/shingles/ hcp/clinical-overview.html 3. Centers for Disease Control and Prevention. Shingles (Herpes zoster) complications of shingles. Accessed April 28, 2021. https://www.cdc.gov/ shingles/about/complications.html 4. Wareham DW, Breuer J. Herpes zoster. BMJ. 2007;334(7605):1211-1215. 5. Centers for Disease Control and Prevention. Frequently asked questions about Shingrix. Accessed June 16, 2021, https://www.cdc.gov/vaccines/vpd/ shingles/hcp/shingrix/faqs.html 6. Harpaz R, Ortega-Sanchez IR, Seward JF; Advisory Committee on Immunization Practices (ACIP). Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2008;57(RR-5):1-30. 7. Dooling KL, Guo A, Patel M, et al. Recommendations of the Advisory Committee on Immunization Practices for use of herpes zoster vaccines. MMWR Morb Mortal Wkly Rep. 2018;67(3):103-108. 8. Hesse EM, Shimabukuro TT, Su JR, et al. Postlicensure safety surveillance of recombinant zoster vaccine (Shingrix) — United States, October 2017–June 2018. MMWR Morb Mortal Wkly Rep. 2019;68(4)91-94. 9. Terlizzi EP, Black LI. Shingles vaccination among adults aged 60 and over: United States, 2018. NCHS Data Brief, no 370. Hyattsville, MD: National Center for Health Statistics. 2020. 10. Centers for Disease Control and Prevention. Vaccination coverage among adults in the United States, National Health Interview Survey, 2016. Updated February 8, 2018. Accessed June 16, 2021. https://www.cdc.gov/vaccines/imzmanagers/coverage/adultvaxview/pubs-resources/NHIS-2016.html#ref03 11. Centers for Disease Control and Prevention. Shingles vaccination. Updated January 25, 2018. Accessed June 16, 2021. https://www.cdc.gov/ vaccines/vpd/shingles/public/shingrix/index.html 12. Centers for Disease Control and Prevention. Standards for adult immunization practice. Updated May 2, 2016. Accessed June 16, 2021. https://www.cdc.gov/vaccines/hcp/adults/for-practice/standards/index.html 13. Shimabukuro TT, Miller ER, Strikas RA, et al. Notes from the field: vaccine administration errors involving recombinant zoster vaccine – United States, 2017–2018. MMWR Morb Mortal Wkly Rep. 2018;67(20): 585-586.
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Spinal Muscular Atrophy: Early Diagnosis for Proactive Management
SMA targets motor neurons in the CNS, resulting in progressive muscle atrophy, weakness, and paralysis.
Spinal muscular atrophy (SMA) is a severe genetic condition that targets motor neurons in the central nervous system (CNS), resulting in progressive muscle atrophy, weakness, and paralysis.1,2 The condition a ects 1 in 11,000 births but often eludes diagnosis based on clinical assessment ndings.1 The availability of new treatments for SMA has changed the natural history of this disease. Early diagnosis and treatment of SMA can limit disease progression in children and adults, extending life expectancy and improving quality of life (QOL).
SMA is categorized into 5 types according to age at onset and maximum motor function achieved (Table 1).1,2 Type 0, the most severe form of SMA, begins in utero; after birth, babies have di culty moving, swallowing, and breathing and survive days to months if they are not treated.2 Type 1, the most common form, is diagnosed during infancy and associated with the inability to sit unsupported by the expected developmental stage (age, 9 months).1,2 Type 2 includes children who can sit unsupported but are unable to walk.1,2 Type 3 includes patients who can walk during childhood but have weak motor function, and type 4 begins in adulthood in patients with no previously identi ed neurologic motor de cits.1,2
Each type of SMA is associated with symmetric muscle weakness in the periphery with the more noticeable weakness in the lower extremities initially.1,2 Cognitive function is not a ected in any type of this disease. The disease is a leading
TABLE 1. Spinal Muscular Atrophy Symptoms by Type1,2
Type Age of Onset Associated Findings
0 Prenatal • Decreased fetal movements • Severe weakness and neonatal hypotonia • Areflexia • Respiratory failure at birth • Facial diplegia • Atrial septal defects
1 (Infantile SMA or Werdnig-Hoffmann disease) <6 mo • Motor deficits, including loss of head control • Variable suck and swallow difficulties • Mild joint contractures • Normal or minimal facial weakness • Rapid disease progression leading to respiratory failure
2 (Intermediate form or Dubowitz disease) 6-18 mo • Weakness affects the lower extremities more than upper • Independent standing/walking is likely not achieved • Decreased or absent deep tendon reflexes • Finger tremor
3 (Juvenile form or Kugelberg-Welander disease) >18 mo • Can walk independently • Symptoms present as proximal muscle weakness (eg, falling and trouble climbing stairs)
4 (Late onset) Adulthood • Onset not clearly defined; often age 20-40 years • Motor milestones all achieved before proximal muscle weakness develops • Lifespan is not reduced
cause of infant mortality because of a single gene but longevity typically is not affected in SMA types 3 and 4.2-4
Epidemiology
This disorder is most commonly caused by genetic deletions or mutations in the survival motor neuron 1 (SMN1) gene, causing it to produce low levels of SMN protein. The inheritance pattern is autosomal recessive, and carrier frequency ranges from 1 in 45 to 1 in 100 people.2 Asian ethnicity is associated with the highest carrier frequency (2.4%).1
Because of the high mortality of SMA types 0 and 1, as well as the QOL implications of all types of SMA, carrier screening should be considered across ethnicities.4
Clinical Presentation of SMA Types
In SMA type 1, infants exhibit hypotonia of the extremities but demonstrate normal facial expressions.2 Cries often are weak and bulbar symptoms are present, leading to progressive feeding problems and aspiration.2 Infants with SMA type 1 presenting late in the disease process exhibit signs of respiratory distress and failure.2 Respiratory distress may be the presenting symptom in infants not seen for routine wellness exams.2
SMA type 2 has similar clinical diagnostic clues, but bulbar symptoms and respiratory concerns are not as profound as in SMA type 1.2 Infants fail to reach motor development milestones of pulling up and walking by age 15 months.2
In types 3 and 4, patient and parental history is key to diagnosis.2 Because patients can walk and function as expected until adolescence or adulthood, clinical symptoms of muscle weakening often are ignored or missed, leading to delayed diagnosis (see Delayed Diagnosis of SMA Type 3: A Case Study).2
Clinicians should be aware of the genetic prevalence of SMA and consider the condition in the differential diagnosis of new-onset muscular weakness (Table 2, page 32).2
Screening and Diagnosis of SMA
In 2018, SMA genetic screening was added to the Recommended Uniform Screening Panel for newborns in the United States.5,6 In addition, more states are adding SMA to their newborn screening panel. A positive newborn screening result allows for immediate confirmatory genetic testing and treatment to prevent SMA disease symptoms from starting or progressing.
Continues on page 32
TABLE 2. Differential Diagnosis of New-Onset Muscle Weakness in Children and Adults2
Duchenne and Becker muscular dystrophy • Most often identi ed in early childhood (3-4 y)
Limb-girdle muscular atrophy • Weakness of the shoulder or pelvic regions
Myasthenia gravis
Guillain-Barré syndrome
Amyotrophic lateral sclerosis
Spinal and bulbar muscular atrophy • Ocular symptoms of ptosis or diplopia is the most common clinical nding (50% of patients) • Onset often in second or third decade
• Bilateral ascending motor paralysis • Often preceded by an infection
• Asymmetric muscle weakness of extremities is the most common clinical presentation • Next most frequent clinical symptom is bulbar weakness
• Onset from age 20-60 y, with slow progressive weakness • Associated with endocrine dysfunction, often involving androgen resistance
For all patients, genetic testing for both the SMN1 and SMN2 genes is recommended to con rm the diagnosis.1,2,7 This testing should be be o ered to patients presenting with SMA symptoms to allow for early intervention with newly developed pharmacotherapeutics that can slow or stop disease progression.7 Previously, electromyography and muscle biopsy were required to diagnose SMA but genetic testing now is considered the gold standard for diagnosis.2 Additional laboratory tests, including creatinine kinase levels, often are within normal range.1
For adult-onset SMA (type 4), history is key to the diagnosis and may include muscle fatigue not previously experienced, di culty with long ights of stairs, and changes in walking/ running stride and coordination. Patient history should be thorough to uncover any alterations in activity due to occupational changes or new hobbies/exercise habits. Patients should be queried about changes in functional abilities with each encounter. Functional assessment instruments help standardize evaluations between examiners. Examples of motor function assessment screening tools are the Timed Up and Go Test and the Assessment of Motor Function.8,9
Physical examination ndings in older children and adults may include bilateral diminished deep tendon re exes in the lower extremities. Re exes should be quanti ed on a 0 to 4+ scale with each patient encounter. Strength testing of the extremities should be quanti ed on a 0 to 5+ scale and monitored in serial assessments.9 This ongoing clinical assessment helps evaluate peak muscle function, which is a predictor of disease severity and life expectancy.
Pharmacologic Treatment
Management of SMA requires a multidisciplinary approach led by a pediatric neurologist (Figure).1 Given the various types of SMA and multiple clinical manifestations, treatment is individualized based on each patient’s functioning.10
Pharmacologic management of SMA became a reality in December 2016 with the approval of the rst SMN-enhancing therapy, nusinersen, for all SMA types in patients of all ages.11 Since then, 2 other SMN-enhancing therapies have been approved: onasemnogene abeparvovec-xioi for patients up to 2 years of age and risdiplam for patients 2 months and older.12,13
Nusinersen Nusinersen binds with SMN2 genes to increase SMN protein production.11 The drug is administered intrathecally in
Spine care
Physical/ occupational therapy Medication: •Nusinersen •Onasemnogene •Risdiplam
Pediatric neurologist
Orthopedic consult Respiratory therapy
Nutrition/ speech therapy
FIGURE. Multidisciplinary care plan for spinal muscular atrophy.10
4 loading doses, delivered every 2 weeks for 3 doses and then after 30 days for the fourth dose. Maintenance treatment should be given every 4 months for life.11 Nusinersen is associated with an increase in the achievement of motor milestones and motor function for patients with SMA type 1. In patients with SMA types 2 and 3, this treatment has been associated with improvements in or maintenance of motor function.11
Onasemnogene abeparvovec-xioi Gene therapy with onasemnogene abeparvovec-xioi is approved for the treatment of SMA in infants and children younger than 2 years.12 The treatment replaces the defective or missing SMN1 gene with a working copy and is given as a single intravenous infusion.12 Gene therapy works best when given early in the disease course, can be administered before symptom onset, and increases survival rates without permanent ventilation and the ability to sit unsupported in clinical trials.12
Risdiplam The newest agent, risdiplam, is approved for patients 2 months and older.13 This SMN2 pre‐mRNA splicing modifier increases SMN production and distribution in the CNS and peripheral tissues.13 Risdiplam is administered orally once daily.13 In clinical trials, risdiplam was linked to an increased rate of survival without permanent ventilation and ability to sit unsupported in infants and improved motor function in adults.
Supportive Therapy
The SMA treatment team also includes rehabilitation professionals such as respiratory, physical, occupational, and speech therapists. Rehabilitation treatment involves care related to positioning, mobility, activities of daily living, stretching, and use of adaptive equipment to maximize functioning and QOL.1
Respiratory therapists are key health care professionals involved in the care of patients with SMA.10 Respiratory assessments should include pulse oximetry and capnography, along with an assessment of cough effectiveness. Also, patients with SMA types 1 and 2 often require airway support, including noninvasive positive pressure ventilation, continuous positive airway pressure, or tracheotomy ventilation. Parents of children with these airway support devices will require extensive education. Part of respiratory management for this patient population includes chest physiotherapy and mechanical cough assistance.
Patients with SMA type 3 may have a higher risk for complications during acute illness and should be monitored closely for any signs of respiratory impairment.10 Because of the high risk for respiratory complications, patients with SMA should receive annual influenza (after 6 months of age) and pneumococcal vaccinations. In addition, for the first 24 months, infants diagnosed with SMA should receive therapy to prevent respiratory syncytial virus infection (palivizumab).
Delayed Diagnosis of SMA Type 3: A Case Study
Clay, a 12-year-old budding athlete, presents to his pediatrician having met every developmental milestone up to this point but showing subtle changes in leg strength. His mother notices changes in his running stride. In addition, he has fallen, both on and off the field, and has difficulty pedaling a bike.
At age 13 years, Clay notices a slight tremor in his hands during meals. The tremors are worse with purposeful activity. He is diagnosed with essential tremor by his pediatrician.
At age 16 years, Clay presents with progressive weakness in his legs. He struggles to get up from a kneeling position on the lacrosse field. His pediatrician observes physical changes, but Clay blames his weakness on a lack of conditioning.
That same year, obvious atrophy is apparent in his upper thighs and his pediatrician notes a difference in the muscular tone of his quadriceps versus his lower legs. At this point, 4 years after the initial visit to the primary care provider for the concern of a change in strength, Clay is referred to a pediatric neurologist.
At the initial appointment, the pediatric neurologist reviews developmental milestones, and Clay’s mother explains the history of falling, hand tremors, change in running stride, and inability to pedal a bike or get up from a kneeling position. Clay continues to deny that anything is wrong, saying he does not notice any physical changes. During the exam, the neurologist notes markedly impaired quadriceps strength and hypotonic reflexes in Clay’s lower extremities. The neurologist expresses concern that the patient may have a degenerative muscular disorder and orders laboratory tests, including creatine kinase, which is elevated to 4 times the normal level.
The neurologist refers the patient to the Mayo Clinic for further evaluation by a neuromuscular specialist. After the second specialty consult, EMG is scheduled to rule out SMA. The EMG findings suggest a neurologic source of the muscular weakness, which narrows down the differential diagnosis. The final and definitive diagnosis for SMA is obtained from blood work showing a SMN1 gene mutation and 4 SMN2 copies.
This case provides an example of diagnostic delays in a patient with SMA type 3 who met all infant and childhood milestones and developed progressive weakness in adolescence.
Orthopedic professionals involved in SMA care help manage associated scoliosis, which is more common in SMA types 1 and 2.1,2 Patients may have chest deformity and hip instability that require treatment by an orthopedic specialist.2 Patients with limited mobility are at higher risk for osteoporosis and vitamin D deficiencies related to disuse and may experience fragility fractures.
The multidisciplinary team caring for patients with SMA includes speech therapists and nutritional specialists, who help to manage impaired swallowing and dysphagia.1,10 Regular growth and development assessments, including weight, height, and length measurements, are essential to help guide nutritional status. Additional gastrointestinal issues commonly include gastroesophageal reflux, constipation, and delayed gastric emptying, which may require surgical or pharmacologic interventions. Maintenance of a healthy weight is critical for patients with SMA because extra weight reduces mobility and increases the risk for comorbidities such as high blood pressure and diabetes and can exacerbate respiratory and orthopedic issues.1,2 Nonambulatory patients are at high risk for obesity because of a lack of physical activity.2
Spinal muscular atrophy is a complex disease requiring lifetime management involving a multidisciplinary team of health care providers. It also requires effective communication between the health care team, the patient, and their family as much of the care for patients with SMA types 1 and 2 is provided in the home. Although SMA types 3 and 4 may be less severe, patients and their health care providers need to be aware of how to manage this chronic disorder and optimize QOL. Knowing the essential assessments for monitoring disease progression, treatment outcomes, and potential complications is key to proactively caring for patients with SMA. ■
Mellisa Hall, DNP, AGPCNP-BC, FNP-BC, is a professor of nursing and chair of the Master of Science in Nursing Program at University of Southern Indiana College of Nursing and Health Professions, in Evansville, Indiana; Jennifer Titzer Evans, DNP, RN, NC-BC, is an associate professor of nursing and program chair of the undergraduate nursing program at the University of Southern Indiana.
References
1. Mercuri E, Finkel RS, Muntoni F, et al. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28(2):103-115. 2. Prior TW, Leach ME, Finanger E. Spinal muscular atrophy. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington; 1993-2021. Updated December 3, 2020. Accessed June 30, 2021. https://www.ncbi.nlm.nih.gov/books/NBK1352/ 3. Butchbach ME. Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front Mol Biosci. 2016;3:7. 4. Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet. 2012;20(1):27-32. 5. Kraszewski JN, Kay DM, Stevens CF, et al. Pilot study of population-based newborn screening for spinal muscular atrophy in New York state. Genet Med. 2018;20(6):608-613. 6. Chien YH, Chiang SC, Weng WC, et al. Presymptomatic diagnosis of spinal muscular atrophy through newborn screening. J Pediatr. 2017;190: 124-129.e1. 7. Arnold WD, Kassar D, Kissel JT. Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle Nerve. 2015;51(2):157-167. 8. Centers for Disease Control and Prevention. Assessment: Timed Up & Go (TUG). Accessed June 30, 2021. https://www.cdc.gov/steadi/pdf/TUG_ Test-print.pdf 9. London Health Sciences Centre. Critical Care Trauma Centre. Assessment of motor function. Accessed June 30, 2021. https://www.lhsc.on.ca/criticalcare-trauma-centre/assessment-of-motor-function 10. Finkel RS, Mercuri E, Meyer OH, et al. Diagnosis and management of spinal muscular atrophy: part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28(3):197-207. 11. Spinraza (nusinersen) injection, for intrathecal use. Prescribing information. Biogen; 2020. Accessed June 30, 2021. https://www.spinraza.com/content/dam/ commercial/spinraza/caregiver/en_us/pdf/spinraza-prescribing-information.pdf 12. Zolgensma (onasemnogene abeparvovec-xioi) suspension, for intravenous infusion. Prescribing information. AveXis; 2021. Accessed June 30, 2021. https://www.novartis.us/sites/www.novartis.us/files/zolgensma.pdf 13. Evrysdi (risdiplam) for oral solution. Prescribing information. Genentech; 2020. Accessed June 30, 2021. https://www.gene.com/download/pdf/evrysdi_ prescribing.pdf
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