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Spinal Muscular Atrophy

Overview

Child with spinal muscular atrophy in wheelchair, raising arms in the air, smiling
Image courtesy of Cure SMA
Image courtesy of Cure SMA
Spinal muscular atrophy (SMA) is an autosomal recessive disorder that causes decreased survival of the anterior horn cells in the spinal cord (lower motor neurons), which innervate voluntary muscles. This results in progressive muscle atrophy and weakness. As more is learned about SMA, it is becoming clear that motor neurons are not the only part of the body affected, and SMA may actually be a multi-system disorder. [Shanmugarajan: 2007] [Hamilton: 2013] SMA is traditionally classified by age of onset and severity. Classification by maximal motor function (non-sitters, sitters, and walkers) may correlate with clinical care needs better than the traditional classifications (type I, type II, and type III). [Wang: 2007] With 3 new treatments available and more in clinical trials, the landscape of SMA is changing quickly. [Michelson: 2018]

Other Names & Coding

Anterior horn cell disease 5q SMA Kugelberg-Welander disease SMA Werdnig-Hoffman disease
ICD-10 coding

G12.0, Spinal muscular atrophy, type I; Werdnig-Hoffman

G12.1, Other inherited spinal muscular atrophy

G12.9, Spinal muscular atrophy, unspecified

ICD-10 for Spinal Muscular Atrophy and Related Syndromes (icd10data.com) provides coding details.

Prevalence

SMA is one of the most common recessively inherited disorders (second only to cystic fibrosis) and occurs in about 1:10,000 births. [Verhaart: 2017] Approximately 1:40 people are genetic carriers for type I SMA. [Verhaart: 2017] Until treatment became available, SMA type I was the leading inherited cause of infant mortality.

Genetics

SMA is an autosomal recessive condition caused by homozygous deletion or mutation involving exon 7 of survival motor neuron 1 gene (SMN1) on chromosome 5q13. Although not well understood, the SMN protein complex appears to be involved in the biogenesis of specific ribonucleoproteins that control regulation of gene transcription. [Kolb: 2007] [Sumner: 2007]
The severity of SMA is dependent on a second gene, SMN2, also on 5q13. SMN2 is the result of an ancestral duplication and is identical to SMN1 except for the presence of a missense mutation on exon 7 that disrupts a splicing enhancer but does not change the predicted protein sequence. This mutation results in mis-splicing of exon 7 and an inactive transcript; however, at a low rate, normal splicing occurs, providing a small amount of normal transcript and normal SMN protein. Severity of clinical symptoms is correlated with the number of copies of SMN2 since patients with more copies of SMN2 produce more normal SMN protein. While not perfectly correlated, most SMA type I patients have 1 or 2 SNM2 copies, and most patients with SMA type III have 3 or more copies. Treatments targeting up-regulation of expression of normal transcript from SMN2 have proven successful clinically, resulting in approval of nusinersen in 2016 and risdiplam in 2020.
With the addition of SMA to the recommended uniform screening panel, newborn screening programs for SMA are rapidly coming online in many states. Early initiation of treatment leads to far better outcomes, especially if treatment is started before the onset of symptoms and before significant loss of motor neurons becomes permanent. In most cases, newborn screening will identify homozygous deletion of SMN1 and will not identify carrier status or SMN2 copy number. Confirmatory testing, including SMN2 copy number after a positive newborn screen, is essential. [Baker: 2019] [Ke: 2019]. As newborn screening only detects infants with SMN1 deletions, about 95% of all cases of SMA but will miss those infants with one SMN1 deletion and one point mutation on the second copy.

Prognosis

In the last few years, 3 FDA-approved treatments have been approved for use for individuals with SMA - nusinersen (Spinraza), risdiplam (Evrysdi), and onasemnogene abeparvovec-xioi (Zolgensma). Each has pros and cons; none has long-term data, so the decision of which to use, or which combination of medications, can be difficult. Before these treatments became available, prognosis was variable and depended on the SMA subtype. Most children with type I SMA died before their second birthday. [Cobben: 2008] [Bach: 2007] [Finkel: 2014]
Individuals with type II and type III SMA can have a normal life span but experience significant disability and respiratory or other complications. Anticipatory care that includes careful attention to respiratory, nutritional, and orthopedic issues can significantly prolong survival.
The availability of treatments, such as nusinersen, risdiplam, and onasemnogene abeparvovec-xioi (detailed in the Management section, below), has greatly changed the natural history and progression of SMA, especially when treatment is initiated early. [Ross: 2019] Although long-term data over a decade or more are not yet available, in many cases, infants who would not have lived past 2 years old are surviving longer and maintaining relatively good health. [De: 2019]

Practice Guidelines

The standard of care guidelines (below) represents expert consensus but lack well-designed clinical trials to validate recommendations. It is expected that the standards of care will be updated in the near future to reflect new data from approved treatments and ongoing studies.

Kirschner J, Butoianu N, Goemans N, Haberlova J, Kostera-Pruszczyk A, Mercuri E, van der Pol WL, Quijano-Roy S, Sejersen T, Tizzano EF, Ziegler A, Servais L, Muntoni F.
European ad-hoc consensus statement on gene replacement therapy for spinal muscular atrophy.
Eur J Paediatr Neurol. 2020;28:38-43. PubMed abstract / Full Text

Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Qian Y, Sejersen T.
Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care.
Neuromuscul Disord. 2018;28(2):103-115. PubMed abstract

Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Qian Y, Sejersen T.
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. PubMed abstract

Michelson D, Ciafaloni E, Ashwal S, Lewis E, Narayanaswami P, Oskoui M, Armstrong MJ.
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. PubMed abstract

Roles of the Medical Home

Optimally, care of children with SMA should take place in a multi-disciplinary clinic. If one is not available, it is essential that the medical home helps families organize specialty care, remains watchful for changes in function, understands current treatment for acute illnesses, and advocates throughout the life of the child. Children with SMA will need surveillance of respiratory adequacy (awake and asleep), GI/nutritional balance, musculoskeletal status, dental hygiene, and individual and family functioning.
Left: Infant with SMA Type I characteristics; Center: Boy with turtleshell & AFOs; Right: medical provider checks a boys hips while another adult watches
Left to right: Five-month-old girl with SMA type I; Boy with SMA type II with turtle shell and ankle-foot orthoses; Boy with SMA type III being checked for hip weakness

Clinical Assessment

Overview

Clinicians should suspect SMA in infants and children with proximal muscle weakness (shoulder and hip girdles) and absent or reduced deep tendon reflexes. In young infants, respiratory difficulties (e.g., bell-shaped chest or weak cough or cry) and feeding problems may be present from very early in the course. Patients with SMA are rapidly losing motor neurons at onset, and they risk permanent disability if treatment is not started as soon as possible.

Pearls & Alerts for Assessment

Urgent referral when positive newborn screen for SMA

A positive newborn screen for SMA should prompt urgent referral to a neuromuscular center where treatments can be coordinated quickly, before onset of symptoms. Outcomes for pre-symptomatic treatment are far superior to treatment at later stages. In one study of 25 infants with 2 or 3 copies of SMN2, treated pre-symptomatically with nusinersen, 22 of 25 reached independent ambulation. [De: 2019] For pre-symptomatic infants with SMA, symptoms can arise in the first weeks of life and time is critical. Delay of treatment even for a few days can result in permanent disability. [Butterfield: 2021]

Newborn screening will not pick up all cases of SMA

If SMA is suspected even in a child with negative newborn screening, further testing (SMN1 sequencing) is needed as newborn screening only identifies SMN1 deletion and 5% of patients are expected to have other mutations in the SMN1 gene. Children with one SMN1 deletion and a one point mutation on the second copy of SMN1 would have a negative screen.

Address possibility of respiratory failure

Infants with type I SMA are susceptible to respiratory failure due to infection or aspiration. Addressing this possibility early with the family and implementing proactive measures (e.g., non-invasive ventilation, cough assist, and G-tube placement) can prevent emergency situations. Frequent pneumonias or respiratory illnesses may signal impending respiratory failure or aspiration.

Screening

For the Condition

In July of 2018, SMA was added to the list of recommended screening for newborns in the US by the Department of Health and Human Services. Implementation of newborn screening for SMA is progressing at variable rates, depending on the state-specific criteria. As of June 2021, 38 states participate in this screening, including 85% of births in the US. For further details, see Newborn Screening For SMA (Cure SMA). A positive newborn screen for SMA should prompt urgent referral to a neuromuscular center where treatments can be coordinated quickly before onset of symptoms. See Spinal Muscular Atrophy (SMA).

Of Family Members

Siblings of an individual with SMA have a 1:4 chance of being born with the condition and a 2:3 chance of being a carrier if not affected. Carrier testing is available for adults and siblings over age 18. [Carré: 2016] Although testing at-risk younger siblings who are asymptomatic for SMA is controversial, early identification of children with SMA may improve clinical outcome. The American College of Medical Genetics endorses offering SMN1 gene testing for early in pregnancy and all couples considering pregnancy. [Prior: 2008]

Presentations

Presentations and clinical characteristics vary by SMA subtypes which are defined by maximal motor milestones attained. SMA type 1 individuals never reach independent sitting, type 2 individuals sit but never walk, and type 3 walk independently, even if only briefly. Early initiation of treatment has led to dramatic changes in natural history, challenging these traditional subtype distinctions. Regardless, treatment strategies remain based on current motor function as defined by groups of non-sitters, sitters, and walkers. Some families will choose not to treat/be unable to treat, and those children will present with the typical symptoms as noted below.
  • Type I SMA (Werdnig-Hoffman) presents in the first few weeks of life. Children never learn to sit or walk and have severe respiratory and swallowing problems, including difficulty handling oral secretions and a significantly shortened life span. Other features include poor head control, a bell-shaped chest, weak cry and cough, tongue atrophy and fasciculation, and paradoxical breathing.
  • Type II SMA presents later in the first year of life or up to about 2 years of age. Children usually learn to sit but do not walk. Fine tremor-like movements in the hands and fingers may be noted from early in the course. As weakness progresses, children often have respiratory and swallowing problems, including difficulty gaining weight due to bulbar muscle weakness, weak cough, and nighttime hypoventilation. Swallowing problems and difficulties opening the jaw widely have been shown to contribute to malnutrition. [Messina: 2008] Joint contractures and scoliosis develop over time in nearly all affected children and warrant proactive intervention.
  • Type III SMA (Kugelberg-Welander) is much more variable in onset than types I and II, but it usually presents in childhood or early adolescence. Children can sit and walk (although some may lose this ability over time). As with type II SMA, children with type III SMA may have fine tremor-like movements in the hands and fingers. Quadriceps atrophy may be pronounced. Children with type III SMA may have fewer problems with respiratory function and swallowing than children with type I or II SMA. Scoliosis, contractures, and joint pain are often noted in older children.
  • Type 0 SMA presents before birth with decreased fetal movement noted around 30 weeks of gestation. Newborns are severely hypotonic at birth with congenital contractures, swallowing problems, and respiratory failure.
  • Type IV SMA presents in adults and will not be discussed further here.

Diagnostic Criteria

Diagnosis is made by genetic testing for the common deletion of exon 7 of the SMN1 gene in children with appropriate clinical features. This testing is inexpensive and readily available; laboratories offering testing can be found at Testing for SMA (Genetic Testing Registry). Free testing programs are available, minimizing cost to patients and families. In states where newborn screening for SMA is available, diagnosis may come from the newborn screening program at just a few days of age, before clinical symptoms have emerged. A positive newborn screen should prompt urgent neuromuscular referral as symptoms can arise within the first weeks of life and treatment initiated before symptoms arise is the most effective.
Identification of the copy number of the SMN2 gene assists in prognosis and is a standard feature of genetic testing for SMA. While most patients will have the common deletion of exon 7, about 5% of children who present with SMA have negative genetic testing due to presence of a deletion on 1 allele and a point mutation on the other. Clinical suspicion, more detailed gene testing, and electromyography (EMG) play important roles in diagnosis in these cases.

Clinical Classification

Classical clinical classifications are based on the maximal motor function achieved.
  • Children with type I SMA, which is the most common form, present before 6 months of age with generalized muscle weakness and progressive respiratory compromise. These children never achieve independent sitting.
  • Children with type II SMA present between 6 months and 1 year of age with weakness and motor regression. Children with type II SMA sit independently but do not walk.
  • Onset for type III SMA is variable from early childhood to adolescence. Children with type III SMA achieve independent ambulation, although they do not necessarily retain ambulation throughout life.
The type of SMA is generally correlated with the number of SMN2 gene copy numbers.

Differential Diagnosis

SMA is usually readily identified by clinical features and confirmed by genetic testing and, in many states, can now be identified by newborn screening. Differential diagnoses for a child with newly presenting progressive muscle weakness are described below.
Infant botulism occurs in children up to 12 months of age. Symptoms start with constipation in a previously normal baby and are followed by decreased facial expression, poor swallowing, a weak cry, and decreased movement. Over time, the course is more acute than SMA. Diagnosis is made by recognition of clinical features and demonstration of botulinum toxin in the infant's stool. EMG can help to exclude other diagnoses.
Neuropathies are a wide spectrum of syndromes with various time courses. Sensory nerves are usually involved. Family history is often positive (e.g., Charcot-Marie-Tooth disease or hereditary motor sensory neuropathy). Acquired polyneuropathies, such as Guillain-Barre syndrome, have a rapid onset over a few days to a week. These are exceedingly rare in children under 2 years old. Diagnosis is confirmed by EMG and/or tests showing elevated cerebrospinal fluid (CSF) protein.
Metabolic myopathy (e.g., mitochondrial myopathy, Pompe disease) is much less common than SMA, but early features can be clinically similar. Infants with Pompe disease have severe progressive cardiac dysfunction not seen in SMA.
Duchenne muscular dystrophy occurs in boys only. In this condition, calves are large, creatine kinase (CK) is extremely high, and developmental delay is often present. It is diagnosed by genetic testing for mutations in the DMD gene.
X-linked SMA and SMA with respiratory distress (SMARD) may appear clinically similar to SMA, but they have different genetic etiologies and are therefore not currently amenable to treatment. SMARD1 presents as distal (not proximal) muscle weakness, with foot deformities as well as respiratory failure that often occurs suddenly. This condition is due to mutations in the IGHMBP2 gene on chromosome 11q13.3, which encodes the immunoglobulin micro-binding protein 2. [Kaindl: 2008] Infants with X-linked SMA may have a family history showing X-linked inheritance and will have negative SMN1 testing. An increasing number of new genes are being associated with these phenotypes and suspicion should prompt referral to a sub-specialty clinic for assessment.
Congenital myopathy presents with non-progressive weakness and is diagnosed by genetic testing and/or muscle biopsy.

History & Examination

Note that the history and exam features as described below are found in children who have not been treated with nusinersen, risdiplam, or onasemnogene abeparvovec-xioi. Since long-term data are not available in children who have been treated, they should be followed in a dedicated neuromuscular clinic.
Early recognition of weakness is critical to the initial evaluation. Assessment of weakness can be difficult in young children, but close attention to functional ability allows a good assessment of strength. Videos of children with and without weakness are available at the Child Muscle Weakness Organization and can be helpful in identifying subtle weakness.

Current & Past Medical History

Nutrition/GI: Has weight gain been adequate? Note that target weights for patients with muscle atrophy are lower than typical growing children. Ask about GI issues such as reflux, stomach pain, and constipation. Children with any neuromuscular disorder, including SMA, are osteopenic. Is Calcium and Vitamin D intake adequate? Any fractures? [Khatri: 2008] See Osteoporosis and Pathologic Fractures.
Respiratory: Ask about breathing problems while awake, including while eating, for infants. Ask about history of pneumonia, strength of cough, reactive airway disease, recent pulmonary testing (oximetry), use of respiratory support (noninvasive respiratory support such as CPAP and BiPAP and nighttime or continuous ventilation), and use of a cough assist machine. Ask also about sleep, results of previous sleep studies, snoring as evidence of obstructive sleep apnea and hypoventilation, frequency of night waking, daytime sleepiness, and morning headaches. Check immunization history, including pneumococcal and flu vaccines. 
Swallowing problems: Ask about coughing or choking while eating and drinking (especially thin fluids) and strength of cough. Ask if the family has a suction machine at home.
Musculoskeletal: Ask about any recent changes in muscle strength, fatigability, and functional abilities. Ask about fit and maintenance of the wheelchair, stander, or other equipment. Ask if the family has a license plate or placard for individuals with disabilities.
Orthopedic: Ask about orthotics use, joint pain, range of motion, and history of fractures.
HEENT: Ask about chronic ear infections.
Dental: Ask about dental history and the ability to open and close jaw.

Family History

SMA is an autosomal recessive disorder usually occurring with no family history; yet, providers should ask about infant and childhood deaths and consanguinity.

Pregnancy/Perinatal History

Although there is no specific pregnancy history, sometimes mothers of children with type I SMA will report decreased fetal movement in late pregnancy. Children with type 0 and type I SMA may also have arthrogryposis at birth, difficulties with early feeding, and bell-shaped chests.

Developmental & Educational Progress

Early motor milestones, such as the development of head control, will often be delayed. Babies may lie in the classic frog position when supine. Speech and language skills will not be delayed. Developmental testing will show profound delays in gross motor abilities, but cognitive abilities are spared. Measures of daily functioning, such as the Pediatric Evaluation of Disability Inventory (PEDI) (available for a fee), can help evaluate the child's functional abilities over time and are often available from the child's therapists. Ideally, these assessments should be part of the medical home record. Families should sign releases of information to obtain these records or bring copies of them to their appointments. A quick look at changes in the functional abilities of the child will help guide assessment of progression.

Social & Family Functioning

Ask about family and community supports, access to resources, and any social issues for the child and family. Are necessary accommodations being made at school? Do the parents have anyone to stay with their child while they take a break? If the child with SMA is having difficulty with breathing, whether unaided or using BiPAP, how is that impacting the family, and what are their feelings concerning the next step? Is there a plan for an acute respiratory illness?

Physical Exam

General

Babies with SMA are often alert and interactive, and children with SMA are often bright and quite social.

Vital Signs

RR | HR may be elevated in children with weak respiratory muscles.

Growth Parameters

Wt | Ht | BMI: Due to feeding problems, infants with SMA may be underweight or overweight (particularly when using a G-tube to augment feedings). Careful attention to feeding and growth patterns is important. With decreased muscle mass, a relatively low weight for length may be ideal. Standard growth charts for children may be inappropriate.

Skin

Is there evidence of breakdown, cool extremities, mottling of skin, or yeast infection (tongue, body creases)?

HEENT/Oral

Check ability to open jaw and the size of tonsils. Check for bad breath, dental caries, and drooling that may be caused by swallowing problems.

Chest

The chest wall may appear bell-shaped. Listen to the lungs and observe for evidence of breathing difficulties. Check respiratory rate and look for paradoxical abdominal/chest wall movements. Observe cough or cry if possible. Consider spot oximetry, peak flow, and forced vital capacity measures. Measure chest circumference at the nipple line and follow growth. Chest and head circumference should be fairly equal in the first year. If the chest is not growing, the child is at a higher risk of respiratory compromise.

Abdomen

Non-tender mobile masses may represent hard, backed-up stool.

Extremities/Musculoskeletal

Check for progression of joint contractures. Perform muscle strength and functional ability exams. Sensation should be completely preserved. Evaluate for clinical scoliosis and hip dislocation.

Neurologic Exam

Check for tone, proximal muscle strength, and reflexes. Central nervous system function should be normal.

Testing

Sensory Testing

Perform vision and hearing screening as appropriate for age.

Laboratory Testing

No routine testing is needed. Consider labs to evaluate for nutritional inadequacies, carnitine deficiency, hypercalcemia, and iron deficiency anemia. A urinalysis will detect urinary tract infection, etc. In the setting of illness, check for acidosis or electrolyte disturbances. Creatinine levels are normally low. Elevated CK levels are usually considered in those with muscle disorders such as Duchenne muscular dystrophy; however, CK levels can be elevated in patients with SMA undergoing active denervation.

Imaging

Consider a video swallow study to look for aspiration or for children who take a long time to eat, have poor weight gain, or swallowing problems. Since the study is performed with a speech therapist present, strategies for safer feeding (e.g., thickening fluids) may be explored. A chest X-ray will help diagnose chronic aspiration or acute pneumonia; spine and hip X-rays will help diagnose scoliosis or hip dislocation.

Genetic Testing

Genetic testing for SMA by detection of the common SMN1 deletion is readily available, and in many cases, can be obtained for free through various genetic testing programs. With urgency to treat quickly, many labs can provide results within a few days. Most children with SMA will have 2 copies of the common SMN1 deletion (1 from each parent). In some cases, the child has a single copy of the common SMN1 deletion and a second rare mutation on the other copy of SMN1. In this case, genetic testing requires sequencing of the SMN1 gene to identify missense, nonsense, or frameshift mutations. A small percentage of children with SMA will be negative for the common exon 7 deletion, but when more detailed testing is performed, the child may have a mutation on SMN1 not included in the routine genetic testing.
Although the number of SMN2 copies is not needed to diagnose SMA, guidelines recommend that this be obtained to allow assessment of the predicted SMA phenotype. In most cases, those with type I SMA have 2 copies, type II SMA have 3 copies, and type III SMA have 4 copies of SMN2. In addition, eligibility for medication trials for SMA may depend on SMN2 copy number. [Mercuri: 2018] See Testing for SMA (Genetic Testing Registry).

Other Testing

Other possible testing:
  • Electromyography (EMG) can indicate probable SMA, in which case, genetic testing should follow.
  • Pulmonary function tests and sleep studies are used to evaluate respiratory status as needed.
  • Nutritional assessments are helpful for evaluation of children who are underweight or overweight.
  • DEXA scans are performed if the child has a history of fractures or, as a baseline if the child has been immobile and confined to a wheelchair for an extended period, especially if the child is on valproic acid or proton pump inhibitors.

Specialty Collaborations & Other Services

When available, an SMA-specific clinic for children is preferred for evaluation and management. Depending on the location, additional involvement of sub-specialists, such as those in physical medicine & rehabilitation and pulmonology, can be helpful.

Neuromuscular Clinics (see NW providers [1])

Multidisciplinary care for children with SMA and other neuromuscular disorders is often available through clinics sponsored by the Muscular Dystrophy Association. In partnership with the primary care team, these clinics can coordinate anticipatory care, subspecialty referrals, and treatment with newly approved therapies.

Medical Genetics (see NW providers [1])

Genetics and genetic counseling may be available in an SMA-specific or neuromuscular clinic. If not, an initial visit for genetic testing and discussion of test results, and periodic visits to address new issues, may be helpful.

Pediatric Pulmonology (see NW providers [0])

Referral is particularly important for children with type 0 and type I SMA because of the risk for respiratory compromise. Nighttime ventilation is often affected first; deterioration may be subtle. Early pulmonology consultation is recommended, even for children with SMA that are doing well.

Pediatric Gastroenterology (see NW providers [0])

Nutrition support is available in most subspecialty clinics with expertise in SMA. Referral may be helpful for evaluation and management of eating and nutrition problems. Swallowing difficulty, reflux, constipation, or failure to gain weight appropriately should also prompt consideration of referral.

Pediatric Orthopedics (see NW providers [4])

Most children with SMA of any type will benefit from periodic referrals for evaluation and management of musculoskeletal complications. If the child with SMA has been born with arthrogryposis, early involvement is critical.

Pediatric Physical Medicine & Rehabilitation (see NW providers [3])

Referral can help optimize mobility and the activities of daily living, and it usually includes physical, occupational, and speech therapy.

Pediatric Otolaryngology (ENT) (see NW providers [1])

Consider a referral if obstructive sleep apnea is a concern.

Treatment & Management

Pearls & Alerts for Treatment & Management

New specific treatments are available for SMA

Nusinersen (Spinraza) is now approved by the FDA for individuals with all types of SMA. There is emerging data supporting dramatic benefits even in severely affected patients, but long-term outcomes are not known. Nusinersen has generally been well-tolerated. There is Class III evidence that infants with homozygous mutations/deletions of SMN1 have improved, ventilation-free survival at age 24 months. Finally, there is evidence that in children aged 2-12 diagnosed after 6 months of age (SMA type II patients) nusinersen results in greater improvement in motor function after 15 months of treatment.
Nusinersen is extremely expensive, and there are many inequalities between children without insurance and children with various types of insurance. It needs to be given by lumbar puncture and a controlled environment and sedation are needed. Nusinersen is given by 4 loading doses (the first 3 at 14-day intervals and the 4th 30 days after the third dose) and then 1 dose every 4 months indefinitely. Administration of nusinersen may be particularly difficult in children who develop scoliosis and in the setting of spine surgery. In addition to the price of nusinersen, administration costs also need to be considered.
Onasemnogene abeparvovec-xioi (Zolgensma) was approved by the FDA in2019 for children under 2 years of age with SMA. Onasemnogene abeparvovec-xioi is administered by IV as a one-time dose as soon as possible after diagnosis. To qualify currently, children must be under 2 with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene and absent antibody to the vector, AAV9. Children are treated with steroids one day prior to dosing with Zolgensma and for about 60 days thereafter to mitigate the chance for liver inflammation and other adverse effects. Liver function, platelet count, and troponin-I are monitored after Zolgensma infusion. See Zolgensma Package Insert (PDF Document 210 KB). Current pricing is >$2 million for this 1-time dose.
Risdiplam (Evrysdi) is an oral medication given daily that works similarly to nusinersen. It was approved by the FDA in August 2020 for children 2 months of age and older, including adults with SMA. It should be avoided in pregnancy and may cause problems with male fertility. Price is about $300,000 to $400,000 annually and is given indefinitely. See EVRYSDI Prescribing Information (PDF Document 514 KB).
Which treatment to pick is a complex question and should be discussed carefully with the neuromuscular specialist. Data are evolving rapidly and treatment should be tailored to the specific risks/benefits of the child. Outcome with any of the 3 medications is better if given/started younger than 3 months of age and with good baseline motor function. [Ramdas: 2020] Zolgensma is only available for children younger than 2, and those children must not have antibodies to the AAV9 vector. Both risdiplam and nusinersen are approved for use in types 1, 2, and 3, although risdiplam cannot be given to infants younger than 2 months of age. Nusinersen must be given by lumbar puncture and risdiplam may cause birth defects and male infertility. These factors and others must be weighed by the family in consultation with the Neuromuscular specialist. Additionally, families may wish to try a second medication based on outcome of the first medication tried. [Ramdas: 2020]

Expectant management during hospital visits improves outcomes

Expectant management includes increased nutritional management and attention to respiratory status before and after surgery and during acute hospital visits. Temporary supplementation with nasogastric tubes or nasojejunal tubes, or peripheral or total parental nutrition, may be helpful.

Written care plans facilitate emergency care

Emergency room visits for families of children with SMA are challenging because of the need for families to detail their histories and preferences, as well as the reason for their visit. Plans for what to do in case of respiratory failure should be made and revised at non-acute medical home visits. Provide families with documentation so their resuscitation desires can be shared with other clinicians.

Early postoperative ambulation helps maintain strength

Required inactivity following major surgery (e.g., for scoliosis or hip dislocation) may precipitate the loss of ambulation. Early re-institution of ambulation in these settings can help significantly in maintaining strength.

How should common problems be managed differently in children with Spinal Muscular Atrophy?

Growth or Weight Gain

Standard growth charts often are not appropriate for children with SMA. Children who are following “normal” growth curves may be functionally obese and at risk for insulin resistance and complications of a metabolic syndrome. Muscle atrophy complicates management of nutritional issues; close monitoring is essential. Children with type I SMA have early dysphagia; early placement of G-tube with Nissen fundoplication is often necessary to prevent aspiration and pneumonia.

Development (Cognitive, Motor, Language, Social-Emotional)

Cognitive and emotional development is normal in children with SMA. While language is normal from a neurologic perspective, communication, especially with type I SMA, can be difficult due to weakness. Children may need adaptive devices to assist communication.

Viral Infections

Due to weakness of respiratory muscles and poor cough, children with SMA are at risk for significant upper respiratory infections. Families should be encouraged to take appropriate precautions (e.g., handwashing and limiting exposure to sick individuals). Patients should receive annual flu vaccine; RSV prophylaxis is appropriate in infants with type I SMA.

Bacterial Infections

Children with SMA are at risk for bacterial pneumonia as a primary feature or as a complication of viral upper respiratory infection or aspiration. Age-appropriate pneumococcal vaccination is recommended. Early use of non-invasive ventilation and Cough Assist are appropriate preventive measures.

Systems

Neurology

The clinical course of SMA is variable and difficult to predict, especially with the new treatment options available. Proactive management of complications has led to increased quality of life and prolonged life expectancy. Although no medication definitively treats SMA, several clinical trials are in progress. [Parente: 2018]

Specialty Collaborations & Other Services

Neuromuscular Clinics (see NW providers [1])

Multidisciplinary care for children with SMA and other neuromuscular disorders is recommended. In partnership with the primary care team, these clinics can coordinate treatment, anticipatory care, and subspecialty referrals.

Pediatric Neurology (see NW providers [0])

In areas without specialty clinics, pediatric neurologists with expertise in neuromuscular disorders should be involved in the management of children with SMA.

Respiratory

Non-sitters, and sometimes sitters, may have severe respiratory problems. Bell-shaped chests and paradoxical breathing reflect weak respiratory musculature (sparing the diaphragm). Difficulties with swallowing and chronic aspiration exacerbate this situation.
Infant with SMA Type I wearing BiPAP device
A weak cough makes the clearing of secretions difficult. Scoliosis may add to respiratory problems. Pulmonary referral should occur soon after diagnosis for both non-sitters and sitters. General guidelines for respiratory care in type I and many type II SMA patients include airway clearance techniques, such as Cough Assist, and nocturnal non-invasive ventilation, such as BiPAP. [Schroth: 2009]
Consider a sleep study for identification of obstructive sleep apnea and central hypoventilation. These problems may occur before the child has obvious daytime problems. Nighttime BiPAP is usually necessary when the vital capacity is less than 40% of the predicted value. BiPAP can also be used in daytime during periods of increased need, such as with a respiratory illness or following surgery. The Medical Home Portal's CPAP & BIPAP Therapy for Children topic provides more information about indications for use and follow-up care.
Optimal preventive treatment includes nutritional optimization, especially with surgeries and illnesses. For some children, breath stacking methods and incentive spirometry can be taught, usually by staff at the pulmonology clinic. Breath stacking involves repetitions of taking a breath and holding it. Daily practice can be helpful for children who are losing lung capacity, but adherence is difficult.
If the child has a weak cough, percussion and postural drainage should be initiated; management of secretions is further improved by use of a cough-assist device. [Fauroux: 2008] Respiratory secretions should be managed with the help of an ENT if necessary. Consider medications to reduce secretions, botulinum toxin injections, and salivary gland ligation for children who cannot manage secretions. Swallowing problems should be managed optimally, for example, with thickened liquids and G-tube feeds; Nissen fundoplication may be helpful when reflux is present.
Ensure that immunizations, especially pneumococcal and yearly flu vaccines, are up to date. RSV prophylaxis should be given to non-sitters and most sitters. Respiratory infections and symptoms of reactive airway disease should be treated early and aggressively. If hospitalization is necessary for acute, severe respiratory illness, consider the use of non-invasive ventilation; children with SMA often have difficulty weaning from a ventilator. Supplemental oxygen without mechanical ventilation should be used with care as it may decrease respiratory drive, leading to hypercarbia and atelectasis.

Specialty Collaborations & Other Services

Pediatric Pulmonology (see NW providers [0])

Pulmonology should manage most children with SMA concurrently with the medical home. Children should be referred at diagnosis and periodically for management.

Sleep Disorders (see NW providers [0])

Children with SMA may need breathing assistance during sleep before they demonstrate problems while awake; refer for sleep evaluations and management as needed.

Pediatric Otolaryngology (ENT) (see NW providers [1])

Consider referral for drooling, swallowing problems, or sleep apnea.

Nutrition/Growth/Bone

If nutrition is oral, malnutrition may occur. Risk factors include being easily fatigued at mealtime, needing excessive time to eat, and often choking or coughing while eating. Standard weight charts are not applicable due to the reduced muscle mass that occurs despite caloric supplementation. BMI, weight for height, or skinfold measurements of the triceps area are often available as part of a nutritional assessment and may help determine nutritional reserves. Maximize Calcium and Vitamin D intake, and consider bisphosphonates with a history of fractures. (See Osteoporosis and Pathologic Fractures.)
Poor weight gain is common and often attributed to the decreased intake of food and the increased energy demands required for the work of breathing. Registered dieticians should be involved when infants are grossly underweight. Increasing calories may involve Boosting Calories for Babies, Toddlers, and Older Children, pureeing foods, or gastrostomy feeds (either exclusively or in addition to oral feeding). Although the decision to proceed with G-tube placement can be difficult, prolonged feeding time may make the logistics of caring for non-sitters with SMA very difficult. Families may prefer to start with a nasogastric tube before proceeding with G-tube placement. For an introduction to various kinds of feeding tubes and an overview of the role of the medical home in feeding tube care, see Feeding Tubes & Gastrostomies in Children.
Excessive weight gain can also occur in sitters and walkers and can make mobility even more difficult; preventing excessive weight gain is easier than losing weight. Nutrition experts should be involved when a trend toward becoming overweight is first noted.

Specialty Collaborations & Other Services

Dieticians and Nutritionists (see NW providers [1])

Referral may be helpful in underweight and overweight children with SMA.

Pediatric Endocrinology (see NW providers [1])

Consider referral for children who have low bone mineral density on DEXA scans and history of fractures.

Musculoskeletal

Preventive and ongoing management for musculoskeletal problems, including joint contractures, hip dislocation, and scoliosis, should be initiated at time of diagnosis. Refer to early intervention services, physical therapy, physiatry, and orthopedics depending on preferences and local expertise.
Devices for upright positioning are prescribed for non-sitters to help with lung function, gastrointestinal function, and developmental goals. For sitters and non-sitters, standing equipment should be prescribed and used for a goal of 1 to 2 hours a day. This can help with lung and gastrointestinal function, decrease fracture risk, and delay scoliosis and contracture development. Orthotics and walking equipment should be provided, even if functional walking for all activities is not a practical goal. Prescribe scooters, wheelchairs (manual and/or powered), or other equipment, as necessary, for all children with SMA to allow participation in age-appropriate community activities. To avoid progression of contractures, implement daily range of motion exercises and early return to weight-bearing activities after surgeries.
Boy leaning over while medical provider checks spine and a woman looks on
Boy with SMA type III being checked for scoliosis
Scoliosis develops in more than half of children with SMA, and many of these children will require surgery. Optimal timing for surgery will depend on the respiratory status, progression of the curve, and growth of the child, although most experts recommend that surgical treatment should be delayed until after age 4 (Guidelines 1). Bracing is sometimes used to postpone surgery as long as possible and allow more linear growth before fusion; however, bracing can compromise respiratory function and should be used with caution, particularly in weaker children. Respiratory function should be monitored routinely; scoliosis surgery should be performed before respiratory function significantly declines. Surgery is performed before or when the scoliosis curve has reached approximately 40 degrees. Problems with surgery include blood loss, difficulty weaning the child from the ventilator, and prolonged rehabilitation time.
Hip subluxation and dislocation are common problems for non-sitters, sitters, and, occasionally, walkers. Imaging of the hip should be performed bi-annually or annually. Hip dislocation can make sitting balance difficult, interfere with already compromised respiratory function, and lead to chronic pain. The risks and benefits of surgery for hip subluxation should be weighed by the family who is consulting with an experienced orthopedic surgeon. When surgery is being considered for walkers, be aware that the period of inactivity may lead to contractures or changes in functional walking patterns.

Specialty Collaborations & Other Services

Pediatric Orthopedics (see NW providers [4])

Refer early for evaluation and management of hip dislocation, scoliosis, and joint contractures; ideally, the sub-specialist will have experience treating children with SMA.

Hospitals (see NW providers [3])

Shriners Hospitals offer orthopedic care to children with SMA. For a map of locations, see Shriners Hospitals for Children.

Pediatric Physical Medicine & Rehabilitation (see NW providers [3])

Refer to optimize functional abilities, including activities of daily living and mobility.

Physical Therapy (see NW providers [0])

Consider early referral to assist with range of motion, strengthening, mobility equipment, and prevention of contractures.

Early Intervention for Children with Disabilities/Delays (see NW providers [3])

Young children are usually eligible for different types of therapies (physical, occupational, speech, etc.) through Early Intervention or programs administered at the local community level.

Nose/Throat/Mouth/Swallowing

Swallowing problems are common in non-sitters and sitters and may cause aspiration of oral secretions and food, bad breath, dental caries, and drooling. Feeding specialists (who may be occupational therapists or speech therapists) should optimize feeding methods. If children have difficulty with chewing and swallowing foods, pureed foods may be helpful. For children who cough, choke, silently aspirate thin liquids, or have lung problems consistent with aspiration, thickening liquids with an agent, such as Simply Thick or Thick It, may be helpful (see Thickened Liquids & Modified Foods). Ultimately, particularly in non-sitters and sitters, placement of a feeding tube, nasogastric, nasojejunal, or G-tube may be necessary. Note that while G-tubes are able to deliver sufficient calories, they do not protect the airway against aspiration of oral secretions. Feeding Tubes & Gastrostomies in Children provides further clinical details.

Specialty Collaborations & Other Services

Pediatric Gastroenterology (see NW providers [0])

Referral may be helpful for children who are underweight, aspirating, or who are having difficulty swallowing. Placement of a G-tube may be beneficial.

Pediatric General Surgery (see NW providers [0])

Referral may be helpful for G-tube insertion, especially if a fundoplication is also being considered.

Gastro-Intestinal & Bowel Function

Gastrointestinal problems such as reflux, delayed gastric emptying, and constipation are common. See Gastroesophageal Reflux Disease for medications that may be useful in treatment. In non-sitters, Nissen fundoplication may be needed for airway protection, especially if inadequate oral intake and aspiration are problems as well. Constipation should be treated aggressively as it may lead to discomfort, more problems with gastric emptying, decreased appetite, and reflux. The Portal's Constipation has management information.

Specialty Collaborations & Other Services

Pediatric Gastroenterology (see NW providers [0])

Consider referral for children who do not respond to typical management.

Pediatric General Surgery (see NW providers [0])

Depending on local expertise, children requiring G-tube placement may be referred.

Developmental - Behavioral Pediatrics (see NW providers [1])

Depending on local expertise, behavioral and medical management of constipation may benefit from referral.

Dental

Due to contractures, many children with SMA have difficulty opening their mouths wide. This often causes problems with eating and can complicate dental care. Children with SMA need early referral and treatment to pediatric dentists. If children with SMA need surgery for other reasons, such as G-tube placement, piggy-backing dental cleaning, sealant application, and cavity treatment should be considered. If sedation is necessary for procedures, providers should be aware of increased risk due to respiratory problems in children with SMA.

Specialty Collaborations & Other Services

Pediatric Dentistry (see NW providers [2])

Children with SMA should be referred early and visit at least every 6 months for ongoing care.

General Dentistry (see NW providers [1])

The dentists in this list have expressed interest and experience in treating children and youth with special health care needs.

Recreation & Leisure

Children with SMA need opportunities to participate in recreational activities, and adaptive sports are one of the fastest growing leisure activities in the US. Toys and games can be modified to suit a child’s abilities; driver education alternatives can be considered for older children with SMA. The Portal's page Switches has information about adapting toys. Recreation Activities provides more ideas for activities. Play (Cure SMA) has tips about play and care packages available with toys that other families affected by SMA have recommended based on their personal experience.

Specialty Collaborations & Other Services

Adaptive Sports (see NW providers [8])

Encourage families to seek out recreational outlets for their child.

Funding & Access to Care

Families may have difficulty assessing resources but can find help from organizations, such as Cure SMA. Since resources differ among states, families should also contact their local Division of Services for People with Disabilities or a similar state agency for information. Muscular Dystrophy Association (MDA) clinics, found in many cities nationally, are great resources for children and adults with SMA. (List of MDA Care Centers (MDA)) Families should ask about eligibility for supplemental security income (SSI) by either contacting the government directly or by working with coordinators through Early Intervention or education services. See Financing Your Child's Healthcare for other helpful ideas. With the high cost of newly-approved treatments, there are financial assistance programs provided through the drug makers to help cover co-pays and other costs associated with these treatments.

Specialty Collaborations & Other Services

Neuromuscular Clinics (see NW providers [1])

Clinics that provide care for a variety of conditions, including muscular dystrophy and spinal muscular atrophy.

Family

Refer families to support organizations, such as Cure SMA and the Muscular Dystrophy Association, which can connect them with others who have children with SMA. Families should also be referred to Wish Granting Groups, such as the Dream Factory, Make a Wish Foundation, and Starlight Foundation when children are between 2 1/2 and 18 years of age.
Appropriate care for children with SMA encompasses many options, and open discussion of alternatives are very helpful for families. Some families will choose to forego diagnostic and therapeutic interventions that they feel are invasive, whereas others will choose to proceed aggressively with interventions that might prolong life. All caregivers need to understand the family’s preferences. Discussions are best accomplished over time and in non-acute settings, rather than in the midst of an emergency room visit for pneumonia requiring intubation, for example. Preventive management, such as early implementation of non-invasive ventilation, will help avoid crises. The decision to aggressively manage SMA is a dynamic one that can be reconsidered whenever appropriate. Offer pediatric hospice in situations where aggressive intervention is not chosen.

Specialty Collaborations & Other Services

Hospice & Palliative Care (see NW providers [3])

Hospice services that have expertise in the care of children should be involved when necessary.

Wish Foundations (see NW providers [14])

Refer, as appropriate, when children are between 2 1/2 and 18 years of age.

Medical Genetics (see NW providers [1])

Families can benefit from periodic visits to review issues and address new questions (e.g., progress in genetic studies, options for prenatal and preimplantation diagnosis to help with reproductive planning or risks for siblings of a child with SMA). In many cases, a genetic counselor with expertise in neuromuscular disorders is available through Neuromuscular Clinics and Muscular Dystrophy Association clinics.

Ask the Specialist

What are the earliest signs of SMA?

Signs and symptoms depend on a patient’s age and SMA subtype. Classically, children present with hypotonia, proximal weakness (shoulders and hips), feeding difficulties, and/or complications of respiratory insufficiency. Early signs of weakness include:

  • Abdominal breathing or accessory muscle use
  • A feeling of “slipping through hands” when held suspended by examiner under armpits
  • Inability to voluntarily flex neck when supine or has head lag when pulled to sit
  • In older children, difficulty rising from floor (including Gowers maneuver, full or modified)
Video of relevant examination features in children with early weakness, including SMA patients, can be reviewed at the Child Muscle Weakness Organization.

What are the most pertinent issues to focus on during a routine well-child visit for a patient with SMA?

Ongoing and proactive assessment of sitting status, joint range of motion, feeding ability, weight, and respiratory status can enhance the quality of life and life span for children with SMA. Asking about family and community supports and access to resources that may affect the care of a child with SMA is also critical.

How does SMA affect growth and development?

Children with SMA are at risk for nutritional deficiencies and being underweight. Non-sitters, in particular, are commonly underweight secondary to decreased intake and the increased energy expenditure for the work of breathing. Standard weight charts are not applicable due to reduced muscle mass despite caloric supplementation. Children with SMA that are following the “normal” growth curves may be functionally obese and at risk for complications of metabolic syndrome.

Resources for Clinicians

On the Web

Clinical guidelines for SMA (Cure SMA)
A collection of clinical guidelines on various aspects of SMA compiled by CureSMA.

Respiratory Guidelines (Cure SMA) (PDF Document 32 KB)
Respiratory guidelines including ongoing management and equipment

Nutritional Care Guidelines (Cure SMA) (PDF Document 68 KB)
Proactive nutritional management tips for children with SMA.

Musculoskeletal issues in SMA (Cure SMA)
Compiled information about musculoskeletal issues including treatment and equipment that might be needed

Child Muscle Weakness Organization
Information and videos to help increase clinicians’ awareness of peripheral neuromuscular disease as a cause of developmental delay in young children and the early symptoms of neuromuscular disorders; National Task Force for the Early Identification of Childhood Neuromuscular Disorders.

Spinal Muscular Atrophy (GeneReviews)
An expert-authored, peer-reviewed, current disease description that applies genetic testing to diagnosis and management information; U.S. National Library of Medicine.

Spinal Muscular Atrophy Type I (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

Spinal Muscular Atrophy Type II (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

Spinal Muscular Atrophy Type III (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

Helpful Articles

PubMed search for spinal muscular atrophy in children, last 2 years.

Butterfield RJ.
Spinal Muscular Atrophy Treatments, Newborn Screening, and the Creation of a Neurogenetics Urgency.
Semin Pediatr Neurol. 2021;38:100899. PubMed abstract / Full Text

Clinical Tools

Assessment Tools/Scales

Pediatric Evaluation of Disability Inventory (PEDI)
Helps evaluate functional disabilities of children ages 6 months to 7 years old; completion time of 45-60 minutes; manual scoring; purchase required.

Patient Education & Instructions

Living with SMA (Cure SMA)
Excellent resource for families dealing with the day-to-day issues related to SMA. Contains information about standards of care, school, home, equipment needs, and community resources.

Resources for Patients & Families

Find Resources here.

Information on the Web

SMA Foundation
The mission of the SMA Foundation is to accelerate treatment for children with SMA. Families will find detailed information about SMA, up-to-date information about drugs in development, and support.

Spinal Muscular Atrophy (MedlinePlus)
A brief description of SMA, along with numerous links to further information; sponsored by the National Library of Medicine.

Genetic Conditions: Spinal Muscular Atrophy (MedlinePlus)
Excellent, detailed review of condition for patients and families; National Library of Medicine and National Institutes of Health.

National & Local Support

Cure SMA
Offers information about research in SMA, access to support and local chapters, and opportunities for fundraising.

Children's Hospice International
An organization that supports the idea that critically ill children should have access to hospice/palliative care along with curative care from the time their life-threatening illness has been diagnosed.

Never Give Up
Nonprofit organization that engages in leading scientists and policymakers to create treatments and a cure for SMA.

SMA Coalition
A coalition of SMA-focused nonprofits working toward increased awareness and help for those with SMA.

Studies/Registries

Spinal Muscular Atrophy (clinicaltrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Services for Patients & Families Nationwide (NW)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: July 2013; last update/revision: September 2021
Current Authors and Reviewers:
Author: Lynne M. Kerr, MD, PhD
Reviewer: Russell Butterfield, MD, PhD
Authoring history
2019: update: Lynne M. Kerr, MD, PhDA; Russell Butterfield, MD, PhDR
2016: update: Meghan S Candee, MD, MScR; Russell Butterfield, MD, PhDR
2013: first version: Kathy Swoboda, MDA; Lynne M. Kerr, MD, PhDA
AAuthor; CAContributing Author; SASenior Author; RReviewer

Bibliography

Bach JR, Saltstein K, Sinquee D, Weaver B, Komaroff E.
Long-term survival in Werdnig-Hoffmann disease.
Am J Phys Med Rehabil. 2007;86(5):339-45 quiz 346-8, 379. PubMed abstract

Baker M, Griggs R, Byrne B, Connolly AM, Finkel R, Grajkowska L, Haidet-Phillips A, Hagerty L, Ostrander R, Orlando L, Swoboda K, Watson M, Howell RR.
Maximizing the Benefit of Life-Saving Treatments for Pompe Disease, Spinal Muscular Atrophy, and Duchenne Muscular Dystrophy Through Newborn Screening: Essential Steps.
JAMA Neurol. 2019. PubMed abstract

Butterfield RJ.
Spinal Muscular Atrophy Treatments, Newborn Screening, and the Creation of a Neurogenetics Urgency.
Semin Pediatr Neurol. 2021;38:100899. PubMed abstract / Full Text

Carré A, Empey C.
Review of Spinal Muscular Atrophy (SMA) for Prenatal and Pediatric Genetic Counselors.
J Genet Couns. 2016;25(1):32-43. PubMed abstract

Cobben JM, Lemmink HH, Snoeck I, Barth PA, van der Lee JH, de Visser M.
Survival in SMA type I: a prospective analysis of 34 consecutive cases.
Neuromuscul Disord. 2008;18(7):541-4. PubMed abstract

De Vivo DC, Bertini E, Swoboda KJ, Hwu WL, Crawford TO, Finkel RS, Kirschner J, Kuntz NL, Parsons JA, Ryan MM, Butterfield RJ, Topaloglu H, Ben-Omran T, Sansone VA, Jong YJ, Shu F, Staropoli JF, Kerr D, Sandrock AW, Stebbins C, Petrillo M, Braley G, Johnson K, Foster R, Gheuens S, Bhan I, Reyna SP, Fradette S, Farwell W.
Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study.
Neuromuscul Disord. 2019;29(11):842-856. PubMed abstract / Full Text

Fauroux B, Guillemot N, Aubertin G, Nathan N, Labit A, Clément A, Lofaso F.
Physiologic benefits of mechanical insufflation-exsufflation in children with neuromuscular diseases.
Chest. 2008;133(1):161-8. PubMed abstract

Finkel RS, McDermott MP, Kaufmann P, Darras BT, Chung WK, Sproule DM, Kang PB, Foley AR, Yang ML, Martens WB, Oskoui M, Glanzman AM, Flickinger J, Montes J, Dunaway S, O'Hagen J, Quigley J, Riley S, Benton M, Ryan PA, Montgomery M, Marra J, Gooch C, De Vivo DC.
Observational study of spinal muscular atrophy type I and implications for clinical trials.
Neurology. 2014;83(9):810-7. PubMed abstract / Full Text

Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Qian Y, Sejersen T.
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. PubMed abstract

Hamilton G, Gillingwater TH.
Spinal muscular atrophy: going beyond the motor neuron.
Trends Mol Med. 2013;19(1):40-50. PubMed abstract

Kaindl AM, Guenther UP, Rudnik-Schöneborn S, Varon R, Zerres K, Schuelke M, Hübner C, von Au K.
Spinal muscular atrophy with respiratory distress type 1 (SMARD1).
J Child Neurol. 2008;23(2):199-204. PubMed abstract

Ke Q, Zhao ZY, Mendell JR, Baker M, Wiley V, Kwon JM, Alfano LN, Connolly AM, Jay C, Polari H, Ciafaloni E, Qi M, Griggs RC, Gatheridge MA.
Progress in treatment and newborn screening for Duchenne muscular dystrophy and spinal muscular atrophy.
World J Pediatr. 2019;15(3):219-225. PubMed abstract

Khatri IA, Chaudhry US, Seikaly MG, Browne RH, Iannaccone ST.
Low bone mineral density in spinal muscular atrophy.
J Clin Neuromuscul Dis. 2008;10(1):11-7. PubMed abstract

Kirschner J, Butoianu N, Goemans N, Haberlova J, Kostera-Pruszczyk A, Mercuri E, van der Pol WL, Quijano-Roy S, Sejersen T, Tizzano EF, Ziegler A, Servais L, Muntoni F.
European ad-hoc consensus statement on gene replacement therapy for spinal muscular atrophy.
Eur J Paediatr Neurol. 2020;28:38-43. PubMed abstract / Full Text

Kolb SJ, Battle DJ, Dreyfuss G.
Molecular functions of the SMN complex.
J Child Neurol. 2007;22(8):990-4. PubMed abstract

Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Qian Y, Sejersen T.
Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care.
Neuromuscul Disord. 2018;28(2):103-115. PubMed abstract

Messina S, Pane M, De Rose P, Vasta I, Sorleti D, Aloysius A, Sciarra F, Mangiola F, Kinali M, Bertini E, Mercuri E.
Feeding problems and malnutrition in spinal muscular atrophy type II.
Neuromuscul Disord. 2008;18(5):389-93. PubMed abstract

Michelson D, Ciafaloni E, Ashwal S, Lewis E, Narayanaswami P, Oskoui M, Armstrong MJ.
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. PubMed abstract

Parente V, Corti S.
Advances in spinal muscular atrophy therapeutics.
Ther Adv Neurol Disord. 2018;11:1756285618754501. PubMed abstract / Full Text

Prior TW.
Carrier screening for spinal muscular atrophy.
Genet Med. 2008;10(11):840-2. PubMed abstract

Ramdas S, Servais L.
New treatments in spinal muscular atrophy: an overview of currently available data.
Expert Opin Pharmacother. 2020;21(3):307-315. PubMed abstract

Ross LF, Kwon JM.
Spinal Muscular Atrophy: Past, Present, and Future.
Neoreviews. 2019;20(8):e437-e451. PubMed abstract

Schroth MK.
Special considerations in the respiratory management of spinal muscular atrophy.
Pediatrics. 2009;123 Suppl 4:S245-9. PubMed abstract

Shanmugarajan S, Swoboda KJ, Iannaccone ST, Ries WL, Maria BL, Reddy SV.
Congenital bone fractures in spinal muscular atrophy: functional role for SMN protein in bone remodeling.
J Child Neurol. 2007;22(8):967-73. PubMed abstract

Sumner CJ.
Molecular mechanisms of spinal muscular atrophy.
J Child Neurol. 2007;22(8):979-89. PubMed abstract

Verhaart IEC, Robertson A, Wilson IJ, Aartsma-Rus A, Cameron S, Jones CC, Cook SF, Lochmüller H.
Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review.
Orphanet J Rare Dis. 2017;12(1):124. PubMed abstract / Full Text

Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main M, Crawford TO, Trela A.
Consensus statement for standard of care in spinal muscular atrophy.
J Child Neurol. 2007;22(8):1027-49. PubMed abstract