Spinal Muscle Atrophy 

Updated: Aug 11, 2020
Author: Ashish S Ranade, MBBS, MS, MRCS; Chief Editor: Jeffrey A Goldstein, MD 

Overview

Practice Essentials

Spinal muscle atrophy (SMA; also known as spinal muscular atrophy) is a rare debilitating autosomal recessive hereditary disease characterized by progressive hypotonia and muscular weakness. The characteristic muscle weakness occurs because of a progressive degeneration of the alpha motor neuron from anterior horn cells in the spinal cord. The weakness is more severe in the proximal musculature than in the distal segments.

In certain patients, the motor neurons of cranial nerves (especially cranial nerves V-XII) can also be involved. Sensation, which originates from the posterior horn cells of the spinal cord, is spared, as is intelligence. Several muscles are spared, including the diaphragm, the involuntary muscles of the gastrointestinal system, the heart, and the sphincters.[1, 2, 3, 4]

In 1890, Werdnig described for the first time the classic infantile form of SMA.[5]  Many years later, in 1956, Kugelberg and Welander described the less severe form of SMA.[6]  Werdnig, in 1890,[5]  and Hoffman, in 1891,[7]  reported cases of muscular dystrophy occurring in infants that were otherwise similar to cases of muscular dystrophy found in older children and adults (eg, Duchenne muscular dystrophy).

SMA is the most common diagnosis in girls with progressive weakness. It is one of the most common genetic causes of death in children.

No two children with SMA will be exactly the same. Accordingly, treatment and care plans for each family should be tailored to meet specific individual needs. Ideally, a team-based comprehensive supportive approach to care optimizes outcomes in these children. The team should consist of a neurologist, a pulmonologist/intensivist, an orthopedic surgeon, a nutritionist, genetic counselors, social workers, an orthoptist, and occupational and physical therapists.

Pathophysiology

SMA is caused by a mutation in the survival motor neuron (SMN) gene. This gene is normally inactive during the fetal period and allows normal apoptosis in the developing fetus. The gene becomes active in the healthy mature fetus to stabilize the neuronal population.

In a healthy person, this gene produces a protein that is critical to the function of the nerves that control our muscles; without it, those nerve cells cannot properly function and eventually die, leading to debilitating and often fatal muscle weakness. In the absence of the gene, programmed cell death persists.[8] The mechanism and timing of abnormal motor neuron death remain unknown.[9, 10]

Classification

SMA is commonly divided into four types on the basis of the patient's age at onset and the highest physical milestone achieved, as follows:

  • Type I (Werdnig-Hoffmann disease) - Onset between birth and age 6 months
  • Type II - Onset between the ages of 6 and 12 months
  • Type III (Kugelberg-Welander disease) - Onset between the ages of 2 and 15 years
  • Type IV - Adult onset

Etiology

Patients with SMA have a homozygous deletion of the telomeric SMN gene SMN1, which is found in arm 5q13 (bands q11.2-13.3).[9]  This deletion has been demonstrated in as many as 98% of patients with SMA.

SMN1 encodes the SMN protein, which is part of a multiprotein complex required for the biogenesis of small nuclear ribonucleoproteins.[11, 12]  The SMN protein is critical to the health and survival of the nerve cells in the spinal cord that are responsible for muscle contraction (motor neurons). SMN1 has been linked to pre-mRNA splicing, spliceosome biogenesis, and the nucleolar protein fibrillarin. The absence or dysfunction of SMN is reflected by an enhanced neuronal death. A heterozygous deletion leads to an asymptomatic carrier state.[13]

A second gene also plays a role in producing the SMN protein—namely, SMN2, often called the SMA "backup gene." SMN2 is present in most individuals, including those with SMA. It is almost identical to SMN1, differing only by five nucleotides. Several versions of the SMN protein are produced by SMN2, but only one version (isoform d) is complete and functional. The other proteins produced by SMN2 are more labile and are unable to compensate fully for the absence of SMN1.[14] Thus, only 10-15% of all functional SMN protein is produced from SMN2.

Most people have two copies of SMN1 and one or two copies of SMN2. The number of copies of SMN2 is variable, and some people have as many as eight copies. The severity of SMA is inversely related to the number of copies of SMN2. Most severely affected individuals will have fewer copies of this gene.[15] The SMN2 gene copy number is related to, but not predictive of, disease severity, and care decisions should not be made on the basis of copy number alone. Other genetic modifiers, such as the protein plastin-3 (PLS3), may influence disease severity.[16]

A significant increase in nuclear DNA vulnerability was detected in fetuses with SMA at 12-15 weeks' gestational age. This reflected a decrease in the number of anterior horn neurons. This vulnerability is no longer seen in the rest of the antenatal or postnatal period. Abnormal cell morphology was seen only in the postnatal period.[17]

Epidemiology

United States statistics

The incidence of SMA is about 1 case in 10,000 live births. The prevalence of persons with the carrier state is 1 in 50. SMA can affect any race or gender.

In North Dakota, the incidence is about 1 case in 6720 (15 per 100,000) live births, the prevalence is 1.5 cases in 10,000, and the prevalence of persons with the Werdnig-Hoffman disease carrier state is 1 in 41.[18] SMA appears to be three to 10 times more common in North Dakota than in other areas.

SMA is the most common degenerative disease of the nervous system in children. After cystic fibrosis, it is the second most common disease inherited in an autosomal recessive pattern that affects children. It is the leading heritable cause of infant mortality.[19]

International statistics

The incidence of SMA is generally higher in Central and Eastern Europe than in Western Europe.

In England, the incidence is 1 case in 24,100 (4 per 100,000) live births. Prevalence is 1.2 cases per 100,000 population. In Italy, the incidence is 7.8 cases in 100,000 live births (all types). In Germany, the incidence of Werdnig-Hoffmann disease is 1 case in 10,202 (9 per 100,000) live births.[20] The incidence of SMA in Slovakia is 1 case in 5631 (18 per 100,000) live births (all types). In Poland, the incidence of Werdnig-Hoffmann disease is 1 case in 19,474 (5 per 100,000) live births.

Age-related demographics

The three different types of SMA that occur in the pediatric population are genetically similar but differ with respect to patient age at presentation and clinical course, as follows:

  • Type I (Werdnig-Hoffmann disease) - This acute infantile SMA is usually identified in patients from birth to age 6 months; it is the most severe and common form of the disease, accounting for 60% of all cases of SMA, and it is often fatal early in life
  • Type II - This chronic infantile SMA is diagnosed in infants aged 6-24 months
  • Type III (Kugelberg-Welander disease) - This type of SMA is diagnosed in children aged 2-15 years

Sex-related demographics

Males are more commonly affected with SMA than females are. The male-to-female ratio is 2:1. The clinical course in males is more severe. Life expectancy has not been demonstrated to be influenced by sex.[21] As the age at onset increases, incidence of SMA in females decreases. With age at onset older then 8 years, females are affected much less frequently. In cases where the patient is older than 13 years at onset, incidence in females is the exception.

Race-related demographics

The incidence of SMA in black Africans is very low.

Prognosis

The age of onset and the achievement of functional abilities are better predictors of prognosis than the number of copies of SMN2. Genetic modifiers (eg, PLS3) may also influence disease severity and prognosis.[16]

As a general rule, the younger the patient at disease onset, the worse the prognosis. The overall median age at death exceeds 10 years. Intelligence is unaffected by SMA. Patients with type I SMA usually die by age 2 years. Patients with type II SMA have a greater expected lifespan than patients with type I SMA. Some patients with type II SMA live into the fifth decade of life. Patients with type III SMA have nearly normal life expectancy.

Death occurs as a result of respiratory compromise. The lifespan of affected individuals has significantly increased with the use of intermittent positive-pressure ventilation (PPV), with or without a tracheostomy.

Patient Education

Antenatal diagnosis in the first trimester and proper genetic counseling are possible with DNA analysis. This enables more accurate carrier detection.[22] Not all parents of children with SMA are obligate carriers.[23]  The American College of Medical Genetics and Genomics (ACMG) has recommended that because SMA is found in all populations, carrier screening should be offered to couples of all races and ethnicities. The ACMG suggests that the testing be performed either before conception or early in pregnancy to allow carriers to make informed reproductive decisions. Approximately 3% of cases are sporadic.

A potential medicolegal pitfall is poor counseling of parents and patients regarding possible complications before surgical treatment. These patients lose function after spinal stabilization, and their ability to ambulate may be hindered. The possibility of recurrence or worsening of the hip dislocation must be emphasized; the risk of recurrent deformity is present even with foot and ankle procedures.

 

Presentation

History

Spinal muscle atrophy (SMA; also known as spinal muscular atrophy) is a single-gene disorder with a spectrum of clinical presentation. The clinical presentation includes a wide range of phenotypes that are classified into groups on the basis of age of onset and maximum level of motor function achieved, but hypotonia and/or muscle weakness and atrophy are common signs and symptoms.

With type I SMA, most mothers report abnormal inactivity of the fetus in the latter stages of pregnancy. Babies with type I SMA face many physical challenges, including trouble breathing, coughing and swallowing.Patients with type I SMA are unable to roll over or sit. Progressive clinical deterioration occurs. Death usually occurs from respiratory failure and its complications by age 2 years.

Patients with type II SMA have normal development for the first 4-6 months of life. They are able to sit independently but are never able to walk independently. They require a wheelchair for locomotion. They have a longer life span than patients with type I SMA. Some patients with type II SMA live into the fifth decade of life, with more than 70% still living at 25 years of age.

In patients with type III SMA, the presenting complaint is difficulty climbing stairs or getting up from the floor (due to hip extensor weakness). Individuals affected by SMA type III initially are able to walk independently, but as they grow, their mobility is increasingly limited, and they eventually may need to use a wheelchair. The lifespan is nearly normal.[24]

Physical Examination

SMA is often diagnosed clinically on the basis of the child's physical appearance. The diagnosis may be suspected when children are noted to be weak or to have a delay in their developmental milestones, such as holding their head up, rolling over, sitting independently, standing, or walking later than would be expected.

After a thorough medical history is reviewed and a physical examination is performed, the primary care provider may order genetic testing through a blood sample, or the child may be referred to a neurologist who will also perform an examination and then order genetic testing (again through a blood sample) to confirm the diagnosis. 

Type-specific findings

Newborns with type I SMA are floppy and inactive. They move the extremities little, if at all. The hips are flexed, abducted, and externally rotated. The knees are flexed. Because the distal musculature is usually spared, the fingers and toes move. Infants cannot sit independently or control or lift the head. They have a weak cry and cough. They have difficulty with swallowing and feeding. They have a bell-shaped trunk with chest-wall collapse and abdominal protrusion with paradoxical breathing. Areflexia is universal.

Patients with type II SMA have head control and can sit independently, though about 25% may lose this ability in their mid-teenage years. They have bulbar weakness resulting in difficulty with coughing, swallowing and clearing tracheal secretions. They have weak intercostal muscles, diaphragmatic breathing, and fine tremors with extended fingers or with attempted hand grips. Muscular weakness is greater in the lower extremities than in the upper extremities. Patients develop lower-extremity contractures, and about 50% lose the ability to walk by age 12 years.

Patellar reflex is absent in type II SMA. The young may demonstrate bicipital and triceps tendon reflexes. Tongue fasciculations are present, as are upper-extremity tremors. Scoliosis is universal, and most patients develop hip dislocation, either unilateral or bilateral, when younger than 10 years.

Patients with type III SMA are able to walk independently early in life and maintain their ambulatory capacity into adolescence. They may have difficulty with coughing and swallowing with nocturnal hypoventilation.They develop muscle weakness, aching, and joint overuse symptoms. Weakness may cause foot drop, and patients have limited endurance. A third of the patients become wheelchair-bound as adults (mean age, 40 years). 

Functional decline in later-onset SMA types is associated with age of onset of symptoms and maximal function acheived. Loss of function may have a significant impact on their quality of life. Stabilization of functional abilities may be important for individuals with later-onset SMA.[25]

Other findings

A long C-shaped thoracolumbar scoliotic curve is present in patients with type II SMA and in half of patients with type III SMA. The curve progresses to a severe and incapacitating deformity if not treated. About 30% of patients have kyphotic deformities as well.

Pseudohypertrophy of the calf is present, which may confound the diagnosis (ie, with Duchenne muscular dystrophy and Becker muscular dystrophy). Bouwsma et al reported that this finding was associated with elevated serum creatine kinase (CK).[26]  This combination was only observed in males; no females in the series had hypertrophy of the calves.[26]

Tongue fasciculations are pathognomonic of SMA (all types), as opposed to all other neuromuscular diseases of infancy. The presence of tongue fasciculations can aid in the diagnosis, in that 56% of patients exhibit this symptom.

 

DDx

Diagnostic Considerations

Other problems to be considered include the following:

Differential Diagnoses

 

Workup

Laboratory Studies

A simple blood test can confirm whether the child has a mutation that causes spinal muscle atrophy (SMA; also known as spinal muscular atrophy). The SMN1 deletion test is recommended as the first diagnostic step for a patient suspected of having SMA. The deletion status can be tested by using polymerase chain reaction (PCR) to determine if both copies of SMN1 exon 7 are absent, a finding that is noted in 95% of affected individuals. PCR can reliably and accurately measure SMN1 and SMN2 copy numbers over a wide range (ie, 0-8 copies).

If the survival motor neuron (SMN) gene test is positive, the diagnosis is confirmed. However, 5% of children with the symptoms of SMA can have a negative SMN gene test and may require additional diagnostic testing. These tests can include electromyography (EMG), a nerve conduction study (NCS), or muscle biopsy and additional blood tests to help rule out other forms of muscle disease. A congenital hypotonia panel may be ordered to test for SMA. Clinical laboratories may offer panels that include tests for disorders such as SMA, myotonic dystrophy (type 1), Prader-Willi syndrome, Angelman syndrome, and maternal uniparental disomy.[25]

In contrast to findings in patients with Duchenne muscular dystrophy and Becker muscular dystrophy, aldolase and serum creatine kinase (CK) findings are within reference ranges in patients with SMA. In later-onset SMA, these muscle enzymes may be slightly elevated.

Diagnostic delays are common in SMA. A systematic review of the literature conducted to diagnose diagnostic delay reported both age of onset and age at confirmed diagnosis; the delay to diagnosis ranged from months to years.[28] Earlier identification of newborns with SMA will also allow infants to begin treatment even before showing symptoms, when research in human and mouse models suggests it may be most effective.

Imaging Studies

On anteroposterior (AP) and lateral views of the pelvis, most patients with type II SMA are found to have developed hip dislocations. (See the images below.) The dislocations are only temporarily symptomatic and do not influence function in these patients, because they are nonambulatory.

Spinal muscle atrophy. Anteroposterior radiograph Spinal muscle atrophy. Anteroposterior radiograph of pelvis demonstrating right hip dislocation.
Spinal muscle atrophy. Lauenstein lateral view of Spinal muscle atrophy. Lauenstein lateral view of hips on patient with spinal muscle atrophy type I. Note near-universal pelvic dysmorphology (eg, widened obturator foramina) in addition to dislocated right hip.

A complete spine and scoliosis series is indicated. All patients with type II SMA and most patients with type III SMA develop a long C-shaped scoliotic curve. (See the images below.)

Spinal muscle atrophy. At age 4 years, this boy's Spinal muscle atrophy. At age 4 years, this boy's chest radiograph already reveals presence of significant 32° left thoracic scoliosis. Diagnosis is type I spinal muscle atrophy (Werdnig-Hoffmann disease). This radiograph captures the lumbar curvature incompletely.
Spinal muscle atrophy. By age 6 years, child's cur Spinal muscle atrophy. By age 6 years, child's curve is starting to decompensate. Note development of right-side truncal shift. He now has 40° thoracic curve and 60° lumbar curve.
Spinal muscle atrophy. Spine anteroposterior view. Spinal muscle atrophy. Spine anteroposterior view. Spinal curvature is progressing. Lumbar curve now is 70°, and thoracic curve is 35°. It is now clearly apparent that right hip is dislocated. Also note marked pelvic obliquity in this patient.
Spinal muscle atrophy. By age 9 years, this patien Spinal muscle atrophy. By age 9 years, this patient with type I spinal muscle atrophy now has thoracic curve of 60° and lumbar curve of 110°. Note that patient has tracheostomy tube and nasogastric tube as well.

Other Tests

Findings from electromyography (EMG) in patients with SMA are characteristic of a neuropathic disorder, revealing fibrillation potentials, denervation, and increased amplitude. However, nerve conduction velocity test results are normal.

Antenatal DNA analysis is available to diagnose the deletion of arm 5q.[29, 30]

Biopsy

In patients with SMA, incisional muscle biopsies reveal a uniform smaller diameter of all fibers. This contrasts with biopsy findings for other muscular dystrophies, which consist of degenerating muscle with variable muscle-fiber sizes. Biopsies in patients with hypotonic cerebral palsy reveal normal muscle fibers.

Histologic Findings

Two subtypes of SMA deserve special mention with regard to their typical histologic appearance. The first, Werdnig-Hoffmann disease (type I SMA), is typically diagnosed in patients from birth to age 6 months. Its histologic pattern is usually one of extremely small and reasonably uniform small muscle fibers (see the images below).

Spinal muscle atrophy, Werdnig-Hoffman disease. Sm Spinal muscle atrophy, Werdnig-Hoffman disease. Small muscle fibers within separate muscle fascicles.
Spinal muscle atrophy, Werdnig-Hoffman disease. Ma Spinal muscle atrophy, Werdnig-Hoffman disease. Marked variation in muscle fiber size, as well as relative increase in associated connective tissue.

The second subtype, Kugelberg-Welander disease (type III SMA), is usually diagnosed in patients aged 2-15 years. The same tendency toward small muscle fiber diameter is seen but with much less uniformity (see the images below). Substantial variation, with intermixing of larger and smaller muscle fibers, may be observed.

Spinal muscle atrophy, Kugelberg-Welander disease. Spinal muscle atrophy, Kugelberg-Welander disease. Marked variation in muscle fiber size, along with increased perimysial connective tissue.
Spinal muscle atrophy, Kugelberg-Welander disease. Spinal muscle atrophy, Kugelberg-Welander disease. Muscle-fiber variation with some demonstrating internal nuclei.

In both forms of SMA, substantial increases in muscular connective tissue lead to both characteristic histologic findings and clinical findings (eg, increased muscle firmness). Centrally migrated or otherwise internalized nuclei are considered pathologic if they are present in more than about 3% of muscle fibers. Such nuclear findings are common in a variety of muscle diseases, including SMA.

Staging

Once diagnosis has been made, the natural progression of SMA can be assessed by age- and ability-appropriate motor functional scales and electrophysiologic measurement of motor-unit health.[25]

The Hammersmith Infant Neurological Examination (HINE) was designed to be a simple and scorable method for evaluating infants aged 2 months to 2 years. It includes the following three sections, which contain 26 items that assess different aspects of neurologic function:

  • Section 1 - Neurologic examination assessing cranial nerve function, posture, movements, tone, reflexes, and reactions
  • Section 2 - Developmental milestones (head control, sitting, voluntary grasp, ability to kick, rolling, crawling, standing, and walking)
  • Section 3 - Behavioral assessment (state of consciousness, emotional state, social orientation)

The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) was developed by evaluating infants with type I SMA and has been shown to be valid for the assessment of children ranging in age from 3.8 months to over 4 years who have an infant's repertoire of motor skills. It includes 16 items used to assess motor skills, each of which is graded on a scale of 0 to 4 (0 = no response, 4 = complete response; total score, 0-64).

The Hammersmith Functional Motor Scale–Expanded (HFMSE) was developed to evaluate motor function in nonambulatory and ambulatory individuals with later-onset SMA. It has been used in several clinical trials to evaluate the motor function of individuals with later-onset (types II and III) SMA.

The Upper Limb Module (ULM) was developed to assess aspects of function related to everyday life in nonambulatory individuals with SMA. These skills might only be partly captured by the HFMSE in weaker patients.

The 6-Minute Walk Test (6MWT) is an objective evaluation of exercise capacity that may be used to assess function in ambulatory individuals with later-onset SMA.

Electrophysiologic measurementsmay be used to assess the health of motor neurons, as follows:

  • Compound muscle action potential (CMAP) response - This is a measure of the electrophysiologic output from a specific muscle or muscle group following stimulation of the innervating nerve
  • Motor-unit number estimation (MUNE) - This is a method for estimating the number of motor units involved in the contraction of a specific muscle

Measurement and monitoring of quality of life for children with SMA and their families represent an implementable priority for care teams.[31, 32]

Quantitative measurement of lower-extremity contractures may be useful. Minimal hip and knee joint contractures have been associated with diminished motor ability.[33]

 

Treatment

Approach Considerations

No two children with spinal muscle atrophy (SMA; also referred to as spinal muscular atrophy) will be exactly the same. Accordingly, treatment and care plans for each family should be tailored to meet specific individual needs.

It is also important to remember that the brains of children with SMA are not affected at all and that cognitive abilities therefore remain normal. Children with SMA are usually very intelligent, and they should be encouraged to participate in as many age-appropriate and developmentally appropriate activities as possible, with adaptations made whenever necessary. It is essential that children with SMA be assisted in reaching their utmost potential in school, at home, and in their communities.

Ideally, a team-based comprehensive supportive approach to care optimizes outcomes in these children. The team should consist of a neurologist, a pulmonologist/intensivist, an orthopedic surgeon, a nutritionist, genetic counselors, social workers, an orthoptist, and occupational and physical therapists.

Medical Care

Curative therapy for SMA has been elusive. The survival rate is poor among young patients. Interest has arisen in the use of inhibitors of gamma-aminobutyric acid (GABA) synthesis, with promising results. Developments in the use of antisense-based therapy have been described.[34, 35, 36, 37, 38]

Research into genetic therapies, as well as molecular and stem cell–mediated therapies, is ongoing.[39, 40, 41]  The Cure SMA drug pipeline has identified four possible treatment targets[42] :

  • Replacement or correction of the faulty  SMN1
  • Modulation of the low-functioning  SMN2 (the “backup gene”)
  • Neuroprotection of the motor neurons affected by loss of SMN protein
  • Muscle protection to prevent or restore the loss of muscle function in SMA

Pharmacologic therapy

Nusinersen

In December 2016, the US Food and Drug Administration (FDA) approved nusinersen, the first drug approved for treatment of children (including newborns) and adults with SMA. Nusinersen is an antisense oligonucleotide (ASO) designed to treat SMA caused by mutations in chromosome 5q that lead to survival motor neuron (SMN) protein deficiency. Through in-vitro assays and studies in transgenic animal models of SMA, nusinersen was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein.[43]

FDA approval was based on the ENDEAR trial, a phase 3 randomized, double-blind, sham-controlled study (N = 121) in patients with infantile-onset (most likely to develop type I) SMA.[44] At a planned interim analysis, the rate of achieving a motor milestone response was higher in infants treated with nusinersen (40%) than in those not so treated (0%), as measured by the Hammersmith Infant Neurological Examination (HINE). Additionally, a smaller percentage of patients died in the nusinersen group (23%) than in the untreated group (43%).

Interim findings from CHERISH, another phase 3 trial, involved 126 nonambulatory patients with later-onset SMA (consistent with type II), including those with the onset of signs and symptoms at 6 months or later and an age of 2-12 years at screening.[45] Prespecified interim analysis demonstrated a difference of 5.9 points at 15 months between the treatment arm (n = 84) and the sham-controlled arm (n = 42), as measured by the Hammersmith Functional Motor Scale Expanded (HFMSE). From baseline to 15 months of treatment, patients in the nusinersen group achieved a mean improvement of 4.0 points in the HFMSE, whereas those in the control group showed a mean decline of 1.9 points.

A 2020 Cochrane review reported, on the basis of moderate-certainty evidence, that nusinersen improves motor function in type II SMA.[46] Creatine, gabapentin, hydroxyurea, phenylbutyrate, valproic acid, and the combination of valproic acid and acetyl-L-carnitine probably have no clinically important effect on motor function in SMA types II or III (or both), on the basis of low-certainty evidence. Olesoxime and somatropin may also have little to no clinically important effect, but the evidence was of very low certainty.

A 2019 Cochrane review reported, on the basis of very limited evidence, that intrathecal nusinersen probably prolongs ventilation-free and overall survival in infants with type I SMA.[47] It is also probable that a greater proportion of infants treated with nusinersen versus a sham procedure achieve motor milestones and can be classed as responders to treatment on clinical assessments (HINE-2 and Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders [CHOP INTEND]). The proportion of children experiencing adverse events and serious adverse events is no higher with nusinersen than with a sham procedure (moderate-certainty evidence). It is uncertain whether riluzole has any effect in type I SMA.

A multicenter observational study reported that there is some evidence for the safety and efficacy of nusinersen in the treatment of adults with 5q SMA, with clinically meaningful improvements noted in motor function.[48]

The American Academy of Neurology (AAN) stated that evidence of efficacy is currently greatest for treatment of infantile- and childhood-onset SMA in the early and middle symptomatic phases. Whereas approved indications for nusinersen use in North America and Europe are broad, payer coverage for populations outside those in clinical trials remain variable. Evidence, availability, cost, and patient preferences all influence decision-making regarding nusinersen use.[49]

Onasemnogene abeparvovec

Onasemnogene abeparvovec, approved by the FDA in May 2019, is a recombinant adenoassociated virus serotype 9 (AAV9)-based gene therapy designed to deliver a copy of the gene encoding the SMN protein. It is indicated for gene replacement therapy in children aged 2 years or younger with type I SMA (also called Werdnig-Hoffman disease) who have biallelic mutation in SMN1.

Approval was based on the ongoing phase 3 STR1VE trial[50] and the completed phase 1 START trial.[51] In the START trial, patients with type I SMA received a single dose of intravenous (IV) AAV9 carrying SMN complementary DNA encoding the missing SMN protein. As of the data cutoff, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort.

In the high-dose START cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort.[51] Of the 12 patients who had received the high dose, 11 sat unassisted, nine rolled over, 11 fed orally and could speak, and two walked independently. Elevated serum aminotransferase levels occurred in four patients and were attenuated by prednisolone.

Interim data analysis from the ongoing phase 3 STR1VE trial determined that 21 of 22 (95%) patients were alive and event-free.[50] The median age was 9.5 months, with six of seven (86%) patients aged 0.5 months or older surviving event-free. Interim results also showed ongoing improvement of motor milestones (eg, holding head erect, rolling over, sitting without support).

Risdiplam

Risdiplam, approved by the FDA in August 2020, is a survival of an SMN2 mRNA splicing modifier designed to treat mutations in chromosome 5q that lead to SMN protein deficiency. It is indicated for type I, II, and III SMA in adults and children aged 2 months or older. Approval was supported by results from several phase 3 trials (including FIREFISH[52] and SUNFISH[53] ). 

In FIREFISH, an open-label two-part pivotal clinical trial in infants aged 2-7 months with type I SMA, 41% of infants (7/17) achieved ability to sit without support for at least 5 seconds, and 90% (19/21) were alive without permanent ventilation at 12 months.[52] After a minimum of 23 months of treatment and reaching an age of 28 months or older, 81% (17/21) of all patients were alive without permanent ventilation. 

In SUNFISH, a two-part double-blind placebo-controlled pivotal clinical trial in children and young adults (aged 2-25 years) with type II or III SMA, a clinically meaningful and statistically significant improvement in motor function was observed among children and adults, as measured by a change from baseline in the MFM-32 total score.[53] Upper-limb motor function as compared with baseline, as measured by the Revised Upper Limb Module (RULM), a secondary independent motor function endpoint of the study, also showed statistically significant improvement. 

Other therapies

Proper care can improve quality of life for those with SMA.

Patients with SMA often have impaired cough, respiratory insufficiency, dysphagia, gastroparesis, constipation, and evolving orthopedic issues (eg, scoliosis). To address these problems, various types of equipment may be used, from respiratory support during sleep (eg, bilevel positive airway pressure [BiPAP] and mucus clearance devices) to gastrostomy tubes to wheelchairs and braces. Cognitive development typically is not affected. Usual primary care practices (especially care coordination and family support), along with routine pediatric care immunizations, developmental surveillance, and monitoring of growth, contribute to the overall well-being of the child and the family.

Care management includes optimizing breathing and coughing, addressing nutrition and feeding issues, managing mobility and activities of daily living (ADLs), and preparing for illness.

Patients with type I SMA have difficulty in coughing and breathing and will require respiratory care (eg, insufflator-exsufflator/cough assist, oxygen saturation monitor) and support (either noninvasive [BiPAP/ventilator] or invasive [tracheostomy]). They also lose their ability to chew and swallow food and water and will require nutrition (eg, nutritional modification or supplementation) and feeding support (eg, via a nasogastric tube, gastrostomy, or gastrojejunostomy).

Physical therapy (including aquatherapy and hippotherapy) and occupational therapy are required for optimizing positioning, seating, and mobility. Patients with type I SMA, because of their short life span, require little, if any, involvement on the part of an orthopedist. Splinting is used for fractures.

For patients with type II or type III SMA, physical and occupational therapy may be employed for maintaining range of motion (ROM) of joints, preventing contractures, and optimizing positioning, seating, and activities of daily living (ADLs). These patients also require orthotics, standing and walking aids, and mobility devices  (see Surgical Care below).[54, 55, 56]  Nutritional support and respiratory care and support are important as well. Because children with SMA may have decreased bone density, optimizing bone health (eg, with supplemental calcium and vitamin D) is necessary to prevent insufficiency fractures. Bisphosphonates may be considered for cases of decreased bone density.

Scoliosis (curvature of the spine) occurs at some point in virtually all children with type I or II SMA and in some with type III SMA. The degree of the scoliosis is a factor in determining how to treat it. Because scoliosis can restrict breathing and pulmonary function, necessary treatment measures should be implemented early. Options for managing scoliosis include custom seating systems, seating aids, and a body jacket. Later, spinal surgery may have to be considered.

Bracing plays only a limited role in scoliosis associated with SMA. There is a paucity of literature on the subject. In one study, the Garches brace was studied in children with type IB SMA.[57] In this group, use of the brace was shown to help with sitting and upright head posture, thereby contributing to an improvement in quality of life. In 25 children, Garches brace treatment was started at an early age; subsequently, 72% needed spinal fusion after a mean of 10.6 years.

To avoid pulmonary infections or prolonged postoperative intubations, aggressive preoperative pulmonary care must be provided to patients with SMA. In cases of pulmonary compromise in patients with SMA, transfer to the pediatric pneumology service for stabilization and treatment of complications should be considered.

All children with SMA have cognitive and educational needs. SMA does not affect the brain or its development and thus does not limit an individual’s ability to learn and succeed academically. Children with SMA will need early intervention during infancy and early childhood, an individualized educational plan in childhood, and classroom modifications to accommodate their physical needs.

Surgical Care

Posterior spinal fusion and segmental instrumentation

The most common orthopedic problem is scoliosis, which is often severe.[58] It is universal among nonambulatory patients, in whom the curve progression is about 8° annually, despite brace treatment. Half of ambulatory patients develop scoliosis as well, but at a slower rate of progression.

In a cohort of 238 SMA patients, it was found that the lifetime probability of scoliosis surgery was high in types IC and II and was dependent on age at the loss of ambulation in type III.[59]

Posterior spinal fusion with segmental instrumentation is indicated in young patients whose curve cannot be controlled with a brace and in patients older than 10 years with curves greater than 40° and forced vital capacities 40% above normal. The entire thoracic and lumbar spine down to the pelvis should be fused to obtain a balanced trunk and a leveled pelvis. As a rule, concomitant anterior spinal fusion to prevent crankshaft phenomenon is avoided; the risk of potential problems with anterior spinal surgery in a patient with SMA outweighs the benefits.

In ambulatory patients, spinal surgery that excludes the pelvis is preferred. Compensatory lumbar lordosis and pelvic motion have been observed to compensate for the proximal motor weakness in these patients. The ambulatory capacity of some of these patients may be lost after surgery.

Surgery should be delayed as long as medically possible. It should be kept in mind that curve progression is slower in patients with type III SMA and that these patients present later in life. However, when surgery is necessary, it should be performed while the patient is still ambulatory. This is in contrast to the preferred timing for surgery in patients with Duchenne muscular dystrophy. (See the images below.)

Spinal muscle atrophy. Immediate postoperative ant Spinal muscle atrophy. Immediate postoperative anteroposterior radiograph of patient at age 9 years. Thoracic curve is now at 18°, and lumbar curve is 35°, which represents more than 67% curvature correction.
Spinal muscle atrophy. Immediate postoperative lat Spinal muscle atrophy. Immediate postoperative lateral view with good sagittal balance.

Scoliosis correction in children younger than 10 years remains a challenge. Various growing systems (eg, growing rods and the vertical expandable prosthetic titanium rib [VEPTR]) have been used.[60, 61, 62]  

In a study by Chua et al, scoliosis correction was shown to have a beneficial effect on pulmonary function at a mean follow-up of 11.6 years.[63] Before surgery, the rate of decline of the predicted forced vital capacity was 5.31% per year; after surgery, it was reduced to 1.77% per year. In another study, at 10-year follow-up, posterior spinal fusion was found to be effective in controlling curve progression and pelvic obliquity without negatively impacting the space available for lung, trunk height, and pulmonary function.[64]

The role of growth-friendly spine surgery in SMA is evolving. A study by Lenhart et al demonstrated stabilization of respiratory support requirement following the insertion and lengthening of posterior-based growing rods.[65]  

In a study of 28 SMA patients, it was found that the results of definitive spinal fusion were better in children with prior growth-friendly surgery than in untreated patients.[66]

In another study, it was found that prophylactic fusion with implant revision was not necessary in nonambulatory children with SMA, and the growing rods were maintained.[67]

Physical therapy or surgery for contractures

Joint flexion contractures of the hips and knees are associated with nonambulatory status. Surgical releases are performed; the rate of recurrence is extremely high, especially in sitting patients. Equinus is occasionally present. Ambulatory patients rarely have equinus or cavovarus deformities. Surgical releases are rarely needed for patients with type II or III SMA, because the loss of function is due to weakness and not to contractures. Some form of tendon transfer may be needed in patients with type III SMA to correct foot or ankle functional defects.

Careful patient selection is important for optimal results. Postoperative immobilization should be of shorter duration; prolonged immobilization leads to a decline in motor function.[68, 69]

Pelvic stabilization procedures

Hip subluxations or dislocations are due to proximal musculature weakness that leads to coxa valga and loss of femoral head coverage. Half of ambulatory patients have hip pathology. (See the images below.) Unilateral dislocation in nonambulatory patients invariably leads to pelvic obliquity (which may be manifested in uneven sitting pressure sores). Hip reconstruction may be successful, but recurrence of the problem even after surgical stabilization is a concern. Therefore, surgical correction is not indicated in most patients, and treatment remains controversial.

Spinal muscle atrophy. Anteroposterior radiograph Spinal muscle atrophy. Anteroposterior radiograph of pelvis demonstrating right hip dislocation.
Spinal muscle atrophy. Lauenstein lateral view of Spinal muscle atrophy. Lauenstein lateral view of hips on patient with spinal muscle atrophy type I. Note near-universal pelvic dysmorphology (eg, widened obturator foramina) in addition to dislocated right hip.

Management of fractures

Fractures can occur in patients with type II or III SMA, and congenital fractures may be seen in type I SMA.[70]  They occur at an earlier age in type II SMA than in type III SMA. Supracondylar femur and ankle fractures are common in type II SMA, whereas in type III SMA, upper-extremity fractures are common.[71]  

Nonoperative treatment is preferred for nonambulatory patients. For ambulatory patients, osteosynthesis is considered in order to maintain walking/standing ability.

Complications

The most common medical complications associated with SMA are recurrent respiratory system infections.

One of the drawbacks to posterior spinal fusion in patients with SMA is the patients' decreased ability to perform ADLs. The now rigid and straight spine creates several difficulties. Independent feeding and hygiene are impaired, in that the patient can no longer bring the hands to the face because of the proximal upper-extremity weakness. This possibility must be discussed with the family and patient before surgery.

Diet

A history of nutritional intake, nutritional needs, and associated medical conditions, in conjunction with a thorough physical examination, anthropometric measures, body composition, and biochemical markers, should be included in the assessment of patients with SMA.[72, 73] Intervention may include increase or decrease of energy intake. For example, dysphagia may be treated with position changes, volume changes, or thickening of liquids. Percutaneous endoscopic gastrostomy was found to be safe with minimal risks in almost all situations.

Activity

Physical therapy should be instituted for gentle motion exercises to prevent joint contractures. Physical and occupational therapy may be beneficial for maintenance of strength and endurance, independence in self-care, and educational, social, psychological, and vocational activities.[74, 75]

Consultations

A preoperative pulmonology consultation for pulmonary function tests (PFTs) is necessary. There is a clear consensus that curve progression correlates with deterioration of pulmonary function. However, there is no clearcut consensus that surgery improves or halts the pulmonary deterioration in SMA. It is evident, though, that in order to avoid pulmonary infections or prolonged postoperative intubations, aggressive preoperative pulmonary care must be offered.[76]

Consultation with physical and occupational therapists should be considered. Physical therapy may be employed for joint contracture prevention or stretching. Occupational therapy may be employed for adaptive equipment for ADLs.

A geneticist may be consulted for DNA evaluation of the patient and parents for counseling purposes.

An orthotics consultation may be necessary for splinting and spine bracing (eg, with a soft, custom-molded thoracolumbosacral orthosis [TLSO]) for young children with flexible curves of 20-40°.[77, 78]

Long-Term Monitoring

Pediatric patients with SMA must be monitored periodically by a pediatric orthopedic surgeon to assess their nutritional status and their spine and hips, as well as to evaluate for contracture development. (See the image below.)

Spinal muscle atrophy. Follow-up radiographs in pa Spinal muscle atrophy. Follow-up radiographs in patient at age 13 years reveal some spinal decompensation. Note so-called coathanger appearance of ribs in dysplastic right hemithorax.

Physical therapy is useful for joint contracture prevention and stretching. Occupational therapy is useful for adaptive equipment for ADLs.

 

Medication

Medication Summary

In December 2016, the US Food and Drug Administration (FDA) approved nusinersen, the first drug approved to treat children (including newborns) and adults with spinal muscular atrophy (SMA). In May 2019, the recombinant AAV9-based gene therapy onasemnogene abeparvovec was approved for SMA type I in children aged 2 years or younger. In August 2020, risdiplam, an SMN2 splicing modifier, was approved for type I, II, and III SMA in adults and children aged 2 months or older.

Antisense Oligonucleotides

Class Summary

Antisense oligonucleotides (ASO) designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency may be considered for treatment.

Nusinersen (Spinraza)

In studies in transgenic animal models of SMA, nusinersen was shown to increase exon 7 inclusion in SMN2 messenger ribonucleic acid (mRNA) transcripts and production of full-length SMN protein. It is indicated for SMA in pediatric and adults patients.

Gene Therapy

Class Summary

Recombinant gene therapy provides specificity to precisely treat gene deficiency.

Onasemnogene abeparvovec (Zolgensma)

Recombinant AAV9-based gene therapy designed to deliver a copy of the gene encoding the human survival motor neuron (SMN) protein. It is indicated for gene replacement therapy in children aged 2 years or younger with spinal muscular atrophy (SMA) type 1 (also called Werdnig-Hoffman disease) who have biallelic mutation in the survival motor neuron 1 (SMN1) gene.

SMN Splicing Modifiers

Class Summary

Survival of motor neuron 2 (SMN2) mRNA splicing modifiers are designed to treat mutations in chromosome 5q that lead to SMN protein deficiency.

Risdiplam (Evrysdi)

Risdiplam is indicated for spinal muscular atrophy, including types 1, 2, and 3, in adults and children aged 2 months or older.

 

Questions & Answers

Overview

What is spinal muscle atrophy (SMA)?

What is the pathophysiology of spinal muscle atrophy (SMA)?

What are the types of spinal muscle atrophy (SMA)?

What causes spinal muscle atrophy (SMA)?

What is the prevalence of spinal muscle atrophy (SMA) in the US?

What is the global prevalence of spinal muscle atrophy (SMA)?

Which age groups have the highest prevalence of spinal muscle atrophy (SMA)?

What are the sexual predilections of spinal muscle atrophy (SMA)?

What are the racial predilections of spinal muscle atrophy (SMA)?

What is the prognosis of spinal muscle atrophy (SMA)?

What is included in patient education about spinal muscle atrophy (SMA)?

Presentation

Which clinical history findings are characteristic of spinal muscle atrophy (SMA)?

How is spinal muscle atrophy (SMA) diagnosed?

Which physical findings are characteristic of type I spinal muscle atrophy (SMA)?

Which physical findings are characteristic of type II spinal muscle atrophy (SMA)?

Which physical findings are characteristic of type III spinal muscle atrophy (SMA)?

What is the prevalence of a long C-shaped thoracolumbar scoliotic curve in spinal muscle atrophy (SMA)?

What conditions are included in the differential diagnoses of spinal muscle atrophy (SMA) when pseudohypertrophy of the calf is present?

What is the prevalence of tongue fasciculations in spinal muscle atrophy (SMA)?

DDX

Which conditions are included in the differential diagnoses of spinal muscle atrophy (SMA)?

What are the differential diagnoses for Spinal Muscle Atrophy?

Workup

What is the role of lab testing in the workup of spinal muscle atrophy (SMA)?

What is the role of imaging studies in the workup of spinal muscle atrophy (SMA)?

What is the role of EMG in the workup of spinal muscle atrophy (SMA)?

What is the role of genetic testing in the workup of spinal muscle atrophy (SMA)?

What is the role of biopsy in the workup of spinal muscle atrophy (SMA)?

Which histologic findings are characteristic of spinal muscle atrophy (SMA)?

Treatment

What can be done to optimize treatment outcomes for spinal muscle atrophy (SMA)?

How is spinal muscle atrophy (SMA) treated?

How are the pulmonary manifestations of spinal muscle atrophy (SMA) treated?

What is the role of physical therapy in the treatment of spinal muscle atrophy (SMA) treated?

How is scoliosis treated in spinal muscle atrophy (SMA)?

How are pulmonary infections prevented in spinal muscle atrophy (SMA)?

What are the cognitive and educational needs of children with spinal muscle atrophy (SMA)?

What is the role of posterior spinal fusion and segmental instrumentation in the treatment of spinal muscle atrophy (SMA)?

How are contractures treated in spinal muscle atrophy (SMA)?

What is the role of pelvic stabilization procedures in the treatment of spinal muscle atrophy (SMA)?

How are fractures treated in spinal muscle atrophy (SMA)?

What are the possible complications of spinal muscle atrophy (SMA)?

Which dietary modifications are used in the treatment of spinal muscle atrophy (SMA)?

Which activity modifications are used in the treatment of spinal muscle atrophy (SMA)?

Which specialist consultations are beneficial to patients with spinal muscle atrophy (SMA)?

What is included in long-term monitoring of spinal muscle atrophy (SMA)?

Medications

Which medications are FDA-approved for the treatment for spinal muscle atrophy (SMA)?

Which medications in the drug class Antisense Oligonucleotides are used in the treatment of Spinal Muscle Atrophy?