Congenital muscle fiber-type disproportion
May. 29, 2022
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Spinal muscular atrophy is a neurodegenerative disorder predominantly affecting the anterior horn cells. It is an autosomal recessive disorder with deletion of exon 7 of the SMN1 gene. The clinical classification is based on highest motor milestone achieved, and severity is, in part, associated with the number of SMN2 copies, an allelic gene of SMN1. The United States Food and Drug Administration-approved treatments, intrathecal nusinersen (an antisense oligonucleotide), onasemnogene abeparvovec-xioi (SMN1 gene insertion through adenovirus type 9 vector), and risdiplam (oral SMN2 enhancer), show dramatic improvements in motor milestones in patients with spinal muscular atrophy (17).
• Spinal muscular atrophy is a neurodegenerative disorder primarily affecting the anterior horn cells.
• Diagnosis of spinal muscular atrophy is made by genetic testing, which detects homozygous deletion of exon 7 in the SMN1 gene.
• EMG remains a useful tool in the diagnosis of late-onset spinal muscular atrophy (type 3 and type 4).
• An interdisciplinary approach is essential to treat patients with spinal muscular atrophy.
• Nusinersen, the first FDA approved treatment for SMA, is effective and safe.
• Risdiplam, an oral SMN2 enhancer, is FDA approved for use in children 2 months of age and older.
• Gene therapy (Zolgensma - onasemnogene abeparvovec-xioi) is FDA approved for patients with all types of spinal muscular atrophy less than 2 years of age.
Spinal muscular atrophy refers to a group of inherited disorders principally affecting the anterior horn cells. Signs of motor neuron disease such as muscle weakness, muscle atrophy, fasciculations, and reduced or absent deep tendon reflexes can be seen.
When talking about spinal muscular atrophy, the clinician usually refers to the most common form, chromosome 5q-related spinal muscular atrophy, caused by mutations or biallelic deletions in the SMN1 (survival motor neuron 1) gene. Our knowledge about spinal muscular atrophy has greatly expanded in less than 2 decades, recognizing a number of non-5q forms of spinal muscular atrophy.
Werdnig and Hoffmann provided the first clinical description of a disorder with progressive weakness beginning in infancy, resulting in death at an early but inconsistent age, and characterized pathologically by anterior horn cell loss (54; 26). Acute, chronic, and late-onset forms of the disease were subsequently described. The formerly eponymous terms such as “Werdnig-Hoffmann disease,” “Dubowitz disease,” and “Kugelberg-Welander disease” have been replaced by the clinical classification of spinal muscular atrophy types 0 to 4.
Electrophysiological studies showed evidence of acute and chronic denervation, without changes in nerve conduction velocities, confirming involvement of the motor neuron (24). Muscle biopsy showed large groups of atrophic fibers involving both type 1 and 2 fibers interspersed with fascicles of hypertrophied and normal fibers. Postmortem findings included decreased numbers of motor neurons and gliosis in the anterior horns of the spinal cord and motor cranial nerve nuclei 5 and 7 to 12 (23).
The single gene responsible for all types of 5q related spinal muscular atrophy was mapped to chromosome 5q11.12-13.3 in 1990 and was identified as the survival motor neuron gene (18; 37).
On the other hand, the non-5q forms of spinal muscular atrophy are clinically and genetically heterogeneous involving at least 30 different genes/chromosomal loci (04; 44).
This article will focus on 5q spinal muscular atrophy. There is a broad phenotypic spectrum of spinal muscular atrophy ranging from more severely affected infants who are symptomatic at birth to ambulatory adults who develop proximal weakness late in life. Classification is generally based on the age of presentation and highest achieved motor developmental milestone (36). As a result of the heterogeneity of phenotypic severity, a classification using a continuous variable has been described (60; 58; 59).
Type 1. Spinal muscular atrophy type 1 (Werdnig-Hoffmann disease) is characterized by onset before 6 months of age and failure to achieve the ability to sit independently. Infants with symptom onset identified in the prenatal stage are classified as spinal muscular atrophy type 1A (also referred to as spinal muscular atrophy type 0). Infants who experience first symptoms of spinal muscular atrophy between 1 week and 3 months of age are classified as spinal muscular atrophy type 1B, and those with onset between 3 and 6 months of age are classified as spinal muscular atrophy type 1C. The typical presentation of spinal muscular atrophy type 1 is a floppy infant with weakness primarily involving proximal lower limbs more than the upper extremities. Tongue fasciculations are a key clinical sign indicating a lower motor neuron disease along with areflexia. Weakness is progressive. Extraocular and facial muscles are spared. Although there is no diaphragmatic involvement initially, weakness of the other respiratory accessory muscles results in the typical “bell-shaped thorax” with early paradoxical breathing and respiratory insufficiency. Bulbar weakness usually presents later on and can be associated with risk of aspiration pneumonia, failure to thrive, and feeding difficulty (13; 15). Cognition is normal.
Type 2. Spinal muscular atrophy type 2 patients usually experience their first symptoms between the ages of 6 to 18 months, although symptoms may appear earlier. These children present with proximal muscle weakness of the lower extremities. Spinal muscular atrophy type 2 patients ultimately attain independent sitting when placed (although they may eventually lose this ability), and they are never able to walk. Those who lose the ability to sit are classified as spinal muscular atrophy type 2A, and those who maintain this ability are spinal muscular atrophy type 2B (13). Some children have preserved distal reflexes early on. Tongue fasciculations are often present. Many experience a characteristic fine distal tremor called polyminimyoclonus. As in all other spinal muscular atrophy subtypes, cognition is normal and may even be above average. Scoliosis is a significant comorbidity. Some patients develop restrictive lung disease secondary to this (62; 30).
Type 3. Spinal muscular atrophy type 3 (late-onset juvenile spinal muscular atrophy or Kugelberg-Welander disease) children typically become symptomatic after 18 months of age, with greater heterogeneity seen in the degree of functional impairment between each patient. Those with first symptoms before the age of 3 are classified as spinal muscular atrophy type 3A, and those with onset after the age of 3 are spinal muscular atrophy type 3B (60). Diagnosis can be challenging as tendon reflexes remain intact early on. Patients with spinal muscular atrophy type 3 may be mistaken for congenital myopathy or Becker muscular dystrophy. Needle EMG clearly shows a primary neurogenic pattern. They do not develop significant respiratory or orthopedic comorbidity in childhood (29; 08).
Type 4. Spinal muscular atrophy type 4 is characterized by adult onset (after the age of 21) with a very slowly progressive pattern (49). It is considered to be the least prevalent and mildest form of spinal muscular atrophy. The physical examination is similar to that described for spinal muscular atrophy type 3. The diagnosis is suspected clinically and confirmed by genetic testing (SMN1 gene). Tongue fasciculations are seen in most, but not all, patients, along with occasional muscle cramps. Generally, intercostal muscles are unaffected. Bulbar involvement and scoliosis are rare.
Prognosis varies across subtypes, and within each subtype, by degree of clinical severity. Survival with SMN1 homozygous deletion is dependent on the presence of SMN2 copy numbers. Absence of SMN2 in an SMN1-deficient state is embryonically lethal across species. Survival of children with spinal muscular atrophy type 1 with 1 or 2 copies of SMN2 is estimated to be 2 years of age, mainly due to respiratory insufficiency. Prenatal onset spinal muscular atrophy (referred to as type 0) is associated with early death that occurs within weeks after birth from respiratory failure. However, with improved respiratory care (noninvasive respiratory support with BiPAP and mechanical insufflation exsufflation devices) and nutritional support (enteral feeding and avoiding prolonged fasting), life expectancy has changed for the better (42; 52). There is increasing recognition as to the involvement of other organ systems, with several studies finding cardiac malformations in these children. Cardiac evaluation is suggested (47; 52).
Children with spinal muscular atrophy type 2 with 2 to 3 copies of SMN2 live into adolescence and as late as the third or fourth decade without intervention. Survival has been estimated to be 98.5% at 5 years and 68.5% at 25 years. However, these estimates may need to be revisited as they were reported prior to the increasing use of more aggressive nutritional and respiratory supportive care measures (61; 40).
Life expectancy does not differ substantively from the rest of the population for patients with spinal muscular atrophy types 3 (over 3 SMN2 copies) and 4 (4 to 5 SMN2 copies) (61; 58; 06; 40). Nutritional, gastrointestinal, and orthopedic issues are the main concerns in spinal muscular atrophy types 2 and 3. Respiratory status is fragile, and any upper respiratory infection could have an impact on the patient’s condition (40).
A 6-year-old boy was born preterm at 32 weeks with no significant prenatal or postnatal complications. He was followed for delayed fine and motor developmental milestones considered secondary to prematurity. He started to crawl at 10 months, walked at approximately 22 months, and jumped close to 32 months. He was always a little bit clumsy when running. He was regularly followed by occupational therapy and physical therapy. They noticed improvement over the years until he reached 4 years of age, when he started to develop a progressive weakness predominantly involving girdle muscles with a clear Gowers sign. He had diminished deep tendon reflexes. On physical examination, he had decreased muscle bulk with a fibrotic feeling on palpation. There were no tongue fasciculations and no bulbar involvement. Weakness slowly increased over the following years. He had increased difficulties walking more than 200 meters and climbing stairs with alternating steps. CK was at the upper limit of normal. EMG showed mild decreased CMAP amplitude, no fasciculations, and, interestingly, no increased spontaneous activity (fibrillation or positive waves), but chronic neurogenic pattern on needle study. SMN1 testing came back with homozygous deletion of exon 7, and 3 SMN2 copies, confirming the diagnosis of spinal muscular atrophy type 3. He later developed sleep apnea, which was relieved by the introduction of BiPAP. He developed a mild scoliosis, but did not require surgery.
SMN is a ubiquitous protein expressed in all motor neuron cells. SMN is associated with a group of proteins called gemins to create SMN complex essential for the functioning of SM class ribonucleoproteins, which have a predominant role in RNA splicing (16). Anterior horn cells seem to have a lower threshold to dysfunction with low SMN protein levels, leading to defects in multiple functions such as axonal transport, motor neuron connectivity, motor neuron survival, and even neuromuscular junction function. SMN deficiency seems to also have an impact in other cells such as Schwann cells and skeletal muscle (56). The depletion of SMN protein is due to homozygous deletion/mutation of SMN1. However, humans possess SMN2, a centromeric allelic gene. SMN2 has a silent skipping sequence, with transcription yielding a full-length, stable SMN protein less than 25% of the time (28). The amount of full-length SMN protein produced varies between individuals depending in part on the SMN2 gene coding. SMN2 copy number can partially predict the spinal muscular atrophy phenotype, but should not be used exclusively for prognostics. In the absence of SMN1, lack of SMN2 copies is lethal. Most children with spinal muscular atrophy type 1 only have 1 or 2 copies of SMN2; children with type 2 have 3 copies, and children with type 4 usually have 3 to 4 copies (31).
Spinal muscular atrophy is a rare disease. The incidence is 1 per 6000 to 10,000 live births. Amongst adults, the carrier frequency is 1 in 40 to 60 (43; 51). The carrier frequency is higher amongst Caucasians and lowest amongst Hispanics. African Americans are at intermediate frequency (25).
When a sibling is affected and carrier status identified, a prenatal diagnosis can be obtained.
In the assessment of an infant with spinal muscular atrophy type 1, it is important to consider the possibility of botulism in the differential diagnosis because an acute therapeutic intervention could improve the outcome. Other conditions to rule out include severe congenital hypomyelinating neuropathies, Pompe disease, and select non–5q spinal muscular atrophies, including spinal muscular atrophy with respiratory distress type 1 (SMARD1). SMARD1, also known as distal spinal muscular atrophy 1 (DSMA1) is a condition that should be considered in the differential diagnosis of spinal muscular atrophy type 1A. Its key clinical features include low birth weight, diaphragmatic paralysis, hypotonia, distal weakness, and sensory and autonomic nerve involvement, with onset between the ages of 3 and 6 months. SMARD1 is secondary to a mutation in IGHMBP2.
When assessing children with spinal muscular atrophy types 2 and 3, muscular dystrophies or congenital myopathies should be considered and are easy to exclude with creatine kinase and electromyography.
The main differential diagnosis is focused on non–5q spinal muscular atrophies, a heterogeneous group of motor neuron disorders. Non–5q spinal muscular atrophies are classified according to the distribution of weakness (proximal, distal, bulbar) and genetic inheritance (44). Only 5% of proximal spinal muscular atrophies are not related to SMN1.
Other non–5q spinal muscular atrophy. In recent years, our knowledge of motor neuron diseases has greatly expanded. More than 33 genes involved in motor neuron loss have been identified, and thanks to next-generation sequencing, more genes are being identified. Most of these genes encode for proteins essential to RNA metabolism and splicing, axonal transport, motor neuron development, and connectivity.
Proximal spinal muscular atrophy. Spinal muscular atrophy with lower extremity predominance (SMA-LED) is included in this category and results in a dominant mutation of DYNC1H1, the gene coding microtubular motor protein, and BICD2 (21; 22). SMA-LED is characterized by lower extremity weakness and wasting of both proximal and distal muscle groups. Disorders related to mutations in TRPV4 have the potential to present a broad range of phenotypes, from congenital spinal muscular atrophy with contractures to spinal muscular atrophy with scapuloperoneal and laryngeal weakness. Select arthrogryposis multiplex congenital syndromes should also be considered in diagnosing spinal muscular atrophy type 1A.
Distal spinal muscular atrophy. Distal spinal muscular atrophies are more complex, mainly because of substantive overlap with distal hereditary motor neuropathy or neuronopathy (dHMN). This entity should be considered with pure distal motor neuropathy. Types 1 and 2 of dHMN are dominant: HSPB1, HSPB8, HSPB3, GARS, FBX028, DYNC1H1 (39). Mutations in the GARS gene can present as distal spinal muscular atrophy with upper limb predominance; however, it can also present as Charcot-Marie-Tooth disease. This illustrates the complexity of identifying the right gene. For hereditary motor neuropathy types 3 and 4, a linkage analysis has identified only one region of interest in chromosome 11q13. Hereditary motor neuropathy type 5 has an initial presentation of upper limb weakness resulting from mutations in BSCL2, GARS, and REEP1. In cases of vocal cord paralysis, SLC5A7 and DNAJB2 need to be considered, but, once again, some axonal Charcot-Marie-Tooth disease presents with vocal cord paralysis. To increase the complexity already illustrated, some genes bring heterogeneous phenotype with sometimes sensory involvement, as seen in Charcot-Marie-Tooth disease (GARS, BSCL2), hereditary spastic paraplegia (HSPB1), or ataxia (SETX). Distal spinal muscular atrophy associated with PLEKHG5 gene (DSMA 4) is recessive and has to be considered in early-onset spinal muscular atrophy with normal SMN1 gene (21; 46).
Other or nonclassified spinal muscular atrophy. Some other genes, such as TRPV4 and GLE1, present with neonatal onset and a severe phenotype involving contractures. Another group of severe neonatal presentation with recessive pontocerebellar hypoplasia is characterized by postnatal progressive microcephaly, with hypoplastic cerebellar hemispheres at birth. Thus far, 7 pontocerebellar hypoplasia clinical syndromes have been identified, and pontocerebellar hypoplasia could be classified in the “spinal muscular atrophy plus” phenotype. This group includes the VRK1 and EXOCS3 genes. X-linked (Kennedy syndrome, UBA1 gene) and mitochondrial inheritances have been described (38).
Gene panels and next-generation sequencing will help to identify the right gene involved as great heterogeneity exists in non–5q spinal muscular atrophy phenotypes (09; 27).
Diagnostic investigation of spinal muscular atrophy type 1 is straightforward. As a first step, genetic testing for homozygous deletion of exon 7 in the SMN1 gene should be done as this test is highly sensitive and specific (55). EMG should only be used when there is reasonable doubt in the clinical picture. Also, in less than 5% of cases, a deletion and a point mutation in the trans (compound heterozygosity) SMN1 gene makes the diagnosis more challenging (10). A complete sequencing of SMN1 would identify the mutation. It is important to remember that the frequency of de novo mutations is 2%, thus, one of the parents may not be a carrier (45). When an SMN1 deletion is negative or occurs in children with spinal muscular atrophy types 2 and 3, nerve conduction studies help to elaborate on a differential diagnosis such as other hereditary neuropathies, neuromuscular junction disorders, or other lower motor neuron diseases like non–5q spinal muscular atrophy. There is decreased compound muscle action potential (CMAP) with normal or close to normal latencies and velocities. Needle study will show chronic denervation, but not always prominent spontaneous activity such as fasciculations or fibrillation potentials. Some reports regarding muscle MRI show a specific pattern that could potentially help reach a diagnosis in the later onset cases. Finally, muscle biopsies show neurogenic features that are nonspecific and could be found with any inferior motor neuron disease but are rarely performed nowadays.
Disease modifying therapy. The treatment for spinal muscular atrophy has been primarily supportive until the disease modifying therapy with nusinersen was approved by the U.S. Food and Drug Administration in December 2016. Nusinersen is now approved in several other countries including Canada, Brazil, Europe, Australia, etc.
Nusinersen. Nusinersen is an antisense oligonucleotide that modifies pre-mRNA splicing to promote exon 7 inclusion in SMN2 gene, resulting in production of more full-length normal SMN protein. Nusinersen was found to be safe and tolerable as well as beneficial in improving motor function in all types of spinal muscular atrophy patients and in preventing disease onset or progression in presymptomatic patients. FDA approval of nusinersen was primarily based upon the interim analysis of ENDEAR trial (randomized, multicenter, sham-procedure controlled, double-blinded) that enrolled infants with spinal muscular atrophy who were 7 months of age or younger and showed improvement in motor milestones as measured by the Hammersmith Infant Neurological Examination (HINE) in infants treated with nusinersen (12). In the final analysis of the ENDEAR trial, improvement in motor milestones was noted in 37 of 73 (51%) infants treated with nusinersen, versus 0 of 37 (0%) of infants who received the sham procedure. Motor milestones achieved in the nusinersen treated group included head control (22%), rolling over (10%), sitting independently (8%), and standing (1%), whereas no infants achieved motor milestones in the sham procedure group. In addition, the proportion of infants who died or received permanent assisted ventilation was lower in the nusinersen group compared with the sham group (12). The CHERISH double-blind, sham-procedure (placebo) controlled, multinational trial enrolled 126 children 2 to 12 years of age with spinal muscular atrophy type 2 and no significant scoliosis or contractures. An interim analysis at 15 months showed a significant and meaningful increase in Hammersmith Functional Motor Scale Expanded (HFMSE) scores from baseline in nusinersen-treated children compared to sham-control treated children (33). A presymptomatic spinal muscular atrophy treatment study (NURTURE) that enrolled 17 infants who were identified prenatally or at the time of birth showed 100% survival with no infant requiring ventilator support and a favorable developmental milestones achievement (03). Long-term results of the phase 1/2 studies in 28 children up to 15 years of age at study entry with spinal muscular atrophy types 2 or 3 showed motor function improvements (HFMSE, 6MWT, and RULM) and disease stabilization with nusinersen treatment over 3 year period. No children discontinued treatment due to adverse events (05). Safety and feasibility data on nusinersen use in older children and adults are just emerging (50; 57; 11).
Treatment regimen. The recommended treatment regimen consists of intrathecal loading regimen of 12 mg on day 1, 15, 29, and 1 month after, followed by maintenance dose every 4 months. The dosing regimen is the same for all spinal muscular atrophy types (03).
Adverse effects. Safety studies showed that infants tolerated the intrathecal medication well, and there were no significant safety issues related to the medication or the procedure itself. Most side effects were due to spinal muscular atrophy-related respiratory issues. Side effects noted in late-onset spinal muscular atrophy patients were related to lumbar puncture such as headache and back pain, and the rate was comparable to the 10% rate seen with lumbar punctures in non-spinal muscular atrophy subjects. Mild thrombocytopenia was seen in 11% of the nusinersen-treated subjects, and an elevated urine protein was noted in 33%. ASOs are excreted through the kidneys and can be nephrotoxic. Three percent of nusinersen-treated patients had a hemorrhagic complication of lumbar puncture. Due to these potential risks, safety laboratory tests including urine protein, platelet count, and coagulation tests are indicated prior to each intrathecal injection with nusinersen (03).
Gene therapy. A single dose of intravenous infusion of adeno-associated viral vector containing DNA coding for SMN protein resulted in longer survival, superior achievement of motor milestones, and better motor function in patients with type 1 spinal muscular atrophy than in historical cohorts (32). Fifteen patients with spinal muscular atrophy type 1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. Three of the patients received a low dose (6.7 × 1013 vg per kilogram of body weight), and 12 received a high dose (2.0 × 1014 vg per kilogram). The high-dose cohort showed an increase in the CHOP INTEND score from baseline (increase of 9.8 points at 1 month and 15.4 points at 3 months) as compared to a decline in this score in historical cohort. Among the 12 patients that received high-dose gene therapy, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. The ongoing phase 3 trial enrolled 21 infants with spinal muscular atrophy (mean age 3.9 months and range 0.5 to 5.9 months). All patients received the 1.1 × 1014 vg/kg dose of Zolgensma (onasemnogene abeparvovec-xioi). As of the March 2019 data cutoff, 19 patients were alive without the need for permanent ventilation and were 7.9 to 15.4 months of age post-infusion. Sixty-seven percent of patients who received Zolgensma were surviving at 14 months of age compared to only 25% in the available natural history data, and 10% of patients were sitting without support for greater than or equal to 30 seconds compared to none. In addition, 16 of the 19 patients had not required daily NIV use (results presented at 2019 American Academy of Neurology annual meeting). Based on the available efficacy and safety results, the FDA approved a 1-time intravenous infusion of Zolgensma for patients less than 2 years of age with spinal muscular atrophy with biallelic mutations in the SMN1 gene on May 24, 2019. Further long-term studies are undergoing.
Oral therapy. The United States FDA has approved risdiplam for spinal muscular atrophy patients greater than or equal to 2 months old of age. Risdiplam is a small molecule and acts as an SMN2 pre-mRNA splicing modifier to increase functional SMN protein levels. The following FDA studies are ongoing to study the clinical efficacy and safety: JEWELFISH (NCT03032172), FIREFISH (NCT02913482), SUNFISH (NCT02908685), and RAINBOWFISH (NCT03779334).
FIREFISH, enrolling type 1 spinal muscular atrophy and two SMN2 gene copies infants, is a two-part, open-label study (02; 07). This study has proven the efficacy and safety of risdiplam of this population in 12 of 41 infants (29%); post 12 months of treatment, patients were able to sit without support for greater than or equal to 5 seconds. No permanent ventilation was needed in 85% of infants (n=35/41) (07). Although pneumonia (32%) was the most common serious adverse event (SAE), maculopapular rash, upper respiratory tract infection, diarrhea, constipation, and fever were common adverse effects.
In SUNFISH, the risdiplam-treated group was 1.55 points higher on the 32-item Motor Function Measure total score (primary end point) after 12 months, compared to the placebo group (95% CI: 0.3, 2.81; p=0.016). Type 2 or 3 spinal muscular atrophy patients, aged 2 to 25 years, were part of this placebo-controlled study. Adverse effects and serious adverse effects profile was similar to that of the FIREFISH study (34).
Combination therapy. We are continually improving our knowledge on the efficacy and safety of the FDA approved therapies when used in combination, or sequentially. Combined use of nusinersen or risdiplam with gene therapy may be safe and effective (20; 41).
Supportive therapy. The 2007 consensus guidelines established the need for a multidisciplinary approach to spinal muscular atrophy care (53). An update to these guidelines was published as part 1 and part 2 in 2018. Part 1 update describes in detail the recommendations on diagnosis, rehabilitation, orthopedic and spinal management, and it also details nutritional, swallowing, and gastrointestinal management (35). Pulmonary management, acute care, other organ involvement, and ethical issues are discussed in part 2 update (14).
Neuromuscular evaluation. Clinical assessment focusing on the musculoskeletal system and related functional impairments should be performed by trained examiners every 6 months, unless different follow-up is required. Assessments should include muscle strength and range of motion, relevant motor functional scales, and timed tests to monitor the aspects of functioning that relates to activities of daily living.
Rehabilitation. A proactive approach including regular sessions of physical therapy may influence trajectories of progression in spinal muscular atrophy. Services should be goal oriented for different patient groups. Primary goals for non-sitters should include optimization of function and tolerance to various positions, and minimization of impairment. Rehabilitation services to sitters should focus on preventing scoliosis and contractures, and maintaining, restoring, or promoting function and mobility. Services to walkers should be directed to maintain, restore, or promote function, mobility, and adequate joint range, and improve balance and endurance.
Scoliosis. Scoliosis is a major comorbidity and is inevitable, especially in nonambulant children. Spinal management was rarely discussed as an option in non-sitters unless they had stable respiratory and nutritional function due to their limited survival. Rigid braces that allow stable sitting position can be considered as long as they do not compromise respiratory function. For type 1 and 2 spinal muscular atrophy sitters, scoliosis greater than 20 degrees should be monitored every 6 months until skeletal maturity and yearly after skeletal maturity. Spinal orthoses is often advocated to support hypotonic trunk. Surgical treatment decision is primarily based on the curve magnitude, major curve Cobb angle greater than or equal to 50 degrees, and rate of progression—greater than or equal to 10 degrees per year. Surgical treatment should be delayed until after the 4 years of age. Growth friendly rods and magnetically controlled growing rods should be considered for appropriate patients.
Chest deformity. Children with spinal muscular atrophy can have distortion of the rib cage, contributing to “parasol rib” due to truncal weakness and hypotonia. Rib or spine based instrumentation to improve parasol rib deformity is not recommended as studies have shown poor efficacy.
Hip instability. Hip instability should be surgically managed only in patients with significant pain.
Contractures. Surgical management of the upper or lower extremities contractures should be considered when they cause pain or impair function.
Fractures. Fractures are common in children with spinal muscular atrophy type 1 and 2 due to osteoporosis, low vitamin D levels, and disuse. Closed treatment with cast immobilization is recommended for nonambulatory patients, but prolonged immobilization for greater than 4 weeks should be avoided. Surgical stabilization may be beneficial for lower extremity long bone fractures in ambulatory patients and hip fractures in nonambulatory patients to promote quick healing.
Nutrition. An expert nutritionist should be involved in the care of spinal muscular atrophy patients to monitor weight, fluid, macronutrients, and micronutrients intake and to promote appropriate diet. Periodic growth assessment is critical. Gastrointestinal symptoms should be inquired during clinic visits. A full modified barium swallow fluoroscopic study shorty after diagnosis and close monitoring if the test is normal for early detection of feeding difficulties is recommended for non-sitters. Proactive management with short-term nasogastric or nasojejunal tube after a failed swallow study is recommended until long-term gastrostomy tube can be placed in these non-sitter patients. Fasting should be avoided. Nutritional evaluations after diagnosis and every 3 to 6 months and every year thereafter for younger patients are recommended for sitters. Feeding evaluations should be considered as well. Feeding tubes are commonly used for supplementary nutrition in sitters and should be assessed on a case by case basis. Sitters are also at a risk for being overweight or obese. Nutritional evaluation in walkers is recommended if there are any issues as swallowing dysfunction and feeding difficulties are rare in this group. Periodic dual energy x-ray absorptiometry analysis (DEXA) to monitor bone density and vitamin D levels should be monitored at least annually.
Pulmonary management. Pulmonary assessment and interventions are specific for different patient groups (non-sitters, sitters, and walkers). A proactive approach of introducing therapies earlier in the disease process is critical. Nebulized bronchodilators should be available if there is suspicion for asthma. Nebulized mucolytics should not be used long term. Glycopyrrolate should be used with caution to treat hypersalivation. No consensus is available regarding the use of botulinum toxin injection into the salivary glands or other methods to reduced oral secretions in these patients. CPAP should not be used to treat chronic respiratory failure. Palivizumab during the RSV season through the first 24 months of life, annual influenza after 6 months of life, and pneumococcal vaccinations should be administered per standard recommendations.
Non-sitters. Screening for non-sitters should include assessment of hypoventilation with pulse oximetry and capnography or transcutaneous CO2 and sleep study/pneumogram if there is even minimal suspicion of hypoventilation. Every 3 months clinic visits are recommended for this group. Manual chest physiotherapy and cough assist (mechanical insufflation – exsufflation) should be made available to all non-sitters, and oral suctioning with mechanical suction pump and catheter should also be considered for airway clearance. Noninvasive positive pressure ventilation should be used in all symptomatic infants and in non-sitters prior to signs of respiratory failure to prevent or minimize chest wall distortion and alleviate dyspnea. Tracheotomy ventilation can be considered in patients who fail noninvasive ventilation or if there is lack of effective interface to provide ventilation.
Sitters. The assessment should be focused on cough function and spirometry. Sleep study should always be performed or if there is even minimal suspicion of hypoventilation. Clinic visits are recommended every 6 months. Manual chest physiotherapy and cough assist (mechanical insufflation – exsufflation) should be made available to all patients with ineffective cough. Noninvasive positive pressure ventilation should be used in all symptomatic patients. CPAP should be avoided. Need for tracheotomy ventilation is less frequent in this group.
Walkers. Most ambulant patients have normal pulmonary function. Clinical assessment should include careful review of cough effectiveness and search for sleep apnea/hypoventilation symptoms. Pulmonary functional testing and pulmonologist assessment should be considered if there are concerns. No proactive interventions are needed for ambulant patients.
Other treatment trials. Over the past 15 years, several therapeutic agents for spinal muscular atrophy have been in various stages of development. Histone deacetylase inhibitors, nonhistone deacetylase inhibitors, quinazoline, and prolactin have been used in attempts to increase SMN protein. Valproic acid and sodium phenylbutyrate are among the histone deacetylase inhibitors that have been used, but neither was shown to be effective in clinical trials. Pilot results for the nonhistone deacetylase inhibitor albuterol were promising; however, hydroxyurea was ineffective in a randomized trial. Oral salbutamol is well tolerated and seems to increase stamina in pilot studies, although further phase 3 trials are needed.
Newborn screening for spinal muscular atrophy. The natural history data of spinal muscular atrophy demonstrate typical progression, and an approved treatment in presymptomatic infants exhibits significant therapeutic value. Pilot data on screening for spinal muscular atrophy from state public labs utilizing an inexpensive and reliable test are available, and the SMN1 deletion testing has shown to be highly sensitive and specific. Based on these, the advisory committee on Heritable Disorders in Newborns and Children (ACHDNC) voted recommendation to include spinal muscular atrophy in the recommended uniform screening panel (RUSP) (19). This will be implemented in the near future pending Health and Human Services secretary approval. Several states in the United States have implemented permanent statewide newborn screening for spinal muscular atrophy, and many other states have adopted it but have not yet implemented it.
Rudnick-Schoneborn and colleagues reported pregnancy outcomes of 12 women with spinal muscular atrophy (48). Complications in 10 of the 12 women included premature labor in 4, prolonged labor in 3, and delayed postpartum recovery in 6. An article compared different studies available on the pregnancy outcomes in women with spinal muscular atrophy and analyzed the outcomes in different stages of pregnancy. Fertility is not typically affected in spinal muscular atrophy. Ectopic pregnancies, early and late miscarriages, and stillbirths are not more frequent in spinal muscular atrophy pregnancies than that of the general population. Similarly, incidence of fetal complications such as polyhydramnios, IUGR, and macrosomia and maternal complications such as gestational diabetes, hypertension, and preeclampsia are not different in spinal muscular atrophy than that of the general population. Respiratory weakness can occur. Optimal management requires preconceptional evaluation of respiratory function, early referral to specialized care, and monitoring of respiratory function in each trimester. Prematurity is common with spinal muscular atrophy pregnancies. Women with spinal muscular atrophy may experience worsening of their baseline motor function during the antenatal period, which may or may not return after delivery (01).
Sedation and anesthesia should be provided at a tertiary care center with respiratory, neurology, and anesthesia providers familiar with spinal muscular atrophy management available. A low threshold for elective sedation/anesthesia should be considered during intercurrent illness in spinal muscular atrophy patients. Aggressive secretion clearance measures should be an integral part of postanesthetic care. Excessive oxygen supplementation as a substitute for positive pressure ventilation should be avoided. Anesthesia needs and postoperative care during pregnancy in spinal muscular atrophy is discussed in 1 review (01).
Kapil Arya MD
Dr. Arya of Arkansas Children's Hospital/UAMS has no relevant financial relationships to disclose.See Profile
Aravindhan Veerapandiyan MD
Dr. Veerapandiyan of University of Arkansas for Medical Sciences has no relevant financial relationships to disclose.See Profile
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