Spinal muscular atrophy (SMA) is a group of neurodegenerative disorders characterized by chronic and inherited degeneration of spinal motor neurons. Unlike hereditary ALS, there are no UMN signs.
About 95% of SMA cases are caused by homozygous deletions and less frequently point mutations in the SMN1 gene (survival of motor neuron 1) on the long arm of chromosome 5 (5q-SMA), whereas SMA mutations in other genes can also be causative (non-5q-SMA). Autosomal recessive proximal SMA or 5q-SMA, the most common form of SMA, accounting in most series for up to 95% of cases.
There are 2 genes involved in SMA designated as survival motor neuron genes type 1 (SMN1) and type 2 (SMN2). In a normal person, there are 2 copies each of the SMN1 and SMN2 genes.
In order to develop SMA, a homozygous deletion or point mutation affecting both SMN1 genes is required.
SMA is the most common genetic cause of death in infants.
Humans have two nearly identical copies of the SMN gene known as SMN1 (telomeric copy) and SMN2 (centromeric copy). Homozygous deletions of SMN1 accounts for 95% of SMA. Disease-causing mutations in SMN1 inhibit the production of functional SMN protein from this gene. SMA’s highly variable phenotypic spectrum is mainly attributable to variable copy numbers of the neighboring SMN2 gene. This gene is almost homologous to SMN1 except for few nucleotides and is of no relevance in healthy individuals. A single nucleotide transition of SMN2 causes predominant exon 7 skipping and mainly results in an unstable SMN protein. Spinal muscular atrophy, therefore, is caused by loss of the SMN1 gene and retention of the SMN2 gene, leading to low levels of full-length SMN protein in all cell types. High levels of full-length SMN protein are required in motor neurons. In SMA, therefore, SMN1 is non-functional, and SMN2 is functional. In SMA, insufficient levels of the SMN protein lead to degeneration of the anterior horn cells, producing weakness and wasting of the skeletal muscles. This weakness is often more severe in the trunk and upper leg and arm muscles than in muscles of the hands and feet. Non-motor features may occur on occasion. These may include sensory involvement, cardiac defects, gastrointestinal and autonomic dysfunction, and endocrine abnormalities. In the majority of cases, these deletions/mutations are inherited from parents, but de novo deletions have been reported in 2% of SMA.
So what is the difference between SMN1 and SMN2?
Although they both end up making the exact same protein. However, they vary in one important nucleotide change. The coding regions of SMN2 differs from SMN1 by 5 nucleotides (in intron 6, exon 7, intron 7, and noncoding exon 8). Only one of these nucleotide changes (840C-T) which is a C to T substitution at base 840 resulting in exclusion of exon 7 in the mRNA transcript and a non-functional, rapidly degraded SMN protein. This change distinguishes SMN1 from SMN2. This change, however does not alter the encoding of the amino acid but results in a defect in an exon spice modulator. Exon 7 is normally incorporated in the transcript if it is from SMN1, but it does not incorporate or is inefficiently incorporated if it is from SMN2. Homozygous deletions of both the SMN1 and SMN2 genes is incompatible with life. However, homozygous deletion of the SMN1 gene with the presence of a normal SMN2 gene result in low levels of SMN protein and the development of SMA. The copy number of SMN2 correlates with longer survival and inversely with disease severity. Thus, the severity of the disease is generally determined by how many copies of the "backup" SMN2 gene a person has, with more copies predictive of a milder disease course. Ultimately, SMA is the result of a deficiency of SMN protein.
SMN1, on 5q13.2, normally makes SMN protein that is important in RNA processing and for the survival of motor neurons. The SMN protein inhibits the apoptosis of motor neurons. SMN1 protein is important in the formation of splicesomes, which are important agents in the processing of pre-mRNA into mRNA.
Survival motor neuron protein is ubiquitously expressed in the cytoplasm and nucleus of all cells as part of a larger protein complex, the SMN complex. The SMN complex regulates the assembly of small nuclear RNPs (snRNPs) which, in turn, catalyze pre-mRNA splicing at a component of the spliceosome. The reduction of SMN protein is thought to result in reduced snRNP assembly influencing the splicing of a gene that is important for axons.
SMN, is required for efficient assembly of snRNP complexes. snRNP are responsible to "stitch" the exons together once the genes are spliced. SMA may be the result of a genetic defect in the biogenesis and trafficking of the spliceosomal snRNP complexes. Mutated SMN, such as that found in individuals with SMA, lacks the splicing-regeneration activity of wild type SMN. Reduced SMN lowers the capacity of cells to assemble the snRNPs, which leads to altered levels of spliceosomal components and defects in splicing, and impaired capacity to produce specific mRNAs and their encoded proteins that are necessary for cellular growth and function. It remains unclear how a defect of splicing results in a motor neuron-specific disorder
As SMN2 number varies (0-6) in the normal population and 10-15% of the population have no copies of SMN2. So if someone has 8 copies of SMN2, that will result in sufficient SMN being produced.
Homozygous deletions of SMN2 do not appear to have any consequences when SMN1 is intact.
Variants with SMN2 can also influence the phenotype. For example, variant SMNG859C increases the amount of full-length SMN mRNA and the amount of a SMN protein produced, resulting in a less severe phenotype.
There is no absolute correlation of severity with the copy number of SMN as they are other unknown and other modifiers some of which lie outside the SMN locus and influence the severity of disease.
In 1991 the International SMA consortium developed a classification system based on the age of onset of symptoms and maximum motor function achieved. The classification divided childhood SMA into 3 types which were later expanded to include type 0 (prenatal onset) and type IV (adult onset).
SMA type 0 is at prenatal stage, is severe, associated with arthrogryposis (severe contracture of limbs) and associated to respiratory failure at birth and most infants die. It accounts of <5% of SMA. SMA0 has only 1 copy of SMN2 gene.
As an alternative to using the classification of SMA type 0, some prefer to subdivide SMA type 1 into a, b, and c, with type 1a being the most severe form overlapping with type 0.
SMA type I, infantile SMA also called Werdnig-Hoffmann disease, or telomeric form has onset usually at 3 months, almost always evident by the time a child is 6 months old. Accounts for 45% of cases. Patients do not achieve the functional ability to sit independently.
Incidence ranges 1/11,000 birth.
Prevalence: 1-2/100,000 persons.
SMA type 1 typically follows a rapidly progressing course and is the leading genetic cause of death in early infancy with a life expectancy of under 2 years [
Check for SMN1 gene deletion. Infants with SMA1 usually have 1 out of 2 copies of SMN2.
Clinical features:
Hypotonia (severely reduced muscle tone) with symmetrical, generalized, or proximal predominant pattern of weakness. Legs are affected more than arms.
History of decreased fetal movements in utero, poor suck, poor feeding, weak cry, head lag, frog leg posture when supine, diminished limb movements, lack of tendon reflexes, tongue fasciculations, swallowing and feeding difficulties, and impaired breathing.
A bell-shaped deformity of the chest may also be evident, resulting from poor expansion of the ribcage with relative preservation of diaphragm strength. Paradoxical breathing is a characteristic feature, with flattening of the chest wall (rather than expansion) and protrusion of the abdomen during inspiration. Pectus excavatum
Alert with normal facial and ocular muscle movements.
Sparing of the extraocular muscles and relative sparing of facial muscles.
Fasciculations of the tongue is notable, while those of limbs are not clearly discernible due to presence of subcutaneous fat. Tremor is not commonly seen as opposed to SMA II and III.
Affected children are never able to sit and the vast majority usually die of respiratory failure before the age of 1. However, the survival in individuals with SMA type I has increased in recent years, in relation to the growing trend toward more proactive clinical care. 80% survive to 10 years of age. 20 year lifespan is unexpected.
A “floppy” baby or hypotonia. Small or weak muscles. Difficulty breathing/belly breathing. Feeding issues, like choking or trouble swallowing. Weak sucking and labored breathing during feeding. Tongue fluttering. Bell-shaped chest (a result of muscle weakness). Weak cough. Lack of reflexes. “Frog legs” or the inability to kick while lying on back. Lack of motor development, like being unable to lift head or roll over. Inability to sit. Weak cry.
No intellectual impairment. c
SMA type II, the intermediate form, usually begin between 6 and 18 months of age. Accounts for 20% of cases.
It is centromeric form.
Found only in humans.
Accounts for 30% of cases.
SMA2 is usually associated with 3 out of 4 copies of SMN2 gene.
Clinical features:
Children may be able to sit around 9 months of age or more but are unable to stand without support, and may have respiratory difficulties. Never walk independently, but some patients will be able to stand with the assistance of bracing or a standing frame.
Proximal predominant weakness that is most severe in the lower limbs.
Reflexes are usually absent.
A fine tremor (minipolymyoclonus) is often apparent mainly in the distal limbs and has long been associated with intermediate forms of the disease.
Tongue atrophy with fasciculations is also characteristic.
Similar to type 1, facial and eye muscles are spared.
Symptoms related to bulbar function is less of an issue than in SMA I.
Due to the protracted course and inability to sit, patient acquired kyphoscoliosis and joint contractures.. This occurs universally in this group and is a significant contributing factor to restrictive ventilation defects.
98% survive to age of 5 years, while 2/3rds survive to age of 25 years.
SMA type III, or juvenile SMA, (Kugelberg-Welander disease) appear between 2 and 17 years of age
SMA III is subdivided into SMA IIIa ( 18 months to 3 years) and SMA IIIb (3 - 21 to 30 years).
SMA3 patients have 4 out of 4 copies of SMN2 gene.
Clinical features:
Affected individuals develop the ability to stand and walk but then lose it in childhood, adolescence, or adulthood. Present with symptoms of falls, difficulty climbing stairs, and other features of proximal weakness.
Abnormal gait characteristics are common in order to compensate for weakness, and many patients are able to continue ambulation despite severe weakness. Foot deformity may be seen in ambulatory patients.
Proximal weakness in hips and shoulder girdles. The lower extremities are most often affected. Fine action tremor and fasciculations.
Never run. By definition, standing or walking without support is achieved, although many patients lose these abilities later with disease progression.
Scoliosis and joint contractures—chronic shortening of muscles or tendons around joints, caused by abnormal muscle tone and weakness, which prevents the joints from moving freely.
Individuals with SMA type III may be prone to respiratory infections, but with care may have a normal lifespan.
SMA type IV, adult onset, or pseudomyopathic SMA. Accounts for <5% of cases.
Recessive
Least common, and least severe.
Although onset of type 4 is not defined clearly, it is often considered to be at age 21 or later.
SMA4 have 4 - 6copies or more of the SMN2 gene.
The presentation is very similar to type 3 and is distinguished solely on later onset during adulthood.
Symptoms typically begin in the third to fourth decades of life and include proximal muscle weakness, with the hip flexors and extensors and quadriceps prominently involved. The shoulder abductors and elbow extensors are the most affected muscles of the arms.
Tongue and limb fasciculations.
Calf hypertrophy.
Ambulation into late adulthood is common. Cranial nerve and respiratory involvement is rare.
Probability of survival to 20 years of age is 0 to 30% for SMA 1 and 77 to 92% for SMA 2.
Probability of survival to age 40 years decreases to 0% for SMA 1 and 52% for SMA 2.
No changes survival probability is seen in a SMA 3 compared to the general population. Next line patient surviving male presenting into adulthood comprise approximately 35% of all SMA patients and constitute a sizable number that will continue to grow with new treatment options.
Diagnosis of SMA is established in a proband with a history of motor difficulties or regression, proximal muscle weakness, reduced/absent deep tendon reflexes, and evidence of motor unit disease; AND/OR by identification of biallelic pathogenic variants in SMN1 on molecular genetic testing. Increases in SMN2 copy number often modify the phenotype.
Molecular genetic testing using gene-targeted deletion/duplication analysis to determine SMN1 is performed first for the SMN1 exon 7. This will result in a homozygous deletion of SMN1 in 95% of cases. The remaining 5% will have a deletion and a missense mutation so they are compound heterozygous. In the latter patients additional testing by performing sequence analysis of SMN1. If exon 7 is present in both copies of SMN1, consider another diagnosis.
Serum creatine kinase may be significantly elevated (more than 10 times normal), particularly in the younger-onset forms.
EDX: Sensory NCS are normal; EMG shows evidence of acute and chronic denervation and reinnervation, with large polyphasic motor units.
Complex repetitive discharges occur in SMA type 3.
Muscle biopsy shows atrophy of the entire fascicles or groups of fascicles, with normal or hypertrophied neighboring fascicles, and fiber type grouping.
CNS disorders, Dejerine-Sottas or congenital hypomyelination or amyelinating disorder, GAN, infantile botulism, transient neonatal MG, congenital MG syndrome, congenital myopathies (severe nemaline, myotubular), congenital dystrophies, congenital myotonic dystrophy, acid-maltase deficiency, debrancher branching enzyme deficiency, myophosphorylase deficiency, carnitine deficiency, hypothyroidism, mitochondrial myopathies.
Non-SMN infantile SMA
Recessively inherited SMA with respiratory distress type I (SMARD1) caused by mutation in IGHMPP2 on 11q13.2-13.4.
X-linked infantile SMA with arthrogrposis.
AD inherited SMAs including SMA IV (Finkel type), VAPB (fALS)
Mutations of the lamin A/C gene (LMNA)
While being a monogenetic neuromuscular disease, the resulting phenotypic spectrum is complex and SMA is generally perceived as a systemic disease. Accordingly, caring for patients with SMA requires the interdisciplinary management of respiratory, nutritional and gastroenterological, orthopedic, and psychosocial issues. General treatment recommendations were published in 2007 in the first consensus statement on standards of care in SMA. Nevertheless, the implementation of standards of care is highly variable and is influenced by cultural perspectives, socioeconomic factors, and the availability of regional resources.
Advances in respiratory management are largely responsible for increase survival into adulthood. FVC and SNIP (sniff nasal inspiratory pressure) show progressive decline in respiratory function at younger ages with a relatively stable period during adulthood. Studies have shown that respiratory function in SMA IIIa resembles that seen in SMA II rather than SMA IIIb.
It is important that patients transitioning into an adult care clinic become established with a pulmonologist who understands SMA. Respiratory muscle weakness, impaired cough and sleep disordered breathing contribute to respiratory failure in SMA. Respiratory muscle weakness is most significant in inspiratory (external intercostal muscles) and expiratory (the internal intercostal muscles), with relative sparing of the diaphragm. Bilevel routine surveillance of PFT is recommended to identify signs of hypoventilation so that bilevel noninvasive ventilation can be initiated as early as possible. CPAP should be avoided when evidence of restrictive lung disease is also present as it may cause muscle fatigue and does not increase tidal volumes. CPAP does not assist inspiratory muscle function but can be considered in patient with isolated obstructive sleep apnea. In patients who cannot tolerate noninvasive ventilation or remove failed treatment, there should be a discussion regarding tracheostomy. Any such discussion should reflect the patient's goals of care.
Poor airway clearance can lead to pulmonary infections, aspirations, and hospitalizations. Those with a peak cough flow (PCF) of <270 L/min are at risk for respiratory failure in the setting of of simple viral respiratory tract infection secondary to secretion retention. The use of manual chest physiotherapy such as air stacking, combined with a mechanical insufflation-exsuffulation device represents a positive approach and supporting airway clearance in those with an ineffective cough. Additionally, medication options such as glycopyrrolate may control secretions. When using glycopyrrolate, patient are strictly counseled and monitored for anticholinergic side effects including urinary retention and constipation. Oral suctioning can also be used for secretion management.
As standard of care, patient should receive annual influenza vaccinations and pneumococcal vaccinations with periodic revaccination typically every 5 years, depending upon the specific brand of pneumococcal vaccine used.
Nutritional assessments are routinely important part of the surveillance of all adult SMA patients. A nutritional specialist must be part of the multidisciplinary team. There is altered body composition in individuals with SMA. Despite low body mass indices, patient with SMA are at increasing risk of becoming overweight secondary to decreased mobility which results in increased body fat percentages. Progressive obesity reduces mobility and increases morbidity. Additionally, possible metabolic abnormalities, such as abnormal fatty acid metabolism, are becoming increasingly evident. SMA patients are more likely to develop dyslipidemia and liver steatosis than the age-matched controls.
SMA patients should be monitored annually for new or worsening feeding difficulties, including challenges with chewing and fatigue with eating and not just choking episodes. Decreased mandibular movement, resulting in jaw contractures and decreased bite force, limit the patient's ability to maintain adequate oral intake. Swallow study should be completed when there is concern for safe swallowing techniques and/or risk of aspiration. In individuals who cannot maintain adequate nutrition safety, discussion for placement of percutaneous endoscopy gastrostomy (PEG) tube is warranted. Modified diets in combination with feeding tubes can reduce the risk of aspiration, though the risk of aspiration from oral secretions remains. Additionally, other GI concerns should be considered and addressed, including GERD, gastroparesis, and constipation.
Motor function must be closely monitored to provide anticipatory supportive care, and specific changes can lead to several musculoskeletal concerns including scoliosis. Assessment of function should occur routinely and include evaluation of strength and range of motion. Motor functional scales that are relevant can be incorporated as patient reported loss of function that cannot otherwise be appreciated on physical examination. Examples of functional scales include the 6-minute walk test (6MWT), Hammersmith Functional Motor Scale Expanded (HFMSE); Revised Hammersmith Scale (RHS), Motor Funciton Measure (MFM), and Revised Upper Limb Module (RULM) in non-ambulatory patients. As they take a long time to administer their utility is limited. Sudden decline in function in adults with SMA has been linked to increase joint contractures, weight gain, and deterioration of scoliosis, reaffirming the need for routine surveillance.
Nearly 100% of patients with SMA type II and III have scoliosis which is complicated by chest cage deformities, impingement of the ribs, pelvic tilt, and constriction of vital capacity. Bracing will not impede progression and surgical correction is determined by curve magnitude, rate of progression and adverse effects of respiratory function. As such, most adult SMA patients will have a history of spinal fusion. Those who remain ambulatory are likely to have scoliosis non-surgically treated.
There is a high propensity for hi-dislocations in non-ambulatory SMA patients as a result of diminished weight bearing and profound gluteal muscle weakness. It is estimated that subluxation occur in 30-40% of patients with SMA type II and 10-30% with SMA type 1. Recurrent subluxations can occur despite correction. Conservative treatment is typically recommended as the risks associated with surgery, including the use of anesthesia in the setting of respiratory dysfunction, may outweigh the uncertain benefit.
Patients with SMA are at an increased risk for fracture with loss of ambulation. Demineralization and osteopenia are driven by the loss of weight bearing and exacerbated by interaction between osteoclast stimulating factor and SMN protein. Yearly DEXA scans are recommended with monitoring of vitamin D levels as standard of care.
Recommendations for the evaluation of patients with SMA by the SMArtCARE-project. RULM: revised-upper-limb-module; 6-MWT: six-minute-walking-test,
Baseline data (First visit only)
Current medical history and clinical examination ncluding WHO motor milestones.
Physiotherapeutic assessments:
CHOP INTEND
All children <2 years of age
All patients >2 years of age without ability to sit.
Bayley-III Scale (motor part)
Only for children <2 years of age with CHOP INTEND score >50
HFMSE
All patients >2 years of age with ability to sit
If CHOP INTEND score >50: CHOP INTEND and HFMSE
If CHOP INTEND score >60: HFMSE instead of CHOP INTEND
RULM
All patients >2 years of age with ability to sit (in a wheelchair)
6-MWT
All ambulant patients >3 years of age.
Early proactive interventional therapies including physical and occupational therapies can prevent further impaired mobility, contractures, spinal deformities, and pain, and can aid in assistive and adaptive equipment. Non-ambulatory and younger patients with SMA receive more PT than adult. Passive range of motion, stretching, and orthotics for proper positioning can delay contracture development.
Scoliosis, hip dislocations, and improper wheelchair seating and positioning contribute to overall gain. A well fitted power wheelchair is not only important for mobility but supports psychosocial development and enables participation in social activities. A referral to a wheelchair seating and positioning clinic should be considered for customization to make sure proper head and trunk support is provided. Additionally, features including adjustable tilt and standing function should be discussed.
Limited studies evaluating the effect of exercise in SMA have found to be a safe and effective way of improving aerobic capacity. Adult SMA patients have lower than predicted maximum oxygen uptake (VO2 Max) which may blunt their response to exercise training. They have been no detrimental effect shown in adult SMA patients using exercise volumes recommended all Americans. In a pilot study, however, most patient did complain of fatigue and muscle overuse. Exercise induced muscle fatigue has been suggested to result from fatigability of collateral reinnervation to denervated muscle. NMJ dysfunction, and muscle impairment resulting in mitochondrial depletion and impaired mitochondrial biogenesis.
Psychosocial wellbeing is important in the management event of SMA. SMA patient's identified stability of function as a meaningful measure given the fear of progressive loss of function especially after a long period of stability. Patient's note pride in the resilience, personal accomplishments, and social relationships. Question raised regarding personal hygiene, dressing, walking, caregiver burden and fatigue are asked during every visit. Continue evaluation by mental health professionals should be considered in patients with concerns regarding progression of the disease as it can impact treatment for an emotional state.
When counseling patients on pregnancy, a discussion should occur between the patient, neuromuscular physician, high-risk obstetrician, and pulmonologist. There is no evidence that SMA affects fertility. If both parents are carriers, the child has 50% chance of being a carrier, 25% chance of being affected, or 25% chance of being unaffected. If one parent is a carrier and the other is normal, the child has 50% chance of being a carrier and 50% chance of being unaffected. If both affected parents have the same recessive phenotype, all their offsprings will be affected.
Ectopic pregnancies and miscarriages do not occur at a higher rate when compared to normal population.
It is important that PFT be monitored in the 2nd and 3rd trimester. Lung function may worsen during pregnancy and improve afterwards. NIV may need to be introduced during pregnancy, even if it is not required at baseline. Respiratory status is important when determining anesthetics given during delivery as they may worsen respiratory function. There is an increase in the risk of preterm labor and C-section in adult SMA type II patients. While the uterus has normal contractility, pelvic deformities may prevent a vaginal delivery. Prolonged labor and delayed pushing during vaginal deliveries have been reported. Reasons for C-sections include maternal respiratory distress and weakness of pelvic floor and abdominal muscles. Altered pelvic anatomy and contractures in the lower extremities may cause difficulties with positioning on operating table and access to the uterus during C-section.
One retrospective study of 33 adult SMA patients showed increased weakness in 31% occurring during or immediately following delivery which did not resolve post-partum. Caregiver support and education regarding physical adaptation and equipment needed to care for an infant should be implemented for a safe post-partum period.
SMA has long been classified as motor neuron disease, though SMB protein is ubiquitously expressed in all cells. Case reports and animal models have reported pathology of peripheral nerve, brain, muscles, heart, vasculature, and pancreas, through such additional organ involvement does not appear in most patients with SMA. There are no current recommendations for routine cardiac surveillance in adults with SMA. However, in one setting of patient with SMA type I and ventilatory support, 24% of patients had severe symptomatic bradycardia. Few case reports also documented heart abnormalities in patients with SMA type III. While there is no standard of care, cardiac and other organs surveillance should be considered based on symptom development.
Currently the therapeutic interventions that are available work to increase SMN protein and are as such not avaiable for non-5q SMA.
There is currently no curative treatment available for adults with SMA. The mainstay of treatment is focused on preventative measures and symptom management to allow patients to maintain the functional quality of life. A multidisciplinary approach is thought to be the most important element to the management of these patients. Recent guidelines suggest that management of patients with SMA may be best served by such categorizing these patients based on functional status. Patient are separated into the following categories: Non-sitter, and walker.
The approach to managing adult SMA remains to focus of the care of sitters and walkers, and no sitters do not typically survive into adulthood.
Transition from pediatrics to adult. A structured and supportive transmission from the pediatric to adult care team is recommended between the ages of 18 and 21 years. For adult SMA patients often there is a greater focus on patient autonomy and decision making. This can be challenging for young adults with chronic diseases such as SMA. A palliative medicine consultation may sometimes be warranted to discuss goals of care.
SMN is a candidate for gene therapy: alternative gene splicing can remove the most commonly affected region in the SMN1 gene (exon 7), which lead to less robust, but functional, protein product.
Splicing modification of SMN2 therapies:
Spinraza (Nusinersen) is the first agent to be approved by FDA in December 2016 for the treatment of SMA in pediatric and adult patients (ENDEAR) trial. It is an antisense-oligonucleotide ASO). In the ENDEAR study, 121 infants with SMA type 1 and younger than 7 months of age underwent either repeated intrathecal injections of nusinersen or a sham-intervention entailing no drug application. Those receiving nusinersen demonstrated a prolonged time to death or need for permanent ventilation compared to the sham-control group . The criteria for being a “motor-milestone-responder” (achievement of motor milestones in HINE-2 scale; Hammersmith Infant Neurological Examination) were fulfilled by 51% in the treatment group but by 0% in the sham-control group. Although the treatment group’s motor development differed strongly from the disease’s natural history, only a minority of patients (6/73) achieved independent sitting during the nusinersen treatment period lasting about one year. In the CHERISH study, the effects of nusinersen were studied in 126 older children (median age 4 years) with SMA type 2 and onset of symptoms after the age of 6 months. Again, the nusinersen group exhibited a gain in motor functions (mean + 4.0 points in HFMSE scale; Hammersmith Functional Motor Scale Expanded version), whereas the sham control group deteriorated slightly (–1.9 points in HFMSE scale). Both studies were terminated prematurely after these results became apparent in interim analysis and all participants were switched to the treatment group. The effects of pre-symptomatic nusinersen treatment were studied in the NURTURE study in 25 infants under 6 weeks of age with 2 (n = 15) or 3 (n = 10) SMN2 copies. All 25 patients acquired the ability to sit independently and 22/25 achieved independent walking Nusinersen was approved by the Federal Drug Agency (FDA) in December 2016 and by the European Medicines Agency (EMA) in May 2017. The first patients with SMA type 1 had been treated beforehand within an Expanded Access Program (EAP) in some countries.
Nusinersen was approved by the U.S. Food and Drug Administration (FDA) in December 2016 to treat SMA caused by SMN gene mutations. It is administered intrathecally. It is an antisense oligonucleotide (synthetic nucleic acids 8-20 bases in length) that bind to pre-mRNA and alter protein synthesis. It increases the production of full-length SMN proteins by binding to a specific sequence, intronic splicing silencer N1 (ISS-N1). ISS-N1 is a negative regulator of exon 7 and does not allow inclusion of exon 7 in SMN2. So, by binding and blocking to ISS-N1 (the negative regulator of exon 7) in SMN2 the antisense oligonucleotide acts downstream of exon 7 of the SMN2 messenger RNA (mRNA) script and affects the inclusion of exon 7 in SMN2. Therefore, it enhances the inclusion of exon 7 in mRNA transcripts of SMN2. The inclusion of exon 7 in SMN2 results in production of a functioning survival motor neuron (SMN) protein by SMN2. So the therapy makes SMN2 act like SMN1 and thus restoring full length SMN protein.
Infants who received nusinersen reached motor milestones not achieved by infants who underwent placebo treatments.
The recommended dosage is 12 mg (5 mL) per administration. Initiate SPINRAZA treatment with 4 loading doses: the first three loading doses should be administered at 14-day intervals; the 4th loading dose should be administered 30 days after the 3rd dose. A maintenance dose should be administered once every 4 months thereafter.
While typically administered through a lumbar puncture in children, administration in adults is often complicated by significant scoliosis and spinal fusion requiring alternative interventions to administer medication. Such intervention have included interventional radiology guided transforaminal injections, Ommaya reservoir placement, and laminectomies. Coordination between multiple specialties and post-procedural monitoring in addition to the cost of medication, can be challenging in these patients.
An approach to altering the splicing of SMN2 and thus increasing the amount of functional SMN prote is also taken by small molecules such as RG7916 (risdiplam) and LMI070 (branaplam). These compounds are taken orally, cross the blood-brain barrier, and have been shown to increase the amount of full length SMN-protein. The most advanced compound is the pyridazine derivative RG7916 (risdiplan) investigated in several trials: In the open label FIREFISH-study, 21 infants with SMA type 1 between 1 to 7 months of age received low-dose risdiplam (Part 1, n = 4) with the primary objective of safety-assessment, or a high dose (following Part 2, n = 17) with the primary objective of assessing efficacy (independent sitting after 12 months of treatment). After a medium treatment duration of 14.8 months, the primary endpoint of independent sitting was attained by 33% of all infants (n = 7/21), and by 41% of those infants receiving the higher dose in Part 2 (n = 7/17). No treatment-related safety concerns were reported. Older patients with SMA type 2 and 3 received RG7916 (risdiplam) in the SUNFISH-study. Again, that study was divided in Part 1 (dose-finding) and double-blind, placebo controlled Part 2 (confirmatory). Of the 43 patients included in Part 1, 58% revealed an improvement in at least 3 points in the Motor Function Measure-32 (MFM32) scale. Further ongoing studies the JEWELFISH-study, include patients with all types of SMA (age 6 months to 60 years) treated previously with SMN-targeting therapies, gene therapy, or olesoxime, and the RAINBOWFISH-study for presymptomatic babies with SMA. In May 2022 it extended its label to include babies under 2 months old, based on interim efficacy and safety data from the RAINBOWFISH study in newborns which showed that the majority of pre-symptomatic babies treated with drug achieve key milestones such as sitting and standing, with half walking after 12 months of treatment.
LMI070 (branaplam) is nowbeing investigated in a phase I/II study (that recently finished recruiting) with SMA type 1 patients after an almost two-year halt because of safety concerns in animal data.
Risdiplam (Evrysdi). In August of 2020, risdiplam joined the list of FDA approved medication for patients over the age of 2 months. Risdiplam is an orally administered RNA splicing modifier directed at SMN2 which increases the production of full length SMN protein. FDA approval was granted on clinical trials evaluating its effects in infants. No clinical trials of risdiplam for adult patients have been completed. Dosage is based on age and body weight. Indicated for age ≥2 months. Administer orally as a liquid once daily after a meal using the provided oral syringe to be taken <5 minutes.
Replacement of SMN1-gene. Gene therapy of SMA is the most advanced medical approach that directly targets the dysfunctional SMN1-gene in SMA. Studies employing an Adeno-Associated Viral serotype 9 (AAV9) vector to deliver an intact copy of wild-type SMN in murine models showed that these constructs cross the brain-blood barrier and lead to prolonged survival of treated SMA-mice. The first clinical trial with zolgensma (AVXS-101) included 15 infants with SMA type 1 with 2 SMN2 copies (<8 months of age). All patients received a single intravenous dose of the compound in either low (n = 3) or high dose (n = 12). Transient elevation of liver-enzymes occurred in two patients, all patients received steroid treatment. Marked improvement in CHOP INTEND scores (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders) was observed in the high-dose cohort, with 11 patients attaining scores >40 points – a cutoff not usually attained in the natural history of SMA 1. During the follow-up period, 9 of the 12 children receiving high-dose zolgensma were able to sit without support for >30 seconds. One patient in the low-dose cohort needed permanent ventilation at age 29 months. Comparison to a natural history cohort confirmed the improvement of survival, motor function and milestones by AVXS-101 treatment. Safety and efficacy are now being investigated in several ongoing studies: the phase-3 STR1VE study involves 20 patients with SMA type 1 under 6 months of age at the time of infusion with the primary endpoint of achieving independent sitting; similar studies for Europe and Asia are ongoing or planned. The SPR1NT study will investigate the pre-symptomatic treatment of SMA patients of all subtypes (<6 weeks of age). Zolgensma was approved by the FDA for intravenous application in patients with SMA under 2 years of age in May 2019. While infants undergo the systemic intravenous application of gene therapy, intrathecal application might be necessary for older patients to achieve sufficient transduction of motor neurons. Initial trials addressing intrathecal gene therapy in mice and pigs have demonstrated improved gene expression that was achieved with a lower dose of viral vectors. The effects of intrathecal application of zolgensma in children with SMA type 2 (<6 years of age) are now being examined in the STRONG study.
Zolgenesma (onasemnogene abeparvovec-xioi) is a suspension for intravenous infusion. It contains self-complementary AAV9 (adeno-associated virus vector) and this vector based gene therapy is indicated for the treatment of pediatric patients less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1). The AAV containing the SMN gene homes crosses the blood brain barrier and transfects the entire SMN1 gene into the DNA of motor neuron. It replaces the function of the missing or nonworking SMN1 gene with a new, working copy of a human SMN gene. It does not change or become a part of the child’s DNA.
Treatment with ZOLGENSMA® (onasemnogene abeparvovec-xioi) allows people with SMA to make SMN protein. However, they still have 2 nonworking or missing copies of the SMN1 gene. This means that a person who’s been treated with ZOLGENSMA will pass on 1 of these nonworking or missing genes to any children he or she may have. If this person’s partner is also a carrier, then there is a chance their children will have SMA.
Upregulation of muscle growth. Therapeutic approaches that do not directly target the genetic cause of SMA include the improvement of muscle mass and function. Two compounds are the most advanced: Myostatin-inhibitors and Fast Skeletal Muscle Troponin Activators (FSTA).
Myostatin is a member of the TGF superfamily of growth factors that inhibits muscle over-growth and is primarily expressed in skeletal muscle. Myostatin deficient animals are known to have considerably increased muscle mass and strength, and the use of the myostatin-inhibitor SRK-015 in SMA-mice resulted in improved muscle mass and function. The safety of SRK-015 is being studied in a phase II trial whose first results are pending. Apitegromab is one such inhibitor that is being investigated. Its use along with nusinersen in SMA type 2 and 3 from ages 2 to 21 years showed promising results.
FSTAs like CK-2127107 (reldesemtiv), on the other hand, slow the release of calcium leading to improved contractibility. Reldesemtiv, a fast skeletal muscle troponin activator is a potential therapeutic drug being intestigated to improve skeletal muscle contractility in patients with SMA.. Its use in SMA was studied in 70 patients with SMA type 2–4 with official results also pending. The interim analyses reported a mild but statistically significant improvement in the six minute walk test (6MWT) after 4 and 8 weeks of treatment.
Therapeutic approaches in preclinical development
A growing number of compounds are in preclinical or early clinical development. Those comprise small molecules aiming to stabilize the SMN-protein and other types of ASOs targeting SMN2, but also SMN-independent approaches. The latter include myostatin-inhibition via Activin Receptor Type IIB antagonists and stand-alone approaches like inhibition of the p38MAPK pathway.
SMA type 1 patients showed higher levels of plasma phosphorylated neurofilament heavy chain (pNF-H) than healthy controls. Furthermore, higher pNF-H levels correlated positively with earlier onset of symptoms and inversely with motor function at start of nusinersen treatment. Under treatment with nusinersen, these levels decreased faster in the verum group than in sham control group. This decrease was more pronounced the earlier the therapy was started. In CSF of an adult SMA cohort, levels of pNF-H in CSF were below detection limit, but levels of NSE and pTAU protein showed a significant decrease under treatment. Electrophysiological biomarkers include the examination of the compound muscle action potential (CMAP) and the motor unit number estimation (MUNE), which have already been used in clinical trial. Availability of validated biomarkers would ideally allow predicting the clinical course of disease and the response to any drug treatment. This would improve clinical decision-making and significantly reduce the time and resources for clinical drug development.
A consistent finding across clinical trials for both SMN2 splicing modification and gene therapy is the fact that the effect size depends on the age at treatment initiation: the earlier treatment is started, the greater the clinical benefit is. The most impressive results have been observed when treatment is initiated before the first clinical symptoms become apparent. As we know that denervation progresses rapidly during the first 6 months of life, the ‘rescue’ of these motoneurons before clinical deterioration appears to be essential. Nevertheless, the mean age of diagnosis in SMA type 1 is around 6 months of age. Newborn screening (NBS) thus enables us to identify these patients at a pre-symptomatic stage. Four pilot projects of NBS programs in SMA have been conducted and published so far, all using quantitative polymerase chain reaction (qPCR) assays detecting homozygous deletions in either exon 7 or intron 7 of SMN1 via dried blood spot analysis. Only one of these assays was validated as also detecting heterozygous carrier deletions, and none of the assays was able to detect point mutations or quantify SMN2 copy numbers. In the NBS pilot studies in Taiwan, New York State and Germany, verification of NBS results by sequencing yielded a positive predictive value of 100% . To lower the costs of analysis, different PCR-based assays have been developed that allow simultaneous screening for SMA (with or without SMN2 copy number quantification) and severe combined immunodeficiency (SCID). SMA was added to the Recommended Uniform Screening Panel (RUSP) in July 2018; NBS for SMA is being implemented in a few US states and southern Belgium, and pilot screening projects are ongoing in other states and countries. Nevertheless, the issue regarding who should be treated is highly controversial. The correlation between SMN2 copy numbers and disease severity was recently examined in a larger Spanish cohort of 625 patients with SMA of all subtypes. Two SMN2 copies were associated with SMA type1 in almost 90% of patients. In patients presenting three and more copies, the individual age of onset and severity are more difficult to predict, but those factors still correlate with the copy number. An algorithm for treatment decisions for children diagnosed with SMA by NBS has been proposed by the SMA NBS Multidisciplinary Working Group, supported by CureSMA. There was consensus among the experts participating in this delphi-technique-based process, namely that treatment should be initiated immediately in truly asymptomatic infants with one SMN2 copy and in infants with two or three copies with or without symptoms, while those with four or more copies should be closely monitored and only treated after the onset of signs or symptoms. However, this pragmatic proposition does not incorporate the presence of possible genetic modifiers in SMA other than the number of SMN2 copies that can mitigate or exacerbate the clinical course. This is also reflected in the observation that disease severity can differ even in siblings possessing the same SMA genotype. The fact that parents of an apparently healthy baby are confronted by a severe diagnosis and difficult treatment decisions furthers adds to the complexity of NBS programs. To address these problems, greater awareness for SMA in the public and the availability of qualified genetic counseling are necessary to help parents make an informed decision.
Since the introduction of new drug treatments for SMA, we have observed disease trajectories that differ significantly from the known natural history of the disease. These new phenotypes now also cross the traditional subtypes of SMA. For example, patients with onset before six months of age (typical for SMA type 1) might achieve independent sitting (SMA type 2 by definition) if treatment is initiated early. It is now more appropriate to rely on a combination of age of onset, number of SMN2 copies, and age at start of drug treatment rather than the traditional subtypes to define a clinical phenotype of SMA.
These new disease trajectories also mean we must modify and adapt the clinical approach taken. For example, longer survival without ventilatory support following the initiation of drug treatment needs to be considered when counseling the parents of patients with early-onset types of SMA. On the one end of the spectrum, namely in very severe cases entailing a prenatal onset (SMA type 0), drug treatment is not likely to lead to any relevant improvement in motor function, nor will it prevent the need for permanent ventilation; it might therefore be inadvisable. On the other end, initiating treatment in a presymptomatic patient might result in almost normal motor development.
Additional organ involvement, including occurrence of cardiac defects, autonomic dysregulation or abnormal fatty acid metabolism has been reported in SMA. SMN protein is known to be highly expressed prenatally in most organs, so that a significant role in organogenesis has been discussed. Further research is needed to understand if systemic treatment of SMN deficiency is of clinical benefit compared to restricted treatment of the central nervous system.
The conventional disease trajectories of the pretreatment- era are now often modified by new drug treatments. This involves unprecedented challenges and issues regarding motor and non-motor symptoms. In many aspects, this requires that we reconsider earlier blueprints to enable individualized and the most appropriate decision-making. Despite the improved survival and motor development of symptomatic patients with early onset SMA, these children also exhibit a higher rate of scoliosis during the first years of life. Greater awareness of this risk, and close monitoring of spinal deformities appear crucial to react early and enable the spine to be stabilized via medical orthoses. As many braces interfere with breathing in the more severely affected patients, choosing the ideal device can be difficult. Surgical interventions entailing ‘growing rod’ systems have been reported to be feasible in children with SMA type 1 as young as 4 to 6 years of age and might be an option for younger children with severe scoliosis. However, further experience in this field is needed to balance the risks and benefits of these interventions. Certain orthopedic devices such as standing frames have not been used in most SMA type 1 patients, but they appear promising for the prophylaxis of joint contractures and to allow age-appropriate positioning even in more severely affected patients.
Intrathecal application of drugs like nusinersen can be difficult in patients with severe scoliosis. Fluoroscopy may be necessary for lumbar access in these patients, but that involves high cumulative radiation exposure in potentially lifelong therapy in case of nusinersen. Lumbar puncture is especially challenging in patients who have already undergone spinal fusion; some surgeons suggest creating artificial bone gaps during spinal surgery for later lumbar puncture, but we are still waiting for their longterm data. Alternative routes of application, via intrathecal catheter systems or even via cervical puncture have been suggested, despite the fact that nusinersen has only been approved for application via lumbar puncture.
When medications for rare diseases come up for approval, there is often only limited evidence available on its long-term effects and safety, and conducting randomized investigations to deliver such evidence is often impossible. Therefore, the only way to generate additional evidence is to collect and analyze real-world data via high-quality, well-monitored patient registries that attempt to avoid bias, so that they provide meaningful results. Keeping in mind the recent success of drug treatment in SMA, it is important that we do not disregard individual interdisciplinary clinical management, which remains the backbone of SMA treatment, since many patients are left with a significant disease burden despite drug treatment.
Patients with SMA are at increased risk of severe complications should they acquire coronavirus disease 2019 (COVID-19). Many of these patients required frequent visits to healthcare providers for administration of therapeutics, PFT and management of acute and chronic illnesses, related to underlying diagnosis. Telemedicine has allowed patients to continue to receive needed care while avoiding hospital setting in cases where administration of therapeutics requires inperson visit.