SMA (spinal muscular atrophy)

Definition

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. 

Genetics and Pathogenesis

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. 

Classification

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).

Diagnostics

DDx

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

Therapeutic approaches and symptomatic management

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.

Pulmonary.

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.

Nutrition.

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.

Musculoskeletal

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,

Rehabilitation

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. 

Mental Health

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.

Pregnancy

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. 

Other organ involvement

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.

Therapeutics 


Emerging Therapeutics

Biomarkers in SMA

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.

Emerging New-Born Screening

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.

New Phenotypes and Challenges

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.

Management of Adult SMA and COVID-19

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.