Spinal Muscle Atrophy

Etiology

In 95% of cases, SMA results from a homozygous deletion of SMN1 on chromosome 5q13; however, this does not explain how there can be significant clinical heterogeneity in phenotype.[6] The answer lies in there being two versions of SMN: 1) telemoeric version (SMN1) 2) centromeric version (SMN2) with individuals varying in the number of copies of SMN2 they possess.[7] SMN1 transcription produces a functionally complete mRNA, that can then be encoded to create the SMN protein. SMN2 transcription results in functionally complete mRNA 10 to 15% of the time, resulting in far fewer SMN protein being encoded than SMN1.[1] 

SMN2 is identical to SMN1 except for a single C-T substitution in exon 7. This substitution promotes splicing 80 to 85% of the time during transcription and resultant removal of exon 7.[1] This truncated mRNA causes similarly truncated non-functional proteins. Patients with SMA are lacking SMN1 and are therefore dependent on residual SMN2 production of functional SMN protein for alpha motor neuron function and subsequent survival.[8] There is, therefore, a positive correlation seen between the number of copies of SMN2 and phenotype severity with SMA type 1 typically having 1 to 2 copies of SMN2 and SMA type 4 having 3 to 5 SMN2 copies.[8]

There is not a perfect correlation as there are anomalies in phenotypic variation in SMN2, leading to varying amounts of functional SMN protein production in different individuals. Therefore a low number of SMN2 copies with a milder clinical phenotype have been described.[9]

Epidemiology

SMA incidence has been estimated at 1 in 6000 to 11000, with a carrier frequency in the of mutations in SMN1 of 2 to 3% (1 in 40) in the general population.[10][2] Incidence varies according to ethnicity, with the incidence reported as 8/100,000 for people of white ethnicity when compared with 0.89 in 100,000 for black ethnicity and 0.96/100,000 for those of mixed ethnicity.[11] Extrapolating from carrier frequency in the general population, one should expect a higher incidence of live births with SMA, one hypothesis is that fetuses possessing 0 copies of SMN1+SMN2 fail to develop as is seen in other species with this genotype.[12]

Pathophysiology

The precise role SMN protein plays in neuronal function and development is not fully understood, and its subsequent absence causing such devastating deficits has so far eluded precise pathophysiological descriptions. SMN protein is found in all eukaryotic cells and has shown to play a crucial role in all cells with regards to homeostatic cellular pathways.[13] 

Several hypotheses surrounding SMN protein and its role in SMA exist, two main hypotheses relate to SMN protein’s role in 1) The neuronal cytoplasm and 2) the neuronal nucleus. SMN protein in the cytoplasm has demonstrated a vital role in mRNA transport through axons, actin dynamics, and vesicle release in the synapse. In the nucleus, SMN protein forms small nuclear RNA’s (snRNA) and therefore plays a key role in the formation of the spliceosome, which removes introns in pre- mRNA into functional mRNA.[14][3]

This explanation hypothesizes the damage motor neurons specifically to either neuronal sensitivity to spliceosome malfunction directly or indirectly through incorrectly spliced mRNA creating dysfunctional proteins key to neuronal function.[3][15] Recent developments in the understanding of SMN protein regarding its ubiquitous presence and multiple functions in all eukaryotic cells have led to conclusions that SMA is not purely a motor neuron disorder with congenital heart disorder associations and sensory nerve pathology noted in type 1 SMA patients.[16][17]

History and Physical

The natural history and examination findings in SMA are dependent on phenotypic variation and are classified clinically into SMA ‘types’.[18] In all SMA types, notably, cognition is not affected, and patients reportedly have average to above-average intelligence.[19] Below outlines the four main types of SMA:

• Type 0 (aka type 1a, congenital SMA)- Present in the neonatal period with hypotonia, early respiratory failure, severe weakness, and typically decreased fetal movements with associated arthrogryposis. Death usually occurs at birth or within the first month of life; this is a rare phenotype.[20][4]
• Type I (aka Werdnig-Hoffman disease, ‘non-sitters,’ severe SMA) - Present in the first six months of life with limited head control, hypotonia and areflexia. Type I is defined as ‘non-sitters’ with a frog-like posture when supine. The weakness of intercostal muscles and preserved diaphragmatic function leads to a paradoxical breathing pattern and a bell-shaped chest. Swallowing difficulties are a typical feature with tongue fasciculations and associated complications such as failure to thrive and aspiration. Other cranial nerves are not normally affected at presentation, but facial nerve weakness typically develops later in the course of the disease. Notably, cognition is not affected, and patients are often described as alert and bright when diagnosed. Without ventilatory support, most succumb to the disease before two years of age. Type I is sometimes further divided into IA (or type 0, see above), IB: onset <3 months, IC: onset 3-6 months.[4][15][21]
• Type II (aka Dubowitz disease, ‘sitters,’ intermediate SMA) - Presents at 6 to 18 months old; able to sit but with hypotonia, areflexia, a progressive proximal weakness that disproportionately affects the legs over arms. Progressive scoliosis and intercostal muscle weakness result in restrictive lung disease. Other notable characteristics are polyminimyoclonus of the hands, ankylosis of the mandible, and joint contractures. Around 70% of patients will survive until 25, with some surviving into the third decade; respiratory compromise is the major cause of mortality.[4][22]
• Type III (aka Kugelberg-Welander disease, ‘walkers,’ mild SMA) - Presents after 18 months similarly to type II with progressive proximal weakness disproportionately affecting legs over arms, however, patients are ambulatory but can require a wheelchair as the disease progresses. Patients do not typically suffer from restrictive lung disease, and life expectancy is not affected. Type III sometimes further subdivides into IIIA: presents 18 months-3 years and IIIB: presents >3 years.[4][22]
• Type IV (aka adult SMA) - Patients present in adulthood (>21 years old) and is the mildest phenotype of SMA. Patients are ambulatory and present with mild leg weakness and develop progressive proximal weakness. Life expectancy is not typically affected.[23]

Evaluation

If a clinician clinically suspects SMA following a thorough history and clinical exam, genetic testing is usually sufficient to confirm a diagnosis of SMA.[21] Polymerase chain reaction (PCR) or multiplex ligation probe amplification (MLPA) can help to detect homozygous exon 7 deletion in the SMN1 gene.[24] This test has 95% sensitivity and almost 100% specificity. Around 5% of individuals with SMA are heterogeneous and have one allele exon 7 deletion in SMN1 and another allele with an atypical point mutation. SMN2 detection is often performed at the same time to give an added prognostic indicator with higher SMN2 copies associated with less severe phenotypes.[25]

Other diagnostic tests are options if initial genetic testing fails to detect homozygous SMN1 gene exon 7 deletion:

• Creatinine kinase - normal (although can be very mildly elevated) [25]
• Nerve conduction studies- sensory nerves demonstrate normal action potentials, motor nerves may show diminished motor action potentials [25]
• Needle electromyography (EMG) - SMA type I: denervation changes without reinnervation. SMA II+III: Neurogenic patterns (action potentials with prolonged duration, increased amplitude, and diminished recruitment) [25]
• Muscle biopsy - mostly obsolete as a diagnostic tool due to advances in genetic and less invasive testing but when performed in a patient with SMA shows a neurogenic pattern [25]

Treatment / Management

Historically there have been no disease-modifying treatments for SMA, and treatment has largely been supportive with early involvement of pediatric palliative care specialists, especially for types 0, I, and II.[15] Novel therapies have recently been developed that are showing considerable promise in combating the extremely poor morbidity and mortality associated with SMA I and II.[9](B3)

Pulmonary - restrictive lung disease seen in type 0, I, and II causes respiratory failure and is ultimately the cause of death. Non-invasive ventilation, usually in the form of BiPAP (bilevel positive airway pressure), has been used as a way of increasing quality of life and life expectancy.[26][27] Patients requiring this form of support will also have a weak cough and have an increased risk of respiratory compromise in the form of mucus plugging, aspiration, recurrent infections, and subsequent hypoxemia.[26] The involvement of chest physiotherapists is key for cough assessments, mucous clearing, and tracking of forced vital capacity in children >5 years of age.[27] Where non-invasive ventilation is no longer sufficient difficult discussions regarding tracheostomy and permanent invasive ventilation need to be made, this should take place in a multi-disciplinary setting with early involvement of palliative care specialists.[26](B3)

Gastrointestinal - Due to associated muscle weakness, patients are prone to tire quickly and have swallowing difficulties that can lead to a failure to thrive and have a negative compounding effect on muscle weakness. Other gastrointestinal symptoms include constipation, delayed gastric emptying, and reflux.[15] For patients with type I SMA early consideration of laparoscopic gastrostomy and Nissen fundoplication is important and can improve nutritional status and decrease the frequency of aspiration.[28] Patients with type II require close attention to nutritional status as although they may plot as being in the normal range on a growth chart for their age, they are more likely to have increased adiposity, the involvement of nutritionists is therefore vital in ensuring optimal nutritional management.[29][30] (B2)

Orthopedic - Patients suffer from orthopedic complications such as scoliosis, hip subluxation, and susceptibility to fractures. Type I and II are particularly affected by these complications, with type III being variably affected.[31] Physiotherapy involvement is important in optimizing and preserving function, and mobility with the use of stretching exercises and passive movement of joints helps to avoid joint contractures.[31] Similarly, orthotic specialist involvement is important to utilize frames, orthotics, and wheelchairs to improve quality of life and mobility. Orthopedic surgical monitoring is required for scoliosis with periodic consideration for spinal fusion and bracing.[31][15](B3)

Novel therapies - Traditionally, there has been no disease altering agents, and management has focused on optimizing the various clinical manifestations of SMA. Due to advances in understanding the underlying pathophysiology and breakthroughs in genetic therapeutics, there are now several promising novel agents that have shown to improve life span and decrease morbidity.[9] (B3)

Nusinersen - Is an intrathecally delivered antisense oligonucleotide (ASO) that promotes functional SMN2 production by inhibiting ISS-N1 (an SMN2 exon 7 splicer) and thereby increasing the amount of functional SMN protein produced.[32] ENDEAR - a phase III clinical trial assessing Nusinersen effectiveness in SMA type I patients (with 2 SMN2 copies showed 51% achievement of motor milestones compared to 0% in the placebo group.[33] Motor improvements also occurred in type II and III patients.[32] Nusinersen has received approval for use in the USA, Europe, Japan, Australia, for example. It costs $118,000 for one vial and costs $708,000 for the first year of treatment.[34][9](B3)

Onasemnogene abeparvovec - This onetime intravenous injection gene therapy utilizes the properties of adeno-associated virus serotype 9 and uses it to deliver the SMN1 gene into cells and thereby allowing the body to produce functioning SMN protein.[35] A phase I/II study testing safety and efficacy of onasemnogene abeparvovec in 15 patients with SMA I showed all patients were alive at 20 months compared to an expected 8% in historical cohorts. Furthermore, significant motor improvements were seen, with 11/15 able to sit unassisted in a cohort of patients classically defined by their inability to sit.[35] Onasemnogene abeparvovec is priced at $2.125 million for a single injection and has been reported to be the most expensive drug in the world.[36] Onasemnogene abeparvovec is currently licensed for use in the USA.[34][37]

Risdiplam - This drug is an oral medication that works via modifying SMN2 splicing and thereby increasing functional SMN protein levels. There have been numerous phase II/III trials that have shown efficacy with regards to improvement in motor function for patients with type II and III. Clinical trials are still ongoing and are currently under review in the US, Europe, and the UK for licensing.[38]

Differential Diagnosis

If SMA is clinically suspected, but genetic testing fails to identify pathological biallelic versions/absence of SMN1, there are a plethora of extremely rare conditions of varying etiology (usually secondary to a genetic disorder) that can present similarly to SMA but often with distinguishing features not seen in SMA. These are sometimes referred to as non-5q13-associated-SMAs.[4]

A thorough history, examination as well as CK, EMG, nerve conduction studies, muscle biopsy, MRI, as well as referral to a geneticist can all be key to determining the correct diagnosis.[25][2] A detailed review of differential diagnosis is beyond the scope of this article, but the following list is a brief synopsis of differentials grouped by age as summarised by GeneReviews:[2]

Congenital - <6months: Pompe disease, Prader-Willi syndrome, Myotonic dystrophy type 1, Sellweger spectrum disorder, Congenital myasthenic syndromes, X-linked infantile spinal muscular atrophy. It is essential to consider congenital myopathies, disorders of metabolism, and disorders of mitochondria.

Childhood: Botulism, hexosaminidase A deficiency, Guillain-Barré, Duchenne muscular dystrophy, Fazio-Londe syndrome, Hirayama disease

Adulthood: Amyotrophic lateral sclerosis, spinal, and bulbar muscular atrophy[2][4]

Prognosis

Historically prognosis has been dependent on SMA type with type 0 being the worst and individuals dying within the first months of life and type IV having a mild disease that does not affect the life expectancy.[3] However, with the recent introduction of disease-modifying agents such as onasemnogene abeparvovec, there have already been reported cases of SMA type I patients living longer than the historical cohort data would suggest, prognosis, therefore could potentially be much improved and is the source of ongoing study.[39]

Complications

Individuals with SMA suffer from respiratory, gastrointestinal, orthopedic complications that affect the quality of life and can potentially be life-threatening, for example, chest infections secondary to aspiration due to inadequate swallowing and muscle weakness.[15] Patients with SMA are prone to suffer from metabolic acidosis, especially during periods of illness or fasting, the underlying etiology of this predisposition is unknown, and there have been suggestions that dysfunctional glucose metabolism secondary to pancreatic abnormalities may play a role.[40]