Spinal muscular atrophy (SMA) denotes a collection of inherited clinical syndromes causing degeneration of anterior horn cells in the spinal cord with associated destruction of alpha motor cells and presents clinically with characteristic proximal muscle weakness and atrophy.[1] Homozygous deletion at 5q13 (the coding region for the survival motor neuron (SMN1) gene) is responsible for 95% of cases of SMA, and after cystic fibrosis is the second most common cause of autosomal recessive inherited related mortality with an estimated incidence of 1 in 6000 to 11000.[2][3]
Homozygous deletion at 5q13 is also referred to as classical proximal SMA and will be the focus of this article with differentials and other causes of SMA discussed below. SMA is heterogeneous in presentation and ranges from death within weeks of birth to mild proximal weakness developing during adulthood. Earlier presentations are typically associated with poorer function and prognosis: classification of SMA subtypes are determined by the age of onset as well as clinical severity and life expectancy.[4]
SMA was first described in the 1890s, first by Guido Werdnig in describing intermediate and severe SMA in 2 brothers and then 7 cases by Johan Hoffmann; type I SMA is sometimes eponymously referred to as Werdnig-Hoffmann disease. Similarly, milder forms of SMA (type III) detailed by Kugelberg and Welander is sometimes eponymously referred to as Kugelberg-Welander disease.[5]
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]
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]
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]
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:
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:
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
As with any disease that has a significant genetic component, genetic counseling to patients (if age appropriate) and family members is important for patients and families to make informed decisions. Due to SMA's autosomal recessive inheritance pattern, manner siblings have a 25% chance of being affected, 50% chance of being carriers, and 25% of being unaffected and not being carriers. Ninety-eight percent of parents of an individual with SMA are heterozygote carriers, with the remaining 2% being explained by the de novo pathogenic variant in the child. Preconception counseling should be offered to affected individuals and screening provided for the planned reproductive partner.[2]
Effective use and co-ordination of care via the utilization of an interprofessional team is required to optimize treatment, treatment planning, and share decision making. Members of an interprofessional team are likely to include but not restricted to: pediatricians, pediatric nurses, neurologists, geneticists, pediatric surgeons, orthotics, orthopedic surgeons, physiotherapists, nutritionists, palliative care specialists, and nurse practitioners.[27][39] [Level 5]
[1] | Kolb SJ,Kissel JT, Spinal muscular atrophy: a timely review. Archives of neurology. 2011 Aug; [PubMed PMID: 21482919] |
[2] | Prior TW,Leach ME,Finanger E, Spinal Muscular Atrophy 1993; [PubMed PMID: 20301526] |
[3] | D'Amico A,Mercuri E,Tiziano FD,Bertini E, Spinal muscular atrophy. Orphanet journal of rare diseases. 2011 Nov 2; [PubMed PMID: 22047105] |
[4] | Darras BT, Spinal muscular atrophies. Pediatric clinics of North America. 2015 Jun; [PubMed PMID: 26022173] |
[5] | Dubowitz V, Ramblings in the history of spinal muscular atrophy. Neuromuscular disorders : NMD. 2009 Jan; [PubMed PMID: 18951794] |
[6] | Lefebvre S,Bürglen L,Reboullet S,Clermont O,Burlet P,Viollet L,Benichou B,Cruaud C,Millasseau P,Zeviani M, Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995 Jan 13; [PubMed PMID: 7813012] |
[7] | Mailman MD,Heinz JW,Papp AC,Snyder PJ,Sedra MS,Wirth B,Burghes AH,Prior TW, Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genetics in medicine : official journal of the American College of Medical Genetics. 2002 Jan-Feb; [PubMed PMID: 11839954] |
[8] | Prior TW,Krainer AR,Hua Y,Swoboda KJ,Snyder PC,Bridgeman SJ,Burghes AH,Kissel JT, A positive modifier of spinal muscular atrophy in the SMN2 gene. American journal of human genetics. 2009 Sep; [PubMed PMID: 19716110] |
[9] | Ludolph AC,Wurster CD, Therapeutic advances in SMA. Current opinion in neurology. 2019 Oct; [PubMed PMID: 31425176] |
[10] | Crawford TO,Pardo CA, The neurobiology of childhood spinal muscular atrophy. Neurobiology of disease. 1996 Apr; [PubMed PMID: 9173917] |
[11] | Zaldívar T,Montejo Y,Acevedo AM,Guerra R,Vargas J,Garofalo N,Alvarez R,Alvarez MA,Hardiman O, Evidence of reduced frequency of spinal muscular atrophy type I in the Cuban population. Neurology. 2005 Aug 23; [PubMed PMID: 16116135] |
[12] | Prior TW, Spinal muscular atrophy: newborn and carrier screening. Obstetrics and gynecology clinics of North America. 2010 Mar; [PubMed PMID: 20494255] |
[13] | Kolb SJ,Battle DJ,Dreyfuss G, Molecular functions of the SMN complex. Journal of child neurology. 2007 Aug; [PubMed PMID: 17761654] |
[14] | Bowerman M,Becker CG,Yáñez-Muñoz RJ,Ning K,Wood MJA,Gillingwater TH,Talbot K, Therapeutic strategies for spinal muscular atrophy: SMN and beyond. Disease models [PubMed PMID: 28768735] |
[15] | Kolb SJ,Kissel JT, Spinal Muscular Atrophy. Neurologic clinics. 2015 Nov; [PubMed PMID: 26515624] |
[16] | Wijngaarde CA,Blank AC,Stam M,Wadman RI,van den Berg LH,van der Pol WL, Cardiac pathology in spinal muscular atrophy: a systematic review. Orphanet journal of rare diseases. 2017 Apr 11; [PubMed PMID: 28399889] |
[17] | Rudnik-Schöneborn S,Goebel HH,Schlote W,Molaian S,Omran H,Ketelsen U,Korinthenberg R,Wenzel D,Lauffer H,Kreiss-Nachtsheim M,Wirth B,Zerres K, Classical infantile spinal muscular atrophy with SMN deficiency causes sensory neuronopathy. Neurology. 2003 Mar 25; [PubMed PMID: 12654964] |
[18] | Zerres K,Rudnik-Schöneborn S, Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Archives of neurology. 1995 May; [PubMed PMID: 7733848] |
[19] | von Gontard A,Zerres K,Backes M,Laufersweiler-Plass C,Wendland C,Melchers P,Lehmkuhl G,Rudnik-Schöneborn S, Intelligence and cognitive function in children and adolescents with spinal muscular atrophy. Neuromuscular disorders : NMD. 2002 Feb; [PubMed PMID: 11738354] |
[20] | Dubowitz V, Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 1999; [PubMed PMID: 10700538] |
[21] | Arnold WD,Kassar D,Kissel JT, Spinal muscular atrophy: diagnosis and management in a new therapeutic era. Muscle [PubMed PMID: 25346245] |
[22] | Zerres K,Rudnik-Schöneborn S,Forrest E,Lusakowska A,Borkowska J,Hausmanowa-Petrusewicz I, A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients. Journal of the neurological sciences. 1997 Feb 27; [PubMed PMID: 9077498] |
[23] | Piepers S,van den Berg LH,Brugman F,Scheffer H,Ruiterkamp-Versteeg M,van Engelen BG,Faber CG,de Visser M,van der Pol WL,Wokke JH, A natural history study of late onset spinal muscular atrophy types 3b and 4. Journal of neurology. 2008 Sep; [PubMed PMID: 18575920] |
[24] | Taylor JL,Lee FK,Yazdanpanah GK,Staropoli JF,Liu M,Carulli JP,Sun C,Dobrowolski SF,Hannon WH,Vogt RF, Newborn blood spot screening test using multiplexed real-time PCR to simultaneously screen for spinal muscular atrophy and severe combined immunodeficiency. Clinical chemistry. 2015 Feb; [PubMed PMID: 25502182] |
[25] | Han JJ,McDonald CM, Diagnosis and clinical management of spinal muscular atrophy. Physical medicine and rehabilitation clinics of North America. 2008 Aug; [PubMed PMID: 18625423] |
[26] | Schroth MK, Special considerations in the respiratory management of spinal muscular atrophy. Pediatrics. 2009 May; [PubMed PMID: 19420154] |
[27] | Wang CH,Finkel RS,Bertini ES,Schroth M,Simonds A,Wong B,Aloysius A,Morrison L,Main M,Crawford TO,Trela A, Consensus statement for standard of care in spinal muscular atrophy. Journal of child neurology. 2007 Aug; [PubMed PMID: 17761659] |
[28] | Durkin ET,Schroth MK,Helin M,Shaaban AF, Early laparoscopic fundoplication and gastrostomy in infants with spinal muscular atrophy type I. Journal of pediatric surgery. 2008 Nov; [PubMed PMID: 18970936] |
[29] | Sproule DM,Montes J,Montgomery M,Battista V,Koenigsberger D,Shen W,Punyanitya M,De Vivo DC,Kaufmann P, Increased fat mass and high incidence of overweight despite low body mass index in patients with spinal muscular atrophy. Neuromuscular disorders : NMD. 2009 Jun; [PubMed PMID: 19427208] |
[30] | Davis RH,Godshall BJ,Seffrood E,Marcus M,LaSalle BA,Wong B,Schroth MK,Swoboda KJ, Nutritional practices at a glance: spinal muscular atrophy type I nutrition survey findings. Journal of child neurology. 2014 Nov; [PubMed PMID: 24097849] |
[31] | Haaker G,Fujak A, Proximal spinal muscular atrophy: current orthopedic perspective. The application of clinical genetics. 2013 Nov 14; [PubMed PMID: 24399883] |
[32] | Claborn MK,Stevens DL,Walker CK,Gildon BL, Nusinersen: A Treatment for Spinal Muscular Atrophy. The Annals of pharmacotherapy. 2019 Jan; [PubMed PMID: 30008228] |
[33] | Finkel RS,Mercuri E,Darras BT,Connolly AM,Kuntz NL,Kirschner J,Chiriboga CA,Saito K,Servais L,Tizzano E,Topaloglu H,Tulinius M,Montes J,Glanzman AM,Bishop K,Zhong ZJ,Gheuens S,Bennett CF,Schneider E,Farwell W,De Vivo DC, Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. The New England journal of medicine. 2017 Nov 2; [PubMed PMID: 29091570] |
[34] | Malone DC,Dean R,Arjunji R,Jensen I,Cyr P,Miller B,Maru B,Sproule DM,Feltner DE,Dabbous O, Cost-effectiveness analysis of using onasemnogene abeparvocec (AVXS-101) in spinal muscular atrophy type 1 patients. Journal of market access [PubMed PMID: 31105909] |
[35] | Mendell JR,Al-Zaidy S,Shell R,Arnold WD,Rodino-Klapac LR,Prior TW,Lowes L,Alfano L,Berry K,Church K,Kissel JT,Nagendran S,L'Italien J,Sproule DM,Wells C,Cardenas JA,Heitzer MD,Kaspar A,Corcoran S,Braun L,Likhite S,Miranda C,Meyer K,Foust KD,Burghes AHM,Kaspar BK, Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. The New England journal of medicine. 2017 Nov 2; [PubMed PMID: 29091557] |
[36] | Mahajan R, Onasemnogene Abeparvovec for Spinal Muscular Atrophy: The Costlier Drug Ever. International journal of applied [PubMed PMID: 31392173] |
[37] | Hoy SM, Onasemnogene Abeparvovec: First Global Approval. Drugs. 2019 Jul; [PubMed PMID: 31270752] |
[38] | Ratni H,Ebeling M,Baird J,Bendels S,Bylund J,Chen KS,Denk N,Feng Z,Green L,Guerard M,Jablonski P,Jacobsen B,Khwaja O,Kletzl H,Ko CP,Kustermann S,Marquet A,Metzger F,Mueller B,Naryshkin NA,Paushkin SV,Pinard E,Poirier A,Reutlinger M,Weetall M,Zeller A,Zhao X,Mueller L, Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 ( SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA). Journal of medicinal chemistry. 2018 Aug 9; [PubMed PMID: 30044619] |
[39] | Chen TH, New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand? International journal of molecular sciences. 2020 May 7; [PubMed PMID: 32392694] |
[40] | Bowerman M,Swoboda KJ,Michalski JP,Wang GS,Reeks C,Beauvais A,Murphy K,Woulfe J,Screaton RA,Scott FW,Kothary R, Glucose metabolism and pancreatic defects in spinal muscular atrophy. Annals of neurology. 2012 Aug; [PubMed PMID: 22926856] |