This article is about the genetic disorder associated with the SMN1 gene on chromosome 5q. For a list of conditions with similar names, seeSpinal muscular atrophies. For the series of video game ports, seeSuper Mario Advance.
Spinal muscular atrophy (SMA) is a rareneuromuscular disorder that results in the loss ofmotor neurons and progressivemuscle wasting.[3][4][5] It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic cause of infant death.[6] It may also appear later in life and then have a milder course of the disease. The common feature is the progressive weakness of voluntary muscles, with the arm, leg, andrespiratory muscles being affected first.[7][8] Associated problems may include poor head control, difficulties swallowing,scoliosis, andjoint contractures.[2][8]
The age of onset and the severity of symptoms form the basis of the traditional classification of spinal muscular atrophy into several types.[4]
Spinal muscular atrophy is due to an abnormality (mutation) in theSMN1 gene[1][2] which encodesSMN, aprotein necessary for the survival ofmotor neurons.[8] Loss of these neurons in the spinal cord prevents signalling between thebrain andskeletal muscles.[8] Another gene,SMN2, is considered a disease modifying gene, since usually the moreSMN2 copies are present, the milder is the course of the disease. The diagnosis of SMA is based on symptoms and confirmed bygenetic testing.[9][1]
Usually, the mutation in theSMN1 gene isinherited from both parents in anautosomal recessive manner, although in around 2% of cases it occurs duringearly development (de novo).[1][10] The incidence of spinal muscular atrophy worldwide varies from about 1 in 4,000 births to around 1 in 16,000 births,[11] with 1 in 7,000 and 1 in 10,000 commonly quoted for Europe and the US respectively.[2]
5q SMA is a single disease that manifests over a wide range of severity, affecting infants through adults. Before its genetics was understood, its varying manifestations were thought to be different diseases –Werdnig–Hoffmann disease when young children were affected andKugelberg–Welander disease for late-onset cases.[13]
In 1990, it was realised that these separate diseases formed a spectrum of the same disorder. Spinal muscular atrophy was then classified into 3–5 clinical types based either on the age of symptom onset or on the maximum motor function achieved.[10][13] Currently, the consensus is that the phenotype of spinal muscular atrophy spans a continuum of symptoms without clear delineation of subtypes.[10] However, the traditional classification, outlined in the table below, is still used today both in clinical research and sometimes, controversially, as a criterion of access to therapies.
Symptoms are observed at birth and often become apparent in the prenatal period as reduced foetal movement. Affected children typically have only a single copy of theSMN2 gene and usually survive only a few weeks, even with 24/7 respiratory support. This form is very rare – accounts for approx. 2% of cases.
SMA 1 (Infantile)
Werdnig–Hoffmann disease
0–6 months
This form is diagnosed in around 50% of patients, in whom the disease manifests in the first few weeks or months of life. SMA then has a quick and unexpected onset, with various muscle groups failing progressively. Infants never learn to sit unsupported, and most gradually lose most of their muscle function. Death is usually caused by the failure of therespiratory muscles induced bypneumonia (frequently,aspiration pneumonia). Unless offered respiratory support and/or pharmacological treatment early, babies diagnosed with SMA type 1 do not generally survive past two years of age. With proper respiratory support, those with milder SMA type 1 phenotypes, which account for around 10% of SMA 1 cases, are known to survive into adolescence and adulthood even without pharmacological treatment, although they always require round-the-clock care.
The intermediate form, diagnosed in around 20% of patients, denotes people who were able to maintain a sitting position at least some time in their life but never learned to walk unsupported. The onset of weakness is usually noticed some time between 6 and 18 months of life. The progress is known to vary greatly; some people gradually grow weaker over time, while others, through careful maintenance, remain relatively stable. Body muscles are weakened, and the respiratory system is a major concern, as are muscle contractures and spinal curvature. Life expectancy is reduced, even as most people with SMA 2 live well into adulthood, even without treatment.
The juvenile form, diagnosed in around 30% of patients, manifests after 12 months of age, or after the children have already learned to make at least a few independent steps. The disease progresses slowly, and most people with SMA 3 lose walking ability sometime in their lives, requiring mobility support. Respiratory involvement is rare, and life expectancy is normal or near-normal.
This denotes the adult-onset form, sometimes also classified as a late-onset SMA type 3. It occurs in approximately 5% of patients and usually manifests in the third or fourth decade of life. The symptoms consist of gradual weakening of leg muscles, which frequently makes it necessary for the patient to use walking aids. Other complications are rare, and life expectancy is unaffected.
For convenience, care-focused publications classify patients into "non-sitters", "sitters" and "walkers" based on their actual functional status.
Motor development and disease progression in people with SMA is usually assessed using validated functional scales – CHOP-INTEND (The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) or HINE (Hammersmith Infant Neurological Examination) in infants; and either the MFM (Motor Function Measure) or one of several variants of the HFMS (Hammersmith Functional Motor Scale)[14][15][16][17] in older patients.
The eponymous labelWerdnig–Hoffmann disease (sometimes misspelled with a singlen) refers to the earliest clinical descriptions of childhood SMA byJohann Hoffmann andGuido Werdnig.[13] (Werdnig-Hoffmann disease should not be confused withHoffmann syndrome, which is a type of adult-onsethypothyroid myopathy.)[18] The eponymous termKugelberg–Welander disease named afterErik Klas Hendrik Kugelberg (1913–1983) andLisa Welander (1909–2001), who first documented the late-onset form and distinguished it from muscular dystrophy.[13] Very rarely usedDubowitz disease (not to be confused withDubowitz syndrome) is named afterVictor Dubowitz, an English neurologist who authored several studies on the intermediate SMA phenotype.[citation needed]
X-ray showing bell-shaped torso due to atrophy of intercostal muscles and using abdominal muscles to breathe. Bell-shaped torso is not specific to individuals with SMA.
The symptoms vary depending on the SMA type, the stage of the disease, as well as individual factors. Signs and symptoms below are most common in the severe SMA type 0/I:[19][medical citation needed]
Humanchromosome 5 contains two nearly identical genes atlocation 5q13: atelomeric copySMN1 and acentromeric copySMN2. In healthy individuals, theSMN1gene codes for thesurvival of motor neuron protein (SMN) which, as its name suggests, plays a crucial role in the survival ofmotor neurons. TheSMN2 gene, on the other hand – due to a variation in a singlenucleotide (840.C→T) – undergoesalternative splicing at the junction ofintron 6 toexon 8, with only 10–20% ofSMN2 transcripts coding a fully functionalsurvival of motor neuron protein (SMN-fl) and 80–90% of transcripts resulting in a truncated protein compound (SMNΔ7) which is rapidly degraded in the cell.[21]
In individuals affected by SMA, theSMN1 gene ismutated in such a way that it is unable to correctly code the SMN protein – due to either adeletion[22] occurring at exon 7[23] or to otherpoint mutations (frequently resulting in the functional conversion of theSMN1 sequence intoSMN2). Almost all people, however, have at least one functional copy of theSMN2 gene (with most having 2–4 of them), which still codes 10–20% of the usual level of the SMN protein, allowing some neurons to survive. In the long run, however, the reduced availability of the SMN protein results in the gradual death of motor neuron cells in theanterior horn of spinal cord and the brain.Skeletal muscles, which all depend on these motor neurons for neural input, now have decreased innervation (also calleddenervation), and therefore have decreased input from the central nervous system (CNS). Decreased impulse transmission through the motor neurons leads to decreased contractile activity of the denervated muscle. Consequently, denervated muscles undergo progressiveatrophy (waste away).[citation needed]
Muscles of lowerextremities are usually affected first, followed by muscles of the upper extremities, spine, and neck, and, in more severe cases, pulmonary and mastication muscles.Proximal muscles are usually affected earlier and to a greater degree thandistal muscles.[24]
The severity of SMA symptoms is broadly related to how well the remainingSMN2 genes can make up for the loss of function ofSMN1. This partly depends on the number of copies of theSMN2 gene present on the chromosome. Whilst healthy individuals usually carry twoSMN2 gene copies, people with SMA can have anything between 1 and 5 (or more) of them; the greater the number ofSMN2 copies, the milder the disease severity. Thus, most SMA type I babies have one or twoSMN2 copies; people with SMA II and III usually have at least threeSMN2 copies; and people with SMA IV normally have at least four of them. However, the correlation between symptom severity andSMN2 copy number is not absolute and there seem to exist other factors affecting the disease phenotype.[25]
Spinal muscular atrophy is inherited in anautosomal recessive pattern, which means that the defective gene is located on anautosome. Two copies of the defective gene – one from each parent – are required to inherit the disorder: the parents may be carriers and not personally affected. SMA seems to appearde novo (i.e., without any hereditary causes) in around 2–4% of cases.[citation needed]
Spinal muscular atrophy affects individuals of all ethnic groups, unlike other well-known autosomal recessive disorders, such assickle cell disease andcystic fibrosis, which have significant differences in occurrence rate among ethnic groups. The overallprevalence of SMA, of all types and across all ethnic groups, is in the range of 1 per 10,000 individuals; the gene frequency is around 1:100; therefore, approximately one in 50 persons are carriers.[26][27] There are no known health consequences of being a carrier. A person may learn carrier status only if one's child is affected by SMA or by having theSMN1 gene sequenced.[citation needed]
Affected siblings usually have a very similar form of SMA. However, occurrences of different SMA types among siblings do exist – while rare, these cases might be due to additionalde novo deletions of theSMN gene, not involving theNAIP gene, or the differences inSMN2 copy numbers.[citation needed]
SMA is diagnosed usinggenetic testing that detects homozygous deletion of theSMN1 gene in over 95% of cases,[19] and a compoundSMN1 mutation in the remaining patients. Genetic testing is usually carried out using a blood sample, andMLPA is one of the more frequently used genetic testing techniques, as it also allows establishing the number ofSMN2 gene copies, which has clinical importance.[19]
Symptomatically, SMA can be diagnosed with a degree of certainty only in children with the acute form who manifest a progressive illness withparadoxical breathing, bilaterallow muscle tone, and absent tendon reflexes.[citation needed]
Early diagnosis of SMA, at the asymptomatic stage of the disease, allows for the introduction of causative therapies early enough to prevent the manifestation of symptoms.[citation needed]
Routine newborn screening for SMA is becoming increasingly commonplace in developed countries, given the availability of causative treatments that are most effective at the asymptomatic stage of the disease.[29][30][31] In 2018, newborn screening for SMA was added to the US list of recommended newborn screening tests[32][33][34] and as of April 2020, it has been adopted in 39 US states.[35][36] As of February 2023, SMA screening has been incorporated in national newborn screening programmes in around 15 countries and pilot projects are under way in further countries.[37]
Those at risk of beingcarriers ofSMN1 deletion, and thus at risk of having offspring affected by SMA, can undergo carrier analysis using a blood or saliva sample. TheAmerican College of Obstetricians and Gynecologists recommends that all people thinking of becoming pregnant be tested to see if they are a carrier.[38] The carrier frequency of SMA is comparable to other disorders like thalassemia and in a north Indian cohort is 1 in 38.[39] However, genetic testing will not be able to identify all individuals at risk since about 2% of cases are caused byde novo mutations and 5% of the normal population have two copies of SMN1 on the same chromosome, which makes it possible to be a carrier by having one chromosome with two copies and a second chromosome with zero copies. This situation will lead to afalse negative result, as the carrier status will not be correctly detected by a traditional genetic test.[40][41]
The management of SMA varies based on the severity and type. In the most severe forms (types 0/1), individuals have the greatest muscle weakness, requiring prompt intervention. Whereas in the least severe form (type 4/adult onset), individuals may not seek certain aspects of care until later (decades) in life. While types of SMA and individuals among each type may differ, specific aspects of an individual's care can differ.[medical citation needed]
Onasemnogene abeparvovec (marketed as Zolgensma) is agene therapy treatment which uses self-complementary adeno-associated virus type 9 (scAAV-9) as a vector to deliver theSMN1 transgene.[49][50] The therapy was first approved in the US in May 2019 as anintravenous formulation for children below 24 months of age.[51][52] Approval in the European Union, Japan and other countries followed, albeit often with different approval scopes.[53][54]
Risdiplam (marketed as Evrysdi) is a medication takenby mouth in liquid form.[55][56] It is apyridazine derivative that works by increasing the amount of functionalsurvivor motor neuron protein produced by theSMN2 gene throughmodifying its splicing pattern.[57][58] Risdiplam aims to increase the amount of SMN protein so that there is enough protein to sustain the peripheral nervous system tissues which are usually the most damaged by SMA.[59] Risdiplam was first approved for medical use in the United States in August 2020[55] and has since been approved in over 30 countries.[citation needed]
The respiratory system is the most common system to be affected, and the complications are the leading cause of death in SMA types 0/1 and 2. SMA type 3 can have similar respiratory problems, but it is rarer.[24] Complications arise due to weakened intercostal muscles because of the lack of stimulation from the nerve. The diaphragm is less affected than the intercostal muscles.[24] Once weakened, the muscles never fully recover the same functional capacity to help in breathing and coughing, as well as other functions. Therefore, breathing is more difficult and poses a risk of not getting enough oxygen/shallow breathing, and insufficient clearance of airway secretions. These issues more commonly occur while asleep, when muscles are more relaxed. Swallowing muscles in the pharynx can be affected, leading to aspiration coupled with a poor coughing mechanism increases the likelihood of infection/pneumonia.[60] Mobilizing and clearing secretions involve manual or mechanical chest physiotherapy with postural drainage, and manual or mechanical cough assistance device. To assist in breathing,Non-invasive ventilation (BiPAP) is frequently used andtracheostomy may be sometimes performed in more severe cases;[61] both methods of ventilation prolong survival to a comparable degree, although tracheostomy prevents speech development.[62]
The more severe the type of SMA, the more likely to have nutrition-related health issues. Health issues can include difficulty in feeding, jaw opening, chewing, and swallowing. Individuals with such difficulties can be at increased risk of over- or undernutrition, failure to thrive, and aspiration. Other nutritional issues, especially in individuals who are non-ambulatory (more severe types of SMA), include food not passing through the stomach quickly enough, gastric reflux, constipation, vomiting, and bloating.[63][medical citation needed] Therein, it could be necessary in SMA type I and people with more severe type II to have afeeding tube orgastrostomy.[63][64][65] Additionally, metabolic abnormalities resulting from SMA impairβ-oxidation offatty acids in muscles and can lead toorganic acidemia and consequent muscle damage, especially when fasting.[66][67] It is suggested that people with SMA, especially those with more severe forms of the disease, reduce intake offat and avoid prolonged fasting (i.e., eat more frequently than healthy people)[68] as well as choosing softer foods to avoid aspiration.[60] During an acute illness, especially in children, nutritional problems may first present or can exacerbate an existing problem (example: aspiration) as well as cause other health issues such as electrolyte and blood sugar disturbances.[69][medical citation needed]
Skeletal problems associated with weak muscles in SMA include tight joints with limited range of movement, hip dislocations, spinal deformity, osteopenia, an increased risk of fractures, and pain.[24] Weak muscles that normally stabilize joints, such as the vertebral column, lead to the development ofkyphosis and/orscoliosis and joint contracture.[24]Spine fusion is sometimes performed in people with SMA I/II once they reach the age of 8–10 to relieve the pressure of a deformed spine on the lungs. Furthermore, immobile individuals, posture and position on mobility devices as well as range of motion exercises, and bone strengthening can be important to prevent complications.[69] People with SMA might also benefit greatly from various forms ofphysiotherapy andoccupational therapy.[citation needed]
Orthotic devices can be used to support the body and to aid walking. For example, orthotics such as AFOs (ankle foot orthoses) are used to stabilise the foot and to aid gait, TLSOs (thoracic lumbar sacral orthoses) are used to stabilise the torso.Assistive technologies may help in managing movement and daily activities and greatly increase the quality of life.[citation needed]
Although theheart is not a matter of routine concern, a link between SMA and certain heart conditions has been suggested.[70][71][72][73]
Children with SMA do not differ from the general population in their behaviour; theircognitive development can be slightly faster, and certain aspects of theirintelligence are above the average.[74][75][76] Despite their disability, SMA-affected people report high degree of satisfaction from life.[77]
Palliative care in SMA has been standardised in theConsensus Statement for Standard of Care in Spinal Muscular Atrophy[24] which has been recommended for standard adoption worldwide.[citation needed]
In the absence of pharmacological treatment, people with SMA tend to deteriorate over time. Recently, survival has increased in severe SMA patients with aggressive and proactive supportive respiratory and nutritional support.[78]
If left untreated, the majority of children diagnosed with SMA types 0 and 1 do not reach the age of 4, recurrent respiratory problems being the primary cause of death.[79] With proper care, milder SMA type I cases (which account for approx. 10% of all SMA1 cases) live into adulthood.[80] Long-term survival in SMA type I is not sufficiently evidenced; however, as of 2007 advances in respiratory support seem to have brought down mortality.[81]
In untreated SMA type II, the course of the disease is slower to progress, andlife expectancy is less than the healthy population. Death before the age of 20 is frequent, although many people with SMA live to become parents and grandparents. SMA type III has normal or near-normal life expectancy if standards of care are followed. Type IV, adult-onset SMA usually means only mobility impairment and does not affect life expectancy.[citation needed]
Since the underlying genetic cause of SMA was identified in 1995,[22] several therapeutic approaches have been proposed and investigated that primarily focus on increasing the availability of SMN protein in motor neurons.[82] The main research directions have been as follows:
This approach aims at modifying thealternative splicing of theSMN2 gene to force it to code for a higher percentage of full-length SMN protein. Sometimes it is also called gene conversion, because it attempts to convert theSMN2 gene functionally into theSMN1 gene. It is the therapeutic mechanism of the approved medicationsnusinersen andrisdiplam.[citation needed]
Branaplam is anotherSMN2 splicing modulator that has reached the clinical stage of development.[84]
Historically, this research direction has also investigated other molecules. RG3039, also known as Quinazoline495, was a proprietaryquinazoline derivative developed byRepligen and licensed toPfizer in March 2014, which was discontinued shortly after, having only completed phase I trials. PTK-SMA1 was a proprietary small-molecule splicing modulator of thetetracyclines group developed by Paratek Pharmaceuticals and about to enter clinical development in 2013 which, however, never happened due to Paratek downsizing at that time. RG7800, developed by Hoffmann-La Roche, was a molecule akin to risdiplam that has undergone phase I testing but was discontinued due to animal toxicity.[85] Early leads also includedsodium orthovanadate[86] andaclarubicin.[87]
A promising new avenue involves one-time gene editing to achieve permanent splicing modulation. This preclinical approach, demonstrated in non-human primate models and further detailed in mouse studies, utilizes a CRISPR/Cas9 system delivered by an AAV9 vector (the same viral vector type used foronasemnogene abeparvovec, Zolgensma). Instead of replacing theSMN1 gene, this strategy makes a permanent change to theSMN2 gene itself by disrupting intronic splicing silencers like ISS-N1 and ISS+100. A single intravenous treatment in primate models has shown durable and high-level correction ofSMN2 splicing in the spinal cord, restoring SMN protein to near-normal levels and rescuing motor functions. This gene editing approach, if proven safe and effective in humans, could combine the mechanism of splicing modulation with the permanence of a one-time gene therapy, potentially offering a lasting cure for SMA.[91]
This approach aims at increasing the expression (activity) of theSMN2 gene, thus increasing the amount of full-length SMN protein available.
Oralsalbutamol (albuterol), a popularasthma medicine, showed therapeutic potential in SMA bothin vitro[92] and in three small-scale clinical trials involving patients with SMA types 2 and 3,[93][94][95] besides offering respiratory benefits.
A few compounds initially showed promise but failed to demonstrate efficacy in clinical trials.Butyrates (sodium butyrate andsodium phenylbutyrate) held some promise inin vitro studies[96][97][98] but a clinical trial in symptomatic people did not confirm their efficacy.[99] Another clinical trial in pre-symptomatic types 1–2 infants was completed in 2015 but no results have been published.[100]
Valproic acid (VPA) was used in SMA on an experimental basis in the 1990s and 2000s becausein vitro research suggested its moderate effectiveness.[101][102] However, it demonstrated no efficacy in achievable concentrations when subjected to a large clinical trial.[103][104][105] It has also been proposed that it may be effective in a subset of people with SMA but its action may be suppressed byfatty acid translocase in others.[106] Others argue it may actually aggravate SMA symptoms.[107] It is currently not used due to the risk of severe side effects related to long-term use. A 2019 meta-analysis suggested that VPA may offer benefits, even without improving functional score.[108]
Hydroxycarbamide (hydroxyurea) was shown effective in mouse models[109] and subsequently commercially researched byNovo Nordisk, Denmark, but demonstrated no effect on people with SMA in subsequent clinical trials.[110]
SMN stabilisation aims at stabilising the SMNΔ7 protein, the short-lived defective protein coded by theSMN2 gene, so that it is able to sustain neuronal cells.[121]
No compounds have been taken forward to the clinical stage.Aminoglycosides showed the capability to increase SMN protein availability in two studies.[122][123]Indoprofen offered some promisein vitro.[124]
Neuroprotective drugs aim at enabling the survival of motor neurons even with low levels of SMN protein.
Olesoxime was a proprietary neuroprotective compound developed by the French companyTrophos, later acquired byHoffmann-La Roche, which showed stabilising effect in a phase-II clinical trial involving people with SMA types 2 and 3. Its development was discontinued in 2018 in view of competition from nusinersen and underwhelming data from an open-label extension trial.[125]
This approach aims to counter the effect of SMA by targeting the muscle tissue instead of neurons.
Reldesemtiv (CK-2127107, CK-107) is a skeletaltroponin activator developed by Cytokinetics in cooperation withAstellas. The drug aims at increasing muscle reactivity despite lowered neural signalling. The molecule showed some success in phase II clinical trial in adolescent and adults with SMA types 2, 3, and 4.[137]
Apitegromab (SRK-015) ismonoclonal antibody that blocks the activation of the skeletal muscle proteinmyostatin, thereby promoting muscle tissue growth. As of 2021, the molecule showed success as an experimental add-on treatment in paediatric and adult patients treated with nusinersen.[138]
GYM329 (RO7204239), developed by Hoffman-La Roche, works similarly to apitegromab by blocking myostatin activation. As of 2022, it is undergoing clinical development in non-ambulant children with SMA aged 2–10, combined with risdiplam.[139]
Whilst stem cells never form a part of any recognised therapy for SMA, a number of private companies, usually located in countries with lax regulatory oversight, take advantage ofmedia hype and market stem cell injections as a "cure" for a vast range of disorders, including SMA. The medical consensus is that such procedures offer no clinical benefit whilst carrying significant risk, therefore people with SMA are advised against them.[140][141] In 2013–2014, a small number of SMA1 children in Italy received court-mandated stem cell injections following theStamina scam, but the treatment was reported having no effect[142][143]
^abcPrior, Thomas W.; Leach, Meganne E.; Finanger, Erika (1993), Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.),"Spinal Muscular Atrophy",GeneReviews®, Seattle (WA): University of Washington, Seattle,PMID20301526, retrieved25 October 2020
^Main M, Kairon H, Mercuri E, Muntoni F (2003). "The Hammersmith functional motor scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation".European Journal of Paediatric Neurology.7 (4):155–9.doi:10.1016/S1090-3798(03)00060-6.PMID12865054.
^O'Hagen JM, Glanzman AM, McDermott MP, Ryan PA, Flickinger J, Quigley J, Riley S, Sanborn E, Irvine C, Martens WB, Annis C, Tawil R, Oskoui M, Darras BT, Finkel RS, De Vivo DC (October 2007). "An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients".Neuromuscular Disorders.17 (9–10):693–7.doi:10.1016/j.nmd.2007.05.009.PMID17658255.S2CID10365924.
^Glanzman AM, O'Hagen JM, McDermott MP, Martens WB, Flickinger J, Riley S, Quigley J, Montes J, Dunaway S, Deng L, Chung WK, Tawil R, Darras BT, De Vivo DC, Kaufmann P, Finkel RS, et al. (Pediatric Neuromuscular Clinical Research Network for Spinal Muscular Atrophy (PNCR)) (December 2011). "Validation of the Expanded Hammersmith Functional Motor Scale in spinal muscular atrophy type II and III".Journal of Child Neurology.26 (12):1499–507.doi:10.1177/0883073811420294.PMID21940700.S2CID206549483.
^abcdefWang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main M, Crawford TO, Trela A (August 2007). "Consensus statement for standard of care in spinal muscular atrophy".Journal of Child Neurology.22 (8):1027–49.doi:10.1177/0883073807305788.PMID17761659.S2CID6478040.
^Ar Rochmah M, Awano H, Awaya T, Harahap NI, Morisada N, Bouike Y, Saito T, Kubo Y, Saito K, Lai PS, Morioka I, Iijima K, Nishio H, Shinohara M (November 2017). "Spinal muscular atrophy carriers with two SMN1 copies".Brain & Development.39 (10):851–860.doi:10.1016/j.braindev.2017.06.002.PMID28676237.S2CID26504674.
^Bach JR, Niranjan V, Weaver B (April 2000). "Spinal muscular atrophy type 1: A noninvasive respiratory management approach".Chest.117 (4):1100–5.doi:10.1378/chest.117.4.1100.PMID10767247.
^Bach JR, Saltstein K, Sinquee D, Weaver B, Komaroff E (May 2007). "Long-term survival in Werdnig-Hoffmann disease".American Journal of Physical Medicine & Rehabilitation.86 (5): 339–45 quiz 346–8, 379.doi:10.1097/PHM.0b013e31804a8505.PMID17449977.S2CID9942245.
^abMessina S, Pane M, De Rose P, Vasta I, Sorleti D, Aloysius A, Sciarra F, Mangiola F, Kinali M, Bertini E, Mercuri E (May 2008). "Feeding problems and malnutrition in spinal muscular atrophy type II".Neuromuscular Disorders.18 (5):389–93.doi:10.1016/j.nmd.2008.02.008.PMID18420410.S2CID23302291.
^Chen YS, Shih HH, Chen TH, Kuo CH, Jong YJ (March 2012). "Prevalence and risk factors for feeding and swallowing difficulties in spinal muscular atrophy types II and III".The Journal of Pediatrics.160 (3): 447–451.e1.doi:10.1016/j.jpeds.2011.08.016.PMID21924737.
^Tilton AH, Miller MD, Khoshoo V (June 1998). "Nutrition and swallowing in pediatric neuromuscular patients".Seminars in Pediatric Neurology.5 (2):106–15.doi:10.1016/S1071-9091(98)80026-0.PMID9661244.
^Tein I, Sloane AE, Donner EJ, Lehotay DC, Millington DS, Kelley RI (January 1995). "Fatty acid oxidation abnormalities in childhood-onset spinal muscular atrophy: primary or secondary defect(s)?".Pediatric Neurology.12 (1):21–30.doi:10.1016/0887-8994(94)00100-G.PMID7748356.
^von Gontard A, Zerres K, Backes M, Laufersweiler-Plass C, Wendland C, Melchers P, Lehmkuhl G, Rudnik-Schöneborn S (February 2002). "Intelligence and cognitive function in children and adolescents with spinal muscular atrophy".Neuromuscular Disorders.12 (2):130–6.doi:10.1016/S0960-8966(01)00274-7.PMID11738354.S2CID46694209.
^Billard C, Gillet P, Signoret JL, Uicaut E, Bertrand P, Fardeau M, Barthez-Carpentier MA, Santini JJ (1992). "Cognitive functions in Duchenne muscular dystrophy: a reappraisal and comparison with spinal muscular atrophy".Neuromuscular Disorders.2 (5–6):371–8.doi:10.1016/S0960-8966(06)80008-8.PMID1300185.S2CID22211725.
^Laufersweiler-Plass C, Rudnik-Schöneborn S, Zerres K, Backes M, Lehmkuhl G, von Gontard A (January 2003). "Behavioural problems in children and adolescents with spinal muscular atrophy and their siblings".Developmental Medicine and Child Neurology.45 (1):44–9.doi:10.1017/S0012162203000082 (inactive 26 September 2025).PMID12549754.{{cite journal}}: CS1 maint: DOI inactive as of September 2025 (link)
^de Oliveira CM, Araújo AP (January 2011). "Self-reported quality of life has no correlation with functional status in children and adolescents with spinal muscular atrophy".European Journal of Paediatric Neurology.15 (1):36–9.doi:10.1016/j.ejpn.2010.07.003.PMID20800519.
^Darras B, Finkel R (2017).Spinal Muscular Atrophy. United Kingdom, United States: Elsevier. p. 417.ISBN978-0-12-803685-3.
^Yuan N, Wang CH, Trela A, Albanese CT (June 2007). "Laparoscopic Nissen fundoplication during gastrostomy tube placement and noninvasive ventilation may improve survival in type I and severe type II spinal muscular atrophy".Journal of Child Neurology.22 (6):727–31.doi:10.1177/0883073807304009.PMID17641258.S2CID38799022.
^Kletzl, Heidemarie; Marquet, Anne; Günther, Andreas; Tang, Wakana; Heuberger, Jules; Groeneveld, Geert Jan; Birkhoff, Willem; Mercuri, Eugenio; Lochmüller, Hanns; Wood, Claire; Fischer, Dirk; Gerlach, Irene; Heinig, Katja; Bugawan, Teodorica; Dziadek, Sebastian; Kinch, Russell; Czech, Christian; Khwaja, Omar (2019). "The oral splicing modifier RG7800 increases full length survival of motor neuron 2 mRNA and survival of motor neuron protein: Results from trials in healthy adults and patients with spinal muscular atrophy".Neuromuscular Disorders.29 (1). Elsevier BV:21–29.doi:10.1016/j.nmd.2018.10.001.ISSN0960-8966.PMID30553700.S2CID54315649.
^Zhang ML, Lorson CL, Androphy EJ, Zhou J (October 2001). "An in vivo reporter system for measuring increased inclusion of exon 7 in SMN2 mRNA: potential therapy of SMA".Gene Therapy.8 (20):1532–8.doi:10.1038/sj.gt.3301550.PMID11704813.S2CID29685631.
^Angelozzi C, Borgo F, Tiziano FD, Martella A, Neri G, Brahe C (January 2008). "Salbutamol increases SMN mRNA and protein levels in spinal muscular atrophy cells".Journal of Medical Genetics.45 (1):29–31.doi:10.1136/jmg.2007.051177.PMID17932121.S2CID29911453.
^Pane M, Staccioli S, Messina S, D'Amico A, Pelliccioni M, Mazzone ES, Cuttini M, Alfieri P, Battini R, Main M, Muntoni F, Bertini E, Villanova M, Mercuri E (July 2008). "Daily salbutamol in young patients with SMA type II".Neuromuscular Disorders.18 (7):536–40.doi:10.1016/j.nmd.2008.05.004.PMID18579379.S2CID34334434.
^Morandi L, Abiusi E, Pasanisi MB, Lomastro R, Fiori S, Di Pietro L, Angelini C, Sorarù G, Gaiani A, Mongini T, Vercelli L (2013). "P.6.4 Salbutamol tolerability and efficacy in adult type III SMA patients: Results of a multicentric, molecular and clinical, double-blind, placebo-controlled study".Neuromuscular Disorders.23 (9–10): 771.doi:10.1016/j.nmd.2013.06.475.S2CID54398218.
^Mercuri E, Bertini E, Messina S, Solari A, D'Amico A, Angelozzi C, Battini R, Berardinelli A, Boffi P, Bruno C, Cini C, Colitto F, Kinali M, Minetti C, Mongini T, Morandi L, Neri G, Orcesi S, Pane M, Pelliccioni M, Pini A, Tiziano FD, Villanova M, Vita G, Brahe C (January 2007). "Randomized, double-blind, placebo-controlled trial of phenylbutyrate in spinal muscular atrophy".Neurology.68 (1):51–5.doi:10.1212/01.wnl.0000249142.82285.d6.PMID17082463.S2CID30429093.
^Clinical trial numberNCT00528268 for "Study to Evaluate Sodium Phenylbutyrate in Pre-symptomatic Infants With Spinal Muscular Atrophy (STOPSMA)" atClinicalTrials.gov
^Tsai LK, Tsai MS, Ting CH, Li H (November 2008). "Multiple therapeutic effects of valproic acid in spinal muscular atrophy model mice".Journal of Molecular Medicine.86 (11):1243–54.doi:10.1007/s00109-008-0388-1.PMID18649067.S2CID24565272.
^Rak K, Lechner BD, Schneider C, Drexl H, Sendtner M, Jablonka S (December 2009). "Valproic acid blocks excitability in SMA type I mouse motor neurons".Neurobiology of Disease.36 (3):477–87.doi:10.1016/j.nbd.2009.08.014.PMID19733665.S2CID34657615.
^Elshafay A, Hieu TH, Doheim MF, Kassem MA, ELdoadoa MF, Holloway SK, Abo-Elghar H, Hirayama K, Huy NT (March 2019). "Efficacy and Safety of Valproic Acid for Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis".CNS Drugs.33 (3):239–250.doi:10.1007/s40263-019-00606-6.PMID30796634.S2CID73495750.
^Grzeschik SM, Ganta M, Prior TW, Heavlin WD, Wang CH (August 2005). "Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells".Annals of Neurology.58 (2):194–202.doi:10.1002/ana.20548.PMID16049920.S2CID19509393.
^Chen TH, Chang JG, Yang YH, Mai HH, Liang WC, Wu YC, Wang HY, Huang YB, Wu SM, Chen YC, Yang SN, Jong YJ (December 2010). "Randomized, double-blind, placebo-controlled trial of hydroxyurea in spinal muscular atrophy".Neurology.75 (24):2190–7.doi:10.1212/WNL.0b013e3182020332.PMID21172842.S2CID25858890.
^Riessland M, Brichta L, Hahnen E, Wirth B (August 2006). "The benzamide M344, a novel histone deacetylase inhibitor, significantly increases SMN2 RNA/protein levels in spinal muscular atrophy cells".Human Genetics.120 (1):101–10.doi:10.1007/s00439-006-0186-1.PMID16724231.S2CID24804136.
^Garbes L, Riessland M, Hölker I, Heller R, Hauke J, Tränkle C, Coras R, Blümcke I, Hahnen E, Wirth B (October 2009). "LBH589 induces up to 10-fold SMN protein levels by several independent mechanisms and is effective even in cells from SMA patients non-responsive to valproate".Human Molecular Genetics.18 (19):3645–58.doi:10.1093/hmg/ddp313.PMID19584083.
^Dayangaç-Erden D, Bora G, Ayhan P, Kocaefe C, Dalkara S, Yelekçi K, Demir AS, Erdem-Yurter H (March 2009). "Histone deacetylase inhibition activity and molecular docking of (e )-resveratrol: its therapeutic potential in spinal muscular atrophy".Chemical Biology & Drug Design.73 (3):355–64.CiteSeerX10.1.1.515.8424.doi:10.1111/j.1747-0285.2009.00781.x.PMID19207472.S2CID764215.
^Takeuchi Y, Miyanomae Y, Komatsu H, Oomizono Y, Nishimura A, Okano S, Nishiki T, Sawada T (July 1994). "Efficacy of thyrotropin-releasing hormone in the treatment of spinal muscular atrophy".Journal of Child Neurology.9 (3):287–9.doi:10.1177/088307389400900313.PMID7930408.S2CID41678161.
^Tzeng AC, Cheng J, Fryczynski H, Niranjan V, Stitik T, Sial A, Takeuchi Y, Foye P, DePrince M, Bach JR (2000). "A study of thyrotropin-releasing hormone for the treatment of spinal muscular atrophy: a preliminary report".American Journal of Physical Medicine & Rehabilitation.79 (5):435–40.doi:10.1097/00002060-200009000-00005.PMID10994885.S2CID20416253.
^Kato Z, Okuda M, Okumura Y, Arai T, Teramoto T, Nishimura M, Kaneko H, Kondo N (August 2009). "Oral administration of the thyrotropin-releasing hormone (TRH) analogue, taltireline hydrate, in spinal muscular atrophy".Journal of Child Neurology.24 (8):1010–2.doi:10.1177/0883073809333535.PMID19666885.S2CID29321906.
^Wadman RI, Bosboom WM, van den Berg LH, Wokke LH, Iannaccone ST, Vrancken AF, et al. (The Cochrane Collaboration) (7 December 2011). Wadman RI (ed.). "Drug treatment for spinal muscular atrophy type I".Cochrane Database of Systematic Reviews (12) CD006281. John Wiley & Sons, Ltd.doi:10.1002/14651858.cd006281.pub3.PMID22161399.
^Haddad H, Cifuentes-Diaz C, Miroglio A, Roblot N, Joshi V, Melki J (October 2003). "Riluzole attenuates spinal muscular atrophy disease progression in a mouse model".Muscle & Nerve.28 (4):432–7.doi:10.1002/mus.10455.PMID14506714.S2CID10300057.
^Clinical trial numberNCT00774423 for "Study to Evaluate the Efficacy of Riluzole in Children and Young Adults With Spinal Muscular Atrophy (SMA)" atClinicalTrials.gov
^Carrozzi M, Amaddeo A, Biondi A, Zanus C, Monti F, Alessandro V (November 2012). "Stem cells in severe infantile spinal muscular atrophy (SMA1)".Neuromuscular Disorders.22 (11):1032–4.doi:10.1016/j.nmd.2012.09.005.PMID23046997.S2CID42093152.
Parano E, Pavone L, Falsaperla R, Trifiletti R, Wang C (August 1996). "Molecular basis of phenotypic heterogeneity in siblings with spinal muscular atrophy".Annals of Neurology.40 (2):247–51.doi:10.1002/ana.410400219.PMID8773609.S2CID42514712.
Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main M, Crawford TO, Trela A (August 2007). "Consensus statement for standard of care in spinal muscular atrophy".Journal of Child Neurology.22 (8):1027–49.doi:10.1177/0883073807305788.PMID17761659.S2CID6478040.
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