Spinal muscular atrophy

{{Short description|Rare congenital neuromuscular disorder}} {{About|the genetic disorder associated with the SMN1 gene on chromosome 5q|a list of conditions with similar names|Spinal muscular atrophies|the series of video game ports|Super Mario Advance}} {{Use dmy dates|date=August 2021}} {{Infobox medical condition (new) | name = Spinal muscular atrophy | synonyms = Autosomal recessive proximal spinal muscular atrophy, 5q spinal muscular atrophy | image = Polio spinal diagram-en.svg | caption = Location of neurons affected by spinal muscular atrophy in the spinal cord | pronounce = | field = Neurology | symptoms = Progressive muscle weakness<ref name="NIH20192"/> | complications = Scoliosis, joint contractures, pneumonia<ref name="NORD20192"/> | onset =Mutation is congenital; symptom start varies by type | duration =Lifelong | types = Type 0 to type 4<ref name="NORD20192"/> | causes = Mutation in ''SMN1''<ref name="NORD20192"/> | risks = | diagnosis = Genetic testing<ref name="NIH20192"/> | differential = Congenital muscular dystrophy, Duchenne muscular dystrophy, Prader-Willi syndrome<ref name="NORD20192"/> | prevention = | treatment = Supportive care, medications<ref name="NIH20192"/> | medication = Nusinersen, onasemnogene abeparvovec, Risdiplam | prognosis = Varies by type<ref name="NORD20192"/> | frequency = 1 in 10,000 people<ref name="NORD20192"/> | deaths = }}

<!-- Definition and symptoms --> '''Spinal muscular atrophy''' ('''SMA''') is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting.<ref>{{Cite web|date=2017-10-23|title=Spinal muscular atrophy|url=https://www.nhs.uk/conditions/spinal-muscular-atrophy-sma/|access-date=2020-10-24|website=nhs.uk|language=en}}</ref><ref name=":3">{{Cite web|title=Spinal muscular atrophy: MedlinePlus Genetics|url=https://medlineplus.gov/genetics/condition/spinal-muscular-atrophy/|access-date=2020-10-24|website=medlineplus.gov|language=en}}</ref><ref>{{Cite web|title=Spinal Muscular Atrophy (SMA) {{!}} Boston Children's Hospital|url=https://www.childrenshospital.org/conditions-and-treatments/conditions/s/spinal-muscular-atrophy-sma|access-date=2020-10-25|website=www.childrenshospital.org}}</ref> It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic cause of infant death.<ref name="FDA20192">{{cite web|date=24 May 2019|title=FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality|url=https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease|archive-url=https://web.archive.org/web/20190524182226/https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease|archive-date=24 May 2019|access-date=27 May 2019|website=FDA|language=en}}</ref> 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, and respiratory muscles being affected first.<ref name="NINDS20192">{{cite web|title=Spinal Muscular Atrophy Fact Sheet {{!}} National Institute of Neurological Disorders and Stroke|url=https://www.ninds.nih.gov/health-information/disorders/spinal-muscular-atrophy|access-date=27 May 2019|website=NINDS}}</ref><ref name="GHR20192">{{cite web|title=Spinal muscular atrophy|url=https://medlineplus.gov/genetics/condition/spinal-muscular-atrophy/|access-date=27 May 2019|website=Genetics Home Reference|language=en}}</ref> Associated problems may include poor head control, difficulties swallowing, scoliosis, and joint contractures.<ref name="NORD20192">{{cite web|title=Spinal Muscular Atrophy|url=https://rarediseases.org/rare-diseases/spinal-muscular-atrophy/|access-date=27 May 2019|website=NORD (National Organization for Rare Disorders)}}</ref><ref name="GHR20192" />

The age of onset and the severity of symptoms form the basis of the traditional classification of spinal muscular atrophy into several types.<ref name=":3" />

<!--Cause and diagnosis--> Spinal muscular atrophy is due to an abnormality (mutation) in the ''SMN1'' gene<ref name="NIH20192">{{cite web|title=Spinal muscular atrophy|url=https://rarediseases.info.nih.gov/diseases/7674/spinal-muscular-atrophy|access-date=27 May 2019|website=Genetic and Rare Diseases Information Center (GARD) – an NCATS Program}}</ref><ref name="NORD20192" /> which encodes SMN, a protein necessary for the survival of motor neurons.<ref name="GHR20192" /> Loss of these neurons in the spinal cord prevents signalling between the brain and skeletal muscles.<ref name="GHR20192" /> Another gene, ''SMN2'', is considered a disease modifying gene, since usually the more ''SMN2'' copies are present, the milder is the course of the disease. The diagnosis of SMA is based on symptoms and confirmed by genetic testing.<ref>{{Cite web|title=Spinal Muscular Atrophy – Conditions {{!}} Children's National|url=http://childrensnational.org/visit/conditions-and-treatments/genetic-disorders-and-birth-defects/spinal-muscular-atrophy|access-date=2020-10-25|website=childrensnational.org}}</ref><ref name="NIH20192"/>

Usually, the mutation in the ''SMN1'' gene is inherited from both parents in an autosomal recessive manner, although in around 2% of cases it occurs during early development (''de novo'').<ref name="NIH20192" /><ref name=":4">{{Citation|last1=Prior|first1=Thomas W.|title=Spinal Muscular Atrophy|date=1993|url=https://www.ncbi.nlm.nih.gov/books/NBK1352/|work=GeneReviews®|editor-last=Adam|editor-first=Margaret P.|place=Seattle (WA)|publisher=University of Washington, Seattle|pmid=20301526|access-date=2020-10-25|last2=Leach|first2=Meganne E.|last3=Finanger|first3=Erika|editor2-last=Ardinger|editor2-first=Holly H.|editor3-last=Pagon|editor3-first=Roberta A.|editor4-last=Wallace|editor4-first=Stephanie E.}}</ref> The incidence of spinal muscular atrophy worldwide varies from about 1 in 4,000 births to around 1 in 16,000 births,<ref>{{Cite journal|last1=Verhaart|first1=Ingrid E. C.|last2=Robertson|first2=Agata|last3=Leary|first3=Rebecca|last4=McMacken|first4=Grace|last5=König|first5=Kirsten|last6=Kirschner|first6=Janbernd|last7=Jones|first7=Cynthia C.|last8=Cook|first8=Suzanne F.|last9=Lochmüller|first9=Hanns|date=July 2017|title=A multi-source approach to determine SMA incidence and research ready population|journal=Journal of Neurology|language=en|volume=264|issue=7|pages=1465–1473|doi=10.1007/s00415-017-8549-1|issn=0340-5354|pmc=5502065|pmid=28634652}}</ref> with 1 in 7,000 and 1 in 10,000 commonly quoted for Europe and the US respectively.<ref name="NORD20192"/>

<!--Treatment, prognosis, and epidemiology--> Outcomes in the natural course of the disease vary from death within a few weeks after birth in the most acute cases to normal life expectancy in the protracted SMA forms.<ref name="GHR20192" /> Medications that target the genetic cause of the disease include nusinersen, risdiplam,<ref>{{Cite patent|number=US9879007B2|title=Compounds for treating spinal muscular atrophy|gdate=2018-01-30|invent1=Qi|invent2=Choi|invent3=Dakka|invent4=Karp|inventor1-first=Hongyan|inventor2-first=Soongyu|inventor3-first=Amal|inventor4-first=Gary Mitchell|url=https://patents.google.com/patent/US9879007B2/en?oq=9879007}}</ref> and the gene therapy medication onasemnogene abeparvovec. Supportive care includes physical therapy, occupational therapy, respiratory support, nutritional support, orthopaedic interventions, and mobility support.<ref name="NIH20192" />

==Classification== 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 and ''Kugelberg–Welander disease'' for late-onset cases.<ref name=":5">{{Cite journal|last=Dubowitz|first=Victor|date=2009|title=Ramblings in the history of spinal muscular atrophy|url=https://linkinghub.elsevier.com/retrieve/pii/S096089660800672X|journal=Neuromuscular Disorders|language=en|volume=19|issue=1|pages=69–73|doi=10.1016/j.nmd.2008.10.004|pmid=18951794|s2cid=37576912|url-access=subscription}}</ref>

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.<ref name=":4" /><ref name=":5" /> Currently, the consensus is that the phenotype of spinal muscular atrophy spans a continuum of symptoms without clear delineation of subtypes.<ref name=":4" /> 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.

{|class="wikitable" style="font-size: 90%" |- !Type !Eponym !Usual&nbsp;age&nbsp;of&nbsp;onset !Natural history (without pharmacological treatment) !OMIM |- |'''SMA 0''' | |Prenatal |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 the ''SMN2'' 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'''<br />(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 the respiratory muscles induced by pneumonia (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. |{{OMIM|253300||none}} |- |'''SMA 2'''<br />(Intermediate) |'''Dubowitz disease''' |6–18 months |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. |{{OMIM|253550||none}} |- |'''SMA 3'''<br />(Juvenile) |'''Kugelberg–Welander disease''' |>12 months |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. |{{OMIM|253400||none}} |- |'''SMA 4'''<br />(Adult onset) | |Adulthood |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. |{{OMIM|271150||none}} |}

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)<ref>{{cite journal | vauthors = Main M, Kairon H, Mercuri E, Muntoni F | title = The Hammersmith functional motor scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation | journal = European Journal of Paediatric Neurology | volume = 7 | issue = 4 | pages = 155–9 | year = 2003 | pmid = 12865054 | doi = 10.1016/S1090-3798(03)00060-6 }}</ref><ref>{{cite journal | vauthors = Krosschell KJ, Maczulski JA, Crawford TO, Scott C, Swoboda KJ | title = A modified Hammersmith functional motor scale for use in multi-center research on spinal muscular atrophy | journal = Neuromuscular Disorders | volume = 16 | issue = 7 | pages = 417–26 | date = July 2006 | pmid = 16750368 | pmc = 3260054 | doi = 10.1016/j.nmd.2006.03.015 }}</ref><ref>{{cite journal | vauthors = 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 | title = An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients | journal = Neuromuscular Disorders | volume = 17 | issue = 9–10 | pages = 693–7 | date = October 2007 | pmid = 17658255 | doi = 10.1016/j.nmd.2007.05.009 | s2cid = 10365924 }}</ref><ref>{{cite journal | vauthors = 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 | title = Validation of the Expanded Hammersmith Functional Motor Scale in spinal muscular atrophy type II and III | journal = Journal of Child Neurology | volume = 26 | issue = 12 | pages = 1499–507 | date = December 2011 | pmid = 21940700 | doi = 10.1177/0883073811420294 | s2cid = 206549483 | collaboration = Pediatric Neuromuscular Clinical Research Network for Spinal Muscular Atrophy (PNCR) }}</ref> in older patients.

The eponymous label ''Werdnig–Hoffmann disease'' (sometimes misspelled with a single ''n'') refers to the earliest clinical descriptions of childhood SMA by Johann Hoffmann and Guido Werdnig.<ref name=":5" /> (''Werdnig-Hoffmann disease'' should not be confused with ''Hoffmann syndrome'', which is a type of adult-onset hypothyroid myopathy.)<ref>{{Cite journal |last1=Mangaraj |first1=Swayamsidha |last2=Sethy |first2=Ganeswar |date=2014 |title=Hoffman's syndrome – A rare facet of hypothyroid myopathy |journal=Journal of Neurosciences in Rural Practice |volume=5 |issue=4 |pages=447–448 |doi=10.4103/0976-3147.140025 |issn=0976-3147 |pmc=4173264 |pmid=25288869 |doi-access=free }}</ref> The eponymous term ''Kugelberg–Welander disease'' named after Erik Klas Hendrik Kugelberg (1913–1983) and Lisa Welander (1909–2001), who first documented the late-onset form and distinguished it from muscular dystrophy.<ref name=":5" /> Very rarely used ''Dubowitz disease'' (not to be confused with Dubowitz syndrome) is named after Victor Dubowitz, an English neurologist who authored several studies on the intermediate SMA phenotype.{{citation needed|date=March 2016}}

==Signs and symptoms== thumb|right|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:<ref name=":2">{{cite book | veditors = Sumner CJ, Paushkin S, Ko CP |title=Spinal Muscular Atrophy: Disease Mechanisms | vauthors = Oskoui M, Darras BT, DeVivo DC |publisher=Elsevier |year=2017|isbn=978-0-12-803685-3 |chapter=Chapter 1}}</ref>{{medical citation needed|date=December 2017}} * Areflexia, particularly in extremities * Overall muscle weakness, poor muscle tone, limpness or a tendency to flop * Difficulty achieving developmental milestones, difficulty sitting/standing/walking * In small children: adoption of a frog-leg position when sitting (hips abducted and knees flexed) * Loss of strength of the respiratory muscles: weak cough, weak cry (infants), accumulation of secretions in the lungs or throat, respiratory distress * Bell-shaped torso (caused by using only abdominal muscles for respiration) in severe SMA type * Fasciculations (twitching) of the tongue * Difficulty sucking or swallowing, poor feeding

==Causes== thumb|Spinal muscular atrophy has an autosomal recessive pattern of inheritance. Spinal muscular atrophy is caused by a genetic mutation in the ''SMN1'' gene.<ref>{{cite journal | vauthors = Brzustowicz LM, Lehner T, Castilla LH, Penchaszadeh GK, Wilhelmsen KC, Daniels R, Davies KE, Leppert M, Ziter F, Wood D | title = Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2–13.3 | journal = Nature | volume = 344 | issue = 6266 | pages = 540–1 | date = April 1990 | pmid = 2320125 | doi = 10.1038/344540a0 | bibcode = 1990Natur.344..540B | s2cid = 4259327 }}</ref>

Human chromosome 5 contains two nearly identical genes at location 5q13: a telomeric copy ''SMN1'' and a centromeric copy ''SMN2''. In healthy individuals, the ''SMN1'' gene codes for the survival of motor neuron protein (SMN) which, as its name suggests, plays a crucial role in the survival of motor neurons. The ''SMN2'' gene, on the other hand – due to a variation in a single nucleotide (840.C→T) – undergoes alternative splicing at the junction of intron 6 to exon 8, with only 10–20% of ''SMN2'' transcripts coding a fully functional survival 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.<ref>{{cite web |url= https://medlineplus.gov/genetics/condition/spinal-muscular-atrophy/ |title=Spinal muscular atrophy |website=Genetics Home Reference |access-date=2019-05-15 }}</ref>

In individuals affected by SMA, the ''SMN1'' gene is mutated in such a way that it is unable to correctly code the SMN protein – due to either a deletion<ref name="ReferenceA">{{cite journal | vauthors = Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M | title = Identification and characterization of a spinal muscular atrophy-determining gene | journal = Cell | volume = 80 | issue = 1 | pages = 155–65 | date = January 1995 | pmid = 7813012 | doi = 10.1016/0092-8674(95)90460-3 | s2cid = 14291056 | doi-access = free }}</ref> occurring at exon 7<ref>{{cite journal | vauthors = Passini MA, Bu J, Richards AM, Kinnecom C, Sardi SP, Stanek LM, Hua Y, Rigo F, Matson J, Hung G, Kaye EM, Shihabuddin LS, Krainer AR, Bennett CF, Cheng SH | title = Antisense oligonucleotides delivered to the mouse CNS ameliorate symptoms of severe spinal muscular atrophy | journal = Science Translational Medicine | volume = 3 | issue = 72 | pages = 72ra18 | date = March 2011 | pmid = 21368223 | pmc = 3140425 | doi = 10.1126/scitranslmed.3001777 }}</ref> or to other point mutations (frequently resulting in the functional conversion of the ''SMN1'' sequence into ''SMN2''). Almost all people, however, have at least one functional copy of the ''SMN2'' 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 the anterior horn of spinal cord and the brain. Skeletal muscles, which all depend on these motor neurons for neural input, now have decreased innervation (also called denervation), 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 progressive atrophy (waste away).{{citation needed|date=March 2016}}

Muscles of lower extremities 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 than distal muscles.<ref name="2007consensus" />

The severity of SMA symptoms is broadly related to how well the remaining ''SMN2'' genes can make up for the loss of function of ''SMN1''. This partly depends on the number of copies of the ''SMN2'' gene present on the chromosome. Whilst healthy individuals usually carry two ''SMN2'' gene copies, people with SMA can have anything between 1 and 5 (or more) of them; the greater the number of ''SMN2'' copies, the milder the disease severity. Thus, most SMA type I babies have one or two ''SMN2'' copies; people with SMA II and III usually have at least three ''SMN2'' copies; and people with SMA IV normally have at least four of them. However, the correlation between symptom severity and ''SMN2'' copy number is not absolute and there seem to exist other factors affecting the disease phenotype.<ref>{{cite journal | vauthors = Jedrzejowska M, Milewski M, Zimowski J, Borkowska J, Kostera-Pruszczyk A, Sielska D, Jurek M, Hausmanowa-Petrusewicz I | title = Phenotype modifiers of spinal muscular atrophy: the number of SMN2 gene copies, deletion in the NAIP gene and probably gender influence the course of the disease | journal = Acta Biochimica Polonica | volume = 56 | issue = 1 | pages = 103–8 | year = 2009 | pmid = 19287802 | doi = 10.18388/abp.2009_2521 | doi-access = free }}</ref>

Spinal muscular atrophy is inherited in an autosomal recessive pattern, which means that the defective gene is located on an autosome. 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 appear ''de novo'' (i.e., without any hereditary causes) in around 2–4% of cases.{{citation needed|date=August 2021}}

Spinal muscular atrophy affects individuals of all ethnic groups, unlike other well-known autosomal recessive disorders, such as sickle cell disease and cystic fibrosis, which have significant differences in occurrence rate among ethnic groups. The overall prevalence 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.<ref>{{cite journal | vauthors = Su YN, Hung CC, Lin SY, Chen FY, Chern JP, Tsai C, Chang TS, Yang CC, Li H, Ho HN, Lee CN | title = Carrier screening for spinal muscular atrophy (SMA) in 107,611 pregnant women during the period 2005–2009: a prospective population-based cohort study | journal = PLOS ONE| volume = 6 | issue = 2 | article-number = e17067 | date = February 2011 | pmid = 21364876 | pmc = 3045421 | doi = 10.1371/journal.pone.0017067 | veditors = Schrijver I | bibcode = 2011PLoSO...617067S | doi-access = free }}</ref><ref>{{cite journal | vauthors = Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM, Flynn K, Hendrickson BC, Scholl T, Sirko-Osadsa DA, Allitto BA | title = Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens | journal = European Journal of Human Genetics | volume = 20 | issue = 1 | pages = 27–32 | date = January 2012 | pmid = 21811307 | pmc = 3234503 | doi = 10.1038/ejhg.2011.134 }}</ref> 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 the ''SMN1'' gene sequenced.{{citation needed|date=October 2021}}

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 additional ''de novo'' deletions of the ''SMN'' gene, not involving the ''NAIP'' gene, or the differences in ''SMN2'' copy numbers.{{citation needed|date=May 2016}}

== Diagnosis == SMA is diagnosed using genetic testing that detects homozygous deletion of the ''SMN1'' gene in over 95% of cases,<ref name=":2" /> and a compound ''SMN1'' mutation in the remaining patients. Genetic testing is usually carried out using a blood sample, and MLPA is one of the more frequently used genetic testing techniques, as it also allows establishing the number of ''SMN2'' gene copies, which has clinical importance.<ref name=":2" />

Symptomatically, SMA can be diagnosed with a degree of certainty only in children with the acute form who manifest a progressive illness with paradoxical breathing, bilateral low muscle tone, and absent tendon reflexes.{{citation needed|date=August 2021}}

=== Early diagnosis ===

==== Preimplantation testing ==== Preimplantation genetic diagnosis can be used to screen for SMA-affected embryos during in-vitro fertilisation.{{citation needed|date=August 2021}}

==== Prenatal testing ==== Prenatal testing for SMA is possible through chorionic villus sampling, cell-free fetal DNA analysis, and other methods.{{citation needed|date=August 2021}}

==== Newborn screening ==== Routine newborn screening for SMA is becoming increasingly commonplace in developed countries, given the availability of treatments that are most effective at the asymptomatic stage of the disease.<ref>{{cite journal|vauthors=Serra-Juhe C, Tizzano EF|date=December 2019|title=Perspectives in genetic counseling for spinal muscular atrophy in the new therapeutic era: early pre-symptomatic intervention and test in minors|journal=European Journal of Human Genetics|volume=27|issue=12|pages=1774–1782|doi=10.1038/s41431-019-0415-4|pmc=6871529|pmid=31053787}}</ref><ref>{{cite journal|display-authors=6|vauthors=Glascock J, Sampson J, Haidet-Phillips A, Connolly A, Darras B, Day J, Finkel R, Howell RR, Klinger K, Kuntz N, Prior T, Shieh PB, Crawford TO, Kerr D, Jarecki J|date=2018-05-29|title=Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy through Newborn Screening|journal=Journal of Neuromuscular Diseases|volume=5|issue=2|pages=145–158|doi=10.3233/JND-180304|pmc=6004919|pmid=29614695}}</ref><ref>{{cite journal|vauthors=Dangouloff T, Burghes A, Tizzano EF, Servais L|date=January 2020|title=244th ENMC international workshop: Newborn screening in spinal muscular atrophy May 10-12, 2019, Hoofdorp, The Netherlands|journal=Neuromuscular Disorders|volume=30|issue=1|pages=93–103|doi=10.1016/j.nmd.2019.11.002|pmid=31882184|doi-access=free|hdl=2268/242772 |url=https://orbi.uliege.be/bitstream/2268/242772/1/Dangouloff%20ENMC.pdf}}</ref> In 2018, newborn screening for SMA was added to the US list of recommended newborn screening tests<ref>{{Cite web|last=Lopes|first=Jose Marques|name-list-style=vanc|date=2018-07-16|title=SMA Added to List of Recommended Screenings for Disease Given to...|url=https://smanewstoday.com/2018/07/16/sma-added-to-us-list-of-diseases-recommended-for-newborn-screening/|access-date=2020-05-04|website=SMA News Today|language=en-US}}</ref><ref>{{Cite web|last=Stephenson|first=Kristin|name-list-style=vanc|date=2018-07-05|title=SMA Added to National List of Disorders to Screen for at Birth|url=https://strongly.mda.org/sma-added-national-list-disorders-to-screen-for-at-birth/|access-date=2020-05-04|website=Muscular Dystrophy Association|language=en-US}}</ref><ref>{{Cite web|date=2017-07-03|title=Recommended Uniform Screening Panel|url=https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp/index.html|access-date=2020-05-04|website=Official web site of the U.S. Health Resources & Services Administration|language=en}}</ref> and as of April 2020, it has been adopted in 39 US states.<ref>{{Cite web|last=McCall|first=Sarah|name-list-style=vanc|title=Newborn Screening for Spinal Muscular Atrophy|url=https://www.curesma.org/newborn-screening-for-sma/|access-date=2020-05-04|website=Cure SMA|language=en-US}}</ref><ref>{{cite journal|display-authors=6|vauthors=Kraszewski JN, Kay DM, Stevens CF, Koval C, Haser B, Ortiz V, Albertorio A, Cohen LL, Jain R, Andrew SP, Young SD, LaMarca NM, De Vivo DC, Caggana M, Chung WK|date=June 2018|title=Pilot study of population-based newborn screening for spinal muscular atrophy in New York state|journal=Genetics in Medicine|volume=20|issue=6|pages=608–613|doi=10.1038/gim.2017.152|pmid=29758563|doi-access=free}}</ref> 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.<ref>{{Cite web |title=SMA Newborn Screening Alliance – SMA: Test at birth, save a life |url=https://www.sma-screening-alliance.org/ |access-date=2023-02-05 |language=en-GB}}</ref>

=== Carrier testing === Those at risk of being carriers of ''SMN1'' deletion, and thus at risk of having offspring affected by SMA, can undergo carrier analysis using a blood or saliva sample. The American College of Obstetricians and Gynecologists recommends that all people thinking of becoming pregnant be tested to see if they are a carrier.<ref>{{cite web|title=Carrier Screening in the Age of Genomic Medicine – ACOG|url=http://www.acog.org/Resources-And-Publications/Committee-Opinions/Committee-on-Genetics/Carrier-Screening-in-the-Age-of-Genomic-Medicine|website=www.acog.org|access-date=24 February 2017}}</ref> The carrier frequency of SMA is comparable to other disorders like thalassemia and in a north Indian cohort is 1 in 38.<ref>{{cite journal |vauthors=Nilay, M, Moirangthem, A, Saxena, D, Mandal, K, Phadke, SR|title=Carrier frequency of SMN1 related spinal muscular atrophy in north Indian population: The need for population based screening program.|journal=American Journal of Medical Genetics Part A|date=October 2020|volume=185|issue=1|pages=274–277|doi=10.1002/ajmg.a.61918|pmid=33051992|s2cid=222353383}}</ref> However, genetic testing will not be able to identify all individuals at risk since about 2% of cases are caused by de 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 a false negative result, as the carrier status will not be correctly detected by a traditional genetic test.<ref name="pmid18941424">{{cite journal |vauthors=Prior TW |title=Carrier screening for spinal muscular atrophy |journal=Genetics in Medicine |volume=10 |issue=11 |pages=840–2 |date=November 2008 |pmid=18941424 |pmc=3110347 |doi=10.1097/GIM.0b013e318188d069 }}</ref><ref name="pmid28676237">{{cite journal |vauthors=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 |title=Spinal muscular atrophy carriers with two SMN1 copies |journal=Brain & Development |volume=39 |issue=10 |pages=851–860 |date=November 2017 |pmid=28676237 |doi=10.1016/j.braindev.2017.06.002 |s2cid=26504674 }}</ref>

== Management == 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|date=December 2017}}

===Medication=== Nusinersen (marketed as Spinraza) is used to treat spinal muscular atrophy.<ref name="FDA Spinraza label">{{cite web | title=Spinraza- nusinersen injection, solution | website=DailyMed | date=30 June 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=dd70cd5f-b0fc-4ba4-a5ea-89a34778bd94 | access-date=8 August 2020}}</ref> It is an antisense nucleotide that modifies the alternative splicing of the ''SMN2'' gene.<ref name="FDA Spinraza label" /> It is given directly to the central nervous system using an intrathecal injection.<ref name="FDA Spinraza label" /><ref>{{cite news|url=https://www.wsj.com/articles/surprise-drug-approval-is-holiday-gift-for-biogen-1482856447|title=Surprise Drug Approval Is Holiday Gift for Biogen|last=Grant|first=Charley|date=2016-12-27|newspaper=The Wall Street Journal|access-date=2016-12-27|issn=0099-9660|name-list-style=vanc|url-access=subscription}}</ref> Nusinersen prolongs survival and improves motor function in infants with SMA.<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy | journal = New England Journal of Medicine | volume = 377 | issue = 18 | pages = 1723–32 | date = November 2017 | pmid = 29091570 | doi = 10.1056/NEJMoa1702752 | s2cid = 4771819 | url = https://discovery.ucl.ac.uk/id/eprint/10046147/ | doi-access = free | hdl = 1959.4/unsworks_49227 | hdl-access = free }}</ref><ref>{{Cite journal|last1=Wadman|first1=Renske I.|last2=van der Pol|first2=W. Ludo|last3=Bosboom|first3=Wendy Mj|last4=Asselman|first4=Fay-Lynn|last5=van den Berg|first5=Leonard H.|last6=Iannaccone|first6=Susan T.|last7=Vrancken|first7=Alexander Fje|date=1 June 2020|title=Drug treatment for spinal muscular atrophy types II and III|journal=The Cochrane Database of Systematic Reviews|volume=1|issue=1 |article-number=CD006282|doi=10.1002/14651858.CD006282.pub5|issn=1469-493X|pmc=6995983|pmid=32006461}}</ref> It was approved for use in the US in 2016, and for use in the EU in 2017.<ref>{{cite web | title=Spinraza (nusinersen) Injection | website=U.S. Food and Drug Administration (FDA) | date=18 January 2017 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209531Orig1s000TOC.cfm | access-date=8 August 2020}}</ref><ref name="Spinraza EPAR">{{cite web | title=Spinraza EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/spinraza | access-date=8 August 2020}}</ref><ref>{{cite news|url=https://www.afp.com/en/news/1315/spinrazar-nusinersen-approved-european-union-first-treatment-spinal-muscular-atrophy|title=Spinraza (Nusinersen) Approved in the European Union as First Treatment for Spinal Muscular Atrophy|date=2017-06-01|access-date=2017-06-01|publisher=Agence France-Presse (AFP)}}</ref>

Onasemnogene abeparvovec (marketed as Zolgensma) is a gene therapy treatment which uses self-complementary adeno-associated virus type 9 (scAAV-9) as a vector to deliver the ''SMN1'' transgene.<ref>{{cite web|title=Zolgensma 2 x 1013 vector genomes/mL solution for infusion|url=https://www.medicines.org.uk/emc/product/11572/smpc|website=www.medicines.org.uk|access-date=8 August 2020}}</ref><ref name="FDA Zolgensma label">{{cite web | title=Zolgensma- onasemnogene abeparvovec-xioi kit | website=DailyMed | date=24 May 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68cd4f06-70e1-40d8-bedb-609ec0afa471 | access-date=8 August 2020}}</ref> The therapy was first approved in the US in May 2019 as an intravenous formulation for children below 24 months of age.<ref name="FDA2019">{{cite press release|title=FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality|url=https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease|archive-url=https://web.archive.org/web/20190524182226/https://www.fda.gov/news-events/press-announcements/fda-approves-innovative-gene-therapy-treat-pediatric-patients-spinal-muscular-atrophy-rare-disease|archive-date=24 May 2019|website=U.S. Food and Drug Administration (FDA)|access-date=27 May 2019|date=24 May 2019}} {{PD-notice}}</ref><ref>{{cite web | title=Zolgensma | website=U.S. Food and Drug Administration (FDA) | date=24 May 2019 | url=https://www.fda.gov/vaccines-blood-biologics/zolgensma | access-date=8 August 2020}}</ref> Approval in the European Union, Japan and other countries followed, albeit often with different approval scopes.<ref name="Zolgensma EPAR">{{cite web | title=Zolgensma EPAR | website=European Medicines Agency (EMA) | date=24 March 2020 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/zolgensma | access-date=8 August 2020}}</ref><ref>{{Cite press release|url=https://www.novartis.com/news/media-releases/novartis-receives-approval-from-japanese-ministry-health-labour-and-welfare-zolgensma-only-gene-therapy-patients-spinal-muscular-atrophy-sma|title=Novartis receives approval from Japanese Ministry of Health, Labour and Welfare for Zolgensma the only gene therapy for patients with spinal muscular atrophy (SMA)|website=Novartis|access-date=8 August 2020}}</ref>

Risdiplam (marketed as Evrysdi) is a medication taken by mouth in liquid form.<ref name="FDA risdiplam" /><ref name="Evrysdi label">{{cite web |url=https://www.gene.com/download/pdf/evrysdi_prescribing.pdf | publisher=Genentech | title=Evrysdi (risdiplam) for oral solution | access-date=8 August 2020}}</ref> It is a pyridazine derivative that works by increasing the amount of functional survivor motor neuron protein produced by the ''SMN2'' gene through modifying its splicing pattern.<ref>{{cite web| url=https://smanewstoday.com/rg7916-rg7800-roche-ptc-smaf | title=RG7916 | author=Maria Joao Almeida | publisher=BioNews Services | date=2016-09-08 | access-date=2017-10-08 }}</ref><ref>{{cite journal | vauthors = Zhao X, Feng Z, Ling KK, Mollin A, Sheedy J, Yeh S, Petruska J, Narasimhan J, Dakka A, Welch EM, Karp G, Chen KS, Metzger F, Ratni H, Lotti F, Tisdale S, Naryshkin NA, Pellizzoni L, Paushkin S, Ko CP, Weetall M | display-authors = 6 | title = Pharmacokinetics, pharmacodynamics, and efficacy of a small-molecule SMN2 splicing modifier in mouse models of spinal muscular atrophy | journal = Human Molecular Genetics | volume = 25 | issue = 10 | pages = 1885–1899 | date = May 2016 | pmid = 26931466 | pmc = 5062580 | doi = 10.1093/hmg/ddw062 }}</ref> 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.<ref>{{cite journal |last1=Zhu |first1=Xiaoying |title=Comparison of Nusinersen and Evrysdi in the Treatment of Spinal Muscular Atrophy |journal=E3S Web of Conferences |date=15 June 2021 |volume=271 |issue= |page=03035 |doi=10.1051/e3sconf/202127103035 |bibcode=2021E3SWC.27103035Z |s2cid=236740376 |url=https://www.e3s-conferences.org/articles/e3sconf/abs/2021/47/e3sconf_icepe2021_03035/e3sconf_icepe2021_03035.html |access-date=11 December 2023}}</ref> Risdiplam was first approved for medical use in the United States in August 2020<ref name="FDA risdiplam">{{cite press release | title=FDA Approves Oral Treatment for Spinal Muscular Atrophy | website=U.S. Food and Drug Administration (FDA) | date=7 August 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-oral-treatment-spinal-muscular-atrophy | access-date=7 August 2020}}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}}</ref> and has since been approved in over 30 countries.{{citation needed|date=November 2023}}

=== Breathing === 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.<ref name="2007consensus">{{cite journal | vauthors = Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main M, Crawford TO, Trela A | title = Consensus statement for standard of care in spinal muscular atrophy | journal = Journal of Child Neurology | volume = 22 | issue = 8 | pages = 1027–49 | date = August 2007 | pmid = 17761659 | doi = 10.1177/0883073807305788 | s2cid = 6478040 }}</ref> 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.<ref name="2007consensus" /> 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.<ref name="uptodate">{{cite web|url= https://www.uptodate.com/contents/spinal-muscular-atrophy?source=search_result&search=spinal%20muscular%20atrophy&selectedTitle=1~51#H21 |title=Spinal Muscular Atrophy |last=Bodamer |first=Olaf | name-list-style = vanc |date=November 2017|website=uptodate.com |access-date=1 December 2017}}</ref> 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 and tracheostomy may be sometimes performed in more severe cases;<ref>{{cite journal | vauthors = Bach JR, Niranjan V, Weaver B | title = Spinal muscular atrophy type 1: A noninvasive respiratory management approach | journal = Chest | volume = 117 | issue = 4 | pages = 1100–5 | date = April 2000 | pmid = 10767247 | doi = 10.1378/chest.117.4.1100 }}</ref> both methods of ventilation prolong survival to a comparable degree, although tracheostomy prevents speech development.<ref>{{cite journal | vauthors = Bach JR, Saltstein K, Sinquee D, Weaver B, Komaroff E | title = Long-term survival in Werdnig-Hoffmann disease | journal = American Journal of Physical Medicine & Rehabilitation | volume = 86 | issue = 5 | pages = 339–45 quiz 346–8, 379 | date = May 2007 | pmid = 17449977 | doi = 10.1097/PHM.0b013e31804a8505 | s2cid = 9942245 }}</ref>

=== Nutrition === 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.<ref name=":1" />{{medical citation needed|date=December 2017}} Therein, it could be necessary in SMA type I and people with more severe type II to have a feeding tube or gastrostomy.<ref name=":1">{{cite journal | vauthors = Messina S, Pane M, De Rose P, Vasta I, Sorleti D, Aloysius A, Sciarra F, Mangiola F, Kinali M, Bertini E, Mercuri E | title = Feeding problems and malnutrition in spinal muscular atrophy type II | journal = Neuromuscular Disorders | volume = 18 | issue = 5 | pages = 389–93 | date = May 2008 | pmid = 18420410 | doi = 10.1016/j.nmd.2008.02.008 | s2cid = 23302291 }}</ref><ref>{{cite journal | vauthors = Chen YS, Shih HH, Chen TH, Kuo CH, Jong YJ | title = Prevalence and risk factors for feeding and swallowing difficulties in spinal muscular atrophy types II and III | journal = The Journal of Pediatrics | volume = 160 | issue = 3 | pages = 447–451.e1 | date = March 2012 | pmid = 21924737 | doi = 10.1016/j.jpeds.2011.08.016 }}</ref><ref>{{cite journal | vauthors = Tilton AH, Miller MD, Khoshoo V | title = Nutrition and swallowing in pediatric neuromuscular patients | journal = Seminars in Pediatric Neurology | volume = 5 | issue = 2 | pages = 106–15 | date = June 1998 | pmid = 9661244 | doi = 10.1016/S1071-9091(98)80026-0 }}</ref> Additionally, metabolic abnormalities resulting from SMA impair β-oxidation of fatty acids in muscles and can lead to organic acidemia and consequent muscle damage, especially when fasting.<ref>{{cite journal | vauthors = Tein I, Sloane AE, Donner EJ, Lehotay DC, Millington DS, Kelley RI | title = Fatty acid oxidation abnormalities in childhood-onset spinal muscular atrophy: primary or secondary defect(s)? | journal = Pediatric Neurology | volume = 12 | issue = 1 | pages = 21–30 | date = January 1995 | pmid = 7748356 | doi = 10.1016/0887-8994(94)00100-G }}</ref><ref>{{cite journal | vauthors = Crawford TO, Sladky JT, Hurko O, Besner-Johnston A, Kelley RI | title = Abnormal fatty acid metabolism in childhood spinal muscular atrophy | journal = Annals of Neurology | volume = 45 | issue = 3 | pages = 337–43 | date = March 1999 | pmid = 10072048 | doi = 10.1002/1531-8249(199903)45:3<337::AID-ANA9>3.0.CO;2-U | s2cid = 23808651 }}</ref> It is suggested that people with SMA, especially those with more severe forms of the disease, reduce intake of fat and avoid prolonged fasting (i.e., eat more frequently than healthy people)<ref>{{cite journal | vauthors = Leighton S |year=2003|title=Nutrition issues associated with spinal muscular atrophy|journal=Nutrition & Dietetics|volume=60|issue=2|pages=92–96}}</ref> as well as choosing softer foods to avoid aspiration.<ref name="uptodate" /> 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.<ref name=":0" />{{medical citation needed|date=December 2017}}

=== Orthopaedics === 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.<ref name="2007consensus" /> Weak muscles that normally stabilize joints, such as the vertebral column, lead to the development of kyphosis and/or scoliosis and joint contracture.<ref name="2007consensus" /> 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.<ref name=":0">{{cite web|url=http://www.curesma.org/documents/support--care-documents/the-musculoskeletal-system.pdf|title=SMA CARE SERIES – Musculoskeletal System|last=Apkon|first=Susan|name-list-style=vanc|date=Summer 2017|website=www.curesma.org|access-date=7 December 2017|archive-date=19 February 2018|archive-url=https://web.archive.org/web/20180219060609/http://www.curesma.org/documents/support--care-documents/the-musculoskeletal-system.pdf}}</ref> People with SMA might also benefit greatly from various forms of physiotherapy and occupational therapy.{{citation needed|date=August 2021}}

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|date=August 2021}}

===Other=== Although the heart is not a matter of routine concern, a link between SMA and certain heart conditions has been suggested.<ref>{{cite journal | vauthors = Rudnik-Schöneborn S, Heller R, Berg C, Betzler C, Grimm T, Eggermann T, Eggermann K, Wirth R, Wirth B, Zerres K | title = Congenital heart disease is a feature of severe infantile spinal muscular atrophy | journal = Journal of Medical Genetics | volume = 45 | issue = 10 | pages = 635–8 | date = October 2008 | pmid = 18662980 | doi = 10.1136/jmg.2008.057950 | s2cid = 7170069 }}</ref><ref>{{cite journal | vauthors = Heier CR, Satta R, Lutz C, DiDonato CJ | title = Arrhythmia and cardiac defects are a feature of spinal muscular atrophy model mice | journal = Human Molecular Genetics | volume = 19 | issue = 20 | pages = 3906–18 | date = October 2010 | pmid = 20693262 | pmc = 2947406 | doi = 10.1093/hmg/ddq330 }}</ref><ref>{{cite journal | vauthors = Shababi M, Habibi J, Yang HT, Vale SM, Sewell WA, Lorson CL | title = Cardiac defects contribute to the pathology of spinal muscular atrophy models | journal = Human Molecular Genetics | volume = 19 | issue = 20 | pages = 4059–71 | date = October 2010 | pmid = 20696672 | doi = 10.1093/hmg/ddq329 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Bevan AK, Hutchinson KR, Foust KD, Braun L, McGovern VL, Schmelzer L, Ward JG, Petruska JC, Lucchesi PA, Burghes AH, Kaspar BK | title = Early heart failure in the SMNDelta7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery | journal = Human Molecular Genetics | volume = 19 | issue = 20 | pages = 3895–905 | date = October 2010 | pmid = 20639395 | pmc = 2947399 | doi = 10.1093/hmg/ddq300 }}</ref>

Children with SMA do not differ from the general population in their behaviour; their cognitive development can be slightly faster, and certain aspects of their intelligence are above the average.<ref>{{cite journal | vauthors = von Gontard A, Zerres K, Backes M, Laufersweiler-Plass C, Wendland C, Melchers P, Lehmkuhl G, Rudnik-Schöneborn S | title = Intelligence and cognitive function in children and adolescents with spinal muscular atrophy | journal = Neuromuscular Disorders | volume = 12 | issue = 2 | pages = 130–6 | date = February 2002 | pmid = 11738354 | doi = 10.1016/S0960-8966(01)00274-7 | s2cid = 46694209 }}</ref><ref>{{cite journal | vauthors = Billard C, Gillet P, Signoret JL, Uicaut E, Bertrand P, Fardeau M, Barthez-Carpentier MA, Santini JJ | title = Cognitive functions in Duchenne muscular dystrophy: a reappraisal and comparison with spinal muscular atrophy | journal = Neuromuscular Disorders | volume = 2 | issue = 5–6 | pages = 371–8 | year = 1992 | pmid = 1300185 | doi = 10.1016/S0960-8966(06)80008-8 | s2cid = 22211725 }}</ref><ref>{{cite journal | vauthors = Laufersweiler-Plass C, Rudnik-Schöneborn S, Zerres K, Backes M, Lehmkuhl G, von Gontard A | title = Behavioural problems in children and adolescents with spinal muscular atrophy and their siblings | journal = Developmental Medicine and Child Neurology | volume = 45 | issue = 1 | pages = 44–9 | date = January 2003 | pmid = 12549754 | doi = 10.1017/S0012162203000082 | doi-broken-date = 26 September 2025 }}</ref> Despite their disability, SMA-affected people report high degree of satisfaction from life.<ref>{{cite journal | vauthors = de Oliveira CM, Araújo AP | title = Self-reported quality of life has no correlation with functional status in children and adolescents with spinal muscular atrophy | journal = European Journal of Paediatric Neurology | volume = 15 | issue = 1 | pages = 36–9 | date = January 2011 | pmid = 20800519 | doi = 10.1016/j.ejpn.2010.07.003 }}</ref>

Palliative care in SMA has been standardised in the ''Consensus Statement for Standard of Care in Spinal Muscular Atrophy''<ref name="2007consensus" /> which has been recommended for standard adoption worldwide.{{citation needed|date=November 2023}}

==Prognosis== 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.<ref>{{cite book|title=Spinal Muscular Atrophy|last1=Darras | first1 = Basil | last2=Finkel | first2=Richard | name-list-style = vanc |publisher=Elsevier|year=2017|isbn=978-0-12-803685-3|location=United Kingdom, United States|page=417}}</ref>

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.<ref>{{cite journal | vauthors = Yuan N, Wang CH, Trela A, Albanese CT | title = Laparoscopic Nissen fundoplication during gastrostomy tube placement and noninvasive ventilation may improve survival in type I and severe type II spinal muscular atrophy | journal = Journal of Child Neurology | volume = 22 | issue = 6 | pages = 727–31 | date = June 2007 | pmid = 17641258 | doi = 10.1177/0883073807304009 | s2cid = 38799022 }}</ref> With proper care, milder SMA type I cases (which account for approx. 10% of all SMA1 cases) live into adulthood.<ref>{{cite journal | vauthors = Bach JR | title = Medical considerations of long-term survival of Werdnig-Hoffmann disease | journal = American Journal of Physical Medicine & Rehabilitation | volume = 86 | issue = 5 | pages = 349–55 | date = May 2007 | pmid = 17449979 | doi = 10.1097/PHM.0b013e31804b1d66 | s2cid = 39989993 }}</ref> 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.<ref>{{cite journal | vauthors = Oskoui M, Levy G, Garland CJ, Gray JM, O'Hagen J, De Vivo DC, Kaufmann P | title = The changing natural history of spinal muscular atrophy type 1 | journal = Neurology | volume = 69 | issue = 20 | pages = 1931–6 | date = November 2007 | pmid = 17998484 | doi = 10.1212/01.wnl.0000290830.40544.b9 | s2cid = 7528894 }}</ref>

In untreated SMA type II, the course of the disease is slower to progress, and life 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|date=October 2021}}

==Research directions==

Since the underlying genetic cause of SMA was identified in 1995,<ref name="ReferenceA"/> several therapeutic approaches have been proposed and investigated that primarily focus on increasing the availability of SMN protein in motor neurons.<ref>{{cite journal | vauthors = d'Ydewalle C, Sumner CJ | title = Spinal Muscular Atrophy Therapeutics: Where do we Stand? | journal = Neurotherapeutics | volume = 12 | issue = 2 | pages = 303–16 | date = April 2015 | pmid = 25631888 | pmc = 4404440 | doi = 10.1007/s13311-015-0337-y }}</ref> The main research directions have been as follows:

===''SMN1'' gene replacement===

Gene therapy in SMA aims at restoring the ''SMN1'' gene function through inserting specially crafted nucleotide sequence (a ''SMN1'' transgene) into the cell nucleus using a viral vector. This approach has been exploited by the first approved gene therapy for SMA, scAAV-9 based treatment onasemnogene abeparvovec.<ref>{{cite news |agency=Reuters |date=2019-05-25 |title=$2.1m Novartis gene therapy to become world's most expensive drug |newspaper=The Guardian |issn=0261-3077}}</ref>

=== ''SMN2'' alternative splicing modulation ===

This approach aims at modifying the alternative splicing of the ''SMN2'' 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 the ''SMN2'' gene functionally into the ''SMN1'' gene. It is the therapeutic mechanism of the approved medications nusinersen and risdiplam.{{citation needed|date=November 2023}}

Branaplam is another ''SMN2'' splicing modulator that has reached the clinical stage of development.<ref>{{cite web |url=http://www.curesma.org/news/novartis-branaplam-update.html |title=Novartis Releases Update on LMI070 (Branaplam) Clinical Trial |publisher=CureSMA |access-date=2017-10-07 |archive-date=25 November 2017 |archive-url=https://web.archive.org/web/20171125171712/http://www.curesma.org/news/novartis-branaplam-update.html }}</ref>

Historically, this research direction has also investigated other molecules. RG3039, also known as Quinazoline495, was a proprietary quinazoline derivative developed by Repligen and licensed to Pfizer in March 2014, which was discontinued shortly after, having only completed phase I trials. PTK-SMA1 was a proprietary small-molecule splicing modulator of the tetracyclines 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.<ref name="Kletzl Marquet Günther Tang 2019 pp. 21–29">{{cite journal | last1=Kletzl | first1=Heidemarie | last2=Marquet | first2=Anne | last3=Günther | first3=Andreas | last4=Tang | first4=Wakana | last5=Heuberger | first5=Jules | last6=Groeneveld | first6=Geert Jan | last7=Birkhoff | first7=Willem | last8=Mercuri | first8=Eugenio | last9=Lochmüller | first9=Hanns | last10=Wood | first10=Claire | last11=Fischer | first11=Dirk | last12=Gerlach | first12=Irene | last13=Heinig | first13=Katja | last14=Bugawan | first14=Teodorica | last15=Dziadek | first15=Sebastian | last16=Kinch | first16=Russell | last17=Czech | first17=Christian | last18=Khwaja | first18=Omar | title=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 | journal=Neuromuscular Disorders | publisher=Elsevier BV | volume=29 | issue=1 | year=2019 | issn=0960-8966 | doi=10.1016/j.nmd.2018.10.001 | pages=21–29| pmid=30553700 | s2cid=54315649 }}</ref> Early leads also included sodium orthovanadate<ref>{{cite journal | vauthors = Zhang ML, Lorson CL, Androphy EJ, Zhou J | title = An in vivo reporter system for measuring increased inclusion of exon 7 in SMN2 mRNA: potential therapy of SMA | journal = Gene Therapy | volume = 8 | issue = 20 | pages = 1532–8 | date = October 2001 | pmid = 11704813 | doi = 10.1038/sj.gt.3301550 | doi-access = | s2cid = 29685631 }}</ref> and aclarubicin.<ref>{{cite journal | vauthors = Andreassi C, Jarecki J, Zhou J, Coovert DD, Monani UR, Chen X, Whitney M, Pollok B, Zhang M, Androphy E, Burghes AH | title = Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients | journal = Human Molecular Genetics | volume = 10 | issue = 24 | pages = 2841–9 | date = November 2001 | pmid = 11734549 | doi = 10.1093/hmg/10.24.2841 | doi-access = free }}</ref>

Morpholino-type antisense oligonucleotides, with the same cellular target as nusinersen, remain a subject of research in treating SMA and other single-gene diseases, including at the University of Alberta,<ref>{{Cite journal |last1=Aslesh |first1=Tejal |last2=Erkut |first2=Esra |last3=Ren |first3=Jun |last4=Lim |first4=Kenji Rowel Q. |last5=Woo |first5=Stanley |last6=Hatlevig |first6=Susan |last7=Moulton |first7=Hong M. |last8=Gosgnach |first8=Simon |last9=Greer |first9=John |last10=Maruyama |first10=Rika |last11=Yokota |first11=Toshifumi |date=2023-03-08 |title=DG9-conjugated morpholino rescues phenotype in SMA mice by reaching the CNS via a subcutaneous administration |journal=JCI Insight |language=en |volume=8 |issue=5 |article-number=e160516 |doi=10.1172/jci.insight.160516 |pmid=36719755 |issn=0021-9738|pmc=10077475 }}</ref> University College London<ref>{{cite journal | vauthors = Zhou H, Meng J, Marrosu E, Janghra N, Morgan J, Muntoni F | title = Repeated low doses of morpholino antisense oligomer: an intermediate mouse model of spinal muscular atrophy to explore the window of therapeutic response | journal = Human Molecular Genetics | volume = 24 | issue = 22 | pages = 6265–77 | date = November 2015 | pmid = 26264577 | pmc = 4614699 | doi = 10.1093/hmg/ddv329 }}</ref> and at the University of Oxford.<ref>{{cite journal | vauthors = Hammond SM, Hazell G, Shabanpoor F, Saleh AF, Bowerman M, Sleigh JN, Meijboom KE, Zhou H, Muntoni F, Talbot K, Gait MJ, Wood MJ | title = Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 39 | pages = 10962–7 | date = September 2016 | pmid = 27621445 | pmc = 5047168 | doi = 10.1073/pnas.1605731113 | bibcode = 2016PNAS..11310962H | doi-access = free }}</ref>

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 for onasemnogene abeparvovec, Zolgensma). Instead of replacing the ''SMN1'' gene, this strategy makes a permanent change to the ''SMN2'' 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 of ''SMN2'' 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.<ref>{{Cite journal |last1=Li |first1=J. J. |last2=Lin |first2=X. |last3=Tang |first3=C. |last4=Lu |first4=Y. Q. |last5=Hu |first5=X. |last6=Zuo |first6=E. |last7=Li |first7=H. |last8=Ying |first8=W. |last9=Sun |first9=Y. |last10=Lai |first10=L. L. |last11=Chen |first11=H. Z. |last12=Guo |first12=X. X. |last13=Zhang |first13=Q. J. |last14=Wu |first14=S. |last15=Zhou |first15=C. |last16=Shen |first16=X. |last17=Wang |first17=Q. |last18=Lin |first18=M. T. |last19=Ma |first19=L. X. |last20=Wang |first20=N. |last21=Krainer |first21=A. R. |last22=Shi |first22=L. |last23=Yang |first23=H. |last24=Chen |first24=W. J. |title=Disruption of splicing-regulatory elements using CRISPR/Cas9 to rescue spinal muscular atrophy in human iPSCs and mice |journal=National Science Review |date=2019 |volume=7 |issue=1 |pages=92–101 |doi=10.1093/nsr/nwz131 |pmid=34691481 |pmc=8446915 }}</ref>

===''SMN2'' gene activation===

This approach aims at increasing the expression (activity) of the ''SMN2'' gene, thus increasing the amount of full-length SMN protein available. * Oral salbutamol (albuterol), a popular asthma medicine, showed therapeutic potential in SMA both ''in vitro''<ref>{{cite journal | vauthors = Angelozzi C, Borgo F, Tiziano FD, Martella A, Neri G, Brahe C | title = Salbutamol increases SMN mRNA and protein levels in spinal muscular atrophy cells | journal = Journal of Medical Genetics | volume = 45 | issue = 1 | pages = 29–31 | date = January 2008 | pmid = 17932121 | doi = 10.1136/jmg.2007.051177 | s2cid = 29911453 }}</ref> and in three small-scale clinical trials involving patients with SMA types 2 and 3,<ref>{{cite journal | vauthors = 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 | title = Daily salbutamol in young patients with SMA type II | journal = Neuromuscular Disorders | volume = 18 | issue = 7 | pages = 536–40 | date = July 2008 | pmid = 18579379 | doi = 10.1016/j.nmd.2008.05.004 | s2cid = 34334434 }}</ref><ref>{{cite journal | vauthors = Tiziano FD, Lomastro R, Pinto AM, Messina S, D'Amico A, Fiori S, Angelozzi C, Pane M, Mercuri E, Bertini E, Neri G, Brahe C | title = Salbutamol increases survival motor neuron (SMN) transcript levels in leucocytes of spinal muscular atrophy (SMA) patients: relevance for clinical trial design | journal = Journal of Medical Genetics | volume = 47 | issue = 12 | pages = 856–8 | date = December 2010 | pmid = 20837492 | doi = 10.1136/jmg.2010.080366 | s2cid = 21825049 | url = https://hal.archives-ouvertes.fr/hal-00565394/file/PEER_stage2_10.1136%252Fjmg.2010.080366.pdf }}</ref><ref>{{cite journal | vauthors = Morandi L, Abiusi E, Pasanisi MB, Lomastro R, Fiori S, Di Pietro L, Angelini C, Sorarù G, Gaiani A, Mongini T, Vercelli L | doi = 10.1016/j.nmd.2013.06.475 | title=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 | journal=Neuromuscular Disorders | date=2013 | volume=23 | issue=9–10 | page=771 | s2cid = 54398218 }}</ref> besides offering respiratory benefits.

A few compounds initially showed promise but failed to demonstrate efficacy in clinical trials. Butyrates (sodium butyrate and sodium phenylbutyrate) held some promise in ''in vitro'' studies<ref>{{cite journal | vauthors = Chang JG, Hsieh-Li HM, Jong YJ, Wang NM, Tsai CH, Li H | title = Treatment of spinal muscular atrophy by sodium butyrate | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 17 | pages = 9808–13 | date = August 2001 | pmid = 11504946 | pmc = 55534 | doi = 10.1073/pnas.171105098 | bibcode = 2001PNAS...98.9808C | doi-access = free }}</ref><ref>{{cite journal | vauthors = Andreassi C, Angelozzi C, Tiziano FD, Vitali T, De Vincenzi E, Boninsegna A, Villanova M, Bertini E, Pini A, Neri G, Brahe C | title = Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy | journal = European Journal of Human Genetics | volume = 12 | issue = 1 | pages = 59–65 | date = January 2004 | pmid = 14560316 | doi = 10.1038/sj.ejhg.5201102 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Brahe C, Vitali T, Tiziano FD, Angelozzi C, Pinto AM, Borgo F, Moscato U, Bertini E, Mercuri E, Neri G | title = Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients | journal = European Journal of Human Genetics | volume = 13 | issue = 2 | pages = 256–9 | date = February 2005 | pmid = 15523494 | doi = 10.1038/sj.ejhg.5201320 | doi-access = free }}</ref> but a clinical trial in symptomatic people did not confirm their efficacy.<ref>{{cite journal | vauthors = 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 | title = Randomized, double-blind, placebo-controlled trial of phenylbutyrate in spinal muscular atrophy | journal = Neurology | volume = 68 | issue = 1 | pages = 51–5 | date = January 2007 | pmid = 17082463 | doi = 10.1212/01.wnl.0000249142.82285.d6 | s2cid = 30429093 }}</ref> Another clinical trial in pre-symptomatic types 1–2 infants was completed in 2015 but no results have been published.<ref>{{ClinicalTrialsGov|NCT00528268|Study to Evaluate Sodium Phenylbutyrate in Pre-symptomatic Infants With Spinal Muscular Atrophy (STOPSMA)}}</ref> * Valproic acid (VPA) was used in SMA on an experimental basis in the 1990s and 2000s because ''in vitro'' research suggested its moderate effectiveness.<ref>{{cite journal | vauthors = Brichta L, Hofmann Y, Hahnen E, Siebzehnrubl FA, Raschke H, Blumcke I, Eyupoglu IY, Wirth B | title = Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy | journal = Human Molecular Genetics | volume = 12 | issue = 19 | pages = 2481–9 | date = October 2003 | pmid = 12915451 | doi = 10.1093/hmg/ddg256 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Tsai LK, Tsai MS, Ting CH, Li H | title = Multiple therapeutic effects of valproic acid in spinal muscular atrophy model mice | journal = Journal of Molecular Medicine | volume = 86 | issue = 11 | pages = 1243–54 | date = November 2008 | pmid = 18649067 | doi = 10.1007/s00109-008-0388-1 | s2cid = 24565272 }}</ref> However, it demonstrated no efficacy in achievable concentrations when subjected to a large clinical trial.<ref>{{cite journal | vauthors = Swoboda KJ, Scott CB, Crawford TO, Simard LR, Reyna SP, Krosschell KJ, Acsadi G, Elsheik B, Schroth MK, D'Anjou G, LaSalle B, Prior TW, Sorenson SL, Maczulski JA, Bromberg MB, Chan GM, Kissel JT | title = SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy | journal = PLOS ONE| volume = 5 | issue = 8 | article-number = e12140 | date = August 2010 | pmid = 20808854 | pmc = 2924376 | doi = 10.1371/journal.pone.0012140 | collaboration = Project Cure Spinal Muscular Atrophy Investigators Network | veditors = Boutron I | bibcode = 2010PLoSO...512140S | doi-access = free }}</ref><ref>{{cite journal | vauthors = Kissel JT, Scott CB, Reyna SP, Crawford TO, Simard LR, Krosschell KJ, Acsadi G, Elsheik B, Schroth MK, D'Anjou G, LaSalle B, Prior TW, Sorenson S, Maczulski JA, Bromberg MB, Chan GM, Swoboda KJ | title = SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy | journal = PLOS ONE| volume = 6 | issue = 7 | article-number = e21296 | year = 2011 | pmid = 21754985 | pmc = 3130730 | doi = 10.1371/journal.pone.0021296 | collaboration = Project Cure Spinal Muscular Atrophy Investigators' Network | bibcode = 2011PLoSO...621296K | doi-access = free }}</ref><ref>{{cite journal | vauthors = Darbar IA, Plaggert PG, Resende MB, Zanoteli E, Reed UC | title = Evaluation of muscle strength and motor abilities in children with type II and III spinal muscle atrophy treated with valproic acid | journal = BMC Neurology | volume = 11 | article-number = 36 | date = March 2011 | pmid = 21435220 | pmc = 3078847 | doi = 10.1186/1471-2377-11-36 | doi-access = free }}</ref> It has also been proposed that it may be effective in a subset of people with SMA but its action may be suppressed by fatty acid translocase in others.<ref>{{cite journal | vauthors = Garbes L, Heesen L, Hölker I, Bauer T, Schreml J, Zimmermann K, Thoenes M, Walter M, Dimos J, Peitz M, Brüstle O, Heller R, Wirth B | title = VPA response in SMA is suppressed by the fatty acid translocase CD36 | journal = Human Molecular Genetics | volume = 22 | issue = 2 | pages = 398–407 | date = January 2013 | pmid = 23077215 | doi = 10.1093/hmg/dds437 | doi-access = free }}</ref> Others argue it may actually aggravate SMA symptoms.<ref>{{cite journal | vauthors = Rak K, Lechner BD, Schneider C, Drexl H, Sendtner M, Jablonka S | title = Valproic acid blocks excitability in SMA type I mouse motor neurons | journal = Neurobiology of Disease | volume = 36 | issue = 3 | pages = 477–87 | date = December 2009 | pmid = 19733665 | doi = 10.1016/j.nbd.2009.08.014 | s2cid = 34657615 }}</ref> 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.<ref>{{cite journal | vauthors = Elshafay A, Hieu TH, Doheim MF, Kassem MA, ELdoadoa MF, Holloway SK, Abo-Elghar H, Hirayama K, Huy NT | title = Efficacy and Safety of Valproic Acid for Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis | journal = CNS Drugs | volume = 33 | issue = 3 | pages = 239–250 | date = March 2019 | pmid = 30796634 | doi = 10.1007/s40263-019-00606-6 | s2cid = 73495750 }}</ref> * Hydroxycarbamide (hydroxyurea) was shown effective in mouse models<ref>{{cite journal | vauthors = Grzeschik SM, Ganta M, Prior TW, Heavlin WD, Wang CH | title = Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells | journal = Annals of Neurology | volume = 58 | issue = 2 | pages = 194–202 | date = August 2005 | pmid = 16049920 | doi = 10.1002/ana.20548 | s2cid = 19509393 }}</ref> and subsequently commercially researched by Novo Nordisk, Denmark, but demonstrated no effect on people with SMA in subsequent clinical trials.<ref>{{cite journal | vauthors = Chen TH, Chang JG, Yang YH, Mai HH, Liang WC, Wu YC, Wang HY, Huang YB, Wu SM, Chen YC, Yang SN, Jong YJ | title = Randomized, double-blind, placebo-controlled trial of hydroxyurea in spinal muscular atrophy | journal = Neurology | volume = 75 | issue = 24 | pages = 2190–7 | date = December 2010 | pmid = 21172842 | doi = 10.1212/WNL.0b013e3182020332 | s2cid = 25858890 }}</ref>

Compounds which increased ''SMN2'' activity ''in vitro'' but did not make it to the clinical stage include growth hormone, various histone deacetylase inhibitors,<ref>{{cite journal | vauthors = Evans MC, Cherry JJ, Androphy EJ | title = Differential regulation of the SMN2 gene by individual HDAC proteins | journal = Biochemical and Biophysical Research Communications | volume = 414 | issue = 1 | pages = 25–30 | date = October 2011 | pmid = 21925145 | doi = 10.1016/j.bbrc.2011.09.011 | pmc = 6538936 | bibcode = 2011BBRC..414...25E }}</ref> benzamide M344,<ref>{{cite journal | vauthors = Riessland M, Brichta L, Hahnen E, Wirth B | title = The benzamide M344, a novel histone deacetylase inhibitor, significantly increases SMN2 RNA/protein levels in spinal muscular atrophy cells | journal = Human Genetics | volume = 120 | issue = 1 | pages = 101–10 | date = August 2006 | pmid = 16724231 | doi = 10.1007/s00439-006-0186-1 | s2cid = 24804136 }}</ref> hydroxamic acids (CBHA, SBHA, entinostat, panobinostat,<ref>{{cite journal | vauthors = Garbes L, Riessland M, Hölker I, Heller R, Hauke J, Tränkle C, Coras R, Blümcke I, Hahnen E, Wirth B | title = 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 | journal = Human Molecular Genetics | volume = 18 | issue = 19 | pages = 3645–58 | date = October 2009 | pmid = 19584083 | doi = 10.1093/hmg/ddp313 | doi-access = }}</ref> trichostatin A,<ref>{{cite journal | vauthors = Narver HL, Kong L, Burnett BG, Choe DW, Bosch-Marcé M, Taye AA, Eckhaus MA, Sumner CJ | title = Sustained improvement of spinal muscular atrophy mice treated with trichostatin A plus nutrition | journal = Annals of Neurology | volume = 64 | issue = 4 | pages = 465–70 | date = October 2008 | pmid = 18661558 | doi = 10.1002/ana.21449 | pmc = 10103738 | s2cid = 5595968 }}</ref><ref>{{cite journal | vauthors = Avila AM, Burnett BG, Taye AA, Gabanella F, Knight MA, Hartenstein P, Cizman Z, Di Prospero NA, Pellizzoni L, Fischbeck KH, Sumner CJ | title = Trichostatin A increases SMN expression and survival in a mouse model of spinal muscular atrophy | journal = The Journal of Clinical Investigation | volume = 117 | issue = 3 | pages = 659–71 | date = March 2007 | pmid = 17318264 | pmc = 1797603 | doi = 10.1172/JCI29562 }}</ref> vorinostat<ref>{{cite journal | vauthors = Riessland M, Ackermann B, Förster A, Jakubik M, Hauke J, Garbes L, Fritzsche I, Mende Y, Blumcke I, Hahnen E, Wirth B | title = SAHA ameliorates the SMA phenotype in two mouse models for spinal muscular atrophy | journal = Human Molecular Genetics | volume = 19 | issue = 8 | pages = 1492–506 | date = April 2010 | pmid = 20097677 | doi = 10.1093/hmg/ddq023 | doi-access = free }}</ref>), prolactin<ref>{{cite journal | vauthors = Farooq F, Molina FA, Hadwen J, MacKenzie D, Witherspoon L, Osmond M, Holcik M, MacKenzie A | title = Prolactin increases SMN expression and survival in a mouse model of severe spinal muscular atrophy via the STAT5 pathway | journal = The Journal of Clinical Investigation | volume = 121 | issue = 8 | pages = 3042–50 | date = August 2011 | pmid = 21785216 | pmc = 3148738 | doi = 10.1172/JCI46276 }}</ref> as well as natural polyphenol compounds like resveratrol and curcumin.<ref>{{cite journal | vauthors = Sakla MS, Lorson CL | title = Induction of full-length survival motor neuron by polyphenol botanical compounds | journal = Human Genetics | volume = 122 | issue = 6 | pages = 635–43 | date = January 2008 | pmid = 17962980 | doi = 10.1007/s00439-007-0441-0 | s2cid = 12460406 }}</ref><ref>{{cite journal | vauthors = Dayangaç-Erden D, Bora G, Ayhan P, Kocaefe C, Dalkara S, Yelekçi K, Demir AS, Erdem-Yurter H | title = Histone deacetylase inhibition activity and molecular docking of (e )-resveratrol: its therapeutic potential in spinal muscular atrophy | journal = Chemical Biology & Drug Design | volume = 73 | issue = 3 | pages = 355–64 | date = March 2009 | pmid = 19207472 | doi = 10.1111/j.1747-0285.2009.00781.x | citeseerx = 10.1.1.515.8424 | s2cid = 764215 }}</ref> Celecoxib, a p38 pathway activator, is sometimes used off-label by people with SMA based on a single animal study<ref>{{cite journal | vauthors = Farooq F, Abadía-Molina F, MacKenzie D, Hadwen J, Shamim F, O'Reilly S, Holcik M, MacKenzie A | title = Celecoxib increases SMN and survival in a severe spinal muscular atrophy mouse model via p38 pathway activation | journal = Human Molecular Genetics | volume = 22 | issue = 17 | pages = 3415–24 | date = September 2013 | pmid = 23656793 | doi = 10.1093/hmg/ddt191 | doi-access = free }}</ref> but such use is not backed by clinical-stage research.

===SMN stabilisation===

SMN stabilisation aims at stabilising the SMNΔ7 protein, the short-lived defective protein coded by the ''SMN2'' gene, so that it is able to sustain neuronal cells.<ref>{{cite journal | vauthors = Burnett BG, Muñoz E, Tandon A, Kwon DY, Sumner CJ, Fischbeck KH | title = Regulation of SMN protein stability | journal = Molecular and Cellular Biology | volume = 29 | issue = 5 | pages = 1107–15 | date = March 2009 | pmid = 19103745 | pmc = 2643817 | doi = 10.1128/MCB.01262-08 }}</ref>

No compounds have been taken forward to the clinical stage. Aminoglycosides showed the capability to increase SMN protein availability in two studies.<ref>{{cite journal | vauthors = Mattis VB, Rai R, Wang J, Chang CW, Coady T, Lorson CL | title = Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts | journal = Human Genetics | volume = 120 | issue = 4 | pages = 589–601 | date = November 2006 | pmid = 16951947 | doi = 10.1007/s00439-006-0245-7 | s2cid = 28834037 }}</ref><ref>{{cite journal | vauthors = Mattis VB, Fosso MY, Chang CW, Lorson CL | title = Subcutaneous administration of TC007 reduces disease severity in an animal model of SMA | journal = BMC Neuroscience | volume = 10 | article-number = 142 | date = November 2009 | pmid = 19948047 | pmc = 2789732 | doi = 10.1186/1471-2202-10-142 | doi-access = free }}</ref> Indoprofen offered some promise ''in vitro''.<ref>{{cite journal | vauthors = Lunn MR, Root DE, Martino AM, Flaherty SP, Kelley BP, Coovert DD, Burghes AH, Man NT, Morris GE, Zhou J, Androphy EJ, Sumner CJ, Stockwell BR | title = Indoprofen upregulates the survival motor neuron protein through a cyclooxygenase-independent mechanism | journal = Chemistry & Biology | volume = 11 | issue = 11 | pages = 1489–93 | date = November 2004 | pmid = 15555999 | pmc = 3160629 | doi = 10.1016/j.chembiol.2004.08.024 }}</ref>

===Neuroprotection===

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 company Trophos, later acquired by Hoffmann-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.<ref>{{cite web|url=https://www.fiercebiotech.com/biotech/roche-scraps-eu120m-sma-drug-after-hitting-many-difficulties|title=Roche scraps €120M SMA drug after hitting 'many difficulties'|last=Taylor|first=Nick P. | name-list-style = vanc |date=2018-06-01|website=www.fiercebiotech.com |access-date=2018-06-08}}</ref>

Of clinically studied compounds which did not show efficacy, thyrotropin-releasing hormone (TRH) held some promise in an open-label uncontrolled clinical trial<ref>{{cite journal | vauthors = Takeuchi Y, Miyanomae Y, Komatsu H, Oomizono Y, Nishimura A, Okano S, Nishiki T, Sawada T | title = Efficacy of thyrotropin-releasing hormone in the treatment of spinal muscular atrophy | journal = Journal of Child Neurology | volume = 9 | issue = 3 | pages = 287–9 | date = July 1994 | pmid = 7930408 | doi = 10.1177/088307389400900313 | s2cid = 41678161 }}</ref><ref>{{cite journal | vauthors = Tzeng AC, Cheng J, Fryczynski H, Niranjan V, Stitik T, Sial A, Takeuchi Y, Foye P, DePrince M, Bach JR | title = A study of thyrotropin-releasing hormone for the treatment of spinal muscular atrophy: a preliminary report | journal = American Journal of Physical Medicine & Rehabilitation | volume = 79 | issue = 5 | pages = 435–40 | year = 2000 | pmid = 10994885 | doi = 10.1097/00002060-200009000-00005 | s2cid = 20416253 }}</ref><ref>{{cite journal | vauthors = Kato Z, Okuda M, Okumura Y, Arai T, Teramoto T, Nishimura M, Kaneko H, Kondo N | title = Oral administration of the thyrotropin-releasing hormone (TRH) analogue, taltireline hydrate, in spinal muscular atrophy | journal = Journal of Child Neurology | volume = 24 | issue = 8 | pages = 1010–2 | date = August 2009 | pmid = 19666885 | doi = 10.1177/0883073809333535 | s2cid = 29321906 }}</ref> but did not prove effective in a subsequent double-blind placebo-controlled trial.<ref>{{cite journal | vauthors = Wadman RI, Bosboom WM, van den Berg LH, Wokke LH, Iannaccone ST, Vrancken AF |editor1-first =Renske I |editor1-last =Wadman |title =Drug treatment for spinal muscular atrophy type I |date=2011-12-07 | collaboration = The Cochrane Collaboration |publisher=John Wiley & Sons, Ltd |doi=10.1002/14651858.cd006281.pub3 |journal =Cochrane Database of Systematic Reviews |issue =12 |article-number =CD006281 |pmid =22161399 }}</ref> Riluzole, a drug that offers limited clinical benefit in amyotrophic lateral sclerosis, was proposed to be similarly tested in SMA;<ref>{{cite journal | vauthors = Haddad H, Cifuentes-Diaz C, Miroglio A, Roblot N, Joshi V, Melki J | title = Riluzole attenuates spinal muscular atrophy disease progression in a mouse model | journal = Muscle & Nerve | volume = 28 | issue = 4 | pages = 432–7 | date = October 2003 | pmid = 14506714 | doi = 10.1002/mus.10455 | s2cid = 10300057 }}</ref><ref>{{cite journal | vauthors = Dimitriadi M, Kye MJ, Kalloo G, Yersak JM, Sahin M, Hart AC | title = The neuroprotective drug riluzole acts via small conductance Ca2+-activated K+ channels to ameliorate defects in spinal muscular atrophy models | journal = The Journal of Neuroscience | volume = 33 | issue = 15 | pages = 6557–62 | date = April 2013 | pmid = 23575853 | pmc = 3652322 | doi = 10.1523/JNEUROSCI.1536-12.2013 }}</ref> however, a 2008–2010 trial in SMA types 2 and 3<ref>{{ClinicalTrialsGov|NCT00774423|Study to Evaluate the Efficacy of Riluzole in Children and Young Adults With Spinal Muscular Atrophy (SMA)}}</ref> was stopped early due to the lack of satisfactory results.<ref>{{cite web | url=http://amyotrophies-spinales.blogs.afm-telethon.fr/archives/category/c_-_la_recherche/index-7.html | title=Riluzole: premiers résultats décevants | publisher=AFM Téléthon | date=2010-09-22 | language=fr | access-date=16 March 2017 | archive-date=8 December 2017 | archive-url=https://web.archive.org/web/20171208174814/http://amyotrophies-spinales.blogs.afm-telethon.fr/archives/category/c_-_la_recherche/index-7.html }}</ref> Other compounds that displayed some neuroprotective effect in ''in vitro'' research but never moved on to ''in vivo'' studies include β-lactam antibiotics (e.g., ceftriaxone)<ref>{{cite journal | vauthors = Nizzardo M, Nardini M, Ronchi D, Salani S, Donadoni C, Fortunato F, Colciago G, Falcone M, Simone C, Riboldi G, Govoni A, Bresolin N, Comi GP, Corti S | title = Beta-lactam antibiotic offers neuroprotection in a spinal muscular atrophy model by multiple mechanisms | journal = Experimental Neurology | volume = 229 | issue = 2 | pages = 214–25 | date = June 2011 | pmid = 21295027 | doi = 10.1016/j.expneurol.2011.01.017 | hdl = 2434/425410 | s2cid = 47567316 | url = https://air.unimi.it/bitstream/2434/425410/2/Bhatia_Annals_BetaLactim_2011.pdf | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Hedlund E | title = The protective effects of β-lactam antibiotics in motor neuron disorders | journal = Experimental Neurology | volume = 231 | issue = 1 | pages = 14–8 | date = September 2011 | pmid = 21693120 | doi = 10.1016/j.expneurol.2011.06.002 | s2cid = 26353910 }}</ref> and follistatin.<ref>{{cite journal | vauthors = Rose FF, Mattis VB, Rindt H, Lorson CL | title = Delivery of recombinant follistatin lessens disease severity in a mouse model of spinal muscular atrophy | journal = Human Molecular Genetics | volume = 18 | issue = 6 | pages = 997–1005 | date = March 2009 | pmid = 19074460 | pmc = 2649020 | doi = 10.1093/hmg/ddn426 }}</ref>

=== Muscle restoration ===

This approach aims to counter the effect of SMA by targeting the muscle tissue instead of neurons. * Reldesemtiv (CK-2127107, CK-107) is a skeletal troponin activator developed by Cytokinetics in cooperation with Astellas. 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.<ref>{{cite web | url=http://cytokinetics.com/ck-2127107|title=CK-2127107 }}</ref> * Apitegromab (SRK-015) is monoclonal antibody that blocks the activation of the skeletal muscle protein myostatin, 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.<ref>{{Cite web|date=2021-04-06|title=Scholar Rock Announces Positive 12-Month Top-Line Results From the TOPAZ Phase 2 Clinical Trial Evaluating Apitegromab in Patients With Type 2 and Type 3 Spinal Muscular Atrophy (SMA)|url=https://www.businesswire.com/news/home/20210406005338/en/Scholar-Rock-Announces-Positive-12-Month-Top-Line-Results-From-the-TOPAZ-Phase-2-Clinical-Trial-Evaluating-Apitegromab-in-Patients-With-Type-2-and-Type-3-Spinal-Muscular-Atrophy-SMA|access-date=2021-05-13|website=www.businesswire.com|language=en}}</ref> * 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.<ref>{{Cite web|last=PhD|first=Patricia Inacio|title=Pediatric Phase 2/3 Trial to Test Anti-myostatin Antibody with Evrysdi|date=25 October 2021 |url=https://smanewstoday.com/news-posts/2021/10/25/pediatric-phase-2-3-trial-test-anti-myostatin-antibody-gym329-with-evrysdi/|access-date=2022-01-23|language=en-US}}</ref>

===Stem cells=== 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 of media 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.<ref>{{cite journal | author = Committee for Advanced Therapies and CAT Scientific Secretariat | title = Use of unregulated stem-cell based medicinal products | journal = Lancet | volume = 376 | issue = 9740 | page = 514 | date = August 2010 | pmid = 20709228 | doi = 10.1016/S0140-6736(10)61249-4 | s2cid = 6906599 }}</ref><ref>{{cite web | url=http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2010/04/WC500089472.pdf | title=Concerns over unregulated medicinal products containing stem cells | author=European Medicines Agency | publisher=European Medicines Agency | date=16 April 2010 | author-link=European Medicines Agency | access-date=29 June 2016 | archive-date=10 May 2017 | archive-url=https://web.archive.org/web/20170510173936/http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2010/04/WC500089472.pdf }}</ref> In 2013–2014, a small number of SMA1 children in Italy received court-mandated stem cell injections following the Stamina scam, but the treatment was reported having no effect<ref>{{cite journal|vauthors=Carrozzi M, Amaddeo A, Biondi A, Zanus C, Monti F, Alessandro V|date=November 2012|title=Stem cells in severe infantile spinal muscular atrophy (SMA1)|journal=Neuromuscular Disorders|volume=22|issue=11|pages=1032–4|doi=10.1016/j.nmd.2012.09.005|pmid=23046997|s2cid=42093152}}</ref><ref>{{cite journal|vauthors=Mercuri E, Bertini E|date=December 2012|title=Stem cells in severe infantile spinal muscular atrophy|journal=Neuromuscular Disorders|volume=22|issue=12|page=1105|doi=10.1016/j.nmd.2012.11.001|pmid=23206850|s2cid=43858783}}</ref>

=== Registries ===

People with SMA in the European Union can participate in clinical research by entering their details into registries managed by TREAT-NMD.<ref>{{cite web | url=http://www.treat-nmd.eu/resources/patient-registries/national-registries|title=National registries for DMD, SMA and DM|archive-url=https://web.archive.org/web/20110122230752/http://www.treat-nmd.eu/resources/patient-registries/national-registries/|archive-date=22 January 2011 }}</ref>

== See also == * Motor neuron disease * Distal spinal muscular atrophy type 1 * Distal spinal muscular atrophy type 2

== References == {{Reflist}}

== Further reading == {{refbegin}} * {{cite journal | vauthors = Parano E, Pavone L, Falsaperla R, Trifiletti R, Wang C | title = Molecular basis of phenotypic heterogeneity in siblings with spinal muscular atrophy | journal = Annals of Neurology | volume = 40 | issue = 2 | pages = 247–51 | date = August 1996 | pmid = 8773609 | doi = 10.1002/ana.410400219 | s2cid = 42514712 }} * {{cite journal | vauthors = Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main M, Crawford TO, Trela A | title = Consensus statement for standard of care in spinal muscular atrophy | journal = Journal of Child Neurology | volume = 22 | issue = 8 | pages = 1027–49 | date = August 2007 | pmid = 17761659 | doi = 10.1177/0883073807305788 | s2cid = 6478040 }} {{refend}}

== External links == {{Commons}} * {{NINDS|Spinal-Muscular-Atrophy|SMA}} * [https://smartmoves.curesma.org/ SMArt Moves]. Cure SMA. Retrieved 3 December 2021.

{{Diseases of the nervous system}} {{Nucleus diseases}} {{Medical resources | DiseasesDB = 14093 | ICD10 = {{ICD10|G|12|0|g|10}}-{{ICD10|G|12|1|g|10}} | ICD9 = {{ICD9|335.0}}-{{ICD9|335.1}} | ICDO = | OMIM = 253300 | OMIM_mult = {{OMIM|253550||none}} {{OMIM|253400||none}} {{OMIM|271150||none}} | MedlinePlus = 000996 | eMedicine_mult = {{eMedicine2|article|1181436|Spinal Muscular Atrophy}}<br />{{eMedicine2|article|1264401|Spinal Muscle Atrophy }}<br />{{eMedicine2|article|306812|Kugelberg–Welander SMA}} | MeshID = D014897 | GeneReviewsNBK = NBK1352 | GeneReviewsName = Spinal Muscular Atrophy }} {{Authority control}}

Category:Spinal muscular atrophy Category:Motor neuron diseases Category:Autosomal recessive disorders Category:Nucleus diseases Category:Systemic atrophies primarily affecting the central nervous system Category:Neuromuscular disorders Category:Wikipedia medicine articles ready to translate