spinal muscular atrophy spinal muscular atrophy spinal muscular atrophy (sma) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. it is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic cause of infant death. it may also appear later in life and then have a milder course of the disease. the common feature is progressive weakness of voluntary muscles, with arm, leg and respiratory muscles being affected first. associated problems may include poor head control, difficulties swallowing, scoliosis, and joint contractures. this article is about the genetic disorder associated with the smn1 gene on chromosome 5q. for a list of conditions with similar names, see spinal muscular atrophies. spinal muscular atrophyother namesautosomal recessive proximal spinal muscular atrophy, 5q spinal muscular atrophylocation of neurons affected by spinal muscular atrophy in the spinal cordspecialtyneurologysymptomsprogressive muscle weaknesscomplicationsscoliosis, joint contractures, pneumoniausual onsetmutation is congenital, symptoms start varies by typedurationlifelongtypestype 0 to type 4causesmutation in smn1diagnostic methodgenetic testingdifferential diagnosiscongenital muscular dystrophy, duchenne muscular dystrophy, prader-willi syndrometreatmentsupportive care, medicationsmedicationnusinersen, onasemnogene abeparvovec, risdiplamprognosisvaries by typefrequency1 in 10,000 people the age of onset and the severity of symptoms form the basis of the traditional classification of spinal muscular atrophy into a number of types. spinal muscular atrophy is due to an abnormality (mutation) in the smn1 gene which encodes smn, a protein necessary for survival of motor neurons. loss of these neurons in the spinal cord prevents signalling between the brain and skeletal muscles. another gene, smn2, is considered a disease modifying gene, since usually the more the smn2 copies, the milder is the disease course. the diagnosis of sma is based on symptoms and confirmed by genetic testing. 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). the incidence of spinal muscular atrophy worldwide varies from about 1 in 4,000 births to around 1 in 16,000 births, with 1 in 7,000 and 1 in 10,000 commonly quoted for europe and the us respectively. 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. the introduction of causative treatments in 2016 has significantly improved the outcomes. medications that target the genetic cause of the disease include nusinersen, risdiplam, and the gene therapy medication onasemnogene abeparvovec. supportive care includes physical therapy, occupational therapy, respiratory support, nutritional support, orthopaedic interventions, and mobility support. 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. 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. currently, the consensus is that the phenotype of spinal muscular atrophy spans a continuum of symptoms without clear delineation of subtypes. 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. type eponym usual age of 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(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. 253300 sma 2(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. 253550 sma 3(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. 253400 sma 4(adult onset) adulthood this denotes the adult-onset form, sometimes also classified as a late-onset sma type 3. it occurs in approx. 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. 271150 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) 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. 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. 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. signs and symptoms 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: 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: adopting 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 spinal muscular atrophy has an autosomal recessive pattern of inheritance. spinal muscular atrophy is caused by a genetic mutation in the smn1 gene. 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 the survival of motor neuron protein (smn) which, as its name says, plays a crucial role in 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. 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 occurring at exon 7 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 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). muscles of lower extremities are usually affected first, followed by muscles of 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. 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. 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. 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. 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. 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. diagnosis sma is diagnosed using genetic testing that detects homozygous deletion of the smn1 gene in over 95% of cases, and a compound smn1 mutation in the