Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting.

[2][8] 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.

[4] Spinal muscular atrophy is due to an abnormality (mutation) in the SMN1 gene[1][2] which encodes SMN, a protein necessary for survival of motor neurons.

[9][1] 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).

[2] 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.

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.

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.

)[18] 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.

Signs and symptoms below are most common in the severe SMA type 0/I:[19][medical citation needed] Spinal muscular atrophy is caused by a genetic mutation in the SMN1 gene.

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.

[citation needed] SMA is diagnosed using genetic testing that detects homozygous deletion of the SMN1 gene in over 95% of cases,[19] and a compound SMN1 mutation in the remaining patients.

[19] 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] Prenatal testing for SMA is possible through chorionic villus sampling, cell-free fetal DNA analysis and other methods.

[citation needed] Routine newborn screening for SMA is becoming increasingly commonplace in developed countries, given the availability of causative treatments that are most effective at the asymptomatic stage of the disease.

[45][46][47] 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.

[54][55] 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.

Other nutritional issues, especially in individuals that are non-ambulatory (more severe types of SMA), include food not passing through the stomach quickly enough, gastric reflux, constipation, vomiting and bloating.

[68][medical citation needed] Skeletal problems associated with weak muscles in SMA include tight joints with limited range of movement, hip dislocations, spinal deformity, osteopenia, an increase risk of fractures and pain.

Furthermore, immobile individuals, posture and position on mobility devices as well as range of motion exercises, and bone strengthening can be important to prevent complications.

[69][70][71][72] 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.

[77] If left untreated, the majority of children diagnosed with SMA type 0 and 1 do not reach the age of 4, recurrent respiratory problems being the primary cause of death.

[citation needed] Since the underlying genetic cause of SMA was identified in 1995,[22] several therapeutic approaches have been proposed and investigated that primarily focus on increasing the availability of SMN protein in motor neurons.

[82] This approach aims at modifying the alternative splicing of the SMN2 gene to force it to code for higher percentage of full-length SMN protein.

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.

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.

[116][117] Celecoxib, a p38 pathway activator, is sometimes used off-label by people with SMA based on a single animal study[118] but such use is not backed by clinical-stage research.

[131] 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)[132][133] and follistatin.

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.

[138][139] 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[140][141] People with SMA in the European Union can participate in clinical research by entering their details into registries managed by TREAT-NMD.