Spinal muscular atrophy


Spinal muscular atrophy is a group of neuromuscular disorders that result in the loss of motor neurons and progressive muscle wasting. The severity of symptoms and age of onset varies by the type. Some types are apparent at or before birth while others are not apparent until adulthood. All generally result in worsening muscle weakness associated with muscle twitching. Arm, leg and respiratory muscles are generally affected first. Associated problems may include problems with swallowing, scoliosis, and joint contractures. SMA is a leading genetic cause of death in infants.
Spinal muscular atrophy is due to a genetic defect in the SMN1 gene. They are generally inherited from a person's parents in an autosomal recessive manner. In 2% of cases, one of the mutations occurs during early development and one is inherited from a parent. The SMN1 gene encodes SMN, a protein necessary for survival of motor neurons. Loss of these neurons prevents the sending of signals between the brain and skeletal muscles. Diagnosis is suspected based on symptoms and confirmed by genetic testing.
Treatments include supportive care such as physical therapy, nutrition support, and mechanical ventilation. The medication nusinersen, which is injected around the spinal cord, slows the progression of the disease and improves muscle function. In 2019, the gene therapy onasemnogene abeparvovec was approved in the US as a treatment for children under 24 months. Outcomes vary by type from a life expectancy of a few months to mild muscle weakness with a normal life expectancy. The condition affects about 1 in 10,000 people at birth.

Classification

SMA manifests over a wide range of severity, affecting infants through adults. The disease spectrum has been divided into 3–5 types in accordance with the highest attained milestone in motor development.
The traditional, most commonly used classification is as follows:
TypeEponymUsual age of onsetCharacteristicsOMIM
SMA 0PrenatalA very rare form whose symptoms become apparent before birth. Affected children typically have only 1 copy of the SMN2 gene and usually survive only a few weeks even with intensive respiratory support.
SMA 1
Werdnig–Hoffmann disease0–6 monthsThe severe form manifests in the first months of life, usually with a quick and unexpected onset. Children never learn to sit unsupported. Rapid motor neuron death causes inefficiency of the major bodily organs – especially of the respiratory system. Pneumonia-induced respiratory failure is the most frequent cause of death. Untreated and without respiratory support, 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.
SMA 2
Dubowitz disease6–18 monthsThe intermediate form affects 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. Scoliosis is usually present in these children, and correction with a spinal brace, growing rods or spinal fusion may help improve respiration. Body muscles are weakened, and the respiratory system is a major concern. Life expectancy is reduced but most people with SMA 2 live well into adulthood.
SMA 3
Kugelberg–Welander disease>12 monthsThe juvenile form usually manifests after 12 months of age and describes people who have been able to walk without support at least for some time in their lives, even if they later lost this ability. Respiratory involvement is less frequent, and life expectancy is normal or near normal. Most people with SMA 3 require mobility support.
SMA 4
AdulthoodThe adult-onset form usually manifests after the third decade of life with gradual weakening of leg muscles, frequently requiring the person to use walking aids. Other complications are rare and life expectancy is unaffected.

Newer classifications 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 or HINE in infants; and either the MFM or one of a few variants of the HFMS in older patients.
The eponymous label Werdnig–Hoffmann disease refers to the earliest clinical descriptions of childhood SMA by Johann Hoffmann and Guido Werdnig. The eponymous term Kugelberg–Welander disease is after Erik Klas Hendrik Kugelberg and Lisa Welander, who distinguished SMA from muscular dystrophy. Rarely used Dubowitz disease is named after Victor Dubowitz, an English neurologist who authored several studies on the intermediate SMA phenotype.

Signs and symptoms

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:
Spinal muscular atrophy is linked to 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 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 – 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 and 80–90% of transcripts resulting in a truncated protein compound 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. Almost all people, however, have at least one functional copy of the SMN2 gene which still codes small amounts of SMN protein – around 10–20% of the normal level – allowing some neurons to survive. In the long run, however, reduced availability of the SMN protein results in gradual death of motor neuron cells in the anterior horn of spinal cord and the brain. Muscles that depend on these motor neurons for neural input now have decreased innervation, and therefore have decreased input from the central nervous system. Decreased impulse transmission through the motor neurons leads to decreased contractile activity of the denervated muscle. Consequently, denervated muscles undergo progressive atrophy.
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 always affected earlier and to a greater degree than distal.
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 is partly related to the number of SMN2 gene copies present on the chromosome. Whilst healthy individuals carry two SMN2 gene copies, people with SMA can have anything between 1 and 4 of them, with 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 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

The most severe manifestation on the SMA spectrum can be noticeable to mothers late in their pregnancy by reduced or absent fetal movements. Symptoms are critical which usually result in death within weeks, in contrast to the mildest phenotype of SMA, where muscle weakness may present after decades and progress to the use of a wheelchair but life expectancy is unchanged.
The more common clinical manifestations of the SMA spectrum that prompt diagnostic genetic testing:
While the above symptoms point towards SMA, the diagnosis can only be confirmed with absolute certainty through genetic testing for bi-allelic deletion of exon 7 of the SMN1 gene which is the cause in over 95% of cases. Genetic testing is usually carried out using a blood sample, and MLPA is one of more frequently used genetic testing techniques, as it also allows establishing the number of SMN2 gene copies.

Preimplantation testing

can be used to screen for SMA-affected embryos during in-vitro fertilisation.

Prenatal testing

for SMA is possible through chorionic villus sampling, cell-free fetal DNA analysis and other methods.

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 all people thinking of becoming pregnant be tested to see if they are a carrier.
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 populations 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.

Newborn screening

Given the availability of treatments that appear most effective in early stages of the disease, a number of experts have recommended to routinely test all newborn children for SMA. In 2018, newborn screening for SMA was added to the US list of recommended newborn screening tests and as of May 2020 it has been adopted in 36 US states. Since 2020, SMA newborn screening is mandated in the Netherlands. Additionally, pilot projects in newborn screening for SMA have been conducted in Australia, Belgium, China, Germany, Italy, Japan, Taiwan, and the US.

Management

The management of SMA varies based upon the severity and type. In the most severe forms, individuals have the greatest muscle weakness requiring prompt intervention. Whereas the least severe form, individuals may not seek the certain aspects of care until later in life. While types of SMA and individuals among each type may differ, therefore specific aspects of an individual's care can differ.

Medication

is used to treat spinal muscular atrophy. It is an antisense nucleotide that modifies the alternative splicing of the SMN2 gene. It is given directly to the central nervous system using an intrathecal injection. Nusinersen prolongs survival and improves motor function in infants with SMA. It was approved in the US in 2016 and in the EU in 2017.
Onasemnogene abeparvovec is a gene therapy treatment which uses self-complementary adeno-associated virus type 9 as a vector to deliver the SMN1 transgene. As an intravenous formulation, it was approved in 2019 in the US to treat those below 24 months of age. As of 2019, approvals in the EU and Japan are pending while an intrathecal formulation for older people is in development.

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 more rare. The complications that arise due to weakened intercostal muscles because of the lack of stimulation from the nerve. The diaphragm is less affected than the intercostal muscles. 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 pose a risk of not getting enough oxygen/shallow breathing and insufficient clearance of airway secretions. These issues more commonly occurs 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. 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 is frequently used and tracheostomy may be sometimes performed in more severe cases; both methods of ventilation prolong survival to a comparable degree, although tracheostomy prevents speech development.

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 increase risk of over or undernutrition, failure to thrive and aspiration. Other nutritional issues, especially in individuals that are non-ambulatory, include food not passing through the stomach quickly enough, gastric reflux, constipation, vomiting and bloating. Therein, it could be necessary in SMA type I and people with more severe type II to have a feeding tube or gastrostomy. 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. It is suggested that people with SMA, especially those with more severe forms of the disease, reduce intake of fat and avoid prolonged fasting as well as choosing softer foods to avoid aspiration. During an acute illness, especially in children, nutritional problems may first present or can exacerbate an existing problem as well as cause other health issues such as electrolyte and blood sugar disturbances.

Orthopaedics

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. Weak muscles that normally stabilize joints such as the vertebral column lead to development of kyphosis and/or scoliosis and joint contracture. 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. People with SMA might also benefit greatly from various forms of physiotherapy, occupational therapy and physical therapy.
Orthotic devices can be used to support the body and to aid walking. For example, orthotics such as AFOs are used to stabilise the foot and to aid gait, TLSOs are used to stabilise the torso. Assistive technologies may help in managing movement and daily activity and greatly increase the quality of life.

Other

Although the heart is not a matter of routine concern, a link between SMA and certain heart conditions has been suggested.
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. Despite their disability, SMA-affected people report high degree of satisfaction from life.
Palliative care in SMA has been standardised in the Consensus Statement for Standard of Care in Spinal Muscular Atrophy which has been recommended for standard adoption worldwide.

Prognosis

In lack 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.
If left untreated, the majority of children diagnosed with SMA type 0 and I do not reach the age of 4, recurrent respiratory problems being the primary cause of death. With proper care, milder SMA type I cases live into adulthood. Long-term survival in SMA type I is not sufficiently evidenced; however, recent advances in respiratory support seem to have brought down mortality.
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.

Research directions

Since the underlying genetic cause of SMA was identified in 1995, several therapeutic approaches have been proposed and investigated that primarily focus on increasing the availability of SMN protein in motor neurons. The main research directions are as follows:

''SMN1'' gene replacement

in SMA aims at restoring the SMN1 gene function through inserting specially crafted nucleotide sequence into the cell nucleus using a viral vector; scAAV-9 and scAAV-10 are the primary viral vectors under investigation. In 2019 an AAV9 therapy was approved: Onasemnogene abeparvovec.
Only one programme has reached the clinical stage. Work on developing gene therapy for SMA is also conducted at the Institut de Myologie in Paris and at the University of Oxford. In 2018, also Biogen announced working on a gene therapy product to treat SMA.

''SMN2'' alternative splicing modulation

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. Sometimes it is also called gene conversion, because it attempts to convert the SMN2 gene functionally into SMN1 gene.
The following splicing modulators have reached clinical stage development:
Of discontinued clinical-stage 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 2010 which however never happened. RG7800 was a molecule akin to RG7916, developed by Hoffmann-La Roche and trialled on SMA patients in 2015, whose development was discontonued in 2016 due to long-term animal toxicity.
Basic research has also identified other compounds which modified SMN2 splicing in vitro, like sodium orthovanadate and aclarubicin. Morpholino-type antisense oligonucleotides, with the same cellular target as nusinersen, remain a subject of intense research, including at the University College London and at the University of Oxford.

''SMN2'' gene activation

This approach aims at increasing expression of the SMN2 gene, thus increasing the amount of full-length SMN protein available.
A few compounds initially showed promise but failed to demonstrate efficacy in clinical trials:
Compounds which increased SMN2 activity in vitro but did not make it to the clinical stage include growth hormone, various histone deacetylase inhibitors, benzamide M344, hydroxamic acids, prolactin as well as natural polyphenol compounds like resveratrol and curcumin. Celecoxib, a p38 pathway activator, is sometimes used off-label by people with SMA based on a single animal study 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.
No compounds have been taken forward to the clinical stage. Aminoglycosides showed capability to increase SMN protein availability in two studies. Indoprofen offered some promise in vitro.

Neuroprotection

drugs aim at enabling the survival of motor neurons even with low levels of SMN protein.
Of clinically studied compounds which did not show efficacy, thyrotropin-releasing hormone held some promise in an open-label uncontrolled clinical trial but did not prove effective in a subsequent double-blind placebo-controlled trial. Riluzole, a drug that has mild clinical benefit in amyotrophic lateral sclerosis, was proposed to be similarly tested in SMA, however a 2008–2010 trial in SMA types 2 and 3 was stopped early due to lack of satisfactory results.
Compounds that had some neuroprotective effect in in vitro research but never moved to in vivo studies include β-lactam antibiotics and follistatin.

Muscle restoration

This approach aims to counter the effect of SMA by targeting the muscle tissue instead of neurons.
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.
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.

Registries

People with SMA in the European Union can participate in clinical research by entering their details into registries managed by TREAT-NMD.