Spinal muscular atrophy (SMA)
This article is about a genetic disorder associated with mutation in the SMN1 gene. For a list of other conditions with similar names, see Spinal muscular atrophies.This article is about a genetic disorder associated with mutation in the SMN1 gene. For a list of other conditions with similar names, see Spinal muscular atrophies.
Spinal muscular atrophy (SMA) is a rare neuromuscular disorder characterised by loss of lower motor neurons and progressive muscle wasting, often leading to early death.
The disorder is caused by a genetic defect in the SMN1 gene, which encodes SMN, a protein widely expressed in all eukaryotic cells (that is, cells with nuclei, including human cells) and necessary for survival of motor neurons. Lower levels of the protein results in loss of function of neuronal cells in the anterior horn of the spinal cord and subsequent system-wide atrophy of skeletal muscles.
Spinal muscular atrophy manifests in various degrees of severity, which all have in common progressive muscle wasting and mobility impairment. Proximal muscles, arm and leg muscles that are closer to the torso and respiratory muscles are affected first. Other body systems may be affected as well, particularly in early-onset forms of the disorder. SMA is the most common genetic cause of infant death.
Spinal muscular atrophy is an inherited disorder and is passed on in an autosomal recessive manner. In December 2016, nusinersen (marketed as Spinraza) became the first approved drug to treat SMA while several other compounds remain in clinical trials.
SMA manifests over a wide range of severity, affecting infants through adults. The disease spectrum is variously divided into 3–5 types, in accordance either with the age of onset of symptoms or with the highest attained milestone of motor development.
The most commonly used classification is as follows:
- Type: SMA1 (Infantile)
Eponym: Werdnig–Hoffmann disease
Usual age of onset: 0–6 months
Characteristics: The severe form manifests in the first months of life, usually with a quick and unexpected onset (“floppy baby syndrome”). Rapid motor neuron death causes inefficiency of the major bodily organs – especially of the respiratory system – and pneumonia-induced respiratory failure is the most frequent cause of death. Unless placed on mechanical ventilation, babies diagnosed with SMA type 1 do not generally live past two years of age, with death occurring as early as within weeks in the most severe cases (sometimes termed SMA type 0). With proper respiratory support, those with milder SMA type I phenotypes, which account for around 10% of SMA1 cases, are known to live into adolescence and adulthood.
- Type: SMA2 (Intermediate)
Eponym: Dubowitz disease
Usual age of onset: 6–18 months
Characteristics: The intermediate form affects children who are never able to stand and walk but who are able to maintain a sitting position at least some time in their life. The onset of weakness is usually noticed some time between 6 and 18 months. The progress is known to vary greatly, some people gradually grow weaker over time while others through careful maintenance avoid any progression. Scoliosis may be present in these children, and correction with a brace may help improve respiration. Body muscles are weakened, and the respiratory system is a major concern. Life expectancy is reduced but most people with SMA2 live well into adulthood.
- Type: SMA3 (Juvenile)
Eponym: Kugelberg–Welander disease
Usual age of onset: >12 months
Characteristics: The juvenile form usually manifests after 12 months of age and describes people with SMA3 who are able to walk without support at some time, although many later lose this ability. Respiratory involvement is less noticeable, and life expectancy is normal or near normal.
- Type: SMA4 (Adult-onset)
Usual age of onset: Adulthood
Characteristics: The adult-onset form (sometimes classified as a late-onset SMA type 3) usually manifests after the third decade of life with gradual weakening of muscles – mainly affects proximal muscles of the extremities – frequently requiring the person to use a wheelchair for mobility. Other complications are rare, and life expectancy is unaffected.
The most severe form of SMA type I is sometimes termed SMA type 0 (or, severe infantile SMA) and is diagnosed in babies that are born so weak that they can survive only a few weeks even with intensive respiratory support. SMA type 0 should not be confused with SMARD1 which may have very similar symptoms and course but has a different genetic cause than SMA.
Motor development in people with SMA is usually assessed using validated functional scales – CHOP INTEND (The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders) in SMA1; and either the Motor Function Measure scale or one of a few variants of Hammersmith Functional Motor Scale in SMA types 2 and 3.
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 is after Erik Klas Hendrik Kugelberg (1913–1983) and Lisa Welander (1909–2001), who distinguished SMA from muscular dystrophy. 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
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
CausesSpinal 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 (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 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 (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 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 (or more) 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 (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.
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 (including respiratory distress and poor feeding) which usually result in death within weeks. In comparison to the mildest phenotype of SMA (adult-onset), 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:
Progressive bilateral muscle weakness (Usually upper arms & legs more so than hands and feet) preceded by an asymptomatic period (all but most severe type 0)
Flattening of the chest wall when taking a breath and belly protrusion when taking a breath in.
hypotonia associated with absent reflexes.
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 genetic diagnosis 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.
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.
Routine prenatal or neonatal screening for SMA is controversial, because of the cost, and because of the severity of the disease. Some researchers have concluded that population screening for SMA is not cost-effective, at a cost of $5 million per case averted in the United States as of 2009. Others conclude that SMA meets the criteria for screening programs and relevant testing should be offered to all couples. The major argument for neonatal screening is that in SMA type I, there is a critical time period in which to initiate therapies to reduce loss of muscle function and proactive treatment in regards to nutrition.
The clinical management of an individual with SMA varies based upon the severity/type. Management of individual patients with the same type of SMA can vary. In the most severe forms (types 0/1), individuals have the greatest muscle weakness requiring prompt intervention. Whereas the least severe form (type 4/adult onset), individuals may not seek the certain aspects of care until later (decades) in life. While types of SMA and individuals among each type may differ, therefore specific aspects of an individual’s care can differ.
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 (BiPAP) 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.
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 (more severe types of SMA), 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 (i.e., eat more frequently than healthy people) 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 (example: aspiration) as well as cause other health issues such as electrolyte and blood sugar disturbances.
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 (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 activity and greatly increase the quality of life.
Although the heart is not a matter of routine concern, a link between SMA and certain heart conditions has been suggested.
SMA children 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.
Nusinersen is the only approved medication to treat spinal muscular atrophy. It is administered directly to the central nervous system using an intrathecal injection. It was approved by the European Commission in centralised procedure in June 2017.
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.
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 (which account for approx. 10% of all SMA1 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 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.
In all SMA types, physiotherapy has been shown to delay the progress of disease.
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
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; scAAV-9 and scAAV-10 are the primary viral vectors under investigation.
Only one programme has reached the clinical stage:
- AVXS-101 – a proprietary biologic under development by Avexis (a Novartis company) which uses self-complementary adeno-associated virus type 9 (scAAV-9) as a vector to deliver the SMN1 transgene. A phase I clinical trial conducted in 2015–2017 showed significant improvement in treated infants compared to the natural course of the disorder. As of September 2018, a number of pivotal trials have been initiated in the US and Europe.
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:
- Branaplam (LMI070, NVS-SM1) is a proprietary small-molecule experimental drug administered orally and being developed by Novartis. As of October 2017 the compound remains in phase-II clinical trial in infants with SMA type 1 while trials in other patient categories are under development.
- Risdiplam (RG7916, RO7034067) is a proprietary small-molecule drug administered orally and developed by PTC Therapeutics in collaboration with Hoffmann-La Roche and SMA Foundation. As of September 2018, risdiplam has advanced to phase II/III clinical trials across a wide spectrum of spinal muscular atrophy where it has shown encouraging early results.
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 Pharmaceutical 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 put on hold indefinitely 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 (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 and in three small-scale clinical trials involving patients with SMA types 2 and 3, 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 but a clinical trial in symptomatic people did not confirm their efficacy. Another clinical trial in pre-symptomatic types 1–2 infants was completed in 2015 but no results have been published.
- Valproic acid was used in SMA on an experimental basis in the 1990s and 2000s because in vitro research suggested its moderate effectiveness. However, it demonstrated no efficacy in achievable concentrations when subjected to a large clinical trial. 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. Others argue it may actually aggravate SMA symptoms. It is currently not used due to the risk of severe side effects related to long-term use.
- Hydroxycarbamide (hydroxyurea) was shown effective in mouse models and subsequently commercially researched by Novo Nordisk, Denmark, but demonstrated no effect on people with SMA in subsequent 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 (CBHA, SBHA, entinostat, panobinostat, trichostatin A, vorinostat), 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 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.
Neuroprotective drugs aim at enabling the survival of motor neurons even with low levels of SMN protein.
- Olesoxime is 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 with Spinraza and worse than expected data coming from an open-label extension trial.
Of clinically studied compounds which did not show efficacy, thyrotropin-releasing hormone (TRH) 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 (e.g., ceftriaxone) and follistatin.
This approach aims to counter the effect of SMA by targeting the muscle tissue instead of neurons.
- 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. As of October 2016, the molecule is in a phase II clinical trial in adolescent and adults with SMA types 2, 3, and 4.
As of 2016, there has been no significant breakthrough in stem cell therapy in SMA. An experimental programme to develop a stem cell based therapeutic product for SMA was run, with financial support from the SMA community, by a US company California Stem Cell starting from 2005. It was discontinued in 2010, unable to enter the clinical stage, and the company ceased to exist shortly after.
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.
People with SMA in the European Union can participate in clinical research by entering their details into registries managed by TREAT-NMD.