Spinal muscular atrophy
Spinal muscular atrophy (SMA), also called autosomal recessive proximal spinal muscular atrophy and 5q spinal muscular atrophy in order to distinguish it from other conditions with similar names, is a rare neuromuscular disorder characterised by loss of motor neurons and progressive muscle wasting, often leading to early death.
|Spinal muscular atrophy|
|Synonyms||autosomal recessive proximal spinal muscular atrophy|
|Location of neurons affected by spinal muscular atrophy in the spinal cord|
|Classification and external resources|
|OMIM||253300 253550 253400 271150|
|eMedicine||Spinal Muscular Atrophy
Spinal Muscle Atrophy
|Patient UK||Spinal muscular atrophy|
The disorder is caused by a genetic defect in the SMN1 gene, which encodes SMN, a protein widely expressed in all eukaryotic 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 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 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||Eponym||Usual age of onset||Characteristics||OMIM|
|Werdnig–Hoffmann disease||0–6 months||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.||253300|
|Dubowitz disease||6–18 months||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 somewhat reduced but most people with SMA2 live well into adulthood.||253550|
|Kugelberg–Welander disease||>12 months||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.||253400|
|Adulthood||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.||271150|
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[disambiguation needed] 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 symptomsEdit
The symptoms vary greatly depending on the SMA type involved, the stage of the disease, and individual factors; they commonly include:
- 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 weaker SMA types
- Fasciculations (twitching) of the tongue
- Difficulty sucking or swallowing, poor feeding
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.
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.
Very severe SMA (type 0/1) can be sometimes evident before birth - reduction in fetal movement in the final months of pregnancy. Otherwise SMA1 manifests within the first few weeks or months of life when abnormally low muscle tone is observed in the infant (the "floppy baby syndrome").
For all SMA types,
- Person will present hypotonia associated with absent reflexes;
- Electromyogram will show fibrillation and muscle denervation;
- Serum creatine kinase may be normal or increased;
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. Genetic testing is usually carried out using a blood sample, and MLPA is one of more frequently used gene sequencing techniques, as it also allows establishing the number of SMN2 gene copies.
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.
Nusinersen (trade name: Spinraza) is the only approved drug to treat spinal muscular atrophy. It is a 2’-O-methoxyethyl, phosphorothioate modified antisense oligonucleotide targeting intronic splicing silencer N1 which is administered directly to the central nervous system using an intrathecal injection. Developed by Ionis Pharmaceuticals and Biogen, nusinersen was approved by FDA in December 2016, becoming the first approved pharmacological treatment for SMA. It was approved by the European Commission in centralised procedure in June 2017.
Main areas of concern are as follows:
Weak spine muscles may lead to development of kyphosis, scoliosis and other orthopaedic problems. 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. People with SMA might also benefit greatly from various forms of physiotherapy and occupational therapy.
Orthotic devices can be used to support the body and to aid walking. For example, orthotics such as AFO's (ankle foot orthosis) are used to stabilise the foot and to aid gait, TLSO's (thoracic lumbar sacral orthosis) are used to stabilise the torso. Assistive technologies may help in managing movement and daily activity and greatly increase the quality of life.
The respiratory system requires utmost attention in SMA as once weakened it never fully recovers. Weakened pulmonary muscles in people with SMA type I/II can make breathing more difficult and pose a risk of hypoxiation, especially in sleep when muscles are more relaxed. An impaired cough reflex poses a constant risk of respiratory infection and pneumonia. 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.
Difficulties in jaw opening, chewing and swallowing food might put people with SMA at risk of malnutrition. A feeding tube or gastrostomy can be necessary in SMA type I and people with more severe type II. 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).
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.
In lack of pharmacological treatment, people with SMA tend to deteriorate over time, but prognosis varies with the SMA type and disease progress which shows a great degree of individual variability.
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. With proper care, milder SMA type 1 cases (which account for approx. 10% of all SMA1 cases) live into adulthood. Long-term survival in SMA1 is not sufficiently evidenced; however, recent advances in respiratory support seem to have brought down mortality.
In SMA type 2, the course of the disease is stable or slowly progressing and life expectancy is reduced compared to the healthy population. Death before the age of 20 is frequent, although many people with SMA live to become parents and grandparents. SMA type 3 has normal or near-normal life expectancy if standards of care are followed. Adult-onset SMA usually means only mobility impairment and does not affect life expectancy.
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 replacementEdit
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 which uses self-complementary adeno-associated virus type 9 (scAAV-9) as a vector to deliver the SMN1 transgene. As of June 2016[update], a phase I clinical trial was under way, with published early results showing marked improvement in treated infants compared to the natural course of the disorder. As of February 2017[update], two pivotal trials in SMA1 infants have been announced to start during 2017.
SMN2 alternative splicing modulationEdit
This approach aims at modifying the alternative splicing of the SMN2 gene so that 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 2016[update] the compound remains in phase I–II clinical trials in infants with SMA type 1, with enrollment of new patients suspended since May 2016 due to safety concerns.
- RG7916 is a proprietary small-molecule drug administered orally and developed by PTC Therapeutics in collaboration with Hoffmann-La Roche and SMA Foundation. As of October 2016[update], RG7916 has advanced to phase II trials across all ages and SMA types.
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 activationEdit
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 widely used in SMA on 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.
- 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 which showed stabilising effect in a phase II–III clinical trial involving people with SMA types 2 and 3. The drug is being developed by Hoffmann-La Roche since its acquisition of Trophos in early 2015.
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.
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[update], the molecule is in a phase II clinical trial in adolescent and adults with SMA types 2, 3, and 4.
As of 2016[update], 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.
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.
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