Spinal muscular atrophy
|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|
Proximal spinal muscular atrophy (SMA) is an autosomal recessive disease caused by a genetic defect in the SMN1 gene, which encodes SMN, a protein widely expressed in all eukaryotic cells. SMN is apparently selectively necessary for survival of motor neurons, as diminished abundance of the protein results in loss of function of neuronal cells in the anterior horn of the spinal cord and subsequent system-wide muscle wasting (atrophy).
Spinal muscular atrophy manifests in various degrees of severity, which all have in common progressive muscle wasting and mobility impairment. Proximal muscles and lung muscles are affected first. Other body systems may be affected as well, particularly in early-onset forms.
SMA is the most common genetic cause of infant death.
The term spinal muscular atrophy is used as both a specific term for the genetic disorder caused by deficient SMN, and a general label for a larger number of rare disorders having in common a genetic cause and slow progression of weakness without sensory impairment caused by disease of motor neurons in the spinal cord and brainstem – see spinal muscular atrophies for a comparison chart.
- 1 Signs and symptoms
- 2 Causes
- 3 Diagnosis
- 4 Treatment
- 5 Prognosis
- 6 Research directions
- 7 See also
- 8 References
- 9 External links
Signs and symptoms
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 infants: 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)
- Clenched fists with sweaty hands
- Head often tilted to one side, even when lying down
- Fasciculations (twitching) of the tongue
- Difficulty sucking or swallowing, poor feeding
- Weight loss
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). All patients, however, retain at least one 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). Denervated skeletal muscle is more difficult for the body to control. 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 SMN1. This is partly related to the number of SMN2 gene copies present on the chromosome. Whilst healthy individuals carry two SMN2 gene copies, patients 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; SMA II and III patients usually have at least three SMN2 copies; and SMA IV patients 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 races, unlike other well known autosomal recessive disorders, such as sickle cell disease and cystic fibrosis, which have significant differences in occurrence rate among races. The overall incidence 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.
Finally, there are reports of occurrence of both SMA type I and SMA type II among siblings. Scientific explanation of this phenomenon (intrafamilial variability) has been advanced by Enrico Parano, an Italian researcher of the CNR (The National Rersearch Council of Italy). He suggests that these cases might be due to additional de novo deletion of the SMN gene, not involving the NAIP gene (94).
Prenatal screening is controversial, because of its 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 USA. Others conclude that SMA meets the criteria for screening programs and relevant testing should be offered to all couples.
Very severe SMA (type 0/I) can be sometimes evident before birth - reduction in fetal movement in the final months of pregnancy. Otherwise it 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,
- Patient will present hypotonia associated with absent reflexes;
- Electromyogram will show fibrillation and muscle denervation;
- Serum creatine kinase may be normal or increased;
- Genetic testing will show bi-allelic deletion of exon 7 of the SMN1 gene – this is conclusive of the disease.
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|
|I: Infantile||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. Babies diagnosed with SMA type I 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 SMA I cases, are known to live into adolescence and adulthood.||253300|
|II: Intermediate||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 patients gradually grow weaker over time while others through careful maintenance avoid any progression. Body muscles are weakened, and the respiratory system is a major concern. Life expectancy is somewhat reduced but most SMA II patients live well into adulthood.||253550|
|III: Juvenile||Kugelberg–Welander disease||>18 months||The juvenile form usually manifests after 18 months of age and describes patients 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|
|IV: Adult-onset||Adulthood||The adult-onset form (sometimes classified as a late-onset SMA type III) usually manifests after the third decade of life with gradual weakening of muscles – mainly affects proximal muscles of the extremities – frequently requiring the patient 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.
The eponymous label Werdnig-Hoffmann disease (often 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 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.
There is no known cure for spinal muscular atrophy.
Care is symptomatic. Main areas of concern are as follows:
- Orthopaedics — Weak spine muscles may lead to development of kyphosis, scoliosis and other orthopaedic problems. Spine fusion is sometimes performed in SMA I/II patients once they reach the age of 8-10 to relieve the pressure of a deformed spine on the lungs. Patients with SMA might also benefit greatly from various forms of physiotherapy and occupational therapy.
- Orthotics / Splints — 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.
- Respiratory care — Respiratory system requires utmost attention in SMA as once weakened it never fully recovers. Weakened pulmonary muscles in SMA type I/II patients can make breathing more difficult and pose a risk of hypoxiation, especially in sleep when muscles are more relaxed. 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 in a comparable degree, although tracheostomy prevents speech development.
- Nutritional care — Difficulties in jaw opening, chewing and swallowing food might put patients with SMA at risk of malnutrition. A feeding tube can be necessary in SMA type I and more severe type II patients. 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 patients 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).
- Mobility — Assistive technologies may help in managing movement and daily activity and greatly increase the quality of life.
- Cardiology — Although heart is not a matter of routine concern, a link between SMA and certain heart conditions has been suggested.
- Mental health — 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.
Generally, patients 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/I do not reach the age of 4, recurrent respiratory problems being the primary cause of morbidity. With proper care, milder SMA type I cases (which account for approx. 10% of all SMA I cases) live into adulthood.
In SMA type II, 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 patients live to become parents and grandparents.
SMA type III has 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 mechanism of SMA was described in 1990, several therapeutic approaches have been proposed and investigated. Since a vast number of in vitro and animal modelling studies suggest that restoration of SMN levels reverts SMA symptoms, the majority of emerging therapies focus on increasing the availability of SMN protein to motor neurons.
Gene therapy aims at correcting the SMN1 gene function through inserting specially crafted nucleotide sequences with the help of a viral vector. In the context of SMA, it is currently being researched using the scAAV9 viral vector at the Ohio State University and Nationwide Children's Hospital, USA, and the University of Sheffield, United Kingdom, as well as by Genzyme Corporation, USA, and Généthon, France. Safety and pharmacokinetics of scAAV9 viral vector has been tested in non-human primates. An AAV9 viral vector is in clinical trials for Hemophilia B.
- scAAV9.CB.SMN – a proprietary biologic under development by AveXis, Inc, USA is in Phase I clinical trial as of April 2014 and has both Fast Track Designation and Orphan Drug Designation in the USA. In preclinical studies, this treatment has resulted in the greatest survival increase achieved to-date in a SMNΔ7 mouse model (median survival of 400 days in treated mice as opposed to 15 days in untreated mice).
SMN2 gene conversion
This approach, also known as 'SMN2' alternative splicing modulation, essentially aims at converting the "backup" SMN2 gene (which normally produces only a fraction of needed SMN protein) into a fully functional SMN1 gene so as it is able to code for high quantities of full-length SMN protein. As of 2014[update], the following compounds are part of clinical programmes:
- Antisense oligonucleotides:
- ISIS-SMNRx — a proprietary molecule under development by Isis Pharmaceuticals, USA, and as of July 2014, in phase II clinical trials; has Fast Track Designation in the USA and Orphan Medicinal Product Recommendation in the European Union. According to its manufacturer, it has had remarkable results in earlier human trials and is expected to be available to patients around 2017-2018.
- PTK-SMA1 — a proprietary small molecule splicing modulator of the tetracyclines group under development by Paratek Pharmaceutical, USA
- RG3039 (formerly, Quinazoline495) — a proprietary quinazoline derivative developed by Repligen, USA, and licensed to Pfizer. It has an Orphan Drug Designation and Fast Track Designation in the USA and Orphan Medicinal Product Recommendation in the European Union. As of July 2014[update], it is scheduled for phase II clinical trials.
- Morpholino oligomers, whose way of action resembles that of antisense oligonucleotides. This class of compounds is in pre-clinical studies in UK and Australia.
Additionally, the following splicing regulators have been investigated in SMA with some interesting results:
- Sodium orthovanadate — shown to modulate alternative splicing in one study in vitro
- Aclarubicin — shown effective in human cells from patients with type I SMA, not trialled any further due to toxicity at required dosage
SMN2 gene activation
SMN2 activation aims at increasing expression of the SMN2 gene and thus increasing the amount of full-length SMN available; investigated compounds included:
- Growth hormone
- Histone deacetylase inhibitors:
- Aliphatic compounds:
- Butyrates: sodium butyrate and sodium phenylbutyrate — promising in vitro and demonstrated effective in mouse models, proved ineffective in symptomatic patients (probably due to extremely short half-life), still being trialled in pre-symptomatic type I/II infants
- Valproic acid — formerly used widely on experimental basis due to earlier research showing its effectiveness in vitro and in mouse models, in achievable concentrations demonstrated ineffective in patients with SMA and even shown to aggravate SMA symptoms
- M344 — shown very effective in mouse models, so far not trialled in patients with SMA
- Hydroxamic acids:
- CBHA, SBHA — shown very promising in vitro
- Entinostat (MS-275) — shown very promising in vitro
- Panobinostat (LBH-589) — shown very effective in mouse models, not trialled in patients with SMA due to toxicity at required dosage
- Trichostatin A — shown effective in mouse models, so far not trialled in patients with SMA
- Vorinostat (SAHA) — shown effective in mouse models, so far not trialled in patients with SMA
- Aliphatic compounds:
- Hydroxycarbamide (hydroxyurea) — shown effective in mouse models and subsequently commercially researched by Novo Nordisk, Denmark, but demonstrated no effect on patients with SMA in subsequent clinical trials
- Natural polyphenol compounds: resveratrol, curcumin — moderate effectiveness on muscle strength supported by anecdotal evidence from patients and limited research in vitro
- Prolactin — recently shown effective in mouse models, so far not trialled in patients with SMA
- Salbutamol (albuterol) — demonstrated moderately effective in vitro and in three clinical trials involving SMA II/III patients
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; investigated compounds include:
- Aminoglycosides — shown to increase SMN protein availability
- TC-007 — a proprietary aminoglycoside antibiotic under commercial development by Tikvah Therapeutics, USA
Neuroprotection aims at prolonging survival of motor neurons even with low levels of SMN; investigated compounds include:
- β-lactam antibiotics (e.g., ceftriaxone) — shown promising in vitro
- Follistatin — shown promising in vitro
- Olesoxime — a proprietary compound developed by a French company Trophos, currently (2011-2013) under a phase II clinical trial in USA and Europe
- Riluzole — a compound approved for treatment of ALS, currently being investigated for SMA at University of Angers, France
- Thyrotropin-releasing hormone (TRH) — shown promising in vitro and in open-label uncontrolled clinical trials yet did not prove effective in double-blind placebo-controlled trials
Motor neuron replacement using stem cells
Stem cell therapy aims at replacing the damaged motor neurons using corrected stem cells which are implanted in the spinal cord of the patient and are expected to branch out to form regular motor neurons.
To date, there has been no significant breakthrough in the technique since no methods have been found to incite branching of the newly formed axons from the spine up to the peripheral muscles in legs or hands. An experimental programme in SMA was under development by California Stem Cell, USA, but has been suspended before entering human clinical trials.
There is no scientific evidence that stem cell injections, sometimes carried out in "stem cell clinics" in a number of developing countries, would offer any benefit in spinal muscular atrophy.
An unclear mechanism of action is found in the following compounds currently under research:
- PTC-X — three proprietary compounds under joint development by PTC Therapeutics, USA, and Hoffmann-La Roche, Switzerland
- RE-003 — a compound being developed by Retrophin.
In vivo research is usually conducted using genetically engineered Caenorhabditis elegans, Drosophila, zebrafish and mouse models; larger animal models are under development. Patients with SMA can have a chance of participating in research by entering their details into international SMA patient registries. A list of clinical trials targeting SMA can be found here .
It has to be noted, though, that SMA therapeutics seem to be most effective when given immediately after birth, then losing their efficacy with the patient's age. This might be related to the variation in time of the needs for SMN protein by neuronal cells. However, this also poses a major therapeutic problem as hardly ever is SMA diagnosed at birth.
- SMA Treatment Acceleration Act
- Spinal muscular atrophies
- Motor neuron disease
- Survival of motor neuron
- Spinal muscular atrophy with respiratory distress type 1
- Spinal and bulbar muscular atrophy
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