Spinal muscular atrophy
Classification and external resources
Location of neurons affected by spinal muscular atrophy in the spinal cord
ICD-10	G12.0-G12.1
ICD-9	335.0-335.1
OMIM	253300 253550 253400 271150
DiseasesDB	14093 32911 12315 34537
MedlinePlus	000996
eMedicine	orthoped/304 pmr/62
MeSH	D014897
GeneReviews	Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is an incurable autosomal recessive disease caused by a genetic defect in the SMN1 gene which codes SMN, a protein necessary for survival of motor neurons, and resulting in death of neuronal cells in the anterior horn of spinal cord and subsequent system-wide muscle wasting (atrophy).

Spinal muscular atrophy manifests in various degrees of severity which all have in common general muscle wasting and mobility impairment. 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 sometimes also used with relation to certain very rare hereditary disorders characterised by similar symptoms – see spinal muscular atrophies for a comparison chart.

Types[link]

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:

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 are able to 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.

Development milestone attainment is commonly measured using a specially modified Hammersmith Functional Motor Scale.^[1][2][3][4]

The term Werdnig-Hoffman disease is used after Johann Hoffmann and Guido Werdnig and the term Kugelberg-Welander disease after Erik Klas Hendrik Kugelberg and Lisa Welander, the medical professionals who were among the first to describe the condition.^[5] 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.

Causes[link]

Spinal muscular atrophy is linked to a genetic mutation in the SMN1 gene.^[6]

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.

Spinal muscular atrophy has an autosomal recessive pattern of inheritance.

In SMA-affected individuals, 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 code small amounts of SMN protein - around 10-20% of the normal level - allowing 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. Consequently, motor 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 in 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, SMA patients 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 impacting on the disease phenotype.^[7]

Spinal muscular atrophy is inherited in an autosomal recessive pattern, which means that the defective gene is located on an autosome, and two copies of the defective gene - one from each parent - are required to inherit the disorder: the parents do not need to be themselves 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 like sickle cell disease and cystic fibrosis which have significant differences in occurrence rate between 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 thus around 1:100, therefore, approximately one in 50 persons are carriers.^[8][9] There are no known health consequences of being a carrier, and presently the only way one may know to consider the possibility is if a relative is affected.

Symptoms[link]

The symptoms vary greatly depending on the SMA type involved, the stage of the disease and individual factors and may include:

• Areflexia, particularly in extremities
• Marked hypotonia in legs, arms, rib, chest, and bulbar (facial) muscles, limpness or a tendency to flop
• Difficulty achieving developmental milestones, difficulty sitting/standing/walking
• Adopting of a frog-leg position when sitting (hips abducted and knees flexed)
• Respiratory distress, weak cough/cry
• Bell-shaped torso (caused by using only abdominal muscles for respiration)
• Difficulty sucking or swallowing, poor feeding
• Fasciculations (twitching) of the tongue
• Arthrogryposis (multiple congenital contractures)

Diagnosis[link]

Prenatal screening is controversial, because of its cost on the one hand, and the severity of the disease on the other hand. Some researchers have concluded that population screening for SMA is not cost-effective, at a cost of $5 million per case averted in USA.^[10] Others conclude that SMA meets the criteria for screening programs and relevant testing should be offered to all couples.^[11]

Very severe SMA (type 0/I) can be sometimes evident before birth - reduction in fetal movement in the final months of pregnancy; else, it manifests within the first few weeks or months of life when abnormally low muscle tone is observed (the "floppy baby syndrome").

Further, for all SMA types,

• Patient will present hypotonia associated with absent reflexes
• Electromyogram will show fibrillation and muscle denervation^[12]
• Serum creatine kinase may be normal or increased^{[citation needed]}
• Genetic testing will show bi-allelic deletion of exon 7 of the SMN1 gene – this is conclusive of the disease.

Treatment[link]

There is no known cure for spinal muscular atrophy.

Palliative care[link]

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. SMA patients might also benefit greatly from various forms of physiotherapy and occupational therapy .
• 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;^[13] both methods of ventilation prolong survival in a comparable degree, although tracheostomy prevents speech development.^[14]
• Nutritional care — Difficulties in jaw opening, chewing and swallowing food might pose SMA patients at risk of malnutrition. A feeding tube can be necessary in SMA type I and more severe type II patients.^[15][16][17] 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.^[18][19] It is suggested that SMA patients, especially those with more severe forms of disease, reduce intake of fat and avoid prolonged fasting (i.e., eat more frequently than healthy people).^[20]
• 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.^{[21][22][23][24]}
• 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.^[25][26][27] Despite their disability, SMA-affected people report high degree of satisfaction from life.^[28]

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.

Emerging therapies[link]

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.

The main therapeutic pathways under research as of December 2011 include:^{[29][30][31][32][33][34][35][36][37]}

• Gene therapy — aims at correcting the SMN1 gene function through inserting specially crafted nucleotide sequences with the help of a viral vector.^[38] 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. In one study this method 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).^{[citation needed]} Safety and pharmacokinetics of scAAV9 viral vector has been tested in non-human primates.^[39]
• Stem cell therapy — aims at offering protection to affected neurons through injection of specially prepared human stem cells in the spinal cord which subsequently develop into neuronal cells able to code full-length SMN protein, and is developed commercially in the context of SMA by California Stem Cell, USA. Experimental stem cell therapy is also offered to SMA patients - based on limited research and with unclear outcome - in private clinics in Brazil, China, Russia and Ukraine.
• SMN2 activation — aims at increasing expression of the SMN2 gene and thus increasing the amount of full-length SMN available; compounds under investigation include:

• Growth hormone
• Histone deacetylase inhibitors:^[40]

• Aliphatic compounds:

• Butyrates: sodium butyrate and sodium phenylbutyrate — promising in vitro and demonstrated effective in mouse models,^[41][42][43] proved ineffective in symptomatic SMA patients (probably due to extremely short half-life),^[44] still being trialled in pre-symptomatic type I/II infants^[45]
• Valproic acid — formerly used widely on experimental basis due to earlier research showing its effectiveness in vitro^[46] and in mouse models,^[47] in achievable concentrations demonstrated ineffective in SMA patients^[48][49][50] and even shown to aggravate SMA symptoms^[51]

• Benzamides:

• M344 — shown very effective in mouse models,^[52] so far not trialled in SMA patients

• 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,^[53] not trialled in SMA patients due to toxicity at required dosage
• Trichostatin A — shown effective in mouse models,^[54][55] so far not trialled in SMA patients
• Vorinostat (SAHA) — shown effective in mouse models,^[56] so far not trialled in SMA patients

• Hydroxycarbamide (hydroxyurea) — shown effective in mouse models^[57] and subsequently commercially researched by Novo Nordisk, Denmark, but demonstrated no effect on SMA patients in subsequent clinical trials^[58]
• Natural polyphenol compounds: resveratrol, curcumin — moderate effectiveness on muscle strength supported by anecdotal evidence from patients and limited research in vitro^[59][60]
• Prolactin — recently shown effective in mouse models,^[61] so far not trialled in SMA patients
• Salbutamol (albuterol) — demonstrated moderately effective in vitro^[62] and in two clinical trials involving SMA II/III patients^[63][64]

• SMN2 alternative splicing modulation — targets the alternative splicing of the SMN2 gene so as to achieve a higher proportion of full-length SMN transcripts (forced gene conversion SMN2→SMN1); compounds under investigation include:

• Aclarubicin — shown effective in human cells from type I SMA patients,^[65] not trialled any further due to toxicity at required dosage
• Antisense oligonucleotides:^[66][67][68]

• PTK-SMA1 — a proprietary small molecule splicing modulator under development by Paratek Pharmaceutical, USA, and as of December 2011 under a phase I clinical trial.
• ISIS-SMNx — a proprietary molecule under development by Isis Pharmaceuticals, USA, and as of December 2011 under a phase I clinical trial; has Fast Track Designation (USA) and Orphan Medicinal Product Recommendation (EU)

• Quinazolines:^[69]

• RG3039 (formerly, Quinazoline495) — a proprietary quinazoline derivative under development by Repligen Corporation, USA, and as of December 2011 scheduled for phase II clinical trial; has Fast Track Designation (USA) and Orphan Medicinal Product Recommendation (EU)

• Sodium orthovanadate — shown to modulate alternative splicing in one study in vitro^[70]

• 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;^[71] investigated compounds include:

• Aminoglycosides — shown to increase SMN protein availability^[72][73]

• TC-007 — a proprietary aminoglycoside antibiotic under commercial development by Tikvah Therapeutics, USA

• Indoprofen^[74]

• 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^[75][76]
• Follistatin — shown promising in vitro^[77]
• 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^[78][79][80] yet did not prove effective in double-blind placebo-controlled trials^[33]

• 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^[81]
• RE-003 — a compound being developed by Retrophin.^[82]

In vivo research is usually conducted using genetically engineered Drosophila,^[83] zebrafish^[84] and mouse^[85] models; larger animal models are under development.^[86] SMA patients can have a chance of participating in the research by enering their details into international SMA patient registries. A list of clinical trials targeting SMA can be consulted here [1].

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.^[87][88]

Prognosis[link]

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 10, recurrent respiratory problems being the primary cause of morbidity.^[89] With proper care, milder SMA type I cases have lived into adulthood.^[90]

In SMA type II, the course of the disease is stable or slowly progressing and life expectancy is somewhat reduced compared to the healthy population, although patients usually live to become parents and grandparents.

SMA type III has normal or nearly normal life expectancy if standards of care are followed. Adult-onset SMA usually means only mobility impairment and does not affect life expectancy.

External links[link]

Standards:

• Standards of Care in Spinal Muscular Atrophy

Patient registries:

• Treat-NMD national registries (worldwide)
• International SMA Patient Registry (USA)

SMA organisations:

• Treat-NMD Neuromuscular Network
• Families of SMA (USA)
• Families of SMA (Canada)
• Fight SMA (USA)
• The Jennifer Trust for Spinal Muscular Atrophy (UK)
• SMA Foundation (USA)
• SMA Support (USA)
• Sophia's Cure Foundation (USA)
• SMA Research (Italy)
• The 200 for SMA

SMA patient community support (thank you not to remove these links) :

• SMA Support
• SMA Friends
• SMA Space

See also[link]

• 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

References[link]

Muscle atrophy, or disuse atrophy, is defined as a decrease in the mass of the muscle; it can be a partial or complete wasting away of muscle. When a muscle atrophies, this leads to muscle weakness, since the ability to exert force is related to mass. Muscle atrophy results from a co-morbidity of several common diseases, including cancer, AIDS, congestive heart failure, COPD (chronic obstructive pulmonary disease), renal failure, and severe burns; patients who have "cachexia" in these disease settings have a poor prognosis. Moreover, starvation eventually leads to muscle atrophy. Disuse of the muscles will also lead to atrophy.

Clinical settings of atrophy[link]

There are many diseases and conditions which cause a decrease in muscle mass, known as atrophy, including: Dejerine Sottas syndrome (HSMN Type III), inactivity, as seen when a cast is put on a limb, or upon extended bedrest (which can occur during a prolonged illness); cachexia - which is a syndrome that is a co-morbidity of cancer and Congestive Heart Failure; Chronic Obstructive Pulmonary Disease; burns, liver failure, etc. Other syndromes or conditions which can induce skeletal muscle atrophy are liver disease, and starvation.

Quality of life[link]

Muscular atrophy decreases quality of life as the sufferer becomes unable to perform certain tasks or worsen the risks of accidents while performing those (like walking). Muscular atrophy increases the risks of falling in conditions such as IBM (inclusion body myositis). Muscular atrophy affects a major number of elderly.

Other muscles diseases, distinct from atrophy[link]

During aging, there is a gradual decrease in the ability to maintain skeletal muscle function and mass. This condition is called "sarcopenia". The exact cause of sarcopenia is unknown, but it may be due to a combination of the gradual failure in the "satellite cells" which help to regenerate skeletal muscle fibers, and a decrease in sensitivity to or the availability of critical secreted growth factors which are necessary to maintain muscle mass and satellite cell survival.

In addition to the simple loss of muscle mass (atrophy), or the age-related decrease in muscle function (sarcopenia), there are other diseases which may be caused by structural defects in the muscle (muscular dystrophy), or by inflammatory reactions in the body directed against muscle (the myopathies).

Pathophysiology[link]

Muscle atrophy occurs by a change in the normal balance between protein synthesis and protein degradation. During atrophy, there is a down-regulation of protein synthesis pathways, and an activation protein degradation^[1]. The particular protein degradation pathway which seems to be responsible for much of the muscle loss seen in a muscle undergoing atrophy is the ATP-dependent ubiquitin/proteasome pathway. In this system, particular proteins are targeted for destruction by the ligation of at least four copies of a small peptide called ubiquitin onto a substrate protein. When a substrate is thus "poly-ubiquitinated", it is targeted for destruction by the proteasome. Particular enzymes in the ubiquitin/proteasome pathway allow ubiquitination to be directed to some proteins but not others - specificity is gained by coupling targeted proteins to an "E3 ubiquitin ligase". Each E3 ubiquitin ligase binds to a particular set of substrates, causing their ubiquitination.

Potential treatment[link]

Muscle atrophy can be opposed by the signaling pathways which induce muscle hypertrophy, or an increase in muscle size. Therefore one way in which exercise induces an increase in muscle mass is to downregulate the pathways which have the opposite effect.

One important rehabilitation tool for muscle atrophy includes the use of functional electrical stimulation to stimulate the muscles. This has seen a large amount of success in the rehabilitation of paraplegic patients. ^[2]

Since the absence of muscle-building amino acids can contribute to muscle wasting (that which is torn down must be rebuilt with like material), amino acid therapy may be helpful for regenerating damaged or atrophied muscle tissue. The branched-chain amino acids or BCAAs (leucine, isoleucine, and valine) are critical to this process, in addition to lysine and other amino acids.

In severe cases of muscular atrophy, the use of an anabolic steroid such as methandrostenolone is administered to patients as a potential cure.

Quantification[link]

A CT scan can distinguish muscle tissue from other tissues and thereby estimate the amount of muscle tissue in the body.

Fast loss of muscle tissue (relative to normal turnover), can be approximated by the amount of urea in the urine. The equivalent nitrogen content (in gram) of urea (in mmol) can be estimated by the conversion factor 0.028 g/mmol.^[3] Furthermore, 1 gram of nitrogen is roughly equivalent to 6 gram of protein, and 1 gram of protein is roughly equivalent to 4 gram of muscle tissue. Subsequently, in situations such as muscle wasting, 1 mmol of excessive urea in the urine (as measured by urine volume in litres multiplied by urea concentration in mmol/l) roughly corresponds to a muscle loss of 0.67 gram.

See also[link]

• Brown atrophy of the heart
• Effect of spaceflight on the human body
• Muscle weakness
• Muscular dystrophy
• Myotonic dystrophy

References[link]

External links[link]

• Muscular+atrophy at the US National Library of Medicine Medical Subject Headings (MeSH)