User:Kashmiri/sandbox/Spinal muscular atrophy

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= 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.

Classification
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.

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. 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.

Pathophysiology


Spinal muscular atrophy is linked to a genetic mutation in the SMN1 gene.

Human chromosome 5 contains two nearly identical genes at location 5q13: a telomeric copy SMN1 and a centromeric copy SMN2. In healthy individuals, the SMN1 gene codes the survival of motor neuron protein (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 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.

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. 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.

Diagnosis
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. 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; 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
 * 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.

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


 * Areflexia, particularly in extremities
 * Overall muscle weakness, poor muscle tone, limpness or a tendency to flop (the "floppy baby" syndrome)
 * 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 pulmonary 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
 * Arthrogryposis (multiple congenital contractures)
 * Weight lower than normal

Management
As with the majority of genetic diseases, there is no known cure for spinal muscular atrophy. Management focuses on the following areas of concern:


 * 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; 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 pose SMA patients 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 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).
 * 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.

Prognosis
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 following description is only indicative.


 * Type 0: Babies of this type do not normally survive beyond the first few months.
 * Type I: The majority of children diagnosed with SMA type I do not reach the age of 10, recurrent respiratory problems being the primary cause of morbidity. With proper care, milder SMA type I cases, which account for around 10% of cases, have lived into adolescence.
 * 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.
 * Type III: Patients have normal or nearly normal life expectancy if standards of care are followed.
 * Type IV: This type usually means only mobility impairment and does not affect life expectancy.

Research directions
Since the underlying genetic mechanism of SMA was described in 1990, several therapeutic approaches have been proposed. 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:
 * 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. 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). Safety and pharmacokinetics of scAAV9 viral vector has been tested in non-human primates.
 * 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:
 * Aliphatic compounds:
 * Butyrates: sodium butyrate and sodium phenylbutyrate — promising in vitro and demonstrated effective in mouse models,  proved ineffective in symptomatic SMA 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 SMA patients  and even shown to aggravate SMA symptoms
 * Benzamides:
 * M344 — shown very effective in mouse models, 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, not trialled in SMA patients due to toxicity at required dosage
 * Trichostatin A — shown effective in mouse models, so far not trialled in SMA patients
 * Vorinostat (SAHA) — shown effective in mouse models, so far not trialled in SMA patients
 * Hydroxycarbamide (hydroxyurea) — shown effective in mouse models and subsequently commercially researched by Novo Nordisk, Denmark, but demonstrated no effect on SMA patients 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 SMA patients
 * Salbutamol (albuterol) — demonstrated moderately effective in vitro and in two clinical trials involving SMA II/III patients


 * SMN2 alternative splicing modulation — targets the alternative splicing of the SMN2 gene so as to achieve a higher proportion of full-length SMN transcripts (sometimes called "gene conversion SMN2→SMN1"); compounds under investigation include:
 * Aclarubicin — shown effective in human cells from type I SMA patients, not trialled any further due to toxicity at required dosage
 * Antisense oligonucleotides:
 * ISIS-SMNx — a proprietary molecule under development by Isis Pharmaceuticals, USA, and as of July 2012, posed for a phase II clinical trial; has Fast Track Designation in the USA and Orphan Medicinal Product Recommendation in the European Union
 * PTK-SMA1 — a proprietary small molecule splicing modulator of the tetracyclines group under development by Paratek Pharmaceutical, USA
 * Quinazolines:
 * RG3039 (formerly, Quinazoline495) — a proprietary quinazoline derivative under development by Repligen Corporation, USA, and as of July 2012, scheduled for phase II clinical trial; has an Orphan Drug Designation and Fast Track Designation in the USA and Orphan Medicinal Product Recommendation in the European Union
 * Sodium orthovanadate — shown to modulate alternative splicing in one study in vitro


 * 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
 * Indoprofen


 * 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


 * 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 Drosophila, zebrafish and mouse models; larger animal models are under development. 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.

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.