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Spinal muscular atrophy

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This article is about the specific disease caused by a defect in the SMN1 gene. For a list of similarly-named conditions caused by defects in other genes, see Spinal muscular atrophies.
Spinal muscular atrophy
SpecialtyNeurology Edit this on Wikidata

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. SMN1 is apparently selectively necessary for survival of motor neurons, as diminished abundance of the protein results in death 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 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 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.

Signs and 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 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
  • Arthrogryposis (multiple congenital contractures)
  • Weight lower than normal

Causes

Spinal muscular atrophy has an autosomal recessive pattern of inheritance.

Spinal muscular atrophy is linked to a genetic mutation in the SMN1 gene.[1]

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.[2]

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.[3][4] There are no known health consequences of being a carrier, and presently one may know one's carrier status only if one's child is affected or by sequencing of the SMN1 gene.

Finally, there are also reports of occurrence of SMA type I and SMA type II in the same sibship together; scientific explanation of this phenomena (intrafamilial variability) have been advanced by the Italian researcher of the CNR (The National Rersearch Council of Italy) Enrico Parano, who has suggested that these cases might be due to additional de novo deletion of the SMN gene, not involving the NAIP gene (94).

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.[5] Others conclude that SMA meets the criteria for screening programs and relevant testing should be offered to all couples.[6]

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,

Types

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 cases, are known to live into adolescence and adulthood. Template:OMIM2
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. Template:OMIM2
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. Victims may develop scoliosis (curvature of the spine). Respiratory involvement is less noticeable, and life expectancy is normal or near normal. Template:OMIM2
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. Template:OMIM2

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.

Development milestone attainment is commonly measured using a specially modified Hammersmith Functional Motor Scale.[8][9][10][11]

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.[12] 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.

Treatment

There is no known cure for spinal muscular atrophy.

Palliative care

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.

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 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.[29] With proper care, milder SMA type I cases have lived into adulthood.[30]

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.

Research directions

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:[31][32][33][34][35][36][37][38][39]

Gene therapy

Gene therapy aims at correcting the SMN1 gene function through inserting specially crafted nucleotide sequences with the help of a viral vector.[40] 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.[41]. An AAV9 viral vector is in clinical trials for Hemophilia B.

Stem cell therapy

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, Ukraine and Lebanon.

SMN2 activation

SMN2 activation aims at increasing expression of the SMN2 gene and thus increasing the amount of full-length SMN available; compounds under investigation include:

SMN2 alternative splicing modulation

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,[67] not trialled any further due to toxicity at required dosage
  • Antisense oligonucleotides:[68][69][70]
    • 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:[71]
    • RG3039 (formerly, Quinazoline495) — a proprietary quinazoline derivative formerly under development by Repligen, 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. As of 2014, RG3039 has been licensed to Pfizer.[72]
  • Sodium orthovanadate — shown to modulate alternative splicing in one study in vitro[73]

SMN stabilisation

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;[74] investigated compounds include:

Neuroprotection

Neuroprotection aims at prolonging survival of motor neurons even with low levels of SMN; investigated compounds include:

Other directions

An unclear mechanism of action is found in the following compounds currently under research:

In vivo research is usually conducted using genetically engineered Caenorhabditis elegans,[86][87] Drosophila,[86][88][89] zebrafish[90] and mouse[91] models; larger animal models are under development.[92] SMA patients 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 [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.[93][94]

See also

References

  1. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1038/344540a0, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1038/344540a0 instead.
  2. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19287802, please use {{cite journal}} with |pmid=19287802 instead.
  3. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1371/journal.pone.0017067, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1371/journal.pone.0017067 instead.
  4. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1038/ejhg.2011.134, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1038/ejhg.2011.134 instead.
  5. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/j.ajog.2010.01.032, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/j.ajog.2010.01.032 instead.
  6. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1097/GIM.0b013e318188d069, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1097/GIM.0b013e318188d069 instead.
  7. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1002/mus.21784, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1002/mus.21784 instead.
  8. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/S1090-3798(03)00060-6, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/S1090-3798(03)00060-6 instead.
  9. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/j.nmd.2006.03.015, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/j.nmd.2006.03.015 instead.
  10. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/j.nmd.2007.05.009, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/j.nmd.2007.05.009 instead.
  11. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1177/0883073811420294, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1177/0883073811420294 instead.
  12. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/j.nmd.2008.10.004, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/j.nmd.2008.10.004 instead.
  13. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1378/chest.117.4.1100, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1378/chest.117.4.1100 instead.
  14. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1097/PHM.0b013e31804a8505, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1097/PHM.0b013e31804a8505 instead.
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  17. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1016/S1071-9091(98)80026-0, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1016/S1071-9091(98)80026-0 instead.
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  19. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 10072048, please use {{cite journal}} with |pmid=10072048 instead.
  20. ^ Leighton, S. (2003). "Nutrition issues associated with spinal muscular atrophy". Nutrition & Dietetics. 60 (2): 92–96.
  21. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1136/jmg.2008.057950, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1136/jmg.2008.057950 instead.
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  47. ^ "Study to Evaluate Sodium Phenylbutyrate in Pre-symptomatic Infants With Spinal Muscular Atrophy (STOPSMA)". Retrieved 28 December 2011.
  48. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1093/hmg/ddg256, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1093/hmg/ddg256 instead.
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  72. ^ "Repligen Corporation", SEC Documents, Repligen, p. 1, RGEN 10-K 12/31/2013, retrieved 16 March 2014
  73. ^ Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1038/sj.gt.3301550, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1038/sj.gt.3301550 instead.
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  84. ^ "Roche signs agreement with PTC Therapeutics to advance treatment for Spinal Muscular Atrophy (SMA)". Retrieved 28 December 2011.
  85. ^ "Rethropin: drug pipeline". Retrieved 8 May 2012.
  86. ^ a b Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi:10.1002/bies.201100082, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi=10.1002/bies.201100082 instead.
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  92. ^ "The GSF and FightSMA Announce 100K Research Award for the Development of a Large Animal Model of Spinal Muscular Atrophy". Retrieved 18 December 2011.
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Bibliography
  • Parano, E (1996 Aug). "Molecular basis of phenotypic heterogeneity in siblings with spinal muscular atrophy". Annals of neurology. 40 (2): 247–51. doi:10.1002/ana.410400219. PMID 8773609. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
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