Spinal muscular atrophy

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. Spinal muscular atrophy is the most common genetic cause of infant death.

Sometimes, the term spinal muscular atrophy is used to encompass other hereditary disorders that involve death of motor neurons in the anterior horn of spinal cord - see spinal muscular atrophies.

Contents 1 Types 2 Causes 3 Symptoms 4 Diagnosis 5 Treatment 5.1 Palliative care 5.2 Emerging therapies 6 Prognosis 7 External links 8 See also 9 References

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, milder SMA type I phenotypes are known to live well into 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. Life expectancy is normal or near normal.	253400
IV: Adult-onset		>35 years	The adult-onset form - sometimes regarded as a late-onset SMA type III - usually manifests after 35 years of age with gradual weakening of muscles. The disease progress mainly affects proximal muscles of the extremities, frequently rendering the patient wheelchair-bound. Other complications are rare, and life expectancy is normal.	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 are able to survive only a few weeks even with intensive respiratory support. SMA type 0 should not be confused with SMARD1 which has 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 first described 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 SMA.

Causes

Spinal muscular atrophy is linked to a genetic mutation in the SMN1 gene.^[5]

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 7, 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.^[6]

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.^[7][8] 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

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 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 (twiching) of the tongue
• Arthrogryposis (multiple congenital contractures)

Diagnosis

Very severe SMA (type 0/I) can be sometimes evident before birth - reduction in foetal 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^[9]
• 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.

Population screening for SMA has been found not cost-effective.^[10] However, pregnant women can have an amniocentesis done for the purpose of genetic testing of the foetus towards SMA.

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;^[11] both methods of ventilation prolong survival in a comparable degree, although tracheostomy prevents speech development.^[12]
• Nutritional care — Difficulties in jaw opening, munching 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. ^{[13][14][15][16]}
• 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.^{[17][18][19][20]}
• 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.^[21][22][23] Despite their disability, SMA-affected people report surprisingly high degree of satisfaction from life.^[24]

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

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:^{[25][26][27][28][29][30][31][32][33]}

• Gene therapy — aims at correcting the SMN1 gene by replacing incorrect nucleotides with a correct sequence, usually using a viral vector for RNA delivery.^[34] 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.^[35]
• 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:^[36]

• Aliphatic compounds:

• Butyrates: sodium butyrate and sodium phenylbutyrate — promising in vitro and demonstrated effective in mouse models,^[37][38][39] proved ineffective in symptomatic SMA patients (probably due to extremely short half-life),^[40] still being trialled in pre-symptomatic type I/II infants^[41]
• Valproic acid — formerly used widely on experimental basis due to earlier research showing its effectiveness in vitro^[42] and in mouse models,^[43] in achievable concentrations demonstrated ineffective in SMA patients^[44][45][46] and even shown to aggravate SMA symptoms^[47]

• Benzamides:

• M344 — shown very effective in mouse models,^[48] 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,^[49] not trialled in SMA patients due to toxicity at required dosage
• Trichostatin A — shown effective in mouse models,^[50][51] so far not trialled in SMA patients
• Vorinostat (SAHA) — shown effective in mouse models,^[52] so far not trialled in SMA patients

• Hydroxycarbamide (hydroxyurea) — shown effective in mouse models^[53] and subsequently commercially researched by Novo Nordisk, Denmark, but demonstrated no effect on SMA patients in subsequent clinical trials^[54]
• Natural polyphenol compounds: resveratrol, curcumin — moderate effectiveness on muscle strength supported by anecdotal evidence from patients and limited research in vitro^[55][56]
• Prolactin — recently shown effective in mouse models,^[57] so far not trialled in SMA patients
• Salbutamol (albuterol) — demonstrated moderately effective in vitro^[58] and in two clinical trials involving SMA II/III patients^[59][60]

• 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,^[61] not trialled any further due to toxicity at required dosage
• Antisense oligonucleotides:^[62][63][64]

• PTK-SMA1 — a proprietary small molecule splicing modulator under development by Paratek Pharmaceutical, USA
• 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:^[65]

• 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^[66]

• 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;^[67] investigated compounds include:

• Aminoglycosides — shown to increase SMN protein availability^[68][69]

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

• Indoprofen^[70]

• 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^[71][72]
• Follistatin — shown promising in vitro^[73]
• 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^[74][75][76] yet did not prove effective in double-blind placebo-controlled trials^[29]

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

• PRO105 — a proprietary compound under development by Prosensa BV, The Netherlands
• PTC-X — three proprietary compounds under joint development by PTC Therapeutics, USA, and Hoffmann-La Roche, Switzerland^[77]

In vivo research is usually conducted using genetically engineered drosophila,^[78] zebrafish^[79] and mouse^[80] models; larger animal models are under development.^[81] 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.^[82][83]

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.^[84] With proper care, milder SMA type I cases have lived into adulthood.^[85]

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

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

• Spinal muscular atrophies
• Motor neurone disease
• Survival of motor neuron
• Spinal muscular atrophy with respiratory distress type 1
• Spinal and bulbar muscular atrophy

References

Pathology of the nervous system, primarily CNS (G04–G47, 323–349) Inflammation Brain Encephalitis (Viral encephalitis, Herpesviral encephalitis) · Cavernous sinus thrombosis · Brain abscess (Amoebic) Spinal cord Myelitis: Poliomyelitis · Demyelinating disease (Transverse myelitis) · Tropical spastic paraparesis · Epidural abscess Both/either Encephalomyelitis (Acute disseminated) Meningoencephalitis Brain/ encephalopathy Degenerative Extrapyramidal and movement disorders Basal ganglia disease: Parkinsonism (PD, Postencephalitic, NMS) · PKAN · Tauopathy (PSP) · Striatonigral degeneration · Hemiballismus · HD · OA Dyskinesia: Dystonia (Status dystonicus, Spasmodic torticollis, Meige's, Blepharospasm) · Chorea (Choreoathetosis) · Myoclonus (Myoclonic epilepsy) · Akathesia Tremor (Essential tremor, Intention tremor) · Restless legs · Stiff person Dementia Tauopathy: Alzheimer's (Early-onset) · Frontotemporal dementia/Frontotemporal lobar degeneration (Pick's, Dementia with Lewy bodies) Multi-infarct dementia Mitochondrial disease Leigh's Demyelinating autoimmune (Multiple sclerosis, Neuromyelitis optica, Schilder's disease) · hereditary (Adrenoleukodystrophy, Alexander, Canavan, Krabbe, ML, PMD, VWM, MFC, CAMFAK syndrome) · Central pontine myelinolysis · Marchiafava-Bignami disease · Alpers' disease Episodic/ paroxysmal Seizure/epilepsy Focal · Generalised · Status epilepticus · Myoclonic epilepsy Headache Migraine (Familial hemiplegic) · Cluster · Tension Cerebrovascular TIA (Amaurosis fugax, Transient global amnesia) Stroke (MCA, ACA, PCA, Foville's, Millard-Gubler, Lateral medullary, Weber's, Lacunar stroke) Sleep disorders Insomnia · Hypersomnia · Sleep apnea (Obstructive, Ondine's curse) · Narcolepsy · Cataplexy · Kleine-Levin · Circadian rhythm sleep disorder (Advanced sleep phase syndrome, Delayed sleep phase syndrome, Non-24-hour sleep-wake syndrome, Jet lag) CSF Intracranial hypertension (Hydrocephalus/NPH, Idiopathic intracranial hypertension) · Cerebral edema · Intracranial hypotension Other Brain herniation · Reye's · Hepatic encephalopathy · Toxic encephalopathy Spinal cord/ myelopathy Syringomyelia · Syringobulbia · Morvan's syndrome · Vascular myelopathy (Foix-Alajouanine syndrome) · Spinal cord compression Both/either Degenerative SA Friedreich's ataxia · Ataxia telangiectasia MND UMN only: PLS · PP · HSP LMN only: PMA · PBP (Fazio-Londe, Infantile progressive bulbar palsy) · Spinal muscular atrophies (SMA, SMARD1, SBMA, SMAX2, SMA-PCH) both: ALS M: CNS anat(n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp noco(m/d/e/h/v/s)/cong/tumr, sysi/epon, injr proc, drug(N1A/2AB/C/3/4/7A/B/C/D)

Nucleus diseases Telomere Revesz syndrome Nucleolus Treacher–Collins syndrome · Spinocerebellar ataxia 7 Cajal body: Survival motor neuron spinal muscular atrophy Centromere CENPJ (Seckel syndrome 4) Other AAAS (Triple-A syndrome) · Laminopathy · SMC1A/SMC3 (Cornelia de Lange Syndrome) · SETBP1 (Schinzel–Giedion syndrome) see also nucleus B structural (perx, skel, cili, mito, nucl, sclr) · DNA/RNA/protein synthesis (drep, trfc, tscr, tltn) · membrane (icha, slcr, atpa, abct, othr) · transduction (iter, csrc, itra), trfk