A genetic disorder associated with mutation in the SMN1 gene.
Also called autosomal recessive proximal spinal muscular atrophy.
A rare neuromuscular disorder characterised by loss of motor neurons and progressive muscle wasting, often leading to early death.
The disorder is caused by a genetic defect in the SMN1 gene, which encodes SMN, a protein widely expressed in all eukaryotic cells and necessary for survival of motor neurons.
Lower levels of the protein results in loss of function of neuronal cells in the anterior horn of the spinal cord and subsequent system-wide muscle atrophy.
Spinal muscular atrophy manifests as progressive muscle wasting and mobility impairment.
Proximal muscles and lung muscles are affected first.
The most common genetic cause of infant death.
An inherited disorder and is passed on in an autosomal recessive manner.
Affecting infants through adults.
The disease spectrum is divided into 3-5 types based on age of onset of symptoms, stage of motor development.
The most commonly used classification is as follows:
SMA1-Infantile-Werdnig-Hoffmann disease
0-6 months
This severe form manifests in the first months of life.
Has a quick and unexpected onset referred to as floppy baby syndrome.
Rapid motor neuron death causes failure of major bodily organs
Respiratory system failure and pneumonia-induced respiratory failure is the most frequent cause of death.
Babies do not generally live past two years of age, with death occurring as early as within weeks in the most severe cases.
With proper respiratory support, those with milder SMA type I phenotypes,
are known to live into adolescence and adulthood.
SMA2, 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.
Disease progression varies greatly, some patients gradually grow weaker over time while others through careful maintenance avoid any progression.
Scoliosis, if present, can be corrected with a brace that may help improve respiration.
Life expectancy is somewhat reduced but most SMA2 patients live well into adulthood.
SMA3 Juvenile) Kugelberg-Welander disease.
Onset >12 month, usually manifests after 12 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.
SMA4 Adult-onset form, sometimes classified as a late-onset SMA type 3, 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.
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.
Motor development is usually assessed by functional scales CHOP INTEND and either the Motor Function Measure scale or one of a few variants of Hammersmith Functional Motor Scale.
The symptoms vary greatly depending on the SMA type, stage and include:
Areflexia
Overall muscle weakness, poor muscle tone, limpness or a tendency to flop.
Difficulty achieving developmental milestones.
Difficulty sitting/standing/walking
In small children: adopting of a frog-leg position when sitting.
Loss of strength of the respiratory muscles.
Weak cough, weak cry in infants infants
Accumulation of secretions in the lungs or throat.
Respiratory distress
Bell-shaped torso from using only abdominal muscles for respiration, in milder SMA types.
Tongue fasciculations.
Difficulty sucking or swallowing, and poor poor feeding.
Autosomal recessive pattern of inheritance, linked to a genetic mutation in the SMN1 gene.
Human chromosome 5 contains two nearly identical genes at location 5q13
The SMN1 gene codes the survival of motor neuron protein (SMN).
The motor neuron protein (SMN) plays a crucial role in survival of motor neurons.
In SMA, the SMN1 gene is mutated and unable to correctly code the SMN protein – due to either a deletion occurring at exon 7 or to other point mutations.
All individuals 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.
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 have decreased innervation and decreased input from the central nervous system.
Decreased impulse transmission through the motor neurons leads to decreased contractile activity of the denervated muscle, and such denervated muscles undergo progressive atrophy.
Lower extremity muscles are usually affected first, followed by muscles of upper extremities, spine and neck.
In more severe cases, pulmonary and mastication muscles may be affected.
Proximal muscles are affected earlier and to a greater degree than distal.
Healthy patients carry two SMN2 gene copies.
Patients with SMA can have anything between 1 and 4 SMN2 copies with the greater the number the milder the disease
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.
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 in around 2-4% of cases.
Affects individuals of all ethnic groups.
The overall prevalence 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.
Affected siblings usually have a very similar form of disease.
Different SMA types among siblings do exist due to additional de novo deletions of the SMN gene.
Severe SMA (type 0/1) can be sometimes evident before birth,as manifested by reduction in fetal movement in the final months of pregnancy.
SMA1 usually manifests within the first few weeks or months of life when abnormally low muscle tone is observed in the infant, known as the “floppy baby syndrome”).
Patients present hypotonia associated with absent reflexes.
Electromyogram will show fibrillation and muscle denervation.
Serum creatine kinase may be normal or increased.
Diagnosis can only be confirmed with genetic testing for bi-allelic deletion of exon 7 of the SMN1 gene.
Preimplantation genetic diagnosis can be used to screen for SMA-affected embryos.
Prenatal testing is possible through chorionic villus sampling, and cell-free fetal DNA.
Those at risk of being carriers of SMN1 deletion, can undergo carrier analysis using a blood or saliva sample.
Nusinersen (Spinraza) is the only approved drug to treat spinal muscular atrophy.
It is an antisense oligonucleotide administered directly to the central nervous system using an intrathecal injection once every four months.
Weakness in spine musculature may lead to kyphosis, scoliosis and other orthopaedic problems requiring spinal fusion in patients once they reach the age of 8-10 to relieve the pressure of a deformed spine on the lungs.
Orthotic devices such as ankle foot orthosis are used to stabilize the foot and to aid gait,
Thoracic lumbar sacral orthotics are used to stabilize the torso.
Weakened pulmonary muscles in type I/II patients can make breathing more difficult and pose a risk, especially in sleep when muscles are more relaxed.
Impaired cough reflex poses a constant risk of respiratory infection and pneumonia.
Non-invasive ventilation is frequently used, and tracheostomy may be sometimes required.
Malnutrition may occur as a result of difficulty in jaw opening, chewing and swallowing, and a feeding tube or gastrostomy may be necessary in SMA type I and more severe type II patients.
When fasting metabolic abnormalities impair ?-oxidation of fatty acids in muscles and can lead to acidemia and consequent muscle damage,
Patients should reduce intake of fat and avoid prolonged fasting.
Prognosis varies with the SMA type, but despite their disabilities affected patients report high degree of satisfaction from life.
The disease progress with great degree of individual variability, but patients deteriorate over time.
Children diagnosed with SMA type 0 and 1 generally do not reach the age of 4, due to recurrent respiratory problems.
Patients with milder SMA type 1 cases, patients may live into adulthood, and accounts for 10% of SMA cases.
In SMA type 2, life expectancy is reduced compared to the healthy population.
In SMA type death before the age of 20 is frequent, although many patients live to become parents and grandparents.
SMA type 3 has normal or near-normal life expectancy.
Adult-onset SMA usually means only mobility impairment and does not affect life expectancy.
Physiotherapy has been shown to delay the progress of all types of SMA disease.
SMN1 and SMN2 gene replacement therapy research is ongoing.
Risdiplan Is an oral administered small molecule that modifies SMN two pre-messenger RNA splicing in increases levels of functional SMN proteins in blood.