Spinal muscular atrophy




Spinal muscular atrophy (SMA), also called autosomal recessive proximal spinal muscular atrophy in order to distinguish it from other conditions with similar name – is 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 wasting (atrophy).

Spinal muscular atrophy manifests in various degrees of severity, which all have in common progressive muscle wasting and mobility impairment. The severity of SMA correlates with the amount of SMN protein. People with Type 1 SMA, the most severe life-threatening form, produce very little SMN protein and do not achieve the ability to sit without support or live beyond 2 years without respiratory support. People with Type 2 and Type 3 produce greater amounts of SMN protein and have less severe, but still life-altering forms of SMA.

Spinal muscular atrophy is an inherited disorder and is passed on in an autosomal recessive manner.

As of 2016, no drugs for SMA have been approved, even as a number of therapeutics remain in late-stage clinical trials.


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

  • Areflexia, particularly in extremities
  • Overall muscle weakness, poor muscle tone, limpness or a tendency to flop
  • 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
  • Weight loss


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 individuals affected by SMA, 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 codes small amounts of SMN protein - around 10-20% of the normal level - allowing some 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. Muscles that depend on these motor neurons for neural input now have decreased innervation (also called denervation), and therefore have decreased input from the central nervous system (CNS). Denervated skeletal muscle is more difficult for the body to control. Decreased impulse transmission through the motor neurons leads to decreased contractile activity of the denervated muscle. Consequently, denervated 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 to 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, patients with SMA 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 affecting the disease phenotype.

Spinal muscular atrophy is 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 (i.e., without any hereditary causes) in around 2-4% of cases.

Spinal muscular atrophy affects individuals of all ethnic groups, unlike other well known autosomal recessive disorders, such as sickle cell disease and cystic fibrosis, which have significant differences in occurrence rate among ethnic groups. 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 around 1:100, therefore, approximately one in 50 persons are carriers. There are no known health consequences of being a carrier. A person may learn carrier status only if one's child is affected by SMA or by having the SMN1 gene sequenced.

Finally, there are reports of occurrence of both SMA type I and SMA type II among siblings. Scientific explanation of this phenomenon (intrafamilial variability) has been advanced by Enrico Parano, an Italian researcher of the CNR (The National Rersearch Council of Italy). He suggests that these cases might be due to additional de novo deletion of the SMN gene, not involving the NAIP gene (94).


Genetic counselling is advised. Most forms of spinal muscular atrophy (types I, II, III, and IV, specifically) are inherited in an autosomal recessive pattern. This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

Finkel type spinal muscular atrophy is inherited in an autosomal dominant pattern, which means an affected person only needs a mutation in one copy of the responsible gene in each cell.

X-linked infantile spinal muscular atrophy is inherited in an X-linked pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked disorders much more frequently than females. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.


Prenatal screening is controversial, because of its cost and because of the severity of the disease. 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. Otherwise it manifests within the first few weeks or months of life when abnormally low muscle tone is observed in the infant (the "floppy baby syndrome").

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.


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 4, recurrent respiratory problems being the primary cause of death. With proper care, milder SMA type I cases (which account for approx. 10% of all SMA I cases) live into adulthood.

In SMA type II, the course of the disease is stable or slowly progressing and life expectancy is reduced compared to the healthy population. Death before the age of 20 is frequent, although many patients live to become parents and grandparents.

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


There is no known cure for spinal muscular atrophy.

Approved therapies:

The U.S. Food and Drug Administration (FDA) has approved SPINRAZATM (nusinersen) under Priority Review for the treatment of spinal muscular atrophy (SMA) in pediatric and adult patients. SPINRAZA is the first and only treatment approved in the U.S. for SMA.

SPINRAZA is an antisense oligonucleotide (ASO) that is designed to treat SMA caused by mutations in the chromosome 5q that leads to SMN protein deficiency. It was discovered and co-developed by Ionis Pharmaceuticals, a leader in antisense therapeutics, and Biogen. SPINRAZA is designed to selectively bind to and alter the splicing of a single RNA from the SMN2 gene, a gene that is nearly identical to SMN1, in order to increase production of full length SMN protein. ASOs are short synthetic strings of nucleotides designed to selectively bind to target RNA and regulate gene expression. Through use of this technology, SPINRAZA has the potential to increase the amount of functional SMN protein in infants and children with SMA.

SPINRAZA is administered via intrathecal injection, which delivers therapies directly to the cerebrospinal fluid (CSF) around the spinal cord, where motor neurons degenerate in patients with SMA due to insufficient levels of SMN protein.


Refer to Research Publications.