neurology
Treating spinal
muscular atrophy
Nusinersen is a novel, antisense oligonucleotide for the treatment
of spinal muscular atrophy, a rare, genetic neuromuscular disease
characterised by progressive muscular wasting and loss of function
Rod Tucker PhD
Robert Gordon
University, UK
The term spinal muscular atrophy (SMA) describes
a range of genetic, neuromuscular disorders that
are characterised by progressive muscle wasting
and subsequent loss of function. The first cases
of the condition were described in the 1890s by
Werdnig and Hoffman, whose autopsies revealed
severe loss of alpha-motor neurons in the anterior
horn of the spinal cord and skeletal muscle
atrophy. 1 SMA is a rare autosomal recessive
disorder affecting between 1 in 6000 to 1 in
10,000 live births 2 with a carrier frequency
between 1 in 40 and 1 in 60. 3
Clinical symptoms
There are several phenotypes of SMA, the most
common being infantile onset SMA (see Table 1).
Initial symptoms in those with infantile onset
SMA include hypotonia/floppiness, inability to lift
Table 1
Classification of SMA subtypes
SMA phenotype/
number of SMN2
genes Onset and functional
achievement Natural history
Type 1 – most common
(approx. 58%) and
termed infantile onset.
Patients have at least
two copies of SMN2
gene Symptoms begin before
six months and patients
unable to sit unaided Without supportive
care, most die within
two years usually due to
failure of respiratory
muscles
Type 2 – (approximately
29%). At least three
copies of SMN2 gene Symptom onset after six
months but before two
years. Patients can sit
unaided (and some can
stand) but are unable to
walk Life expectancy varies
between 2 and 40 years
Type 3 (approximately
13%). At least three
copies of SMN2 gene Symptom onset after 18
months. Patients can walk
but never run or jump
well but others might
achieve these feats Normal life expectancy
Symptoms similar to type
3 but distinguished by
adult-onset and patients
gradually lose the ability
to walk properly Normal life expectancy
Type 4 (adult onset)
(approximately 5% of
cases). At least four
copies of the SMN2
gene
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the head and or poor head control with reduced
motor activity. In addition, patients experience
difficulty swallowing and clearing of oral
secretions by one year of age. The clinical course
of the disease is characterised by progressive,
symmetrical limb and trunk paralysis due to
muscular atrophy, 4 leading to low muscle tone
and proximal muscle weakness, which affects the
legs more than the arms.
During normal development, infants would be
expected to sit by six months and learn to walk at
12 months but, as shown in Table 1, some of
these motor milestones are not achieved in those
with SMA and are lost as the disease progresses.
Furthermore, although those with less severe
disease can expect to have a normal lifespan, the
disease places a considerable burden on both
patients and their carers. 5
Pathophysiology
SMA is caused by insufficient levels of a protein
called survival motor neuron (SMN), which is
produced by the survival motor neuron gene
located on chromosome 5. Humans have two
nearly identical copies of this gene termed SMN1
and SMN2. Though both genes produce SMN
protein, SMA occurs when there is a defect in
the SMN1 gene and patients have to rely on
the protein produced by the SMN2 gene.
Unfortunately, during transcription from the
SMN2 gene, one of the exons (exon 7) is not copied
by RNA and 80–90% of the resultant SMN protein
is shorter than normal, unstable and quickly
degrades in cells. Although the remaining SMN
protein made from the SMN2 gene is normal, it is
insufficient to compensate for the lack of SMN
protein formed by the SMN1 gene. 6
However, as shown in Table 1, SMA has at
least four different subtypes, which vary in
disease severity. The pres