HHE Neurology supplement 2018 - Page 23

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 23 HHE 2018 | hospitalhealthcare.com 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 presence of these subtypes is attributed to the fact that patients have &PFR6bFR4"vVRBF6RvFvW"V&W"b6W2fR&WGFW &v626Ɩ6vVV@FVG2vF4&RvVBF&Vv7W'FfR6&R66&FrF6&VV6fPwVF6R&GV6VB#rFW6RwVFVƖW0ffW"Gf6RFv62fvVWF2FW7FrV'v7G&FW7F'FVF2@ƖFfR6&R77VW2rV'F6V6R0"6W6Rb&&FGB'FƗG