Movement disorders Flashcards
SMA (incidence, subtypes, sx and general pathophys)
one of the most frequent monogenic neurodegenerative diseases with an incidence estimated to be around 1 : 6,000 to 1 : 10,000 in newborns
encompasses a wide clinical continuum of disease severity and has been classified into subtypes according to age at onset and the motor milestones achieved
More than half of patients have the severe phenotype of SMA type 1 with onset of symptoms within the first 6 months of age. A ‘floppy infant’ presentation, reduced spontaneous movements, difficulty in swallowing, tongue fasciculations, and a paradoxical breathing pattern are characteristic; these infants fail to achieve the free-sitting milestone. Without drug treatment and ventilator support, SMA type 1 is the leading genetic cause of death in early infancy with a life expectancy of under 2 years
SMA type 2 is characterized by a milder course with onset of symptoms between the ages of 6 and 18 months. Per definition, these patients do manage free sitting, but not independent walking. Have difficulty coughing, joint contractures, and scoliosis. Independent walking is achieved (at least temporarily) in patients with SMA type 3, whose symptoms’ onset is during infancy or adolescence. They later lose walking and also have joint contractures and scoliosis
In addition, some classifications define SMA type 0 and SMA type 4 with prenatal onset or a very mild phenotype entailing an adult onset of symptoms, respectively. The disease’s hallmark is the degeneration of anterior horn cells in the spinal cord, leading to the characteristic symptom of progressive, proximal weakness involving varying degrees of muscle atrophy. Whereas all types of SMA are progressive, the rate of progression differs: SMA type 1 typically follows a rapidly progressing course, while type 3 progresses slowly
denervation progresses rapidly during the first 6 months of life; rescue of these motoneurons before clinical deterioration appears to be essential. Nevertheless, the mean age of diagnosis in SMA type 1 is around 6 months of age; newborn screening thus would be very important and are undergoing trials
SMA genetics
About 95% of SMA cases are caused by homozygous deletions and less frequently point mutations in the SMN1 gene (survival of motor neuron 1) on the long arm of chromosome 5 (5q-SMA), whereas SMA mutations in other genes can also be causative (non-5q-SMA)
disease-causing mutations in SMN1 inhibit the production of functional SMN protein from this gene. SMA’s highly variable phenotypic spectrum is mainly attributable to variable copy numbers of the neighbouring SMN2 gene - almost homologous to SMN1 except for few nucleotides and is of no relevance in healthy individuals, however in SMA pts small amounts of full-length and fully functional SMN-protein can be produced by SMN2, thus higher numbers of SMN2-copies are associated with milder phenotypes
SMA - therapeutic approaches
can be subdivided into therapies aiming to modify the splicing of SMN2, replacing the SMN1 gene, or upregulating muscle growth
first drug approved for SMA treatment was nusinersen, an antisense-oligonucleotide (ASO) that enhances the inclusion of exon 7 in mRNA transcripts of SMN2. Nusinersen binds to an intronic splice-silencing-site in intron 7 of SMN2 and thereby suppresses the binding of other splice-factor, which results in an increased proportion of SMN2-mRNA with included exon 7 and consecutively more functional full-length SMN2 protein
An approach to altering the splicing of SMN2 and thus increasing the amount of functional SMN-protein is also taken by small molecules such as RG7916 (risdiplam) and LMI070 (branaplam). These compounds are taken orally, cross the blood-brain barrier, and have been shown to increase the amount of full length SMN-protein
Gene therapy of SMA is the most advanced medical approach that directly targets the dysfunctional SMN1-gene in SMA. Studies employing an Adeno-Associated Viral serotype 9 (AAV9) vector to deliver an intact copy of wild-type SMN in murine models showed that these constructs cross the brain-blood barrier and lead to prolonged survival of treated SMA-mice; zolgensma is one such approach used in children, approved by various agencies and undergoing clinical trials
Therapeutic approaches that do not directly target the genetic cause of SMA include the improvement of muscle mass and function. Two compounds are the most advanced: Myostatin-inhibitors and F ast Skeletal Muscle Troponin Activators (FSTA). Myostatin is a member of the TGFβ superfamily of growth factors that inhibits muscle over-growth and is primarily expressed in skeletal muscle. Myostatin-deficient animals are known to have considerably increased muscle mass and strength, and inhibitors are undergoing trials
