Page 180 - Motor Disorders Third Edition

162 / chapter 10 to ameliorate disease phenotype. Disorders in which the gene
employing recombinant genetic techniques. Such studies defect results in the introduction of a premature stop codon
can provide valuable information on the natural history of might be effectively managed by compounds such as ataluren
the disorder and the identification of cellular events prior to (PTC124) that allow readthrough (56). The prospects for
the onset of symptoms. On the other hand, the presence of gene therapy remain promising with ERT already available in
murine models that do not exactly mimic the human situ- several lysosomal disorders, including glycogen storage dis-
ation, even when the same gene (ortholog) is involved, has ease type II (Pompe) caused by a-glucosidase deficiency (57,
promoted a shift in interest in the use of patient-derived 58). So far, somatic gene therapy trials involving the trans-
samples, pluripotent stem cells and cells subjected to cellu- plant of transduced myoblasts have failed to demonstrate
lar reprogramming strategies in the investigation of disease efficacy (59).
pathophysiology (54). Such methodologies may also prove
useful in screening of potential therapies. SUMMARY

The delineation of disease pathogenesis can lead to ratio- The pace of gene discovery has accelerated, from initial link-
nal or directed therapies aimed at correcting the root problem age-based studies requiring DNA samples from multiple
instead of relieving symptoms. For many genetic disorders, families of several affected individuals, to candidate gene
management is little more than supportive; however, poten- positional cloning, microarray methods, exome sequenc-
tial therapeutic options directed at genetic, molecular, and ing and next-generation sequence analysis. These advances
biochemical pathways are being intensively scrutinized. Such have significantly reduced cost, and offer a promise of a
strategies have been envisioned in disorders characterized by rapid, cost-effective approach to facilitate the diagnosis
abnormal protein folding in which ER quality control pro- of inherited neurologic motor disorders. Genetic studies
cesses instead divert the newly synthesized protein toward have led to increased understanding of atypical patterns of
premature degradation. These situations have prompted con- inheritance and insights into disease mechanisms that may
sideration of pharmacologic chaperones to rescue mutant ultimately lead to disease-modifying therapies (60–62).
proteins so their maturation and delivery to their appropriate
subcellular localizations can be completed (55). The increase
in residual protein function in these cases may be sufficient

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