Lysosomal Storage Diseases: Past, Present, and Future

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There has never been a better time for patients with lysosomal storage diseases (LSDs) like mucopolysaccharidoses, gangliosidoses, and lipidoses such as Hurler, Scheie, and Sanfilippo syndrome as well as Fabry, Schindler, Tay–Sachs, and Niemann–Pick disease. This is because during the last 4 decades clinicians and researchers have vastly expanded our understanding of these rare diseases, resulting in several new treatments for LSDs, with many deficient enzymes currently manufactured for human use in partnership with pharmaceutical companies. This progress in the care of patients with LSDs has been possible in part because of the support provided by the Food and Drug Administration.
The review article in this issue by Kloesel and Robert1 summarizing the broad range of inborn errors of metabolism including LSDs and their implications on anesthesia care is very timely in the setting of emerging new therapies and therefore improved the survival of patients with these disorders.
It is estimated that there are more than 50 inherited LSDs, thus increasing the likelihood of an anesthesia provider encountering these relatively rare disorders with approximately 1:8000 incidence. LSDs are caused by defects in lysosomal function and result in the accumulation of lipids, glycoproteins, and glycosaminoglycans (mucopolysaccharides) within the cells because they are not broken down by the defective lysosomal enzyme. Intracellular storage of these molecules causes cellular dysfunction and clinically present as organomegaly, developmental delay and intellectual deficits, coarse facial features, airway abnormalities, cardiovascular impairment, joint and bony deformities, as well as visual, and auditory deficits. They are mostly inherited in an autosomal-recessive pattern with a few exceptions.
The Westminster bone marrow transplant team led by Dr J. R. Hobbs in 19812 paved the way to introduce this treatment modality for children with LSDs. This led to the first successful bone marrow transplant in a child with Maroteaux–Lamy syndrome at the University of Minnesota in 1981.3 The 13-year-old child had severe manifestations of this storage disorder and was only able to breathe sitting forward. She required an elective tracheostomy before transplantation. Needless to say, the upper airway for anesthesia induction posed a significant challenge, but, as fate would have it, oral endotracheal intubation was accomplished successfully with the thiopental-succinylcholine sequence, a Macintosh blade, and a properly preformed styleted endotracheal tube directed into the larynx inserted blindly into the laryngeal inlet (barely visible even with significant downward and upward laryngeal pressure) just below the epiglottis. Bone marrow transplantation provided the missing enzyme and reversed organomegaly and significantly improved the life of the patient. She went on to graduate from school as a valedictorian (Figure) and remained alive until April of 2016, when she succumbed to an infection after attempted heart valve surgery at an East Coast Hospital.
Since then other therapies have emerged and include enzyme-replacement therapy, as listed in the Table, substrate reduction of the accumulated product (miglustat and eligustat for Gaucher disease), rescue of misfolded lysosomal glycoproteins (by the use of pharmacologic chaperones), ex vivo and in vivo gene therapy and nanoparticle-based therapies.4 There are several enzyme replacement therapies in clinical trials namely for Niemann–Pick disease, mucopolysaccharidosis (MPS) I, II, IIIA, IVA, VI, Pompe, α-mannosidosis, metachromatic leukodystrophy, and ceroid-lipofuscinosis.5 In general, the children do better if they are diagnosed earlier and given the missing enzyme by one of the methods outlined. After this, they show improvement, including normal development. Gene therapy trials have been completed or are in progress for almost all of the LSDs. In our own institution, we have shown that in children with MPS, if left untreated, the disease progresses significantly with increased airway obstruction secondary to continued intracellular accumulation of unmetabolized substrate such as glycosaminoglycans.
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