Lysosomal storage diseases

Abstract

Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage can be caused not by the enzymatic deficiency of one of the hydrolases, but by the deficiency of an activator protein, as occurs in the AB variant of GM2 gangliosidosis. Still other times, the accumulated lysosomal material results from failed egress of a small molecule as a consequence of a deficient transporter, as in cystinosis or Salla disease. In the last couple of decades, enzyme replacement therapy has become available for a number of lysosomal storage diseases. Examples include imiglucerase, taliglucerase and velaglucerase for Gaucher disease, laronidase for Hurler disease, idursulfase for Hunter disease, elosulfase for Morquio disease, galsulfase for Maroteaux-Lamy disease, alglucosidase alfa for Pompe disease, and agalsidase alfa and beta for Fabry disease. In addition, substrate reduction therapy has been approved for certain disorders, such as eliglustat for Gaucher disease. The advent of treatment options for some of these disorders has led to newborn screening pilot studies, and ultimately to the addition of Pompe disease and Hurler disease to the Recommended Uniform Screening Panel (RUSP) in 2015 and 2016, respectively.

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

“…Patients with Farber disease develop a severe lipogranulomas with subcutaneous nodules, painful and progressive joint deformations, and progressive hoarseness. A moderate nervous dysfunction is related to the primary storage of ceramides, preferentially containing long chain fatty acids and a secondary accumulation of gangliosides in neurons and anterior horns cells of the spinal cord [123,124].…”

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

“…From the original discovery of the lysosome as a membrane-limited bag of hydrolytic enzymes by Christian de Duve in the early 1950’s (174) to beginning of the 21 st century, our understanding of the role of lysosomes was largely informed by monogenic disorders that led to deficiency of individual lysosomal enzymes or proteins (62). Collectively termed lysosomal storage diseases (LSDs), these disorders taken together are among the most common genetic diseases in children with a prevalence of ~1 in 5000–8000 births, second only to cystic fibrosis (104, 132).…”

Induction of the nicotinamide riboside kinase NAD+ salvage pathway in skeletal myopathy of H6PDH KO mice

“…Differential NAD + homeostasis has been demonstrated to be present in muscular pathologies such as muscular dystrophy and infantile onset Pompe disease 32,33 . The latter being a glycogen storage disease and reflective of the H6PD glycogen storage defects 34 . Also in cardiac muscle it has been demonstrated that upregulation of NRK2 occurs as a response to congestive heart failure 7 .…”