Lysosomal disorders

Abstract

Although most lysosomal storage disorders present in infancy or early childhood with a progressive condition often associated with dysmorphism, considerable genetic heterogeneity exists resulting in a range of illnesses that can include a dramatic neonatal presentation. Whilst some conditions present with a characteristic neonatal phenotype (e.g. Niemann-Pick disease type C), the remainder present in a nonspecific way often with non-immune hydrops fetalis. Diagnosis can be helped by appropriate radiological studies and, in some patients, evidence of the storage phenomena can be seen in peripheral blood smears or bone marrow aspirates. Unfortunately, for the majority of affected patients no effective, curative, treatment is possible. New developments in therapy including enzyme replacement therapy and substrate deprivation may improve prognosis in some disorders. It is important to establish an accurate diagnosis, as prenatal testing can then be offered in future pregnancies.

Up-Regulation of Cation-Independent Mannose 6-Phosphate Receptor and Endosomal-Lysosomal Markers in Surviving Neurons after 192-IgG-Saporin Administrations into the Adult Rat Brain

“…This was accompanied by a selective time-dependent increase in EL markers, ie, cathepsin D, Rab5, and LAMP2 in the affected regions of treated rats. Because CI-MPR plays a critical role in delivering lysosomal enzymes to the EL system, which is involved in the turnover of damaged proteins and structural reorganization in response to changing conditions, 5,6,9,11,13 it is likely that the observed increases in CI-MPR levels and that of other EL components in surviving neurons represent an adaptive mechanisms to restore metabolic and structural abnormalities that follow 192-IgG-saporin-induced loss of the forebrain cholinergic neurons.…”

“…2,7,8 A subpopulation of the CI-MPR is located at the plasma membrane, where it regulates internalization of IGF-II and various exogenous M6P-containing ligands for subsequent clearance or activation. However, the majority of the receptors are expressed in the trans-Golgi network/endosomal compartments and are involved in the intracellular trafficking of a battery of lysosomal enzymes including cathepsins B and D. 1,2,5,9,10 Given the evidence that defects in the synthesis/targeting of lysosomal enzymes or dysfunction of the endosomal-lysosomal (EL) system are associated with a variety of neurodegenerative disorders, often with progressive cognitive decline, [11][12][13][14] it is possible that the CI-MPR may have a role in regulating neuronal viability. In fact, a number of studies have shown that loss of CI-MPR function can induce cell proliferation in a variety of cancers.…”

Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase

“…Gangliosides are either recycled by the Golgi 12 or degraded in the lysosomal compartment 11 . Molecular defects in the degradation of GSLs leads to a range of lysosomal storage diseases, including Gaucher, Fabry, Tay-Sachs, Sandhoff and GM1 gangliosidosis 13 . Conversely, until now there have been no proven cases of human disorders resulting from disruption of ganglioside biosynthesis.…”

Selective Screening for Lysosomal Storage Diseases with Dried Blood Spots Collected on Filter Paper in 4,700 High-Risk Colombian Subjects

“…Lysosomal storage disorders (LSDs) include approximately 50 different diseases with a combined incidence of 1:1,500 to 1:7,000 births (Wraith 2002;Staretz-Chacham et al 2009). Each of these diseases occurs due to a deficiency in the enzymes, activating proteins or transport proteins involved in the catabolism of macromolecules that takes place in the lysosomes, causing substrate storage and progressive cell damage (Gieselmann 1995).…”