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Diabetes Mellitus, Obesity, Lipoprotein Disorders and other Metabolic Diseases
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
These are varied and include learning disability, epilepsy, hepatosplenomegaly and bony abnormalities. In sphingolipidoses, retinal degeneration can cause a diagnostic ‘cherry red spot’ appearance at the macula. Mucopolysaccharidoses are associated with coarse facies, thickened skin, clouded corneas and skeletal abnormalities. Mucolipidoses are clinically similar to mucopolysaccharidoses.
Mucolipidosis II and III/ (I-cell disease and pseudo-Hurler polydystrophy) N-acetyl-glucosaminyl-l-phosphotransferase deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
There is genetic heterogeneity in mucolipidosis III caused by the presence of two genes which code for the three subunits of GlcNAc phosphotransferase, α/β and γ [4, 5]. Abnormalities in both genes have been found in different patients with mucolipidosis III. In the absence of phosphorylation of mannose, trafficking of lysosomal hydrolase enzymes is impaired.
Disorders of bone and connective tissue
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
The Hurler and Scheie types are allelic, as are the mild and severe forms of Hunter syndrome. In each case, the two forms run separately in families. Occasional cases intermediate between Hurler and Scheie types represent a ‘genetic compound’ with one allele of each type. The related mucolipidoses are all autosomal recessive in inheritance. Several other rare autosomal recessive lysosomal storage disorders can cause clinical confusion, including mannosidosis, sialidosis and fucosidosis. A detailed account of the individual disorders in this group is given in the online successor to the volume originally compiled by Charles Scriver, ‘The Metabolic and Molecular Bases of Inherited Disease’ (https://ommbid.mhmedical.com/).
Ex vivo gene therapy for lysosomal storage disorders: future perspectives
Published in Expert Opinion on Biological Therapy, 2023
Edina Poletto, Andrew Oliveira Silva, Ricardo Weinlich, Priscila Keiko Matsumoto Martin, Davi Coe Torres, Roberto Giugliani, Guilherme Baldo
Almost all of these rare disorders are autosomal recessive, with a few exceptions (Fabry disease, Mucopolysaccharidosis type II and Danon disease are X-linked) [4]. Most LSDs are caused by deficient activity of a specific soluble lysosomal enzyme. Some variants may completely abolish the enzyme activity, while others cause a major reduction but with residual function. In this last case, the disease frequently is manifested in a less severe form [3]. Defects in other non-hydrolase lysosomal proteins may affect processes such as transport of molecules, like cholesterol in Niemann-Pick disease, or the post-translational maturation of lysosomal enzymes, as seen in Mucolipidoses, and consequently, alter other aspects of lysosomal function [5,6] with accumulation of primary and secondary metabolites or alterations in autophagy, for example [2]. Many factors play key roles in the pathophysiology of LSDs, but the complete mechanisms are still not fully understood in most disorders.
The role of lysosomal ion channels in lysosome dysfunction
Published in Inhalation Toxicology, 2021
Rebekah L. Kendall, Andrij Holian
Because of its importance to cellular homeostasis, lysosomal exocytosis is a carefully regulated process, with ion channel activity playing a crucial role in regulation. The lysosomal Ca2+ release channel, transient receptor potential mucolipin 1 (TRPML1) mediates exocytosis by controlling the intracellular Ca2+ concentrations at the fusion site. TRPML1’s crucial role in lysosome exocytosis is evident in LSD where mutation can result in mucolipidosis type IV. TRPML1’s activity is itself transcriptionally controlled by transcription factor EB (TFEB), the master regulator of lysosome biogenesis and autophagy (Medina et al. 2011). TFEB plays a dual role in exocytosis, first, inducing lysosome localization at the plasma membrane, then inducing the transcriptional activation of TRPML1 (Medina et al. 2011). It should be noted that TFEB is dephosphorylated by TRPML1 Ca2+ activity, in conjunction with calcineurin and protein phosphatase 2 A, creating a self-perpetuating loop between TRPML1 and TFEB (Ballabio and Bonifacino 2020). Recently, it has been suggested that the ion activity of the lysosomal big conductance Ca2+-activated potassium (BK) channel is closely associated with TRPML1 activity, playing a necessary role in maintaining TRPML1 activity during lysosomal exocytosis necessary for large particle phagocytosis (Cao et al. 2015; Sun et al. 2020 ). The impact of BK channel activity on TRPML1 Ca2+ signaling suggests a therapeutic avenue that warrants further exploration.
An update on gene therapy for lysosomal storage disorders
Published in Expert Opinion on Biological Therapy, 2019
Murtaza S. Nagree, Simone Scalia, William M. McKillop, Jeffrey A. Medin
A recombinant AAV2/8 vector with a thyroxin-binding globulin promoter for liver-specific expression developed for the clinical treatment of MPS VI is under investigation in Italy (NCT03173521). This work was initiated after detailed investigational new drug (IND)-enabling studies conducted in mice [76] and a feline model showed excellent efficacy and correction of multiple disorder phenotypes [77]. The same group demonstrated that the absence of pre-existing immunity against AAV8 was important to achieve a benefit; this is now implemented in their protocol as exclusion criteria [78]. AAV-based pre-clinical studies have also been conducted for a number of other LSDs, including the use of AAV2/8 described above [79], AAV2/8 with human elongation factor 1-α promoter [80] or AAV2/6 with an unspecified liver-specific promoter [81] to treat Fabry disease, an AAV2/8 recombinant vector with a β-actin promoter and a cytomegalovirus (CMV) enhancer to treat mucolipidosis II [82], and a recombinant AAV2/8 vector with a thyroxin binding globulin targeting MPS I [83]. Unfortunately, most of these studies do not describe immunogenicity to the transgene product.