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Morquio syndrome/mucopolysaccharidosis type IV/keratan sulfaturia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Some mutations in the β-galactosidase gene have been identified in genetic compounds [63, 64, 65]. Depending on the mutation, the phenotype can vary from that of severe GM1 gangliosidosis (Chapter 89) to Morquio disease type B [21]. In a patient with Morquio B disease, p.Y333H was found on one allele [65]; p.R201H was on the other. The latter allele has been associated with poorly transported protein products through the endoplasmic reticulum.
Inborn errors of metabolism
Published in Martin Andrew Crook, Clinical Biochemistry & Metabolic Medicine, 2013
Here a deficiency of a lysosomal hydrolase is inherited, resulting in the accumulation of sphingolipid. The following are some examples: GM1 gangliosidosis defect of β-galactosidase,GM2 gangliosidosis such as Tay–Sachs disease, due to hexosaminidase deficiency,Gaucher’s disease, due to a deficiency of β-glucosidase (glucocerebrosidase),Niemann–Pick disease, resulting from sphingomyelinase deficiency,Fabry’s disease, resulting from α-galactosidase A deficiency,metachromic leucodystrophy, resulting from arylsulphatase deficiency.
Novel Methods in Preimplantation Genetic Testing: Comprehensive Preimplantation Genetic Testing
Published in Darren K. Griffin, Gary L. Harton, Preimplantation Genetic Testing, 2020
Olga Tsuiko, Joris Robert Vermeesch
Since the first application in the 1990s [1], PGT-M is now performed worldwide to avoid the transmission of Mendelian hereditary conditions that run in the family to the offspring. At the same time, the development of microarray-based technologies and later implementation of next-generation sequencing (NGS), which allow genome-wide chromosome screening for aneuploidy, has facilitated the use of PGT-A to select against embryos with unbalanced karyotype. Traditionally, patients have been referred either to PGT-M/PGT-SR or PGT-A, based on medical indication, but no combined tests have been performed. However, couples undergoing PGT-M can have “unaffected” embryos for a single-gene disorder, but because of high aneuploidy rate in human IVF embryos [2], the seemingly healthy embryos can carry chromosomal aberrations that can lead to implantation failure or adverse pregnancy outcome. For this reason, couples can benefit from PGT-M in conjunction with PGT-A (further referred to as comprehensive PGT), selecting only those embryos that are free of disease and have a normal euploid karyotype. In the past decade, different strategies have been implemented to allow simultaneous detection of monogenic and chromosomal disorders. One of the first attempts to do so used the two-biopsy approach: (i) oocyte polar body was biopsied for chromosome screening via array comparative genomic hybridization (aCGH) and (ii) day 3 biopsy was performed for genetic analysis for cystis fibrosis or von Hippel-Lindau disease using multiplex PCR [3,4]. Later, the use of whole-genome amplified (WGA) product for comprehensive embryo testing made it possible to perform SNP microarray analysis for aneuploidy and PCR-based linkage analysis for GM1 gangliosidoses from the same biopsied material [5]. By combining the data from two independent assays, five embryos out of ten were suitable for transfer, as they were both euploid and disease-free. This approach was later extended to a variety of genetic disorders, and the first systematic analysis demonstrated improved pregnancy rates from 45.4% to 68.4% and a reduction in spontaneous abortion rate from 15.5% to 5.5%, which was especially evident in patients with advanced maternal age [6]. The same beneficial effect of comprehensive PGT was also observed in a recent large-scale study, demonstrating the increase of clinical pregnancy rate per transfer from 33.6% to 49% by avoiding transferring of embryos with low developmental potential [7].
The COX-2/prostanoid signaling cascades in seizure disorders
Published in Expert Opinion on Therapeutic Targets, 2019
Asheebo Rojas, Di Chen, Thota Ganesh, Nicholas H. Varvel, Raymond Dingledine
PGD2 participates in numerous biological functions, including inhibition of platelet aggregation [70], smooth muscle relaxation and contraction [71], vasodilation and vasoconstriction [72], and sleep induction [73]. PGD2 is the most abundant lipid metabolite derived from the release of arachidonic acid in rodent brains [74,75], but it is unlikely to be formed in neurons. Two different synthases convert PGH2 to PGD2, termed hematopoietic (H-PGDS, encoded by the HPGDS gene) and lipocalin PGD2 synthase (L-PGDS, encoded by the PGDS gene), also known as β-trace protein. In the brain the two PGD2 synthases are largely expressed by different cell types, H-PGDS being found in microglia [76] and L-PGDS in leptomeninges, choroid plexus, and oligodendrocytes in adult rats and human [77,78]. L-PGDS is also secreted into serum, urine, and seminal plasma. L-PGDS is the only member of the lipocalin family that has the dual function of converting PGH2 to PGD2 and also binding to and transporting small lipophilic molecules such as retinoids, bilirubin and biliverdin, GM1 and GM2 gangliosides, and amyloid beta. L-PGDS is upregulated in the brain of various animal models of neurodegenerative diseases such as the demyelinating twitcher mouse [79], and mouse models of lysosomal storage diseases including Tay-Sachs’ and Sandhof’s diseases, GM1 gangliosidosis, and Niemann–Pick disease [80].
Digital microfluidics comes of age: high-throughput screening to bedside diagnostic testing for genetic disorders in newborns
Published in Expert Review of Molecular Diagnostics, 2018
David Millington, Scott Norton, Raj Singh, Rama Sista, Vijay Srinivasan, Vamsee Pamula
More recently, in a further demonstration of the versatility of the DMF platform, 10 distinct enzyme assays were combined in a single run [57]. The conditions targeted were Pompe, Hurler, Gaucher, Fabry, Biotinidase, Sanfilippo, Sly, GM1 gangliosidosis, and alpha and beta mannosidoses. The concept for a 10-plex enzyme assay on the same cartridge was presented, in which a dual fluorophore detector system permits combining two reagents in each of 5 reagent input wells that release different fluorophores when exposed to their targeted enzyme. One set of fluorogenic substrates is based on 4MU (detected using excitation and emission wavelengths of 360 and 460 nm, respectively) and the other set based on resorufin (detected using excitation and emission wavelengths of 570 and 590 nm, respectively). The principles of this concept were proven by comparison with data from individual assays. For higher throughput of multiple enzymatic assays of this type, a cartridge capable of analyzing 96 samples and an analyzer with a built-in dual detector would be desirable.
Fetal hydrops – a review and a clinical approach to identifying the cause
Published in Expert Opinion on Orphan Drugs, 2020
Esther Dempsey, Tessa Homfray, John M Simpson, Steve Jeffery, Sahar Mansour, Pia Ostergaard
Most babies with IEM-related hydrops will have a lysosomal storage disease (LSD), 17 of which have been shown to cause nonimmune fetal hydrops to date [140]. In a systematic review by Gimovsky et al. (2015), in 678 cases of nonimmune fetal hydrops, 5.2% were diagnosed with an LSD during the pregnancy. Of those cases labeled as ‘idiopathic’, 17.4% were later diagnosed with an LSD on post-natal investigations [141]. Mucopolysaccharidosis type VII represented 20% of all LSD diagnoses, Gaucher was the next most frequent at 17.1%, followed by GM1-gangliosidosis at 14.3% [141].