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Spinal Cord Disease
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Inherited leukodystrophies: Adrenoleukodystrophy (ALD)/adrenomyeloneuropathy (AMN).Metachromatic leukodystrophy.Krabbe's (globoid cell) leukodystrophy.
Psychology and Human Development EMIs
Published in Michael Reilly, Bangaru Raju, Extended Matching Items for the MRCPsych Part 1, 2018
Acute intermittent porphyria.Adrenoleukodystrophy.Down’s syndrome.Fragile X syndrome.Huntington’s disease.Learning disorder of the right hemisphere.Metachromatic leukodystrophy.Olivopontocerebellar degeneration.Prader-Willi syndrome.
Genetic diseases mimicking multiple sclerosis
Published in Postgraduate Medicine, 2021
Chueh Lin Hsu, Piotr Iwanowski, Chueh Hsuan Hsu, Wojciech Kozubski
Metachromatic leukodystrophy (MLD) is caused by a mutation in the ARSA gene encoding arylsulfatase A, with subsequent buildup of sulfatides in both central and peripheral nervous systems. Sulfatides are most abundant and make up 4% of the sphingolipids of myelin. With a normal amount, they function to maintain myelin [140]. However, the accumulation of excess sulfatides results in demyelination, possibility due to the triggering of apoptosis [141]. MLD is classified into three subtypes based on the age of onset: late-infantile type, juvenile type, and adult type. Late- infantile and juvenile types are characterized by their rapidly progressive disease courses and are distinguished by the first signs of disorder with psychomotor regression and behavior abnormalities, respectively [142]. Genetic testing for mutational ARSA gene and PSAP gene is one of the reliable methods to diagnose MLD. However, a diagnosis should not be confirmed only based on the detection of mutations due to the incompleted identification of all the MLD associated mutations [143].
Synthesis and structure-activity relationships of cerebroside analogues as substrates of cerebroside sulphotransferase and discovery of a competitive inhibitor
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Wenjin Li, Joren Guillaume, Younis Baqi, Isabell Wachsmann, Volkmar Gieselmann, Serge Van Calenbergh, Christa E. Müller
Metachromatic leukodystrophy (MLD) is a rare genetic disease characterised by a dysfunction of the enzyme arylsulphatase A1. This defect leads to the lysosomal accumulation of cerebroside sulphate (sulphatide, 1) in various cells such as tubular kidney cells, bile duct epithelia, some neurons, oligodendrocytes and Schwann cells. In particular accumulation in the latter two results in progressive demyelination finally causing lethal symptoms in patients. Recently haematopoetic stem cell-based gene therapy has been shown to be effective in patients in early preclinical states of disease only2. Thus, there is an urgent need to develop alternative strategies to treat MLD. One of these strategies is substrate reduction therapy in which galactosylceramide (cerebroside) sulphotransferase (CST; EC 2.8.2.11), the enzyme which synthesises sulphatide, is inhibited. This would diminish the load of accumulated sulphatide in the patient. Such a strategy has been shown to be effective in Gaucher disease, another lysosomal sphingolipid storage disorder3. Inhibition of galactosylceramide sulphotransferase has been proposed as a promising new therapeutic strategy for the treatment of MLD1,4. CST catalyses the transfer of a sulphate group from the coenzyme 3′-phosphoadenosine-5′-phosphosulphate (PAPS, 2) to galactosylceramide (3) yielding galactosylceramide sulphate (2) and adenosine-3′,5′-bisphosphate (PAP, 4) (Figure 1)5–7.
Advances in the treatment of neuronal ceroid lipofuscinosis
Published in Expert Opinion on Orphan Drugs, 2019
Jonathan B. Rosenberg, Alvin Chen, Stephen M. Kaminsky, Ronald G. Crystal, Dolan Sondhi
To improve the potency of transplanted cells, most research has targeted the use of a subpopulation of the blood, marrow, or umbilical cord blood – hematopoietic stem cells (HSC) [167]. Clinical trials for metachromatic leukodystrophy (MLD), unrelated to the NCLs, have shown that some of the transplanted stem cells do manage to migrate into the CNS, becoming glial cells [168–173]. Other clinical studies have looked at direct localized delivery of cells to CNS to correct neurodegeneration [174,175]. Several clinical trials with HSC have been completed for CNS disorders unrelated to NCLs (globoid cell leukodystrophy, adrenoleukodystrophy, MLD, and Hurler syndrome) and show safety and limited efficacy [169,176], suggesting that this approach could offer a solution. Based on previous human clinical data, the human stem cell transplant may correct only a small subset of the CNS, and thus fail to provide sufficient amounts of functional enzyme to the target CNS cells [177]. A critical hurdle here is the extent to which transplanted cells can safely and effectively repopulate the CNS.