Metachromatic leukodystrophy: Multiple nonfunctional and pseudodeficiency alleles in a pedigree: Problems with diagnosis and counseling

Francis, Gordon; Bonni, Azad; Shen, Ning; Hechtman, Peter; Yamut, Bassem; Carpenter, Stirling; Karpati, George; Chang, Patricia L.

doi:10.1002/ana.410340218

Cited by 17 publications

(5 citation statements)

References 37 publications

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“…In Fabry disease, an earlier study reported that p.D313Y is a GLA pseudodeficiency mutant with minimal alteration of enzyme structure [24]. Furthermore, there are many reports on the pseudodeficiency alleles on arylsulfatase A (ARSA), an enzyme responsible for metachromatic leukodystrophy [25], [26]. In the case of ARSA, subsequent evidences have shown that there are many pseudodeficiency mutations that are not limited to a restricted area but are global [27], [28].…”

Section: Discussionmentioning

confidence: 99%

Enzyme activities of α-glucosidase in Japanese neonates with pseudodeficiency alleles

Mashima

Okuyama

2017

Molecular Genetics and Metabolism Reports

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Lysosomal storage disorders (LSDs) are caused by defective enzyme activities in lysosomes, characterized by the accumulation of sphingolipids, glycolipids, oligosaccharides, mucopolysaccharides, the oxidation products of cholesterol, and other biological substances. A growing number of clinical studies have suggested the enhanced efficacy of existing therapies, including enzyme replacement therapy, which is effective when it is initiated during the presymptomatic period. Thus, the identification of disease-affected individuals by newborn screening has been considered an effective platform. Previous studies have suggested that the discrimination of infantile-onset Pompe disease (IOPD) requires multi-step examination of GAA enzyme activity using the fluorometric technique. In sharp contrast, the MS/MS-based technique can identify the population of IOPD and the pseudodeficiency alleles of the GAA enzyme [Liao HC et al. Clin Chem (2017) in press; doi: http://dx.doi.org/10.1373/clinchem.2016.269027]. To determine whether MS/MS-based assay can identify these two populations in Japanese neonates, we first performed a validation study of this assay using flow-injection analysis (FIA)-MS/MS and liquid chromatography (LC)-MS/MS followed by examination of GAA enzyme activity in our population. By minimizing the effect of substrate-derived in-source decomposition products, the activities of 6 LSD enzymes were quantified in FIA-MS/MS and LC-MS/MS. The mean value of GAA activity with IOPD, pseudodeficiency alleles, and healthy controls by FIA-MS/MS were 1.0 ± 0.3 μmol/h/L (max, 1.3; min, 0.7; median, 1.2; n = 3), 2.7 ± 0.7 μmol/h/L (max, 4.5; min, 1.5; median, 2.5; n = 19), and 12.9 ± 5.4 μmol/h/L (max, 29.6; min, 2.5; median, 11.0; n = 83), respectively. These results suggest that the population of GAA with pseudodeficiency alleles has approximately 20% of GAA enzyme activity compared to controls, providing the preliminary evidence to estimate the cut-off values in the Japanese population using this technique.

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Section: Discussionmentioning

confidence: 99%

Enzyme activities of α-glucosidase in Japanese neonates with pseudodeficiency alleles

Mashima

Okuyama

2017

Molecular Genetics and Metabolism Reports

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“…The carrier frequency of the ARSA pseudodeficiency alleles in Australia is estimated to be 20% 16. Its correlation with occurrence of other neurodegenerative disorders that occur later in life remains debatable 14. The existence of the ARSA pseudodeficiency alleles demonstrates that the sulfatide degradation can occur normally in the presence of ASA variants functioning at 10–15% of the wild type ASA enzymatic activity.…”

Section: Introductionmentioning

confidence: 99%

Developing therapeutic approaches for metachromatic leukodystrophy

Patil¹,

Maegawa²

2013

DDDT

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Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal disorder caused by the deficiency of arylsulfatase A (ASA), resulting in impaired degradation of sulfatide, an essential sphingolipid of myelin. The clinical manifestations of MLD are characterized by progressive demyelination and subsequent neurological symptoms resulting in severe debilitation. The availability of therapeutic options for treating MLD is limited but expanding with a number of early stage clinical trials already in progress. In the development of therapeutic approaches for MLD, scientists have been facing a number of challenges including blood–brain barrier (BBB) penetration, safety issues concerning therapies targeting the central nervous system, uncertainty regarding the ideal timing for intervention in the disease course, and the lack of more in-depth understanding of the molecular pathogenesis of MLD. Here, we discuss the current status of the different approaches to developing therapies for MLD. Hematopoietic stem cell transplantation has been used to treat MLD patients, utilizing both umbilical cord blood and bone marrow sources. Intrathecal enzyme replacement therapy and gene therapies, administered locally into the brain or by generating genetically modified hematopoietic stem cells, are emerging as novel strategies. In pre-clinical studies, different cell delivery systems including microencapsulated cells or selectively neural cells have shown encouraging results. Small molecules that are more likely to cross the BBB can be used as enzyme enhancers of diverse ASA mutants, either as pharmacological chaperones, or proteostasis regulators. Specific small molecules may also be used to reduce the biosynthesis of sulfatides, or target different affected downstream pathways secondary to the primary ASA deficiency. Given the progressive neurodegenerative aspects of MLD, also seen in other lysosomal diseases, current and future therapeutic strategies will be complementary, whether used in combination or separately at specific stages of the disease course, to produce better outcomes for patients afflicted with this devastating inherited disorder.

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“…The presence of the pseudodeficiency polymorphism confounded the interpretation of the biochemical analysis of our patient and his family, a situation that has been previously reported. 11 We could in any case demonstrate that our patient has the biochemical abnormality of MLD by showing an increased urinary excretion of sulphatides.…”

Section: Discussionmentioning

confidence: 65%

Late onset MLD with normal nerve conduction associated with two novel missense mutations in the ASA gene

Gallo¹,

Randi²,

Bertelli³

et al. 2004

Journal of Neurology, Neurosurgery & Psychiatry

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Metachromatic leukodystrophy: Multiple nonfunctional and pseudodeficiency alleles in a pedigree: Problems with diagnosis and counseling

Cited by 17 publications

References 37 publications

Enzyme activities of α-glucosidase in Japanese neonates with pseudodeficiency alleles

Enzyme activities of α-glucosidase in Japanese neonates with pseudodeficiency alleles

Developing therapeutic approaches for metachromatic leukodystrophy

Late onset MLD with normal nerve conduction associated with two novel missense mutations in the ASA gene

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