Identification of a novel mutation in ARSA gene in three patients of an Iranian family with metachromatic leukodystrophy disorder

Golchin, Neda; Hajjari, Mohammadreza; Malamiri, Reza Azizi; Aminzadeh, Majid; Mohammadi-Asl, Javad

doi:10.1590/1678-4685-gmb-2016-0110

Cited by 10 publications

(8 citation statements)

References 18 publications

(18 reference statements)

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“…False-negative MLD diagnosis could result in withholding treatment opportunities for otherwise eligible patients, especially since experimental therapies including gene therapy and intrathecal enzyme-replacement therapy are evolving. More phenotype information on pathogenic ARSA variants will also help interpreting results from the pilot [31,32]. Finally, Narayanan et al recently reported 36 ARSA variants in MLD patients from India, and no less than sixteen of them were novel [33].…”

Section: Discussionmentioning

confidence: 99%

“…Fortunately, novel ARSA variants in previously less frequently studied ethnicities are increasingly reported. A few examples are the c.847G > A, p.(Asp283Asn), c.853G > A, p.(Asp285Asn), and c.1031C > A, p.(Ala344Asp) variants in Sri Lanka [ 27 ]; the c.256C > G, p.(Arg86Gly), c.344 T > C, p.(Leu115Pro), and c.693C > A, p.(His231Gln) variants in respectively Jordan, Pakistan, and Tunisia [ 28 – 30 ]; and the c.1070G > T, p.(Gly357Val), c.585G > T, p.(Trp195Cys), c.849C > G, p.(Asp283Glu), and c.911A > G, p.(Lys304Arg) variants in Iran [ 31 , 32 ]. Finally, Narayanan et al recently reported 36 ARSA variants in MLD patients from India, and no less than sixteen of them were novel [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

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Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients

et al. 2020

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Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited sulfatide storage disease caused by deficient activity of the lysosomal enzyme arylsulfatase A (ASA). Genetic analysis of the ARSA gene is important in MLD diagnosis and screening of family members. In addition, more information on genotype prevalence will help interpreting MLD population differences between countries. In this study, we identified 31 different ARSA variants in the patient cohort (n = 67) of the Dutch expertise center for MLD. The most frequently found variant, c.1283C > T, p.(Pro428Leu), was present in 43 (64%) patients and resulted in a high prevalence of the juvenile MLD type (58%) in The Netherlands. Furthermore, we observed in five out of six patients with a non-Caucasian ethnic background previously unreported pathogenic ARSA variants. In total, we report ten novel variants including four missense, two nonsense, and two frameshift variants and one in-frame indel, which were all predicted to be disease causing in silico. In addition, one silent variant was found, c.1200C > T, that most likely resulted in erroneous exonic splicing, including partial skipping of exon 7. The c.1200C > T variant was inherited in cis with the pseudodeficiency allele c.1055A > G, p.(Asn352Ser) + * 96A > G. With this study we provide a genetic base of the unique MLD phenotype distribution in The Netherlands. In addition, our study demonstrated the importance of genetic analysis in MLD diagnosis and the increased likelihood of unreported, pathogenic ARSA variants in patients with non-Caucasian ethnic backgrounds.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients

et al. 2020

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“…Analysis of the theoretical 3D structural model showed that deletion of the Guanine nucleotide generates a premature stop codon and therefore a nonfunctional protein, in which the amino acid Histidine at position 140 is modi ed by an isoleucine (H140I) (7). The mutation found is correlated with the heterozygous variant used as a positive control in the identi cation of childhood MLD according to the study by McCreary et al, 2019 (24), a cohort study that included 60 children with suspected genetic neuroin ammation for which a sequencing panel directed at 257 genes was developed, in which a molecular diagnosis was veri ed in 20% of the patients, highlighting some unexpected genotype-phenotype associations and new pathogenic variants.…”

Section: Discussionmentioning

confidence: 99%

“…Currently, approximately 200 different types of mutations are known (6). Most of these are missense and, therefore, lead to de cient expression or structural damage to the enzyme Arylsulfatase A (ARSA) (7). ARSA is a lysosomal hydrolase that catalyzes the rst step in the degradation of cerebroside 3 sulfate, one of the sulfatides found mainly in the white matter of the CNS and SNP (8,9).…”

Section: Introductionmentioning

confidence: 99%

First Description of the Generation of Human Schwann Cells Transfected With CRISPR Cas9 and a Model of Metformin Mitochondrial Metabolism in Metachromatic Leukodystrophy

Alvarez

Bautista-Niño

Trejos-Suárez

et al. 2021

Preprint

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Background: Metachromatic leukodystrophy (MLD) is a neurological lysosomal deposit disease that has an impact on public health despite its low incidence in the population. Existing treatments are expensive and inefficient. Few reports in the literature on pathophysiological events related to enzyme deficiency and subsequent accumulation of sulfatides; therefore, the use of metformin as an alternative treatment was evaluated in vitro to counteract the effects. Methodology: An experimental in vitro study that sought to determine the effect of the use of metformin on the accumulation of sulfates in glycolysis and mitochondrial function in an in vitro model of metachromatic leukodystrophy. Human Schwann cells (CSH) transfected with CRISPR Cas9 and without transfection were treated with different concentrations of sulfatides and metformin. Cell viability was evaluated by MTT and SYTOX Green; mitochondrial and glycolytic function by Seahorse XFe24, determination of reactive oxygen species (ROS) and cell death. Results: In the MTT trials, we found that treatment with different concentrations of sulfates did not affect cell viability. Transfected CSH showed higher cell death and ROS production when exposed to 100 µM sulfatides with a statistically significant difference (p <0.001), compared to nontransfected CSH cells. Sulfatides at concentrations of 10 to 100 µM affect mitochondrial bioenergetics as concentrations increase in transfected cells, in nontransfected cells they respond metabolically to exposure; Furthermore, transfected cells show a decrease in basal respiration and maximum respiration after being exposed to a concentration of 100 µM of sulphates; however, in double treatment of these cells with both sulfates and Metformin, respiration also decreases. Maximum and normal mitochondrial respiratory capacity. Conclusion: This research describes for the first time the generation of transfected CSH and the bioenergetic and mitochondrial effect of sulfates in Schwann cells, treatment with 500 µM of Metformin restores metabolic activity of these cells and decreases ROS production, as well as prevention of cell death.

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“…MLD (OMIM # 250100) is a lysosomal storage disorder with an autosomal recessive pattern of inheritance, so carriers of one copy of the abnormal gene are not affected by the disease 18,19 . MLD is caused by mutations in the ARSA gene, located on chromosome 22q13.33 20 , that encodes the lysosomal enzyme Arylsulfatase A (ARSA) (ARSA; OMIM 607574, GenBank accession number, NG_009260) 21,22 .…”

Section: Metachromatic Leukodystrophy (Mld)mentioning

confidence: 99%

Metachromatic Leukodystrophy: Diagnosis and Treatment Challenges

Sanchez-Alvarez

Bautista-Niño

Trejos-Suárez

et al. 2021

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Metachromatic leukodystrophy is a neurological disease of the lysosomal deposit that has a significant impact given the implications for the neurodegenerative deterioration of the patient. Currently, there is no treatment available that reverses the development of characteristic neurological and systemic symptoms. Objective. Carry out an updated bibliographic search on the most critical advances in the treatment and diagnosis for LDM. A retrospective topic review published in English and Spanish in the Orphanet and Pubmed databases. Current treatment options, such as enzyme replacement therapy and hematopoietic stem cell transplantation aimed at decreasing the rapid progression of the disease, improving patient survival; however, these are costly. The pathophysiological events of intracellular signaling related to the deficiency of the enzyme Arylsulfatase A and subsequent accumulation of sulphatides and glycosylated ceramides have not yet been established. Recently, the accumulation of C16 sulphatides has been shown to inhibit glycolysis and insulin secretion in pancreatic cells. The significant advance in technology has allowed timely diagnosis in patients suffering from LDM; however, they still do not have an effective treatment.

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Identification of a novel mutation in ARSA gene in three patients of an Iranian family with metachromatic leukodystrophy disorder

Cited by 10 publications

References 18 publications

Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients

Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients

First Description of the Generation of Human Schwann Cells Transfected With CRISPR Cas9 and a Model of Metformin Mitochondrial Metabolism in Metachromatic Leukodystrophy

Metachromatic Leukodystrophy: Diagnosis and Treatment Challenges

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