Metachromatic leukodystrophy: Biochemical characterization of two (p.307Glu→Lys, p.318Trp→Cys) arylsulfatase A mutations

Özkan, Adem; Özkara, Hatice Asuman

doi:10.5582/irdr.2016.01085

Cited by 6 publications

(6 citation statements)

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“…Considering that the accumulation of metachromatic material in peripheral nerves in MLD has been previously reported, metachromatic material comprises Schwann cells and endoneurial macrophages that are filled with characteristic lysosomal sulfatide inclusions, also known as inclusion bodies [ 3 , 4 ]. The presence of sulfatide in these cells causes cell death and thus demyelination, leading to the onset of symptoms in patients with MLD [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

“…It is characterized by progressive demyelination of the central nervous system (CNS) and peripheral nervous system (PNS), causing severe neurological symptoms [1][2][3]. MLD is caused by different mutations in the arylsulfatase A gene, hereinafter referred to as ARSA, located on chromosome 22q13.33, comprising eight exons and encoding a 509 amino acid precursor protein [4,5].…”

Section: Introductionmentioning

confidence: 99%

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A model of metformin mitochondrial metabolism in metachromatic leukodystrophy: first description of human Schwann cells transfected with CRISPR-Cas9

et al. 2022

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Metachromatic leukodystrophy is a neurological lysosomal deposit disease that affects public health despite its low incidence in the population. Currently, few reports are available on pathophysiological events related to enzyme deficiencies and subsequent sulfatide accumulation. This research aims to examine the use of metformin as an alternative treatment to counteract these effects. This was evaluated in human Schwann cells (HSCs) transfected or non-transfected with CRISPR-Cas9, and later treated with sulfatides and metformin. This resulted in transfected HSCs showing a significant increase in cell reactive oxygen species (ROS) production when exposed to 100 µM sulfatides ( p = 0.0007), compared to non-transfected HSCs. Sulfatides at concentrations of 10 to 100 µM affected mitochondrial bioenergetics in transfected HSCs. Moreover, these analyses showed that transfected cells showed a decrease in basal and maximal respiration rates after exposure to 100 µM sulfatide. However, maximal and normal mitochondrial respiratory capacity decreased in cells treated with both sulfatide and metformin. This study has provided valuable insights into bioenergetic and mitochondrial effects of sulfatides in HSCs for the first time. Treatment with metformin (500 µM) restored the metabolic activity of these cells and decreased ROS production.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A model of metformin mitochondrial metabolism in metachromatic leukodystrophy: first description of human Schwann cells transfected with CRISPR-Cas9

et al. 2022

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“…It may be worthwhile to perform a cohort study to further examine genotype-phenotype associations in MLD. In addition, experimental animal studies with the same mutations are required to investigate the biochemical characterization of MLD (39). By enlarging the number of samples for mutation analysis, it is possible to screen those subjects at risk or with symptoms to diagnose early.…”

Section: Discussionmentioning

confidence: 99%

Metachromatic leukodystrophy: Characterization of two (p.Leu433Val, p.Gly449Arg)�arylsulfatase A mutations

et al. 2019

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Metachromatic leukodystrophy disorder (MLD) is an autosomal recessive lysosomal storage disease. The disease is primarily caused by a deficiency in the enzyme arylsulfatase A (ASA), which is encoded by the ARSA gene. A total of 254 mutations have been reported in different populations. The present study aimed to detect causative gene mutations in an atypical case presenting with attention deficit hyperactivity disorder through whole-exome sequencing. Of note, the patient's mother is from a consanguineous family. Compound heterozygous variants (c.1297C>G) + (c.1345G>A) [(p.Leu433Val) + (p.Gly449Arg)] were identified in exon 8 in the ARSA gene of the pediatric patient. The two missense mutations identified have not been previously reported, to the best of our knowledge. Furthermore, an in silico analysis and multiple phylogenetic tree analyses of ARSA homologs were performed to predict the effects of the two novel mutations. Serial changes were observed in the patient with MLD at follow-up visits over 6 years. However, brain MRI images demonstrated no notable progression and the number of ASA enzymes was stable. Also, the results of neurodevelopmental assessment showed that the patient was diagnose with ADHD. These data may offer a potential explanation of the genotype-phenotype correlation in MLD and enhance the spectrum of mutations associated with the condition.

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“…Homozygous Similar onset as males Krabbe Disease GALC GALC psychosine Infantile: 3-6 months. premature death between 2-5 years of age • Motor dysfunction • Seizures • Cognitive decline [ 46 , 67 , 90 – 92 ] Juvenile & adult: few years- 73 years • Dementia • Blindness, Psychomotor retardation • Spastic paraparesis Metachromatic Leukodystrophy ASA ASA sulfatide Late infantile: Before 30 months • Hypotonia • Mental regression, Unsteady gait, followed by loss of speech • Incontinence • Blindness • Seizures • Peripheral neuropathy • Complete loss of motor function • Loss of contact with the surroundings is observed before reaching 40 months of age [ 46 , 93 – 95 ] Juvenile: 2.5-16 years • Later in onset but once the ability of walking is lost, the disease progresses as seen in the infantile form • Infertile Adult: After puberty • Variable progression Niemann Pick C1 NPC1 NPC1 Chol and other SLs Perinatal (up to 2 months) Systemic: • Mild thrombocytopenia (newborns or toddlers) • Prolonged neonatal cholestatic jaundice (in perinatal) • Hepatomegaly/ Splenomegaly Neurological: • Vertical supranuclear • Gaze palsy • Gelastic cataplexy • Ataxia • Dystonia • Dysarthria • Dysphagia • Hypotonia • Clumsiness • Delayed developmental milestones • Seizures • Hearing loss Psychiatric • Psychosis • Cognitive decline • Developmental delay [ 96 – 99 ] Niemann Pick C2 NPC2 NPC2 Early-infantile (2 months–2 years of age) Late-infantile (2–6 years of age) Juvenile (6–12 years of age) Adolescent/adult (>12 years of age) Sialidosis ...…”

Section: Sl-related Lsds: Sphingolipidosesmentioning

confidence: 99%

“…Metachromatic Leukodystrophy (MLD) is an autosomal recessive LSD, with an incidence of 1 per 40,000-160,000 live births. It is caused by mutations in the gene encoding arylsulfatase A (ASA) [ 93 ]. ASA, which is assisted by SapB [ 46 ], catalyzes the conversion of O -sulfogalactosylceramide into GalCer and sulfate [ 94 ].…”

Section: Sl-related Lsds: Sphingolipidosesmentioning

confidence: 99%

Sphingolipid lysosomal storage diseases: from bench to bedside

et al. 2021

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Johann Ludwig Wilhelm Thudicum described sphingolipids (SLs) in the late nineteenth century, but it was only in the past fifty years that SL research surged in importance and applicability. Currently, sphingolipids and their metabolism are hotly debated topics in various biochemical fields. Similar to other macromolecular reactions, SL metabolism has important implications in health and disease in most cells. A plethora of SL-related genetic ailments has been described. Defects in SL catabolism can cause the accumulation of SLs, leading to many types of lysosomal storage diseases (LSDs) collectively called sphingolipidoses. These diseases mainly impact the neuronal and immune systems, but other systems can be affected as well. This review aims to present a comprehensive, up-to-date picture of the rapidly growing field of sphingolipid LSDs, their etiology, pathology, and potential therapeutic strategies. We first describe LSDs biochemically and briefly discuss their catabolism, followed by general aspects of the major diseases such as Gaucher, Krabbe, Fabry, and Farber among others. We conclude with an overview of the available and potential future therapies for many of the diseases. We strive to present the most important and recent findings from basic research and clinical applications, and to provide a valuable source for understanding these disorders.

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Metachromatic leukodystrophy: Biochemical characterization of two (p.307Glu→Lys, p.318Trp→Cys) arylsulfatase A mutations

Cited by 6 publications

References 10 publications

A model of metformin mitochondrial metabolism in metachromatic leukodystrophy: first description of human Schwann cells transfected with CRISPR-Cas9

A model of metformin mitochondrial metabolism in metachromatic leukodystrophy: first description of human Schwann cells transfected with CRISPR-Cas9

Metachromatic leukodystrophy: Characterization of two (p.Leu433Val, p.Gly449Arg)�arylsulfatase A mutations

Sphingolipid lysosomal storage diseases: from bench to bedside

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