Materiały źródłowe

• #1 Metachromatic Leukodystrophy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560744/

  Metachromatic leukodystrophy is a rare lysosomal storage disease caused due to deficient activity of arylsulfatase A. […] Metachromatic leukodystrophy is a demyelinating, autosomal recessive genetic leukodystrophy and LSD, caused by an inborn error of metabolism in the arylsulfatase A lysosomal enzyme. This leads to the accumulation of sulfatides, which result in the dysfunction and destruction of the CNS/PNS myelin sheaths. […] Metachromatic leukodystrophy is caused by deficient activity of arylsulfatase A. In almost all cases, mutations are in the arylsulfatase A gene (ARSA gene), on chromosome 22q13.3-qter. […] Metachromatic leukodystrophy is a lysosomal storage disease characterized by the inability to degrade sulfated glycolipids, mainly the galactosyl-3-sulfate ceramides. It is caused by deficient activity of lysosomal enzyme arylsulfatase A, most commonly due to mutations in the arylsulfatase A (ARSA gene). […] Hence, preliminary evidence suggests that gene therapy and hematopoietic stem cell transplantation combined with gene therapy are promising treatment options. […] However, the cellular pathogenesis of metachromatic leukodystrophy is complex.

• #1 A systematic review on the birth prevalence of metachromatic leukodystrophy | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03044-w

  Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency in arylsulfatase A (ASA) activity arising primarily from ASA gene (ARSA) variants. […] Deficiency in ASA activity results in the accumulation of sulfatides in the central and peripheral nervous systems, leading to demyelination, neuronal dysfunction and degeneration. […] At least 200 pathogenic ARSA variants have been described. […] Some of these, such as the splice donor site variants c.465+1GA (the most common variant in late-infantile MLD), result in the production of inactive ASA. […] Other variants, such as the missense variants c.1283CT (the most common variant in adult MLD), result in ASA that retains some residual activity. […] Atypical MLD due to saposin B deficiency is caused by pathogenic variants in the prosaposin gene.

• #1 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  The accumulation of sulfatides leads to neuronal degeneration, astrocyte dysfunction and may trigger an inflammatory response. Several studies support the role of inflammation in MLD. […] Thus, complement activation via an alternative pathway enhances myelin damage, thus inducing or enhancing the immune response against myelin. […] Microglia is also assumed to play an important role in the development of MLD. It has been shown that the microglia immune phenotype changes at the early stages of MLD development and this precedes oligodendrocyte degeneration and myelin damage. […] MLD is caused by the deficiency of arylsulfatase A lysosomal enzyme (ARSA) and sphingolipid activator protein B (SapB or saposin B) as a consequence of mutations in the ARSA and PSAP genes, respectively. […] The physiological substrate of ARSA is sulfatide.

• #1 Metachromatic Leukodystrophy | American Journal of Neuroradiology

  https://www.ajnr.org/ajnr-case-collections-diagnosis/metachromatic-leukodystrophy-0

  Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by a deficiency of the lysosomal enzyme arylsulfatase A, which is necessary for the normal metabolism of sulfatides (which are important constituents of the myelin sheath). […] In MLD, sulfatides accumulate in various tissues, including the brain, peripheral nerves, kidneys, liver, and gallbladder. […] Currently, no effective treatment is available to reverse the deterioration and loss of function caused by MLD.

• #1 Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1220-4

  Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited metabolic disease characterized by deficient activity of the lysosomal enzyme arylsulfatase A. Its deficiency results in accumulation of sulfatides in neural and visceral tissues, and causes demyelination of the central and peripheral nervous system. This leads to a broad range of neurological symptoms and eventually premature death. […] However, the reasons for residual and often progressive peripheral neuropathy after HCT are not fully understood. Preliminary studies suggest that peripheral neuropathy might respond better to gene therapy due to higher enzyme levels achieved than with HCT. However, histopathological and clinical findings also suggest a role of neuroinflammation in the pathology of peripheral neuropathy in MLD.

• #1 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  Metachromatic leukodystrophy is a lysosomal storage disease, which is characterized by damage of the myelin sheath that covers most of nerve fibers of the central and peripheral nervous systems. The disease occurs due to a deficiency of the lysosomal enzyme arylsulfatase A (ARSA) or its sphingolipid activator protein B (SapB) and it clinically manifests as progressive motor and cognitive deficiency. ARSA and SapB protein deficiency are caused by mutations in the ARSA and PSAP genes, respectively. The severity of clinical course in metachromatic leukodystrophy is determined by the residual ARSA activity, depending on the type of mutation. […] However, the exact mechanisms of demyelination in MLD remain unknown. Possible causes are an increase in the sulfatides and a decrease in its cleavage products, which lead to instability of the myelin sheath. In addition, sulfatides cause accumulation of calcium in the cell cytoplasm, which results in a change in calcium homeostasis, cell stress, and apoptosis.

• #1 Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1220-4

  The accumulation of metachromatic material in peripheral nerves in MLD have first been reported by Jacobi. Metachromatic material consists of Schwann cells and endoneural macrophages that are filled with characteristic lysosomal inclusions of sulfatides, also called inclusion bodies. […] Remarkably, no correlation between demyelination and the presence of metachromatic material in peripheral nerves has been found. This raises the question whether peripheral neuropathy in MLD is (partially) due to other causes in addition to sulfatide accumulation. […] Notably, Cravioto et al. and Argyrakis et al. also described several abnormalities other than inclusion bodies. These are morphological alterations of the endoplasmatic reticulum and mitochondria in Schwann cells, and accumulation of glycogen in mitochondria, Schwann cells and axons. These abnormalities could reflect a metabolic derangement of these cells, causing premature cell death, and may explain the lack of a correlation between demyelination and presence of metachromatic material.

• #1 Metachromatic leukodystrophy – Wikipedia

  https://en.wikipedia.org/wiki/Metachromatic_leukodystrophy

  Metachromatic leukodystrophy (MLD) is a lysosomal storage disease which is commonly listed in the family of leukodystrophies as well as among the sphingolipidoses as it affects the metabolism of sphingolipids. […] MLD involves cerebroside sulfate accumulation. […] MLD is directly caused by a deficiency of the enzyme arylsulfatase A (ARSA) and is characterized by enzyme activity in leukocytes that is less than 10% of normal controls. […] Without this enzyme, sulfatides build up in many tissues of the body, eventually destroying the myelin sheath of the nervous system. […] Arylsulfatase A is activated by saposin B (Sap B), a non-enzymatic proteinaceous cofactor. […] When the arylsulfatase A enzyme level is normal but the sulfatides are still high meaning that they are not being broken down because the enzyme is not activated the resulting disease is saposin B deficiency, which presents similar to MLD. […] A 2011 study contended sulfatide is not completely responsible for MLD because it is non-toxic. It has been suggested that lysosulfatide, sulfatide which has had its acyl group removed, plays a role because of its cytotoxic properties in vitro.

• #1 Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1220-4

  The lack of a correlation between demyelination and the presence of metachromatic material raises the question whether the pathology of peripheral neuropathy in MLD can be partially explained by a neuroinflammatory scenario. […] Additional research findings that suggest a neuroinflammatory component in the pathology of MLD are that sulfatide accumulation and demyelination in the PNS are able to 1) induce the release of inflammatory cytokines; 2) activate endoneural macrophages; and 3) recruit inflammatory myeloid cells and lymphocytes from the periphery. […] A neuroinflammatory component in the pathology of the disease is an attractive hypothesis with clear therapeutic implications, but convincing preclinical and clinical evidence has yet to be shown.

• #1 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  Sulfatides are one of the most common sphingolipids in myelin. […] Sulfatides are cleaved in the lysosome, where ARSA hydrolyzes the sulfate group. […] Just 10-15% of the ARSA enzymatic activity is sufficient for sulfatide degradation and maintenance of normal life. […] The PSAP gene encodes a precursor protein, prosaposin (pSap), consisting of 524 amino acids. […] Mutations in the PSAP gene can cause either a single saposin deficiency or a deficiency of the whole pSap protein, which result in severe lethal neurodystrophy. […] The phenotype of SapB defect is similar to classical MLD phenotype caused by ARSA deficiency. […] The clinical manifestations and a degree of neurodegeneration in MLD are diverse and depend on the type of mutation and the level of enzyme deficiency. […] It is hypothesized that the lower the enzyme activity the earlier the disease manifests itself, however such association has yet to be fully demonstrated.

• #1 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  The most common form is the late infantile, which is found in 50–60% of all patients. […] Clinical manifestation of late infantile MLD begins up to 30 months of age. […] The juvenile form develops between the ages of 3 and 16 and is characterized by a less pronounced clinical manifestation in comparison with the late infantile form. […] The adult MLD is the less severe form of the disease. […] In most cases, MLD is not included in the fetus and newborn genetic screening tests given that MLD is a rare disease. […] Prenatal diagnostics can be performed by measuring the activity of ARSA in amniotic fluid cells and evaluating the accumulation of sulfatides to exclude ARSA pseudo-deficiency. […] Diagnosis of late onset forms of MLD is often more difficult. […] To date, MLD is diagnosed by clinical manifestations, using genetic analysis for mutations in the ARSA and PSAP genes, magnetic resonance imaging (MRI) of the brain and biochemical tests of the ARSA enzymatic activity in skin fibroblasts, leukocytes and urine of patients.

• #1 Metachromatic leukodystrophy (MLD) | Britannica

  https://www.britannica.com/science/metachromatic-leukodystrophy

  Specific mutations in ARSA are linked to the timing of MLD onset and the phenotypic patterns (physical manifestations) of MLD, such as the degree of ASA deficiency and the severity of neuropsychiatric symptoms. Other genetic defects, such as those leading to the deficiency of an activator protein involved in the degradation of sulfatides but in which patients have normal ASA levels, can also cause MLD. In addition, there exist individuals who have very low levels of ASA but never develop the disease. This condition is known as pseudoarylsulfatase A deficiency (PASAD) and is the result of two specific polymorphisms that occur simultaneously in the ARSA gene.

• #1 Leukodystrophy – Wikipedia

  https://en.wikipedia.org/wiki/Leukodystrophy

  The pattern of inheritance of the three different alleles affects what type of MLD a person develops. Two null alleles are responsible for the infantile version, and do not allow for any production of ASA. A heterozygous individual (one null allele, one non-null allele) develops the juvenile form and has some production of ASA, while an individual with two mutated non-null alleles develops the adult form.

• #1 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  As MDL is characterized by different clinical manifestations, effective modeling of the disease is important to study the genetic basis of the disease, disease progression, diagnosis, and therapy. […] There are no approved therapies for MLD to date. […] The problem of overcoming the BBB could be solved, for example, by direct injection of the recombinant ARSA enzyme or viral vectors encoding the wild-type gene of the missing enzyme into the brain. […] For pre-symptomatic patients, bone marrow transplantation (BMT) or hematopoietic stem cell (HSC) transplantation may be helpful, but the therapeutic potential of this procedure remains controversial. […] One of the first and most effective approaches to currently treat MLD is BMT and HSC transplantation. […] The introduction of prenatal diagnosis and newborn screening could increase therapy efficacy, since the effectiveness of the treatment is significantly reduced after the onset of symptoms. […] Gene and combined gene-cell therapy are considered new promising methods for MLD therapy.

• #1 Metachromatic Leukodystrophy (MLD) | UPMC Children’s Hospital

  https://www.chp.edu/our-services/rare-disease-therapy/conditions-we-treat/metachromatic-leukodystrophy

  Metachromatic leukodystrophy (MLD) is a disease passed from parent to child through a broken gene. […] In MLD, the body can’t properly make the enzyme arylsulfatase A. This leads to a loss of myelin the special coating that protects the body’s nerves. […] Without enough myelin, the nerves stop working right. […] Nerve damage keeps the brain from sending signals to the body, which leads to MLD symptoms. […] Right now, there’s no cure for MLD. […] An umbilical cord blood transplant has extended the lives of many children with MLD. It can’t undo the damage done, but it may keep it from getting worse.

• #1 Metachromatic Leukodystrophy (MLD) – United Leukodystrophy Foundation

  https://ulf.org/leukodystrophies/metachromatic-leukodystrophy-mld/

  Currently, the only treatment for MLD is bone marrow transplantation; this means that cells that produce normal ASA are introduced into the patient, and the normal ASA protein is then taken up into the deficient cells, allowing sulfatides in those cells to be broken down. […] However, this is only useful for those who are pre-symptomatic or those with very mild neurological manifestations. This highlights the importance of testing asymptomatic brothers and sisters of patients who have MLD. This treatment can slow the disease progress and increase the quality of life for the patient. […] Scientists have been working very hard to learn more about MLD, and their work has led to the identification of the genetic defect involved in the disease. […] Existing studies have focused on gene therapy in a mouse model of MLD. A harmless virus was modified to produce the active ASA protein, and the virus was then introduced into the mouse. This therapy has been shown to protect mice against some of the deteriorations seen with MLD, including learning ability, behavioral deficits, and some of the neuropathology and neurological impairments. However, the demyelination that is characteristic of MLD in humans is not seen in the mouse model, so it is not clear if this sort of treatment would be able to slow the demyelination process.

• #1 SciELO Brazil – Metachromatic leukodystrophy: pediatric presentation and the challenges of early diagnosis Metachromatic leukodystrophy: pediatric presentation and the challenges of early diagnosis

  https://www.scielo.br/j/ramb/a/4Tcf3mYwRfLMdxkTzwXxT5q/

  Even though there is still no curative treatment for this disease, new therapeutic possibilities are emerging, such as intrathecal enzyme replacement and hematopoietic stem-cell transplantation (HSCT) associated with gene therapy. […] Gene therapy is the delivery of genetic material, using viral vectors, to the cells or tissues of an individual for therapeutic purposes. It is possible to modify stem cells and autologous hematopoietic progenitor cells using a lentivirus that expresses a functional ARSA enzyme, this is currently being tested in clinical trials with promising results. […] Enzyme replacement therapy (ERT) is an alternative that benefits from the enzyme provision via the intrathecal route in patients with the late infantile presentation; it requires a trained neurosurgery team for the procedure to be performed and this method is not capable of enabling the patient to produce the enzyme.

• #1 MED.00148 Gene Therapy for Metachromatic Leukodystrophy

  https://www.anthem.com/dam/medpolicies/abcbs/active/policies/mp_pw_e003052.html

  MLD is caused by having an abnormal variant of the arylsulfatase A (ARSA) gene, which leads to a deficiency of the enzyme ARSA. […] Gene therapy for MLD involves extraction of CD34+ stem cells from the affected individuals bone marrow or blood using a process called pheresis. The collected stem cells are genetically modified ex vivo with a lentiviral vector encoded with functional ARSA DNA. […] The aim of the treatment is for the corrected cells to proliferate and migrate to affected tissues where they will produce a functional version of the ARSA enzyme, which will then halt the progression of MLD. […] The condition is caused by mutations in the ARSA gene. Individuals with MLD do not produce sufficient amounts of the ARSA enzyme, and this deficiency leads to the accumulation of a fatty substance called sulfatide within cells. The buildup of sulfatide disrupts the formation and maintenance of the myelin sheath, which is essential for the proper conduction of nerve signals. MLD is progressive in nature and leads to severe neurological impairment. […] Gene therapy is a new approach for treating MLD. The first gene therapy for MLD, atidarsagene autotemcel (Lenmeldy, Orchard Therapeutics), was approved by the FDA in March 2024.

• #1 FDA Approves First Gene Therapy for Children with Metachromatic Leukodystrophy | FDA

  https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-children-metachromatic-leukodystrophy

  Metachromatic leukodystrophy is a debilitating, rare genetic disease affecting the brain and nervous system. It is caused by a deficiency of an enzyme called arylsulfatase A (ARSA), leading to a buildup of sulfatides (fatty substances) in the cells. This buildup causes damage to the central and peripheral nervous system, manifesting with loss of motor and cognitive function and early death. […] The modified stem cells supply the body with myeloid (immune) cells that produce the ARSA enzyme, which helps break down the harmful build-up of sulfatides and may stop the progression of MLD. […] In children with MLD, treatment with Lenmeldy significantly reduced the risk of severe motor impairment or death compared with untreated children.

• #1 Complete Correction of Brain and Spinal Cord Pathology in Metachromatic Leukodystrophy Mice – Sorbonne Université

  https://hal.sorbonne-universite.fr/hal-03254121v1

  Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder characterized by accumulation of sulfatides in both glial cells and neurons. MLD results from an inherited deficiency of arylsulfatase A (ARSA) and myelin degeneration in the central and peripheral nervous systems. […] The LI form results in rapid neurological degradation and early death. ARSA enzyme must be rapidly and efficiently delivered to brain and spinal cord oligodendrocytes of patients with LI MLD in order to potentially stop the progression of the disease. […] Herein, we evaluated the short-term effects of intravenous AAVPHP.eB delivery driving the expression of human ARSA cDNA under the control of the cytomegalovirus/b-actin hybrid (CAG) promoter in 6-month-old MLD mice that already show marked sulfatide accumulation and brain pathology. Within 3 months, a single intravenous injection of AAVPHP.eB-hARSA-HA resulted in correction of brain and spinal cord sulfatide storage, and improvement of astrogliosis and microgliosis in brain and spinal cord of treated animals. These results strongly support to consider the use of AAVPHP.eB-hARSA vector for intravenous gene therapy in symptomatic rapidly progressing forms of MLD.

• #1 Metachromatic Leukodystrophy |

  https://www.huntershope.org/family-care/leukodystrophies/metachromatic-leukodystrophy/

  A proper diagnosis is a confirmation of the deficiency of the missing enzyme and the resulting lowered Arylsulfatase-A (ARSA) activity in the body. […] Individuals affected by MLD who are diagnosed before the disease is too far progressed may be eligible for gene therapy. […] Some may also be able to receive an umbilical cord blood or bone marrow transplant. Through this procedure, stem cells from donated umbilical cord blood or bone marrow containing normal levels of the ARSA enzyme are given to the patient to stop the progression of the disease. […] Unfortunately, this treatment is not effective in repairing myelin that has already been damaged. […] Although there is currently no cure for MLD, symptoms can be well-managed. […] Newborn screening for MLD is currently being validated in a medium-scale pilot study by University of Washington investigators. This would help in early detection of more individuals with MLD who could potentially benefit from transplant. […] Hunter’s Hope is committed to funding research for better treatments and a cure for MLD and other Leukodystrophies.

• #1 Population Carrier Rates of Pathogenic ARSA Gene Mutations: Is Metachromatic Leukodystrophy Underdiagnosed? | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0020218

  The underdiagnosis rate may be particularly high among patients with p.I179S mutation whose disease is characterized mainly by psychotic symptoms. […] The expected prevalence of fetuses conceived with two pathogenic ARSA mutations in Poland (4.1 per 100 000) is substantially higher than the birth prevalence of MLD based on diagnosed cases (0.38 per 100 000 live births as determined by us or 0.53 per 100 000 as previously reported in Poland). […] This discrepancy between our estimate and observed incidence of MLD in Poland may have several causes. […] It is possible that mutations in the ARSA gene resulting in the severe phenotype can lead to prenatal or perinatal loss of affected fetuses thus decreasing prevalence among live born children. […] Our findings may also be influenced by a distinct phenotype associated with the p.I179S and possibly other yet unknown mutations.

• #1 Genetic Basis and Pathophysiology of Metachromatic Leukodystrophy | Insight Medical Publishing

  https://raredisorders.imedpub.com/articles/genetic-basis-and-pathophysiology-of-metachromatic-leukodystrophy.php?aid=52804

  Metachromatic leukodystrophy (MLD) is a rare, inherited lysosomal storage disorder that affects the white matter of the brain and the Central Nervous System (CNS). It is caused by a deficiency of the enzyme arylsulfatase. A leading to the accumulation of sulfatides in cells, particularly those of the nervous system. This accumulation damages the myelin sheath, which insulates nerve fibers, leading to progressive neurological impairment. […] The ARSA gene provides instructions for making the enzyme arylsulfatase A, which is essential for the breakdown of sulfatides. When this enzyme is deficient or absent, sulfatides accumulate, particularly in the nervous system, leading to the progressive destruction of myelin. The myelin sheath is crucial for the rapid transmission of electrical signals between nerve cells. When myelin is damaged or lost, nerve impulses slow down or fail to be transmitted effectively, resulting in a range of neurological symptoms. The accumulation of sulfatides also induces a secondary inflammatory response, further exacerbating the damage to the nervous system.

• #2 Metachromatic Leukodystrophy | Treatment & Management | Point of Care

  https://www.statpearls.com/point-of-care/25045

  Metachromatic leukodystrophy is a demyelinating, autosomal recessive genetic leukodystrophy and LSD, caused by an inborn error of metabolism in the arylsulfatase A lysosomal enzyme. This leads to the accumulation of sulfatides, which result in the dysfunction and destruction of the CNS/PNS myelin sheaths. […] Metachromatic leukodystrophy is caused by deficient activity of arylsulfatase A. In almost all cases, mutations are in the arylsulfatase A gene (ARSA gene), on chromosome 22q13.3-qter. […] Metachromatic leukodystrophy is a lysosomal storage disease characterized by the inability to degrade sulfated glycolipids, mainly the galactosyl-3-sulfate ceramides. It is caused by deficient activity of lysosomal enzyme arylsulfatase A, most commonly due to mutations in the arylsulfatase A (ARSA gene).

• #2 Metachromatic leukodystrophy | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/metachromatic-leukodystrophy?lang=us

  Metachromatic leukodystrophy (MLD) is the most common hereditary (autosomal recessive) leukodystrophy and is one of the lysosomal storage disorders. It arises from a deficiency of the enzyme arylsulfatase A as a result of a mutation in the arylsulfatase A (ARSA) gene located on chromosome 22q13. This results in the accumulation of 3-O-sulfogalactosylceramide (sulfatide) in various organs including the central nervous system (Schwann cells, oligodendrocytes, and some neurons) impairing myelination and function. […] Metachromatic refers to the histologic staining characteristic caused by abnormal accumulations of sulfatides in white matter.

• #2 Metachromatic Leukodystrophy, Genetic Testing – Diagnostic Tests | Diagnostiki Athinon

  https://athenslab.gr/en/diagnostikes-exetaseis/metachromatic-leukodystrophy-genetic-testing-1938

  Metachromatic leukodystrophy (MLD) is a rare, inherited metabolic disorder that affects the nervous system. It is characterized by the buildup of a substance called sulfatide, leading to progressive degeneration of the white matter in the brain and spinal cord. […] MLD is caused by mutations in the ARSA gene, which provides instructions for making the enzyme arylsulfatase A. Deficiency of this enzyme leads to the accumulation of sulfatide. […] More than 200 pathogenic variants associated with metachromatic leukodystrophy have been described. This test analyzes the three most frequent variants causing partial or total disruption of enzyme activity: they are c.465+1GA, c.1283CT (p.Pro428Leu), and c.542TG (p.Ile181Ser). […] The c.769GC (p.Asp257His) mutation has been identified in multiple individuals affected by late infantile and juvenile types of metachromatic leukodystrophy, with significantly reduced enzyme activity levels. […] Metachromatic leukodystrophy genetic testing analyzes the 19 most frequent pathogenic mutations of the ARSA gene.

• #2 Metachromatic leukodystrophy – Wikipedia

  https://en.wikipedia.org/wiki/Metachromatic_leukodystrophy

  Metachromatic leukodystrophy (MLD) is a lysosomal storage disease which is commonly listed in the family of leukodystrophies as well as among the sphingolipidoses as it affects the metabolism of sphingolipids. […] MLD involves cerebroside sulfate accumulation. […] MLD is directly caused by a deficiency of the enzyme arylsulfatase A (ARSA) and is characterized by enzyme activity in leukocytes that is less than 10% of normal controls. […] Without this enzyme, sulfatides build up in many tissues of the body, eventually destroying the myelin sheath of the nervous system. […] Arylsulfatase A is activated by saposin B (Sap B), a non-enzymatic proteinaceous cofactor. […] When the arylsulfatase A enzyme level is normal but the sulfatides are still high meaning that they are not being broken down because the enzyme is not activated the resulting disease is saposin B deficiency, which presents similar to MLD. […] A 2011 study contended sulfatide is not completely responsible for MLD because it is non-toxic. It has been suggested that lysosulfatide, sulfatide which has had its acyl group removed, plays a role because of its cytotoxic properties in vitro.

• #2 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  Sulfatides are one of the most common sphingolipids in myelin. […] Sulfatides are cleaved in the lysosome, where ARSA hydrolyzes the sulfate group. […] Just 10-15% of the ARSA enzymatic activity is sufficient for sulfatide degradation and maintenance of normal life. […] The PSAP gene encodes a precursor protein, prosaposin (pSap), consisting of 524 amino acids. […] Mutations in the PSAP gene can cause either a single saposin deficiency or a deficiency of the whole pSap protein, which result in severe lethal neurodystrophy. […] The phenotype of SapB defect is similar to classical MLD phenotype caused by ARSA deficiency. […] The clinical manifestations and a degree of neurodegeneration in MLD are diverse and depend on the type of mutation and the level of enzyme deficiency. […] It is hypothesized that the lower the enzyme activity the earlier the disease manifests itself, however such association has yet to be fully demonstrated.

• #2 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  Metachromatic leukodystrophy is a lysosomal storage disease, which is characterized by damage of the myelin sheath that covers most of nerve fibers of the central and peripheral nervous systems. The disease occurs due to a deficiency of the lysosomal enzyme arylsulfatase A (ARSA) or its sphingolipid activator protein B (SapB) and it clinically manifests as progressive motor and cognitive deficiency. ARSA and SapB protein deficiency are caused by mutations in the ARSA and PSAP genes, respectively. The severity of clinical course in metachromatic leukodystrophy is determined by the residual ARSA activity, depending on the type of mutation. […] However, the exact mechanisms of demyelination in MLD remain unknown. Possible causes are an increase in the sulfatides and a decrease in its cleavage products, which lead to instability of the myelin sheath. In addition, sulfatides cause accumulation of calcium in the cell cytoplasm, which results in a change in calcium homeostasis, cell stress, and apoptosis.

• #2 Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1220-4

  The accumulation of metachromatic material in peripheral nerves in MLD have first been reported by Jacobi. Metachromatic material consists of Schwann cells and endoneural macrophages that are filled with characteristic lysosomal inclusions of sulfatides, also called inclusion bodies. […] Remarkably, no correlation between demyelination and the presence of metachromatic material in peripheral nerves has been found. This raises the question whether peripheral neuropathy in MLD is (partially) due to other causes in addition to sulfatide accumulation. […] Notably, Cravioto et al. and Argyrakis et al. also described several abnormalities other than inclusion bodies. These are morphological alterations of the endoplasmatic reticulum and mitochondria in Schwann cells, and accumulation of glycogen in mitochondria, Schwann cells and axons. These abnormalities could reflect a metabolic derangement of these cells, causing premature cell death, and may explain the lack of a correlation between demyelination and presence of metachromatic material.

• #2 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  The accumulation of sulfatides leads to neuronal degeneration, astrocyte dysfunction and may trigger an inflammatory response. Several studies support the role of inflammation in MLD. […] Thus, complement activation via an alternative pathway enhances myelin damage, thus inducing or enhancing the immune response against myelin. […] Microglia is also assumed to play an important role in the development of MLD. It has been shown that the microglia immune phenotype changes at the early stages of MLD development and this precedes oligodendrocyte degeneration and myelin damage. […] MLD is caused by the deficiency of arylsulfatase A lysosomal enzyme (ARSA) and sphingolipid activator protein B (SapB or saposin B) as a consequence of mutations in the ARSA and PSAP genes, respectively. […] The physiological substrate of ARSA is sulfatide.

• #2 Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-019-1220-4

  The lack of a correlation between demyelination and the presence of metachromatic material raises the question whether the pathology of peripheral neuropathy in MLD can be partially explained by a neuroinflammatory scenario. […] Additional research findings that suggest a neuroinflammatory component in the pathology of MLD are that sulfatide accumulation and demyelination in the PNS are able to 1) induce the release of inflammatory cytokines; 2) activate endoneural macrophages; and 3) recruit inflammatory myeloid cells and lymphocytes from the periphery. […] A neuroinflammatory component in the pathology of the disease is an attractive hypothesis with clear therapeutic implications, but convincing preclinical and clinical evidence has yet to be shown.

• #2 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  The most common form is the late infantile, which is found in 50–60% of all patients. […] Clinical manifestation of late infantile MLD begins up to 30 months of age. […] The juvenile form develops between the ages of 3 and 16 and is characterized by a less pronounced clinical manifestation in comparison with the late infantile form. […] The adult MLD is the less severe form of the disease. […] In most cases, MLD is not included in the fetus and newborn genetic screening tests given that MLD is a rare disease. […] Prenatal diagnostics can be performed by measuring the activity of ARSA in amniotic fluid cells and evaluating the accumulation of sulfatides to exclude ARSA pseudo-deficiency. […] Diagnosis of late onset forms of MLD is often more difficult. […] To date, MLD is diagnosed by clinical manifestations, using genetic analysis for mutations in the ARSA and PSAP genes, magnetic resonance imaging (MRI) of the brain and biochemical tests of the ARSA enzymatic activity in skin fibroblasts, leukocytes and urine of patients.

• #2 Metachromatic leukodystrophy (MLD) | Britannica

  https://www.britannica.com/science/metachromatic-leukodystrophy

  Specific mutations in ARSA are linked to the timing of MLD onset and the phenotypic patterns (physical manifestations) of MLD, such as the degree of ASA deficiency and the severity of neuropsychiatric symptoms. Other genetic defects, such as those leading to the deficiency of an activator protein involved in the degradation of sulfatides but in which patients have normal ASA levels, can also cause MLD. In addition, there exist individuals who have very low levels of ASA but never develop the disease. This condition is known as pseudoarylsulfatase A deficiency (PASAD) and is the result of two specific polymorphisms that occur simultaneously in the ARSA gene.

• #2 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  As MDL is characterized by different clinical manifestations, effective modeling of the disease is important to study the genetic basis of the disease, disease progression, diagnosis, and therapy. […] There are no approved therapies for MLD to date. […] The problem of overcoming the BBB could be solved, for example, by direct injection of the recombinant ARSA enzyme or viral vectors encoding the wild-type gene of the missing enzyme into the brain. […] For pre-symptomatic patients, bone marrow transplantation (BMT) or hematopoietic stem cell (HSC) transplantation may be helpful, but the therapeutic potential of this procedure remains controversial. […] One of the first and most effective approaches to currently treat MLD is BMT and HSC transplantation. […] The introduction of prenatal diagnosis and newborn screening could increase therapy efficacy, since the effectiveness of the treatment is significantly reduced after the onset of symptoms. […] Gene and combined gene-cell therapy are considered new promising methods for MLD therapy.

• #2 MED.00148 Gene Therapy for Metachromatic Leukodystrophy

  https://www.anthem.com/dam/medpolicies/abcbs/active/policies/mp_pw_e003052.html

  MLD is caused by having an abnormal variant of the arylsulfatase A (ARSA) gene, which leads to a deficiency of the enzyme ARSA. […] Gene therapy for MLD involves extraction of CD34+ stem cells from the affected individuals bone marrow or blood using a process called pheresis. The collected stem cells are genetically modified ex vivo with a lentiviral vector encoded with functional ARSA DNA. […] The aim of the treatment is for the corrected cells to proliferate and migrate to affected tissues where they will produce a functional version of the ARSA enzyme, which will then halt the progression of MLD. […] The condition is caused by mutations in the ARSA gene. Individuals with MLD do not produce sufficient amounts of the ARSA enzyme, and this deficiency leads to the accumulation of a fatty substance called sulfatide within cells. The buildup of sulfatide disrupts the formation and maintenance of the myelin sheath, which is essential for the proper conduction of nerve signals. MLD is progressive in nature and leads to severe neurological impairment. […] Gene therapy is a new approach for treating MLD. The first gene therapy for MLD, atidarsagene autotemcel (Lenmeldy, Orchard Therapeutics), was approved by the FDA in March 2024.

• #2 Population Carrier Rates of Pathogenic ARSA Gene Mutations: Is Metachromatic Leukodystrophy Underdiagnosed? | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0020218

  The problem of misdiagnosed patients is also actual for the adult onset patients in whom the beginning stages of the disease may be mild and difficult to detect. […] One possible reason for the discrepancy between observed and expected prevalence of MLD may be related to disease underdiagnosis, especially among patients with p.I179S mutation.

• #3 A systematic review on the birth prevalence of metachromatic leukodystrophy | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03044-w

  Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency in arylsulfatase A (ASA) activity arising primarily from ASA gene (ARSA) variants. […] Deficiency in ASA activity results in the accumulation of sulfatides in the central and peripheral nervous systems, leading to demyelination, neuronal dysfunction and degeneration. […] At least 200 pathogenic ARSA variants have been described. […] Some of these, such as the splice donor site variants c.465+1GA (the most common variant in late-infantile MLD), result in the production of inactive ASA. […] Other variants, such as the missense variants c.1283CT (the most common variant in adult MLD), result in ASA that retains some residual activity. […] Atypical MLD due to saposin B deficiency is caused by pathogenic variants in the prosaposin gene.

• #3 MLD – Metachromatic Leukodystrophy – Alex – The Leukodystrophy Charity

  https://alextlc.org/condition/metachromatic-leukodystrophy-mld/

  Metachromatic Leukodystrophy (MLD) is a rare lysosomal storage disorder caused by deficient activity of the enzyme arylsulfatase A. This leads to the build-up of sulfatides in cells, primarily affecting the nervous systems white matter. […] MLD is caused by mutations in either the ARSA or PSAP genes. These genes contribute to the break down of sulfatides, so mutations in them lead these sulfatides to build up. This build up is toxic to the nervous system, gradually destroying cells which produce myelin and preventing the ability of nerves to send signals from the brain. […] Arylsulfatase A is activated by saposin B (Sap B), a non-enzymatic proteinaceous cofactor. When the arylsulfatase A enzyme level is normal but the sulfatides are still high meaning that they are not being broken down because the enzyme is not activated the resulting disease is saposin B deficiency, which presents similar to MLD. Saposin B Deficiency is very rare, much rarer than traditional MLD.

• #3 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  Sulfatides are one of the most common sphingolipids in myelin. […] Sulfatides are cleaved in the lysosome, where ARSA hydrolyzes the sulfate group. […] Just 10-15% of the ARSA enzymatic activity is sufficient for sulfatide degradation and maintenance of normal life. […] The PSAP gene encodes a precursor protein, prosaposin (pSap), consisting of 524 amino acids. […] Mutations in the PSAP gene can cause either a single saposin deficiency or a deficiency of the whole pSap protein, which result in severe lethal neurodystrophy. […] The phenotype of SapB defect is similar to classical MLD phenotype caused by ARSA deficiency. […] The clinical manifestations and a degree of neurodegeneration in MLD are diverse and depend on the type of mutation and the level of enzyme deficiency. […] It is hypothesized that the lower the enzyme activity the earlier the disease manifests itself, however such association has yet to be fully demonstrated.

• #3 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  The accumulation of sulfatides leads to neuronal degeneration, astrocyte dysfunction and may trigger an inflammatory response. Several studies support the role of inflammation in MLD. […] Thus, complement activation via an alternative pathway enhances myelin damage, thus inducing or enhancing the immune response against myelin. […] Microglia is also assumed to play an important role in the development of MLD. It has been shown that the microglia immune phenotype changes at the early stages of MLD development and this precedes oligodendrocyte degeneration and myelin damage. […] MLD is caused by the deficiency of arylsulfatase A lysosomal enzyme (ARSA) and sphingolipid activator protein B (SapB or saposin B) as a consequence of mutations in the ARSA and PSAP genes, respectively. […] The physiological substrate of ARSA is sulfatide.

• #3 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  The most common form is the late infantile, which is found in 50–60% of all patients. […] Clinical manifestation of late infantile MLD begins up to 30 months of age. […] The juvenile form develops between the ages of 3 and 16 and is characterized by a less pronounced clinical manifestation in comparison with the late infantile form. […] The adult MLD is the less severe form of the disease. […] In most cases, MLD is not included in the fetus and newborn genetic screening tests given that MLD is a rare disease. […] Prenatal diagnostics can be performed by measuring the activity of ARSA in amniotic fluid cells and evaluating the accumulation of sulfatides to exclude ARSA pseudo-deficiency. […] Diagnosis of late onset forms of MLD is often more difficult. […] To date, MLD is diagnosed by clinical manifestations, using genetic analysis for mutations in the ARSA and PSAP genes, magnetic resonance imaging (MRI) of the brain and biochemical tests of the ARSA enzymatic activity in skin fibroblasts, leukocytes and urine of patients.

• #3 MED.00148 Gene Therapy for Metachromatic Leukodystrophy

  https://www.anthem.com/dam/medpolicies/abcbs/active/policies/mp_pw_e003052.html

  MLD is caused by having an abnormal variant of the arylsulfatase A (ARSA) gene, which leads to a deficiency of the enzyme ARSA. […] Gene therapy for MLD involves extraction of CD34+ stem cells from the affected individuals bone marrow or blood using a process called pheresis. The collected stem cells are genetically modified ex vivo with a lentiviral vector encoded with functional ARSA DNA. […] The aim of the treatment is for the corrected cells to proliferate and migrate to affected tissues where they will produce a functional version of the ARSA enzyme, which will then halt the progression of MLD. […] The condition is caused by mutations in the ARSA gene. Individuals with MLD do not produce sufficient amounts of the ARSA enzyme, and this deficiency leads to the accumulation of a fatty substance called sulfatide within cells. The buildup of sulfatide disrupts the formation and maintenance of the myelin sheath, which is essential for the proper conduction of nerve signals. MLD is progressive in nature and leads to severe neurological impairment. […] Gene therapy is a new approach for treating MLD. The first gene therapy for MLD, atidarsagene autotemcel (Lenmeldy, Orchard Therapeutics), was approved by the FDA in March 2024.

• #4 Metachromatic Leukodystrophy, Genetic Testing – Diagnostic Tests | Diagnostiki Athinon

  https://athenslab.gr/en/diagnostikes-exetaseis/metachromatic-leukodystrophy-genetic-testing-1938

  Metachromatic leukodystrophy (MLD) is a rare, inherited metabolic disorder that affects the nervous system. It is characterized by the buildup of a substance called sulfatide, leading to progressive degeneration of the white matter in the brain and spinal cord. […] MLD is caused by mutations in the ARSA gene, which provides instructions for making the enzyme arylsulfatase A. Deficiency of this enzyme leads to the accumulation of sulfatide. […] More than 200 pathogenic variants associated with metachromatic leukodystrophy have been described. This test analyzes the three most frequent variants causing partial or total disruption of enzyme activity: they are c.465+1GA, c.1283CT (p.Pro428Leu), and c.542TG (p.Ile181Ser). […] The c.769GC (p.Asp257His) mutation has been identified in multiple individuals affected by late infantile and juvenile types of metachromatic leukodystrophy, with significantly reduced enzyme activity levels. […] Metachromatic leukodystrophy genetic testing analyzes the 19 most frequent pathogenic mutations of the ARSA gene.

• #4 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  Sulfatides are one of the most common sphingolipids in myelin. […] Sulfatides are cleaved in the lysosome, where ARSA hydrolyzes the sulfate group. […] Just 10-15% of the ARSA enzymatic activity is sufficient for sulfatide degradation and maintenance of normal life. […] The PSAP gene encodes a precursor protein, prosaposin (pSap), consisting of 524 amino acids. […] Mutations in the PSAP gene can cause either a single saposin deficiency or a deficiency of the whole pSap protein, which result in severe lethal neurodystrophy. […] The phenotype of SapB defect is similar to classical MLD phenotype caused by ARSA deficiency. […] The clinical manifestations and a degree of neurodegeneration in MLD are diverse and depend on the type of mutation and the level of enzyme deficiency. […] It is hypothesized that the lower the enzyme activity the earlier the disease manifests itself, however such association has yet to be fully demonstrated.

• #4 Frontiers | Metachromatic Leukodystrophy: Diagnosis, Modeling, and Treatment Approaches

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2020.576221/full

  The most common form is the late infantile, which is found in 50–60% of all patients. […] Clinical manifestation of late infantile MLD begins up to 30 months of age. […] The juvenile form develops between the ages of 3 and 16 and is characterized by a less pronounced clinical manifestation in comparison with the late infantile form. […] The adult MLD is the less severe form of the disease. […] In most cases, MLD is not included in the fetus and newborn genetic screening tests given that MLD is a rare disease. […] Prenatal diagnostics can be performed by measuring the activity of ARSA in amniotic fluid cells and evaluating the accumulation of sulfatides to exclude ARSA pseudo-deficiency. […] Diagnosis of late onset forms of MLD is often more difficult. […] To date, MLD is diagnosed by clinical manifestations, using genetic analysis for mutations in the ARSA and PSAP genes, magnetic resonance imaging (MRI) of the brain and biochemical tests of the ARSA enzymatic activity in skin fibroblasts, leukocytes and urine of patients.

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