Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Metachromatic Leukodystrophy. Core disease mechanisms, molecular and cellu...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 19
• Snippets retrieved: 20

Relevant Papers

[1] Existing Evidence for the Repurposing of PARP-1 Inhibitors in Rare Demyelinating Diseases

• Authors: Marianna Mekhaeil, K. Dev, Melissa J. Conroy
• Year: 2022
• Venue: Cancers
• URL: https://www.semanticscholar.org/paper/2e4b156e689b975676149de5d6e333c443ea3bd7
• DOI: 10.3390/cancers14030687
• PMID: 35158955
• PMCID: 8833351
• Citations: 22
• Summary: Existing evidence that implicates PARP-1 as a player in the development and progression of both malignancy and demyelinating disease is presented, and the repurposing of these drugs for demYelinating diseases as a desirable therapeutic concept is presented.
• Evidence snippets:
• Snippet 1 (score: 0.615) > Collectively, leukodystrophies have an incidence of 1 in 7700 live births and can present at any age from infancy to adulthood, with a considerable variability in disease progression and clinical presentation [113]. Patients with leukodystrophies experience a large array of significant and disabling symptoms including motor impairment, dysautonomia, cognitive impairment, and ataxia [113]. Most of the diagnosis for leukodystrophies are not precise and are based on a combination of history, expected prevalence, physical and neurologic features, and radiological examination [114]. More promisingly, recent advances in genetic medicine and imaging have led to the identification of specific genetic and biochemical defects associated with individual leukodystrophies including metachromatic leukodystrophy and X-linked adrenoleukodystrophy, which are the most frequent diagnosed among leukodystrophies, and Krabbe disease [115]. > In the past decades, existing dogma has been questioned suggesting that mutations within myelin-or oligodendrocyte-specific genes were the sole causative factors behind leukodystrophies [116]. Nowadays, leukodystrophies are linked to defects in astrocytes, microglia, axons, and blood vessel function [116]. Causes of leukodystrophies have also been associated with pathological mechanisms that share features with the archetypical demyelinating disease, multiple sclerosis, including BBB disruption, disorders of DNA transcription, translation, production of essential proteins for myelin, and neuroinflammation [117]. Both diagnosis and treatment of leukodystrophies possess a significant challenge due to the limited information regarding the mechanisms behind their pathologies. Symptomatic treatments can decrease the burden of events and assist somewhat in the quality of life [115]. To date, however, effective cures for patients with leukodystrophies are greatly lacking. In this scenario, reducing neuroinflammation, which plays a pivotal role in leukodystrophy progression presents a desirable strategy, either possibly as a monotherapy or part of a combinatorial approach.

[2] Gene therapy for the leukodystrophies: From preclinical animal studies to clinical trials

• Authors: J. Metovic, Yedda Li, Yi Gong, Florian S. Eichler
• Year: 2024
• Venue: Neurotherapeutics
• URL: https://www.semanticscholar.org/paper/e55a15b0ccdbd7c57a7518ec748e36720e8b59e9
• DOI: 10.1016/j.neurot.2024.e00443
• PMID: 39276676
• PMCID: 11418141
• Citations: 10
• Summary: The data presented in this review show that gene therapy, while promising, requires systematic monitoring to account for the precarious disease biology and the adverse events associated with new technology.
• Evidence snippets:
• Snippet 1 (score: 0.589) > The definition of leukodystrophies has evolved significantly with advances in next generation sequencing, magnetic resonance imaging (MRI), and molecular biology techniques that together have informed a more nuanced understanding of pathophysiology [3,5,6]. In 2017, van der Knaap and Bugiani [2] proposed a new classification system that grouped leukodystrophies into five categories related to pathologic changes and pathogenic mechanisms (Fig. 1, Table 1). Myelinopathies arise from defects in oligodendrocytes or myelin structure. They are further subcategorized as disorders of hypomyelination, demyelination, and myelin vacuolization which disrupts myelin integrity. Leuko-axonopathies stem from defects in neurons and their axonal processes. Astrocytopathies and microgliopathies disrupt neuroinflammation and CNS repair. Leuko-vasculopathies develop from pathologic processes within the small blood vessels of the brain [2]. Some pathologically relevant CNS cell types, such as microglia, can derive from hematopoietic stem cell precursors with important implications for therapeutic development. > Pathogenic mutations in leukodystrophy genes affect integral cellular functions involved in recycling (peroxisomal and lysosomal metabolism), energy production (mitochondrial electron transport), structural integrity (of myelin, cytoskeleton, extracellular matrix, blood brain barrier (BBB), etc.), and protein synthesis (messenger ribonucleic acid (mRNA) transcription and translation), among others. Understanding these pathogenic mechanisms (Fig. 2) is critical in designing successful gene therapies.

[3] Modified Delphi procedure-based expert consensus on endpoints for an international disease registry for Metachromatic Leukodystrophy: The European Metachromatic Leukodystrophy initiative (MLDi)

• Authors: Daphne H. Schoenmakers, Shanice Beerepoot, Sibren van den Berg, L. Adang, A. Bley et al.
• Year: 2022
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/b5ba47def8777b79f53aa6d659f159586ff3c9cc
• DOI: 10.1186/s13023-022-02189-w
• PMID: 35164810
• PMCID: 8842918
• Citations: 20
• Summary: An expert-based consensus procedure was used to determine a core set of data elements required to answer academic, regulatory, and HTA research questions that will support knowledge about the disease and facilitate regulatory requirements related to the launch of new treatments.
• Evidence snippets:
• Snippet 1 (score: 0.540) > Metachromatic leukodystrophy (MLD, OMIM 250,100 and 249,900) is an autosomal recessively inherited lysosomal storage disorder with an estimated birth prevalence of 1 in 40.000 [1]. The disease is caused by pathogenic variants in the ARSA gene, encoding the lysosomal enzyme arylsulfatase A (ASA), or, more rarely, by variants in the PSAP gene, encoding the activator protein saposin B [2,3]. The deficiency of either one of the two results in sulfatide accumulation in multiple organs, including central and peripheral nervous system, gall bladder, kidneys, and liver. Myelin sheaths of the central and peripheral nervous system are especially affected, resulting in progressive demyelination. This causes neurological deterioration and, if untreated, eventually leads to death [4]. Based on the age of symptom onset, four clinical MLD phenotypes are distinguished: late-infantile (< 2.5 years), early-juvenile (2.5-6 years), late-juvenile (6-16 years), and adult (> 16 years) MLD [5]. Symptom-onset at a younger age is generally associated with a faster disease progression and shorter life expectancy, as shown in Fig. 1 [2,5,6]. > approach, an important step towards harmonization was made. This unique dataset will support knowledge about the disease and facilitate regulatory requirements related to the launch of new treatments. > Keywords: Rare disease registry, Rare diseases, Metachromatic leukodystrophy, MLD, Delphi procedure Fig. 1 Clinical spectrum of MLD Supportive care, including treatment of spasticity, tube feeding, and psychological support is important for all symptomatic patients with MLD. MLD cannot be cured. Causal treatment targeting the enzyme deficiency is an option for a subset of patients. In presymptomatic or early disease stages, patients are eligible to receive causal treatment, including allogeneic hematopoietic stem cell transplantation (HSCT), which provides a clinical and survival benefit for patients with early-juvenile, late-juvenile and adult MLD. Causal treatment outcomes vary.

[4] Molecular Pathogenic Mechanisms of Hypomyelinating Leukodystrophies (HLDs)

• Authors: Tomohiro Torii, J. Yamauchi
• Year: 2023
• Venue: Neurology International
• URL: https://www.semanticscholar.org/paper/8aa5062b1e9d6ec74de0ea9cbd2b06b5b21ed802
• DOI: 10.3390/neurolint15030072
• PMID: 37755363
• PMCID: 10538087
• Citations: 16
• Summary: The genetic/molecular mechanisms underlying the pathogenesis of HLD and the normal cellular functions of the related genes and proteins are described and insight into the mechanisms can provide new findings for the clinical treatments of H LD.
• Evidence snippets:
• Snippet 1 (score: 0.530) > Hypomyelinating leukodystrophies (HLDs) represent a group of congenital rare diseases for which the responsible genes have been identified in recent studies. In this review, we briefly describe the genetic/molecular mechanisms underlying the pathogenesis of HLD and the normal cellular functions of the related genes and proteins. An increasing number of studies have reported genetic mutations that cause protein misfolding, protein dysfunction, and/or mislocalization associated with HLD. Insight into the mechanisms of these pathways can provide new findings for the clinical treatments of HLD.

[5] Safety and Efficacy of Intravenous and Intrathecal Delivery of AAV9-Mediated ARSA in Minipigs

• Authors: A. Mullagulova, A. Shaimardanova, V. Solovyeva, Y. Mukhamedshina, D. Chulpanova et al.
• Year: 2023
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/5b1c45c9de71f4d9d02adf41c731a497da19a278
• DOI: 10.3390/ijms24119204
• PMID: 37298156
• PMCID: 10253118
• Citations: 13
• Summary: Evaluating the safety and efficacy of AAV serotype 9 encoding ARSA (AAV9-ARSA) gene therapy when administered intravenously or intrathecally in minipigs, a large animal model with anatomical and physiological similarities to humans contributes to the understanding of how to improve the effectiveness of MLD gene therapy and offers valuable insights for future clinical applications.
• Evidence snippets:
• Snippet 1 (score: 0.519) > Metachromatic leukodystrophy (MLD) is an autosomal recessive hereditary neurodegenerative disease that belongs to the group of lysosomal storage diseases (LSDs). It is characterized by damage to the myelin sheath, which covers most of the nerve fibers in the central (CNS) and peripheral nervous systems (PNS). MLD is caused by deficiencies in the lysosomal enzyme arylsulfatase A (ARSA) (OMIM: 250100) or the saposin B activator protein (SapB) (OMIM: 249900). Clinically, the disease manifests as progressive motor and cognitive impairments [1]. MLD is one of the most common leukodystrophies, with an incidence rate of 1:40,000. However, in some isolated populations, the incidence rate can be much higher, such as 1:75 among Habbani Jews and 1:2500 among the Navajo [2]. > The term MLD refers to the presence of metachromatic granules in affected cells, which form due to the accumulation of sulfatides and sphingolipids found in myelin. In MLD, sulfatides build up in oligodendrocytes, microglia, CNS neurons, Schwann cells, PNS macrophages, and cells in various internal organs [3][4][5][6][7][8][9]. Demyelination in MLD results in impaired motor function, spastic tetraparesis, ataxia, convulsions, optic nerve atrophy, and cognitive impairment [10,11]. The exact mechanisms of the demyelination remain unknown, but it is believed that increased levels of sulfatides and decreased levels of their cleavage products cause instability in the myelin sheath, ultimately leading to demyelination [12]. Furthermore, the accumulation of sulfatides on the endoplasmic reticulum (ER) membrane triggers calcium release into the cytoplasm, causing changes in calcium homeostasis that lead to cellular stress and apoptosis [8].

[6] The neurovascular unit in leukodystrophies: towards solving the puzzle

• Authors: Parand Zarekiani, H. Nogueira Pinto, Elly M. Hol, M. Bugiani, H. D. de Vries
• Year: 2022
• Venue: Fluids and Barriers of the CNS
• URL: https://www.semanticscholar.org/paper/221ee2c19d3083575da5ef42d55dc9a9b3156d12
• DOI: 10.1186/s12987-022-00316-0
• Citations: 1
• Summary: This review aims to provide further insights into the NVU functioning in leukodystrophies, with a special focus on iPSC-derived models that can be used to dissect neurovascular pathophysiology in these diseases.
• Evidence snippets:
• Snippet 1 (score: 0.516) > Leukodystrophies are classified into several categories depending on the main cellular mechanism of WM injury and other pathological mechanisms that contribute to the disease progression [44]. In this section, we describe the different leukodystrophy classes, and the key components driving the pathology, and we review the knowledge on how the NVU can contribute to disease. The common denominator in leukodystrophies is selectively affected WM, ranging from lack of myelin to complete WM atrophy. Clinically and pathologically, leukodystrophies are highly heterogeneous, therefore the main MRI characteristics, clinical phenotype, and pathological hallmarks are summarized in Table 1. > Hypomyelinating leukodystrophies are characterized by an impaired developmental myelination in the CNS and possibly also the peripheral nervous system (PNS). Leukodystrophies in this category are both clinically and genetically heterogeneous, yet show similarities [46]. The prototypical hypomyelinating leukodystrophy is Pelizaeus-Merzbacher disease (PMD). PMD is an X-linked disorder caused by changes in PLP1, encoding proteolipid protein 1 (PLP1) and the alternative spliced variant DM20 [47]. PLP1 and DM20 are solely expressed by oligodendrocytes in the CNS and Schwann cells in the PNS and are crucial components of the myelin sheath [48]. Therefore, a disruption in PLP1/DM20 has detrimental effects on the structure and functioning of myelin. Depending on the type of PLP1 mutation, histopathology varies, yet some features overlap. There is a significant decrease in the number of mature oligodendrocytes, resulting in a lack of myelin. Altered levels of PLP1 in PMD induce the activation of the unfolded protein response (UPR), which causes apoptosis of oligodendrocytes and neurons [49][50][51]. The UPR in oligodendrocytes, however, may not be the only neurodegenerative mechanism underlying PMD.

[7] The neurovascular unit in leukodystrophies: towards solving the puzzle

• Authors: Parand Zarekiani, H. Nogueira Pinto, E. Hol, M. Bugiani, H. D. de Vries
• Year: 2022
• Venue: Fluids and Barriers of the CNS
• URL: https://www.semanticscholar.org/paper/73916d3407fc52aa787155c18f02f8c5f521211d
• DOI: 10.1186/s12987-022-00316-0
• PMID: 35227276
• PMCID: 8887016
• Citations: 8
• Summary: This review aims to provide further insights into the NVU functioning in leukodystrophies, with a special focus on iPSC-derived models that can be used to dissect neurovascular pathophysiology in these diseases.
• Evidence snippets:
• Snippet 1 (score: 0.493) > Leukodystrophies are classified into several categories depending on the main cellular mechanism of WM injury and other pathological mechanisms that contribute to the disease progression [44]. In this section, we describe the different leukodystrophy classes, and the key components driving the pathology, and we review the knowledge on how the NVU can contribute to disease. The common denominator in leukodystrophies is selectively affected WM, ranging from lack of myelin to complete WM atrophy. Clinically and pathologically, leukodystrophies are highly heterogeneous, therefore the main MRI characteristics, clinical phenotype, and pathological hallmarks are summarized in Table 1. > Hypomyelinating leukodystrophies are characterized by an impaired developmental myelination in the CNS and possibly also the peripheral nervous system (PNS). Leukodystrophies in this category are both clinically and genetically heterogeneous, yet show similarities [46]. The prototypical hypomyelinating leukodystrophy is Pelizaeus-Merzbacher disease (PMD). PMD is an X-linked disorder caused by changes in PLP1, encoding proteolipid protein 1 (PLP1) and the alternative spliced variant DM20 [47]. PLP1 and DM20 are solely expressed by oligodendrocytes in the CNS and Schwann cells in the PNS and are crucial components of the myelin sheath [48]. Therefore, a disruption in PLP1/DM20 has detrimental effects on the structure and functioning of myelin. Depending on the type of PLP1 mutation, histopathology varies, yet some features overlap. There is a significant decrease in the number of mature oligodendrocytes, resulting in a lack of myelin. Altered levels of PLP1 in PMD induce the activation of the unfolded protein response (UPR), which causes apoptosis of oligodendrocytes and neurons [49][50][51]. The UPR in oligodendrocytes, however, may not be the only neurodegenerative mechanism underlying PMD. Increased astrogliosis and
• Snippet 2 (score: 0.483) > hies are characterized by primarily affected WM regardless of the molecular processes involved and the disease course [41]. Before this new definition, leukodystrophies were seen as progressive WM disorders caused by a genetic defect, where myelin was the primary affected structure. The myelin defect observed was either a direct effect on myelin or indirect on oligodendrocytes, the myelin forming cells [42]. Later, magnetic resonance imaging (MRI) pattern recognition paved the way for stratifying patients and subsequent genetic explorations [43]. In the following decades, sequencing techniques also evolved, pathological data became more available and new disease models emerged. These scientific developments have given an enormous boost to the field of leukodystrophies. Usually, the clinical course of leukodystrophies is progressive, and often eventually fatal. So far only symptomatic treatments are available. Therefore, unravelling the underlying mechanisms of these diseases is a priority. As mentioned, the WM comprises different cell types that create a complex network of signalling in synergy, yet each leukodystrophy is caused by a different genetic deficit that results in a distinct WM pathology. Notably, the genetic deficits underlying these diseases are not restricted to myelin-or oligodendrocyte-specific genes. Recent next-generation sequencing studies combined with MRI pattern recognition have shown that a predominant dysfunction of cell types other than oligodendrocytes may drive the WM pathology in leukodystrophies. To distinguish the underlying mechanisms, it is essential to identify distinct pathological hallmarks and the specific cell types affected in this heterogeneous group of diseases. Therefore, a new classification system for leukodystrophies has recently been proposed based on cellular pathology and pathogenic mechanisms [44]. > Strikingly, some cellular components that are primarily affected, such as astrocytes, are part of the NVU. The function of the NVU, however, has been overlooked in these diseases. The problem in the diagnosis of leukodystrophies is that MRI with contrast agents is not always common practice in the clinic. Additionally, leakage of contrast agents in MR imaging only highlights gross abnormalities of the BBB. Especially when looking at heterogeneous diseases, such as

[8] Glial cells in the driver seat of leukodystrophy pathogenesis.

• Authors: L. M. Garcia, J. Hacker, Sunetra Sase, L. Adang, Akshata A Almad
• Year: 2020
• Venue: Neurobiology of disease
• URL: https://www.semanticscholar.org/paper/8ce00b0863364b1b2dc5c3c676ba70b914b74660
• DOI: 10.1016/j.nbd.2020.105087
• PMID: 32977022
• Citations: 22
• Influential citations: 1
• Summary: This review takes a closer look at multiple leukodystrophies, classified based on the primary glial cell type that is affected, and discusses how astrocytes and microglia are affected and impinge on oligodendrocyte, myelin and axonal pathology.
• Evidence snippets:
• Snippet 1 (score: 0.485) > Glia cells are often viewed as support cells in the central nervous system, but recent discoveries highlight their importance in physiological functions and in neurological diseases. Central to this are leukodystrophies, a group of progressive, neurogenetic disease affecting white matter pathology. In this review, we take a closer look at multiple leukodystrophies, classified based on the primary glial cell type that is affected. While white matter diseases involve oligodendrocyte and myelin loss, we discuss how astrocytes and microglia are affected and impinge on oligodendrocyte, myelin and axonal pathology. We provide an overview of the leukodystrophies covering their hallmark features, clinical phenotypes, diverse molecular pathways, and potential therapeutics for clinical trials. Glial cells are gaining momentum as cellular therapeutic targets for treatment of demyelinating diseases such as leukodystrophies, with no current treatment options. Here, we bring the much needed attention to role of glia in leukodystrophies, an integral step to furthering disease comprehension, understanding mechanisms and developing future therapeutics.

[9] Progressive demyelinating polyneuropathy after hematopoietic cell transplantation in metachromatic leukodystrophy: a case series

• Authors: Shanice Beerepoot, J. Boelens, C. Lindemans, M. D. de Witte, S. Nierkens et al.
• Year: 2024
• Venue: Journal of Neurology
• URL: https://www.semanticscholar.org/paper/95ca106f2219efe99d8926a082712a8ab60eb72e
• DOI: 10.1007/s00415-024-12322-3
• PMID: 38564053
• PMCID: 11233286
• Citations: 1
• Summary: This case series illustrates the occurrence of severely progressive polyneuropathy shortly after HCT in two patients with late-infantile, one with late-juvenile, and one with adult MLD, leading to the inability to walk or sit without support.
• Evidence snippets:
• Snippet 1 (score: 0.480) > Metachromatic leukodystrophy (MLD, OMIM #250,100) is an inherited lethal neurometabolic disorder caused by deficiency of the lysosomal enzyme arylsulfatase A (ASA) [1].ASA catalyzes desulfation of 3-O-sulfogalactosyl residues (sulfatides) in glycosphingolipids, and its deficiency results in intralysosomal sulfatide accumulation [2].Myelin sheaths of the central and peripheral nervous system are predominantly affected, leading to progressive demyelination and, to a lesser extent, axonal loss [3,4].The most prominent clinical features are motor and cognitive regression, ataxia, pyramidal signs, and eventually loss of all motor function and speech [5,6].Based on the age of disease onset, four clinical types of MLD can be distinguished, including lateinfantile (< 2.5 years), early-juvenile (2.5-6 years), latejuvenile (6-16 years), and adult (> 16 years).Generally, the Extended author information available on the last page of the article younger the age of onset, the faster the disease progression [7][8][9]. > Allogeneic hematopoietic cell transplantation (HCT) can provide a symptomatic and survival benefit for presymptomatic and early symptomatic patients with MLD [10,11].However, progressive polyneuropathy may cause major disease burden, despite otherwise successful HCT [12].Our systematic review indicates that approximately 75% of the HCT-treated patients show a decline in nerve conduction velocity (NCV) or deterioration of clinical symptoms [12], but information about detailed clinical course of peripheral polyneuropathy progression after HCT is scarce, and its cause and pathology remain unclear.We wondered whether progressive polyneuropathy after HCT should only be attributed to ongoing sulfatide accumulation, especially in case of rapid deterioration shortly after treatment.

[10] Towards a Treatment for Leukodystrophy Using Cell-Based Interception and Precision Medicine

• Authors: B. Coulombe, Alexandra Chapleau, J. Macintosh, T. Durcan, Christian Poitras et al.
• Year: 2024
• Venue: Biomolecules
• URL: https://www.semanticscholar.org/paper/3b5baaf7cd1b2db3d00377fb8cc8a091540962a6
• DOI: 10.3390/biom14070857
• PMID: 39062571
• PMCID: 11274857
• Summary: Recent progress is described towards developing cell-based interception and precision medicine to detect, understand, and advance the development of novel therapeutic approaches through a single-cell omics and drug screening platform, as part of a multi-laboratory collaborative effort, for a group of neurodegenerative disorders named leukodystrophies.
• Evidence snippets:
• Snippet 1 (score: 0.477) > Once affected cells are detected, disease mechanisms can be elucidated using experimental cell models and predictive computational cell trajectory modeling [7]. This approach can identify proteins (including posttranslational modifications, PTMs), protein complexes, and intra-or extra-cellular networks that participate in the disease process and provides the necessary knowledge for the development of disease-modifying therapies. This procedure can be briefly summarized into four steps: detection, understanding, therapy development, and lastly, the implementation of collaborative work to form a multidisciplinary team of experts (Figure 1). As a prototype of step 4, we have initiated the development of a procedure applied to hypomyelinating leukodystrophies. Leukodystrophies are a group of hereditary white matter disorders that predominantly affect children, causing a gradual decline in abilities and often resulting in early mortality within months to years after onset [8]. These conditions selectively affect the brain's white matter, which serves as the protective covering for nerve cells within the brain and spinal cord. Ultimately, this results in abnormalities in myelin formation (classified as hypomyelinating) or disruptions in myelin maintenance (non-hypomyelinating) which compromises the proper functioning of the central nervous system (CNS) leading to neurodegeneration and ensuing sequalae [9][10][11]. To date, there are over 50 different well-defined leukodystrophies with diverse clinical and genetic characteristics and varied Mendelian inheritance patterns. A myriad of genes involved in disparate cellular processes are known to cause leukodystrophies, including those involved in brain development and functioning, metabolism, and housekeeping functions to name a few. Most leukodystrophies remain without a cure or disease-modifying therapy, and interventions are primarily focused on symptomatic treatment [12,13]. Here, we examine the benefits of cell-based interception and precision medicine procedures to hypomyelinating leukodystrophies, with a focus on RNA polymerase III-related leukodystrophy.

[11] Metachromatic Leukodystrophy

• Authors: Marije A B C Asbreuk, Daphne H. Schoenmakers, L. Adang, Shanice Beerepoot, Caroline G. Bergner et al.
• Year: 2025
• Venue: Neurology
• URL: https://www.semanticscholar.org/paper/6c8e1c02d09a6aa062dd4c050995174bda50aef3
• DOI: 10.1212/WNL.0000000000213817
• PMID: 40577679
• PMCID: 12205745
• Citations: 2
• Summary: This review provides a comprehensive overview of the significant progress made in MLD research in the past decade, regarding natural history, disease and treatment mechanisms, and newborn screening (NBS).
• Evidence snippets:
• Snippet 1 (score: 0.467) > Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder caused by disease-causing variants in the gene coding for arylsulfatase A, leading to deficient enzyme activity and subsequent accumulation of sulfatides. MLD is characterized by demyelination and neurodegeneration of the central and peripheral nervous system, manifesting as progressive motor and cognitive defects in affected individuals. This review provides a comprehensive overview of the significant progress made in MLD research in the past decade, regarding natural history, disease and treatment mechanisms, and newborn screening (NBS). Traditionally, MLD has been classified according to age at onset (late-infantile, early-juvenile and late-juvenile, and adult MLD), with earlier forms leading to more rapid neurologic decline. New data show that the type of presenting symptoms further influences the dynamic of disease progression. Patients with a cognitive presentation have a much slower or even no motor decline than patients with a mixed motor and cognitive presentation. Research advancements have enabled improved understanding of the effects of allogeneic hematopoietic stem cell transplantation and the development of novel therapeutic approaches, including hematopoietic stem cell gene therapy, which is now authorized in the EU, United Kingdom, and United States as treatment for selected patients with early-onset forms of MLD. Both hematopoietic stem cell transplantation and hematopoietic stem cell gene therapy are most effective when administered before disease onset. To identify presymptomatic patients, NBS for MLD is becoming available in several countries, resulting in new challenges. Decisions regarding patient eligibility for these treatments in already symptomatic individuals, as well as the timing of treatment for patients identified through NBS, require thorough understanding of disease progression. Biomarkers may be helpful for disease staging and prediction of disease evolution. Moreover, apart from timing, challenges remain regarding optimal treatment strategies across MLD subtypes, especially late-onset MLD, and management of the clinical heterogeneity and course of the disease. Another important issue is ensuring therapy accessibility, which forms a substantial barrier for equitable care. Continued research and international collaboration are essential to address these challenges, with the goal of improving care and outcomes for patients with MLD and

[12] A closer look at ARSA activity in a patient with metachromatic leukodystrophy

• Authors: Kathleen Doherty, S. B. Frazier, M. Clark, Anna Childers, S. Pruthi et al.
• Year: 2019
• Venue: Molecular Genetics and Metabolism Reports
• URL: https://www.semanticscholar.org/paper/55790276b24bbd650810076a25a36f886510744e
• DOI: 10.1016/j.ymgmr.2019.100460
• PMID: 30828547
• PMCID: 6383325
• Citations: 16
• Summary: A 4-year-old female with rapidly progressive developmental regression with loss of motor milestones, spasticity and dysphagia is presented, found to be homozygous for an unusual missense mutation in the arylsulfatase A gene confirming the diagnosis of MLD.
• Evidence snippets:
• Snippet 1 (score: 0.464) > Metachromatic leukodystrophy (MLD) (OMIM # 250100) is an autosomal recessive lysosomal storage disease with a prevalence of approximately 0.6-1.9 per 100,000, which arises from deficient activity of the enzyme arylsulfatase A (ARSA) (EC 3.1.6.8) [5]. Less commonly, a deficiency in sphingolipid activator protein, saposin B, is the cause. ARSA is responsible for the degradation of sulfatides, a major component of myelin in the nervous system. In MLD, excess sulfatides accumulate in the central and peripheral nervous systems as well as other visceral organs resulting in a spectrum of clinical disease. > Clinical manifestations of MLD vary based on functionality of the ARSA enzyme. Late Infantile onset is generally associated with homozygous or compound heterozygous null alleles of the ARSA gene resulting in a rapid accumulation of sulfatides and earlier onset of disease with rapid progression [3]. Patients typically present with regression of motor skills, gait difficulties, ataxia and weakness within the first 3 years of life [5]. The disease is progressive and patients develop dysphagia and feeding intolerance, seizures, hypotonia, and peripheral neuropathy. Patients with late infantile MLD die at a mean age of about 4 years. Individuals with juvenile and adult onset have a variety of mutations in the ARSA gene (OMIM # 607574) that must result in some residual ARSA activity explaining their later onset and the longer progression of disease. Juvenile patients typically present between 3 and 16 years of age with deterioration in intellectual performance along with behavioral difficulties [5]. These individuals are usually compound heterozygotes and have one null allele, resulting in no enzyme activity, and one allele with a mutation that results in some residual ARSA activity. Adult patients often present with a decrease in intellectual capabilities, psychiatric issues and abnormal behavior. Individuals with adult onset disease typically have two mutations that result in some residual enzyme activity [1,3,4]. The clinical course is slower than the late infantile and juvenile forms. Neurological symptoms can include gait disturbance, ataxia, seizures and peripheral ne

[13] Lysosomal storage diseases

• Authors: C. Ferreira, W. Gahl
• Year: 2016
• Venue: Translational Science of Rare Diseases
• URL: https://www.semanticscholar.org/paper/32b30a759f45da424a49edff560557d90cc36e5e
• DOI: 10.3233/TRD-160005
• PMID: 29152458
• PMCID: 5685203
• Citations: 68
• Influential citations: 4
• Summary: In the last couple of decades, enzyme replacement therapy has become available for a number of lysosomal storage diseases, and substrate reduction therapy has been approved for certain disorders, such as eliglustat for Gaucher disease.
• Evidence snippets:
• Snippet 1 (score: 0.463) > encoding 507 amino acids [246]. Over 180 mutations have been identified [31]. MLD-causing mutations are found in 90-95% of patients [246]. > Clinically, metachromatic leukodystrophy is heterogeneous. Three different forms can be distinguished: (i) a severe late-infantile form starting between the ages of 1 and 3 years; (ii) a juvenile form with an age of onset at 3 to 16 years; and (iii) adult forms that may not become apparent before the third decade of life. The progression is slower in the late-onset forms and patients may survive for as much as 20 years after the disease has started. Although the sulfatide storage occurs in all MLD tissues, it mainly affects the nervous system, leading to progressive demyelination. This demyelination is not just seen in the central nervous systems, but it also leads to peripheral neuropathy [248], which can be the presenting sign in adult-onset forms of the disease [249]. Psychiatric symptoms may prevail, particularly in adult patients, before the neurologic symptoms develop [245]. Proximal renal tubular acidosis has been described [250], with subclinical metabolic acidosis at baseline, worsening to a clinically significant acidosis in the acute setting [251]. Sulfatides are known to irritate the gallbladder mucosa, potentially leading to gallbladder papillomatosis [252,253] and hemobilia [254][255][256]. A major determinant of the clinical phenotype is the residual enzyme activity that is associated with a particular genotype. In the typical case the disease starts at the age of about 18 months. Children lose acquired capabilities, develop a spastic tetraparesis, dysarthrias, ataxias, dementias, and finally die in a decerebrate state. In each of the variants, gait disturbance, mental regression, and urinary incontinence are among the earliest signs. In the childhood variants, other common signs are blindness, loss of speech, quadriparesis, peripheral neuropathy, and seizures. In the adult, behavioral disturbances and dementia are the major presenting signs, and the disease

[14] Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms

• Authors: M. S. van der Knaap, M. Bugiani
• Year: 2017
• Venue: Acta Neuropathologica
• URL: https://www.semanticscholar.org/paper/761422457b79efe8107b0fd6413f6fc19984ca89
• DOI: 10.1007/s00401-017-1739-1
• PMID: 28638987
• PMCID: 5563342
• Citations: 309
• Influential citations: 14
• Summary: A novel classification of leukodystrophies is proposed that takes into account the primary involvement of any white matter component, and Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin; astrocytopathies; leuko-axonopathies; microgliopathy; andLeuko-vasculopathies.
• Evidence snippets:
• Snippet 1 (score: 0.461) > The diagnostic approach combining MRI pattern recognition with next generation sequencing has remarkably increased the number of diagnosable genetic white matter disorders, and confirmed that many are due to defects in gene products specifically or also expressed in cell types other than the oligodendrocyte. The last decades have also witnessed a tremendous increase in the knowledge of the white matter demonstrating that all cell types inhabiting it are involved in its development, maintenance, function and repair. This has challenged the traditional myelin-centric view of leukodystrophies that is now proved surpassed. We support a novel definition of leukodystrophy that reflects the current knowledge: leukodystrophies are all genetically determined disorders primarily affecting the CNS white matter, irrespective of the structural white matter component involved, the molecular process affected and the disease course [103]. In the wake of this definition, we here propose a new classification of leukodystrophies based on a cellular pathology approach that takes into account the contribution of cell types other than oligodendrocytes and structures other than myelin driving white matter pathology, including astrocytes, axons, microglia and blood vessels. In reviewing the neuropathology and disease mechanisms of some leukodystrophies, we show that this classification also provides systematic additional information regarding the pathogenesis. The complicated interplay between the different white matter components in the healthy CNS necessarily implies that the diseases mechanisms underlying leukodystrophies are also complex. Our classification therefore also recognizes the possibility that a specific disease does not primarily affect only one cell type or structure and with that belongs to more than one category. Giant axonal neuropathy, for example, is due to defects in gigaxonin that maintains neuroaxonal cytoskeletal integrity and transport, but is also responsible for proper intermediate filament degradation in astrocytes. In other disorders, the neuropathology may be characterized by prominent secondary involvement of selected white matter components. MLC, for example, is due to a defective function of the astrocyte-specific protein MLC1, which is involved in astrocytic control of ion-water homeostasis.

[15] Update on leukodystrophies and developing trials

• Authors: G. Ceravolo, Kristina Zhelcheska, V. Squadrito, D. Pellerin, E. Gitto et al.
• Year: 2023
• Venue: Journal of Neurology
• URL: https://www.semanticscholar.org/paper/c31e5002aba8df7cf105b1de7df616788015ef16
• DOI: 10.1007/s00415-023-11996-5
• PMID: 37755460
• PMCID: 10770198
• Citations: 11
• Summary: This review will explore diagnostic and therapeutic strategies for leukodystrophies, with particular emphasis on new trials.
• Evidence snippets:
• Snippet 1 (score: 0.457) > Bone marrow transplants or hematopoietic stem cell transplantation (HSCT) has shown successful outcomes in attenuating disease progression in leukodystrophies, characterized by the presence of cytotoxic metabolites in the brain (X-ALD, CTX, Krabbe) (Table 3). The rationale behind HSCT in these diseases involves the ability of hematopoietic cells to infiltrate the CNS and express the missing gene or enzyme necessary for the degradation of cytotoxic metabolites. > Lentiviruses have been used as a treatment in patients with pre-symptomatic MLD [71] with clinically relevant benefits [38,72]. > Gene therapy using adeno-associated viruses (AAVs) [73,74] has several advantages over lentiviruses, including a broader tropism for CNS cell populations and the ability to cross the blood-brain barrier (for specific serotypes). An AAV1-GALC gene therapy study demonstrated reduced psychosine levels in the brain of a mouse model, indicating that delivery of the viral vector via the cerebroventricular system can decrease the rate of the disease progression in Krabbe disease [75]. Another study using a viral vector carrying the ASPA gene in patients with Canavan disease demonstrated safety and resulted in some clinical benefits [76]. However, it is possible that gene delivery alone may not be sufficient and may need to be combined with immunomodulation or silencing of the mutant gene. > Antisense oligonucleotides (ASOs) are RNA-based therapies that can alter protein expression (Canavan disease and PMD) [77]. > CRISPR/Cas9 technology has not been studied on leukodystrophies, but it is a promising method for precise gene editing through homology-dependent repair mechanisms and can be used to repair disease-causing alleles by changing the DNA at the desired location of the chromosome.

[16] Phenotypic variation between siblings with Metachromatic Leukodystrophy

• Authors: Saskia Elgün, J. Waibel, C. Kehrer, Diane F. van Rappard, J. Böhringer et al.
• Year: 2019
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/67b3a3375582864cd16e84d342551812aca30e82
• DOI: 10.1186/s13023-019-1113-6
• PMID: 31186049
• PMCID: 6560893
• Citations: 33
• Influential citations: 1
• Summary: A systematic analysis of phenotypic variation in MLD siblings showed a similar variability as unrelated pairs of children with late-infantile MLD, whereas siblings with juvenile MLD showed a more homogeneous phenotype regarding type of first symptoms and disease evolution in comparison to unrelated children with juvenileMLD.
• Evidence snippets:
• Snippet 1 (score: 0.449) > Metachromatic Leukodystrophy (MLD) is an autosomal recessive, monogenic disease caused by mutations in the arylsulfatase A (ARSA) gene, leading to deficiency of the enzyme ARSA and therefore inadequate degradation of sulfatides [1,2]. Sulfatides accumulate especially in the central and peripheral nervous system, and lead to progressive demyelination and neurological symptoms [1,2]. The clinical course can be divided into a pre-symptomatic stage with normal development, followed by onset of first symptoms and a period of developmental stagnation. This plateau phase is shorter in early onset forms, and longer and more variable in late onset forms. Finally, rapid disease progression evolves with a relatively invariable rapid loss of gross motor function, and a final stabilization at a low functional level [3]. > Genotype-phenotype correlation revealed that null alleles, which cause hardly any residual ARSA activity [4,5], result in an early onset and rapid deterioration of motor and cognitive function characterizing the late-infantile form of MLD with first symptoms occurring before 2.5 years of age [6]. In later onset forms (juvenile MLD with disease onset between 2.5 and 16 years, and adult MLD with disease onset after 16 years of age), the prevalent genotypes were associated with some remaining residual activity of the enzyme [4,5]. Although this allows some genotype-phenotype correlation, the exact relationship between genotype, residual enzyme activity, and clinical phenotype remains to be elucidated. Today more than 250 ARSA mutations are known, making it challenging to define more precise genotype-phenotype relationships especially in the later onset forms, which often show compound heterozygosity for different mutations [7][8][9][10][11]. > The phenotypic variability becomes especially relevant when treatment evaluation is based on comparison with an untreated sibling carrying the same mutations [12,13].

[17] Inventory of current practices regarding hematopoietic stem cell transplantation in metachromatic leukodystrophy in Europe and neighboring countries

• Authors: Daphne H. Schoenmakers, Fanny Mochel, L. Adang, J. Boelens, Valeria Calbi et al.
• Year: 2024
• Venue: Orphanet Journal of Rare Diseases
• URL: https://www.semanticscholar.org/paper/2074dcfaeaac025f9e255a04e32b1f7c3e84fd4d
• DOI: 10.1186/s13023-024-03075-3
• PMID: 38326898
• PMCID: 10848395
• Citations: 6
• Summary: This study explores organizational and clinical HSCT practices for MLD in Europe and neighboring countries to enhance optimization and harmonization of cross-border MLD care and underscores physicians’ struggle in providing evidence-based care.
• Evidence snippets:
• Snippet 1 (score: 0.446) > Metachromatic leukodystrophy (MLD) is a rare lysosomal storage disorder with an estimated birth prevalence of 1.4-1.8 per 100.000 [1][2][3]. Deficient arylsulfatase A activity leads to sulfatide accumulation affecting myelin of the central and peripheral nervous system. This central and peripheral demyelination leads to neurological deterioration and early death [4]. MLD is comprised of a spectrum of phenotypes based on the age at onset: late-infantile (LI, onset < 2.5 years old), early-juvenile (EJ, onset 2-6 years old), late-juvenile (LJ, onset ≥ 6-16 years old), and adult (onset ≥ 16 years old) [5]. Almost all MLD cases are caused by biallelic variants in ARSA; cases caused by variants in PSAP are extremely rare [6,7]. The MLD field is rapidly evolving due to new innovations, such as the recently authorized ex vivo gene therapy in the European Union for LI and EJ MLD [8] and development of emerging guidelines and newborn screening programs [9,10]. Gene therapy is not yet universally accessible nor approved in late-onset MLD. This means that hematopoietic stem cell transplantation (HSCT) is still a relevant pillar in the treatment of MLD. > HSCT has been used as a potential treatment in MLD since the 1980s. HSCT, by providing arylsulfatase-A producing donor myeloid cells, may slow or halt disease progression when offered presymptomatically or very early in the disease course. Despite early enthusiasm for this approach, overall, the outcomes have been mixed [5,11,12], with a lack of consensus regarding eligibility criteria and long-term outcomes [13][14][15]. When the disease is too advanced and brain white matter is irreversibly damaged, HSCT is not beneficial and may even trigger fast deterioration [16]. Efficacy of HSCT also depends on age of onset. Patients with late-infantile form have not benefited from HSCT, likely because of the rapidly disease progression [5,17,18].

[18] Early and late outcomes after cord blood transplantation for pediatric patients with inherited leukodystrophies.

• Authors: B. T. van den Broek, K. Page, A. Paviglianiti, Janna A. Hol, H. Allewelt et al.
• Year: 2018
• Venue: Blood advances
• URL: https://www.semanticscholar.org/paper/3518e8e90ffe182a616e7caf6f89bd77e400a231
• DOI: 10.1182/bloodadvances.2017010645
• PMID: 31248906
• Citations: 47
• Influential citations: 3
• Summary: Overall, an encouraging OS was found for LD patients after CBT, especially for those who are presymptomatic before CBT and received adequately dosed grafts.
• Evidence snippets:
• Snippet 1 (score: 0.444) > Leukodystrophies (LD) are a heterozygous group of rare inherited diseases that affect the development and maintenance of brain myelination. Although the age of onset and clinical course varies among this group of diseases, all inherited leukodystrophies are characterized by progressive neurological deterioration and premature death. They often arise from either a lysosomal storage disease (LSD), such as metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy-Krabbe disease (GLD), or a peroxisomal disorder such as X-linked adrenoleukodystrophy (X-ALD). > Hematopoietic stem cell transplantation (HSCT) has been shown to arrest or slow disease progression for MLD, GLD, and X-ALD, particularly when performed in presymptomatic patients or patients with early-stage disease. 1,2 In patients with a LSD, HSCT works through engraftment of donor cells that can cross the blood-brain barrier, providing a source of cellular enzyme replacement through cross-correction of host cells by enzymereplete donor cells. 3 Conversely, in X-ALD, in which the defected protein is not an enzyme but a transporter protein, the exact mechanism of action of HSCT is not completely understood. > Umbilical cord blood (CB), related or unrelated, provides an alternative source of hematopoietic stem cells for transplantation. > After over 2 decades of experience, researchers have well described the benefits of CB. Particularly relevant to patients with LDs, a rapidly progressive disease, CB is readily available, allowing for shorter time to transplant. ][6][7][8][9][10] These studies suggest that CBT is most beneficial when performed early, preferably before the onset of symptoms. > Although it would be ideal to compare the early and late outcomes on the basis of cell source such as those performed for Hurler's disease, 11 this was not possible because of the very limited numbers of patients receiving other cell sources, leading us to focus on cord blood only.

[19] Neuroimmune mechanisms in Krabbe's disease

• Authors: Gregory B Potter, Magdalena A. Petryniak
• Year: 2016
• Venue: Journal of Neuroscience Research
• URL: https://www.semanticscholar.org/paper/201f7962337a320d01bf40c225f3321e3846fafd
• DOI: 10.1002/jnr.23804
• PMID: 27638616
• PMCID: 5129482
• Citations: 53
• Influential citations: 4
• Summary: Mechanistic insight into the inflammatory pathways participating in myelin and axon loss or preservation may lead to novel therapeutic approaches for Krabbe's disease.
• Evidence snippets:
• Snippet 1 (score: 0.444) > Leukodystrophies are the most common cause of pediatric neurodegeneration, associated with profound childhood morbidity and mortality and resulting in significant emotional and financial burden on families and society (Kohlschutter and Eichler, 2011). Although white matter degeneration is a common feature of these disorders, the activation of the CNS's innate immune response is also observed in most leukodystrophies and coincides with white matter pathology, disease progression, and morbidity (Vitner et al., 2010). Despite this, there is a major gap in our knowledge of the contribution of the immune system to disease phenotype. Krabbe's disease (KD), a leukodystrophy caused by an enzymatic defect in lysosomal galactocerebrosidase (GALC), presents in the most severe infantile form by 6 months of age, followed by death at 2 years of age (Wenger, 1997). This Review refers to neuroinflammation as inflammation characterized by reactivation of resident CNS innate immune cells (microglia) and astrogliosis, which has been previously used to describe aspects of KD pathophysiology (Snook et al., 2014;Hawkins-Salsbury et al., 2015;Lin et al., 2015). It is important to note that there is no clear consensus on the definition or application of the term neuroinflammation with regard to neurodegenerative or lysosomal storage disorders. Some researchers draw a distinction between immune-driven pathology in the brain (i.e., as seen in multiple sclerosis) and innate immune cell activation in the brain (Graeber, 2014), whereas others suggest dividing neuroinflammation between innate immunedriven and adaptive immune-driven neuroinflammation (Heppner et al., 2015). Nevertheless, it is clear that inflammation within the nervous system is a defining characteristic of KD. One of the earliest clinical SIGNIFICANCE Although innate immune activation is a central component of Krabbe's disease that precedes and accelerates with disease progression, the mechanisms by which the immune system contributes to neurodegeneration are still unclear.

Notes

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