Outcome of Early Juvenile Onset Metachromatic Leukodystrophy After Unrelated Cord Blood Transplantation: A Case Series and Review of the Literature

Chen, Xuqin; Gill, Deepak; Shaw, Peter J.; Ouvrier, Robert; Troedson, Christopher

doi:10.1177/0883073815595078

Cited by 20 publications

(15 citation statements)

References 26 publications

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“…Besides that, many clinical studies provide information for only a limited number of patients at various stages of the disease. In general, it appears that asymptomatic patients with juvenile and adult MLD experience a clear symptomatic and survival benefit from allogeneic HCT; however, this benefit is transient and often limited to the CNS symptoms [3, 11, 12, 28, 71–76]. Preliminary studies show that PNS symptoms in patients respond better to gene therapy, most likely due to higher enzyme levels achieved than with HCT and thereby increased penetration into the peripheral nerves [76, 77].…”

Section: Therapeutic Approachesmentioning

confidence: 99%

See 1 more Smart Citation

Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective

Beerepoot

Nierkens

Boelens

et al. 2019

Orphanet J Rare Dis

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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. In asymptomatic patients with juvenile and adult MLD, treatment with allogeneic hematopoietic stem cell transplantation (HCT) provides a symptomatic and survival benefit. However, this treatment mainly impacts brain white matter, whereas the peripheral neuropathy shows no or only limited response. Data about the impact of peripheral neuropathy in MLD patients are currently lacking, although in our experience peripheral neuropathy causes significant morbidity due to neuropathic pain, foot deformities and neurogenic bladder disturbances. Besides, 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. In this literature review, we discuss clinical aspects, pathological findings, distribution of mutations, and treatment approaches in MLD with particular emphasis on peripheral neuropathy. We believe that future therapies need more emphasis on the management of peripheral neuropathy, and additional research is needed to optimize care strategies.

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Section: Therapeutic Approachesmentioning

confidence: 99%

“…This makes HCT unsuitable for symptomatic MLD patients or (asymptomatic) patients with the late-infantile MLD. Considering time, unrelated umbilical cord blood is currently preferred over bone marrow and peripheral blood because stored umbilical cord blood can be identified and transplanted faster than other sources [12, 79, 81].…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective

Beerepoot

Nierkens

Boelens

et al. 2019

Orphanet J Rare Dis

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“…In one UCBT study, the long‐term progress of three asymptomatic children (aged 2–5 years) was compared with that of untreated siblings with symptomatic early‐juvenile MLD. In followup examinations after transplantation (at 6 and 14 years), the transplant procedure appeared to slow the progression of the disease significantly (Chen et al, ).…”

Section: Therapeutic Approaches To Mldmentioning

confidence: 99%

“…Furthermore, when GFP-tagged bone marrow cells were transplanted into wild-type C57Bl/6 mice, HSC-derived microglia cell engraftment was enhanced by the local neuropathology, allowing healthy microglia to replace damaged microglia in up to 25% of the regional population (Priller et al, 2001). With regard to clinical trials, there have been multiple reports of MLD patients gradually improving their motor and behavioral function scores following umbilical cord blood transplants (UCBT) but mixed results for allogeneic HSCT (Krivit et al, 1999a;Pierson et al, 2008;Smith et al, 2010;Cable et al, 2011;de Hosson et al, 2011;Martin et al, 2013;van Egmond et al, 2013;Chen et al, 2016;Helman et al, 2015). The early-onset forms of MLD (LI) are problematic for successful HSCT or UCBT even when the patients are still presymptomatic because of the rapidity of disease progression (Bredius, 2007, Martin, 2013.…”

Section: Bone Marrow and Umbilical Cord Blood Transplantationmentioning

confidence: 99%

Gene therapy for metachromatic leukodystrophy

Rosenberg

Kaminsky

Aubourg

et al. 2016

J of Neuroscience Research

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Summary Leukodystrophies are rare white matter genetic disorders of the central nervous system (CNS) with progressive neurologic deterioration. One approach to the treatment of leukodystrophies is by gene therapy. Using metachromatic leukodystrophy (MLD), a leukodystrophy resulting from deficiency of a lysosomal catabolic enzyme arylsulfatase A (ARSA) as the example, this review is focused on the current status of preclinical and clinical development of gene therapy as a viable treatment option for leukodystrophies. In MLD, mutations in the ARSA gene result in excess buildup of sulfatides, which triggers apoptosis of glia and neurons. The disease is characterized by severe cerebral demyelination and atrophy, with progressive loss of oligodendrocytes, neurons and Schwann cells. The optimal therapy for MLD would provide persistent and high level expression of ARSA in the CNS. Gene therapy using adeno-associated virus (AAV) is an ideal choice for clinical development as it provides the best balance of potential for efficacy with a reduced safety risk profile. In this review, we have summarized preclinical data that support the use of a gene therapy with the AAVrh.10 serotype for clinical development as a treatment for MLD.

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“…MLD is a rare disorder with an estimated birth prevalence of 1.4 to 1.8 per 100,000; there are also reports of 1/40,000 to 1/170,000. [5][6] Although a series of potential therapies, such as haematopoietic stem cell transplantation, 7 enzyme replacement therapy 8 and gene therapy 9 have been explored, currently there is no curative treatment for this disease.…”

Section: Introductionmentioning

confidence: 99%

Identification of a missense ARSA mutation in metachromatic leukodystrophy and its potential pathogenic mechanism

Guo

Jin

Zhang

et al. 2019

Preprint

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Background The most common type of metachromatic leukodystrophy (MLD) is an inherited lysosomal disorder caused by recessive mutations in ARSA. The biological process of MLD disease caused by candidate pathogenic mutations in the ARSA gene remains unclear. MethodsWe used whole-exome sequencing (WES) and Sanger sequencing to identify the pathogenic mutation in a Chinese family. Literature review and protein three-dimensional structure prediction were performed to analyse the potential pathogenesis of the identified mutations. Overexpression cell models of wild-type and mutated ARSA genes were constructed to obtain expression profiles, and weighted gene co-expression network analysis (WGCNA), hub gene detection and protein-protein interaction (PPI) analysis were carried out to compare the biological changes caused by candidate pathogenic mutations. ResultsWe identified an ARSA c.925G>A homozygous mutation from a Chinese late-infantile MLD patient, the first report of this mutation in Asia. According to the literature and protein structure analysis, three mutations of c. 925G (c.925G>A, c.925G>T, c.925G>C) in the ARSA gene were pathogenic. The transcriptome of four ARSA overexpression cell models (c.925G, c.925G>A, c.925G>T, c.925G>C) were analysed by WGCNA, Hub genes and PPI complexes.RNA-seq and bioinformatics results indicate that the mutations at c.925G cause comprehensive molecular changes related to energy metabolism, ion binding, vesicle transport and transport. ConclusionWe identified a pathogenic mutation, ARSA homozygosity c.925G>A, from a Chinese MLD family. All three mutations of c.925G in the ARSA gene are pathogenic and may cause disease by dysregulating the molecular processes of ion binding, vesicle transport and ion transport.

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Outcome of Early Juvenile Onset Metachromatic Leukodystrophy After Unrelated Cord Blood Transplantation: A Case Series and Review of the Literature

Cited by 20 publications

References 26 publications

Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective

Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective

Gene therapy for metachromatic leukodystrophy

Identification of a missense ARSA mutation in metachromatic leukodystrophy and its potential pathogenic mechanism

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