Hematopoietic Stem Cell Transplantation in Late‐Onset Krabbe Disease: No Evidence of Worsening Demyelination and Axonal Loss 4 Years Post‐allograft

Laule, Cornelia; Vavasour, Irene M.; Shahinfard, Elham; Mädler, Burkhard; Zhang, Jing; Li, David K.B.; MacKay, Alex L.; Sirrs, Sandra

doi:10.1111/jon.12502

Cited by 32 publications

(20 citation statements)

References 14 publications

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“…Lack of arylsulfatase A Intrathecal enzyme replacement therapy, hematopoetic stem cell transplantation Groeschel et al, 2016 Krabbe disease (GALC) Lack of galactosylceramidase Hematopoetic stem cell transplantation Laule et al, 2018…”

Section: Reduction Of Toxic Metabolitesmentioning

confidence: 99%

Autosomal Recessive Cerebellar Ataxias: Paving the Way toward Targeted Molecular Therapies

Synofzik

Puccio

Mochel

et al. 2019

Neuron

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Autosomal-recessive cerebellar ataxias (ARCAs) comprise a heterogeneous group of rare degenerative and metabolic genetic diseases that share the hallmark of progressive damage of the cerebellum and its associated tracts. This Review focuses on recent translational research in ARCAs and illustrates the steps from genetic characterization to preclinical and clinical trials. The emerging common pathways underlying ARCAs include three main clusters: mitochondrial dysfunction, impaired DNA repair, and complex lipid homeostasis. Novel ARCA treatments might target common hubs in pathogenesis by modulation of gene expression, stem cell transplantation, viral gene transfer, or interventions in faulty pathways. All these translational steps are addressed in current ARCA research, leading to the expectation that novel treatments for ARCAs will be reached in the next decade.

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Section: Reduction Of Toxic Metabolitesmentioning

confidence: 99%

Autosomal Recessive Cerebellar Ataxias: Paving the Way toward Targeted Molecular Therapies

Synofzik

Puccio

Mochel

et al. 2019

Neuron

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“…A mouse model deficient in arylsulfatase presents with early onset accumulation of sulfatides in lysosomes of neurons and oligodendrocytes (Wittke et al, 2004). In both Krabbe disease and metachromatic leukodystrophy, allogenic hematopoietic stem cell transplantation (HSCT) can stabilize/slow-down cerebral demyelinating lesions for pre-or early-symptomatic juvenile or adult patients (van Rappard et al, 2016;Laule et al, 2018).…”

Section: Sphingolipid Degradationmentioning

confidence: 99%

Lipids in the Physiopathology of Hereditary Spastic Paraplegias

2020

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Hereditary spastic paraplegias (HSP) are a group of neurodegenerative diseases sharing spasticity in lower limbs as common symptom. There is a large clinical variability in the presentation of patients, partly underlined by the large genetic heterogeneity, with more than 60 genes responsible for HSP. Despite this large heterogeneity, the proteins with known function are supposed to be involved in a limited number of cellular compartments such as shaping of the endoplasmic reticulum or endolysosomal function. Yet, it is difficult to understand why alteration of such different cellular compartments can lead to degeneration of the axons of cortical motor neurons. A common feature that has emerged over the last decade is the alteration of lipid metabolism in this group of pathologies. This was first revealed by the identification of mutations in genes encoding proteins that have or are supposed to have enzymatic activities on lipid substrates. However, it also appears that mutations in genes affecting endoplasmic reticulum, mitochondria, or endolysosome function can lead to changes in lipid distribution or metabolism. The aim of this review is to discuss the role of lipid metabolism alterations in the physiopathology of HSP, to evaluate how such alterations contribute to neurodegenerative phenotypes, and to understand how this knowledge can help develop therapeutic strategy for HSP.

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“…Myelin water fraction (MWF), defined as the fraction of the total signal which has T 2 < 40 milliseconds at 3 Tesla, has been histologically validated as a marker of myelin density in human tissue, 30–32 and has good scan‐rescan reproducibility (coefficient of variation 4% in cerebral white matter) 33 . MWI has been used to investigate myelin in a wide range of diseases including multiple sclerosis, neuromyelitis optica spectrum disorder, schizophrenia, Niemann‐Pick disease, prenatal alcohol exposure, amyotrophic and primary lateral sclerosis, Krabbe disease, autism, stroke, and traumatic brain injury 34–47 . Rapid myelination has been demonstrated in early childhood and adolescence using multicomponent driven equilibrium single pulse observation of T 1 and T 2 (mcDESPOT), an alternate approach to MWI using a steady‐state acquisition 48–53 .…”

Section: Introductionmentioning

confidence: 99%

“…33 MWI has been used to investigate myelin in a wide range of diseases including multiple sclerosis, neuromyelitis optica spectrum disorder, schizophrenia, Niemann-Pick disease, prenatal alcohol exposure, amyotrophic and primary lateral sclerosis, Krabbe disease, autism, stroke, and traumatic brain injury. [34][35][36][37][38][39][40][41][42][43][44][45][46][47] Rapid myelination has been demonstrated in early childhood and adolescence using multicomponent driven equilibrium single pulse observation of T 1 and T 2 (mcDESPOT), an alternate approach to MWI using a steadystate acquisition. [48][49][50][51][52][53] Adult multi-echo T 2 -based MWF atlases in both brain and cervical spinal cord have recently been published, 54,55 but, to our knowledge, no such atlases exist for children.…”

Section: Introductionmentioning

confidence: 99%

Brain Myelin Water Fraction and Diffusion Tensor Imaging Atlases for 9‐10 Year‐Old Children

Morris

Holmes

Dvorak

et al. 2020

Journal of Neuroimaging

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BACKGROUND AND PURPOSE Myelin water imaging (MWI) and diffusion tensor imaging (DTI) provide information about myelin and axon‐related brain microstructure, which can be useful for investigating normal brain development and many childhood brain disorders. While pediatric DTI atlases exist, there are no pediatric MWI atlases available for the 9‐10 years old age group. As myelination and structural development occurs throughout childhood and adolescence, studies of pediatric brain pathologies must use age‐specific MWI and DTI healthy control data. We created atlases of myelin water fraction (MWF) and DTI metrics for healthy children aged 9‐10 years for use as normative data in pediatric neuroimaging studies. METHODS 3D‐T1, DTI, and MWI scans were acquired from 20 healthy children (mean age: 9.6 years, range: 9.2‐10.3 years, 4 females). ANTs and FSL registration were used to create quantitative MWF and DTI atlases. Region of interest (ROI) analysis in nine white matter regions was used to compare pediatric MWF with adult MWF values from a recent study and to investigate the correlation between pediatric MWF and DTI metrics. RESULTS Adults had significantly higher MWF than the pediatric cohort in seven of the nine white matter ROIs, but not in the genu of the corpus callosum or the cingulum. In the pediatric data, MWF correlated significantly with mean diffusivity, but not with axial diffusivity, radial diffusivity, or fractional anisotropy. CONCLUSIONS Normative MWF and DTI metrics from a group of 9‐10 year old healthy children provide a resource for comparison to pathologies. The age‐specific atlases are ready for use in pediatric neuroimaging research and can be accessed: https://sourceforge.net/projects/pediatric-mri-myelin-diffusion/.

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Hematopoietic Stem Cell Transplantation in Late‐Onset Krabbe Disease: No Evidence of Worsening Demyelination and Axonal Loss 4 Years Post‐allograft

Abstract: Clinical evidence and stability of advanced MR measures related to myelin and axons supports HSCT as an effective treatment strategy for stopping progression associated with late-onset Krabbe disease.

Cited by 32 publications

References 14 publications

Autosomal Recessive Cerebellar Ataxias: Paving the Way toward Targeted Molecular Therapies

Autosomal Recessive Cerebellar Ataxias: Paving the Way toward Targeted Molecular Therapies

Lipids in the Physiopathology of Hereditary Spastic Paraplegias

Brain Myelin Water Fraction and Diffusion Tensor Imaging Atlases for 9‐10 Year‐Old Children

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