The magnetic resonance imaging spectrum of Pelizaeus–Merzbacher disease: A multicenter study of 19 patients

Sumida, Kaoru; Inoue, Ken; Takanashi, Jun‐ichi; Sasaki, Masayuki; Watanabe, Kenji; Suzuki, Michitaka; Kurahashi, Hirokazu; Omata, Taku; Tanaka, Manabu; Yokochi, Kenji; Iio, Jun; Iyoda, Kuniaki; Kurokawa, Toru; Matsuo, Muneaki; Sato, Tamotu; Iwaki, Akiko; Osaka, Hitoshi; Kurosawa, Kenji; Yamamoto, Toshiyuki; Matsumoto, Naomichi; Maikusa, Norihide; Sato, Noriko

doi:10.1016/j.braindev.2015.12.007

Cited by 24 publications

(19 citation statements)

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“…Such MRI is highly representative of children with moderate to severe PMD and demonstrates both the ambiguity and convergence of clinical presentations across people with disparate PLP1 mutations. [54][55][56] To generate a renewable source of PMD-derived cells, we reprogrammed fibroblasts from all 12 individuals to hiPSCs (see Material and Methods). Two independently derived hiPSC lines per individual were ultimately selected for rigorous characterization.…”

Section: Resultsmentioning

confidence: 99%

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

Nevin

Factor

Karl

et al. 2017

The American Journal of Human Genetics

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Pelizaeus-Merzbacher disease (PMD) is a pediatric disease of myelin in the central nervous system and manifests with a wide spectrum of clinical severities. Although PMD is a rare monogenic disease, hundreds of mutations in the X-linked myelin gene proteolipid protein 1 (PLP1) have been identified in humans. Attempts to identify a common pathogenic process underlying PMD have been complicated by an incomplete understanding of PLP1 dysfunction and limited access to primary human oligodendrocytes. To address this, we generated panels of human induced pluripotent stem cells (hiPSCs) and hiPSC-derived oligodendrocytes from 12 individuals with mutations spanning the genetic and clinical diversity of PMD-including point mutations and duplication, triplication, and deletion of PLP1-and developed an in vitro platform for molecular and cellular characterization of all 12 mutations simultaneously. We identified individual and shared defects in PLP1 mRNA expression and splicing, oligodendrocyte progenitor development, and oligodendrocyte morphology and capacity for myelination. These observations enabled classification of PMD subgroups by cell-intrinsic phenotypes and identified a subset of mutations for targeted testing of small-molecule modulators of the endoplasmic reticulum stress response, which improved both morphologic and myelination defects. Collectively, these data provide insights into the pathogeneses of a variety of PLP1 mutations and suggest that disparate etiologies of PMD could require specific treatment approaches for subsets of individuals. More broadly, this study demonstrates the versatility of a hiPSC-based panel spanning the mutational heterogeneity within a single disease and establishes a widely applicable platform for genotype-phenotype correlation and drug screening in any human myelin disorder.

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Section: Resultsmentioning

confidence: 99%

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

Nevin

Factor

Karl

et al. 2017

The American Journal of Human Genetics

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“…In combination with the progressive loss of mutant oligodendrocytes, this leads to dysmyelination and demyelination in PMD [ 11 , 53 , 59 ]. The MRI pattern of diffuse hypomyelination in PMD caused by PLP1 duplication is hence considered consequence of arrested brain maturation and lacks focal or inflammatory demyelination [ 9 , 66 , 71 ]. Despite variable disease severity of PMD duplication patients, hypomyelination improves only to a minor extent over time.…”

Section: Introductionmentioning

confidence: 99%

Ketogenic diet ameliorates axonal defects and promotes myelination in Pelizaeus–Merzbacher disease

et al. 2019

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Pelizaeus-Merzbacher disease (PMD) is an untreatable and fatal leukodystrophy. In a model of PMD with perturbed bloodbrain barrier integrity, cholesterol supplementation promotes myelin membrane growth. Here, we show that in contrast to the mouse model, dietary cholesterol in two PMD patients did not lead to a major advancement of hypomyelination, potentially because the intact blood-brain barrier precludes its entry into the CNS. We therefore turned to a PMD mouse model with preserved blood-brain barrier integrity and show that a high-fat/low-carbohydrate ketogenic diet restored oligodendrocyte integrity and increased CNS myelination. This dietary intervention also ameliorated axonal degeneration and normalized motor functions. Moreover, in a paradigm of adult remyelination, ketogenic diet facilitated repair and attenuated axon damage. We suggest that a therapy with lipids such as ketone bodies, that readily enter the brain, can circumvent the requirement of a disrupted blood-brain barrier in the treatment of myelin disease.

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“…These MRI findings are consistent with the natural history of patients, in that children with PMD commonly develop slowly up to about 10 years of age, but often begin to decline after developmental milestones peak. Recently, we have also reported an MRI study including 19 patients with PMD and found corpus callosum atrophy in 17 of them …”

mentioning

confidence: 87%

“…Recently, we have also reported an MRI study including 19 patients with PMD and found corpus callosum atrophy in 17 of them. 5 What is the cause of the brain atrophy in PMD? The findings of these studies indicate that patients with PMD have little white matter, a phenomenon that is more obvious in patients with severe disease, and that the atrophy progresses after the peak of development.…”

mentioning

confidence: 99%

Brain atrophy in Pelizaeus‐Merzbacher disease

Inoue

2016

Develop Med Child Neuro

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The magnetic resonance imaging spectrum of Pelizaeus–Merzbacher disease: A multicenter study of 19 patients

Cited by 24 publications

References 20 publications

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

Ketogenic diet ameliorates axonal defects and promotes myelination in Pelizaeus–Merzbacher disease

Brain atrophy in Pelizaeus‐Merzbacher disease

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