657 results match your criteria Pelizaeus-Merzbacher Disease


A recurrent TMEM106B mutation in hypomyelinating leukodystrophy: A rapid diagnostic assay.

Brain Dev 2020 Jun 25. Epub 2020 Jun 25.

Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Introduction: Hypomyelinating leukodystrophies (HLDs) are genetically heterogeneous syndromes, presenting abnormalities in myelin development in the central nervous system. Recently, a recurrent de novo mutation in TMEM106B was identified to be responsible for five cases of HLD. We report the first Japanese case of TMEM106B gene mutation. Read More

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http://dx.doi.org/10.1016/j.braindev.2020.06.002DOI Listing

Estimating the relative frequency of leukodystrophies and recommendations for carrier screening in the era of next-generation sequencing.

Am J Med Genet A 2020 Jun 23. Epub 2020 Jun 23.

Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. Read More

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http://dx.doi.org/10.1002/ajmg.a.61641DOI Listing

Rehabilitative management of an infant with Pelizaeus-Merzbacher disease: A case report.

Medicine (Baltimore) 2020 May;99(22):e20110

Department of Physical & Rehabilitation Medicine, Chonnam National University Medical School & Hospital, Gwangju City, Republic of Korea.

Rationale: Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive trait and a rare disease characterized by abnormal myelin formation in the central nervous system. Since Pelizaeus and Merzbacher reported the pathology of PMD in the 1990s most studies have examined pharmacological treatments. No studies have reported the effects of rehabilitation on patients with PMD aimed at improving their functional abilities. Read More

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http://dx.doi.org/10.1097/MD.0000000000020110DOI Listing

Generation of a human iPSC line (MPIi006-A) from a patient with Pelizaeus-Merzbacher disease.

Stem Cell Res 2020 May 7;46:101839. Epub 2020 May 7.

Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, Münster 48149, Germany; Medical Faculty, University of Münster, Domagkstrasse 3, Münster 48149, Germany. Electronic address:

We established a human induced pluripotent stem cells (hiPSC) line (MPIi006-A) from fibroblasts of a 20-year-old male Pelizaeus-Merzbacher disease (PMD) patient with a hemizygous 643C>T mutation in proteolipid protein 1 (PLP1) gene using a retroviral delivery of OCT4, SOX2, KLF4 and c-MYC. The MPIi006-A iPSC line carried the mutation, displayed typical iPSC morphology, expressed pluripotent stem cell makers, exhibited normal karyotype and were capable of differentiating into cells representative of three germ layers. Read More

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http://dx.doi.org/10.1016/j.scr.2020.101839DOI Listing

Neural stem cells restore myelin in a demyelinating model of Pelizaeus-Merzbacher disease.

Brain 2020 May;143(5):1383-1399

School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8TA, UK.

Pelizaeus-Merzbacher disease is a fatal X-linked leukodystrophy caused by mutations in the PLP1 gene, which is expressed in the CNS by oligodendrocytes. Disease onset, symptoms and mortality span a broad spectrum depending on the nature of the mutation and thus the degree of CNS hypomyelination. In the absence of an effective treatment, direct cell transplantation into the CNS to restore myelin has been tested in animal models of severe forms of the disease with failure of developmental myelination, and more recently, in severely affected patients with early disease onset due to point mutations in the PLP1 gene, and absence of myelin by MRI. Read More

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http://dx.doi.org/10.1093/brain/awaa080DOI Listing

Generation of the human induced pluripotent stem cell line (ZJUi005-A) from a patient with Pelizaeus-Merzbacher disease (PMD) carrying a novel hemizygous mutation in PLP1 gene.

Stem Cell Res 2020 May 19;45:101791. Epub 2020 Apr 19.

Department of Reproductive Genetics, Women's Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, China. Electronic address:

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked leukodystrophy caused by mutations in the proteolipid protein 1 gene (PLP1) which is specifically expressed on the myelin sheath of oligodendrocytes. We established an induced pluripotent stem cell (iPSC) line (ZJUi005-A) from peripheral blood mononuclear cells of an 18-year-old male PMD patient with a novel hemizygous c.437T>C mutation in PLP1 gene using episomal reprogramming plasmids. Read More

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http://dx.doi.org/10.1016/j.scr.2020.101791DOI Listing

Epilepsy in children with leukodystrophies.

J Neurol 2020 May 9. Epub 2020 May 9.

Department of Pediatrics, Peking University First Hospital, No. 1 Xi'an Men Street, West District, Beijing, 100034, China.

Background: Epilepsy might be one of the manifestations in children with leukodystrophies, but the incidence of epilepsy in different types of leukodystrophies is unclear yet.

Methods: A retrospective observational cohort study was performed on children diagnosed with leukodystrophies in Peking University First Hospital from January 2004 to June 2019, and the patients were followed for 5.5 years (0. Read More

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http://dx.doi.org/10.1007/s00415-020-09889-yDOI Listing

PP1C and PP2A are p70S6K Phosphatases Whose Inhibition Ameliorates HLD12-Associated Inhibition of Oligodendroglial Cell Morphological Differentiation.

Biomedicines 2020 Apr 16;8(4). Epub 2020 Apr 16.

Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.

Myelin sheaths created by oligodendroglial cells encase neuronal axons to achieve saltatory conduction and protect axons. Pelizaeus-Merzbacher disease (PMD) is a prototypic, hereditary demyelinating oligodendroglial disease of the central nervous system (CNS), and is currently known as hypomyelinating leukodystrophy 1 (HLD1). HLD12 is an autosomal recessive disorder responsible for the gene that encodes vacuolar protein sorting-associated protein 11 homolog (VPS11). Read More

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http://dx.doi.org/10.3390/biomedicines8040089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235839PMC

Clinical and genetic aspects of hereditary spastic paraplegia in patients from Turkey.

Neurol Neurochir Pol 2020 3;54(2):176-184. Epub 2020 Apr 3.

Istanbul University, Istanbul Medical Faculty, Department of Neurology, Istanbul, Turkey.

Objectives: Hereditary spastic paraplegias (HSPs) are a heterogenous group of rare neurodegenerative disorders that present with lower limb spasticity. It is known as complicated HSP if spasticity is accompanied by additional features such as cognitive impairment, cerebellar syndrome, thin corpus callosum, or neuropathy. Most HSP families show autosomal dominant (AD) inheritance. Read More

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http://dx.doi.org/10.5603/PJNNS.a2020.0026DOI Listing

CNP deficiency causes severe hypomyelinating leukodystrophy in humans.

Hum Genet 2020 May 3;139(5):615-622. Epub 2020 Mar 3.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Myelin pathologies are an important cause of multifactorial, e.g., multiple sclerosis, and Mendelian, e. Read More

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http://dx.doi.org/10.1007/s00439-020-02144-4DOI Listing

A male infant with Xq22.2q22.3 duplication containing PLP1 and MID2.

Mol Genet Genomic Med 2020 Mar 17;8(3):e1078. Epub 2020 Jan 17.

Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA.

Background: The Xq22.2 q23 is a complex genomic region which includes the genes MID2 and PLP1 associated with FG syndrome 5 and Pelizaeus-Merzbacher disease, respectively. There is limited information regarding the clinical outcomes observed in patients with deletions within this region. Read More

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http://dx.doi.org/10.1002/mgg3.1078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057127PMC

An update on clinical, pathological, diagnostic, and therapeutic perspectives of childhood leukodystrophies.

Expert Rev Neurother 2020 Jan 12;20(1):65-84. Epub 2019 Dec 12.

Myelin Disorders Clinic, Department of Pediatric Neurology, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran.

: Leukodystrophies constitute heterogenous group of rare heritable disorders primarily affecting the white matter of central nervous system. These conditions are often under-appreciated among physicians. The first clinical manifestations of leukodystrophies are often nonspecific and can occur in different ages from neonatal to late adulthood periods. Read More

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http://dx.doi.org/10.1080/14737175.2020.1699060DOI Listing
January 2020
20 Reads
3.400 Impact Factor

Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants.

Genome Med 2019 12 9;11(1):80. Epub 2019 Dec 9.

Graduate Program in Diagnostic Genetics, School of Health Professions, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: We investigated the features of the genomic rearrangements in a cohort of 50 male individuals with proteolipid protein 1 (PLP1) copy number gain events who were ascertained with Pelizaeus-Merzbacher disease (PMD; MIM: 312080). We then compared our new data to previous structural variant mutagenesis studies involving the Xq22 region of the human genome. The aggregate data from 159 sequenced join-points (discontinuous sequences in the reference genome that are joined during the rearrangement process) were studied. Read More

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http://dx.doi.org/10.1186/s13073-019-0676-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902434PMC
December 2019
4 Reads

Developmental hypomyelination in Wolfram syndrome: new insights from neuroimaging and gene expression analyses.

Orphanet J Rare Dis 2019 12 3;14(1):279. Epub 2019 Dec 3.

Department of Psychiatry, Washington University School of Medicine, 4525 Scott Avenue, St. Louis, MO, 63110, USA.

Wolfram syndrome is a rare multisystem disorder caused by mutations in WFS1 or CISD2 genes leading to brain structural abnormalities and neurological symptoms. These abnormalities appear in early stages of the disease. The pathogenesis of Wolfram syndrome involves abnormalities in the endoplasmic reticulum (ER) and mitochondrial dynamics, which are common features in several other neurodegenerative disorders. Read More

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http://dx.doi.org/10.1186/s13023-019-1260-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889680PMC
December 2019

Pelizaeus-Merzbacher Disease: Molecular and Cellular Pathologies and Associated Phenotypes.

Authors:
Ken Inoue

Adv Exp Med Biol 2019 ;1190:201-216

Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.

Pelizaeus-Merzbacher disease (PMD) represents a group of disorders known as hypomyelinating leukodystrophies, which are characterized by abnormal development and maintenance of myelin in the central nervous system. PMD is caused by different types of mutations in the proteolipid protein 1 (PLP1) gene, which encodes a major myelin membrane lipoprotein. These mutations in the PLP1 gene result in distinct cellular and molecular pathologies and a spectrum of clinical phenotypes. Read More

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http://dx.doi.org/10.1007/978-981-32-9636-7_13DOI Listing
December 2019
4 Reads

Compound heterozygous mutations in SNAP29 is associated with Pelizaeus-Merzbacher-like disorder (PMLD).

Hum Genet 2019 Dec 20;138(11-12):1409-1417. Epub 2019 Nov 20.

Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ, USA.

Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating leukodystrophy, which is clinically and radiologically similar to X-linked Pelizaeus-Merzbacher disease (PMD). PMLD is characterized by early-onset nystagmus, delayed development (motor delay, speech delay and dysarthria), dystonia, hypotonia typically evolving into spasticity, ataxia, seizures, optic atrophy, and diffuse leukodystrophy on magnetic resonance imaging (MRI). We identified a 12-year-old Caucasian/Hispanic male with the classical clinical characteristics of PMLD with lack of myelination of the subcortical white matter, and absence of the splenium of corpus callosum. Read More

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http://dx.doi.org/10.1007/s00439-019-02077-7DOI Listing
December 2019
4.824 Impact Factor

Hypomyelinating leukodystrophy-associated mutation of RARS leads it to the lysosome, inhibiting oligodendroglial morphological differentiation.

Biochem Biophys Rep 2019 Dec 7;20:100705. Epub 2019 Nov 7.

Laboratory of Molecular Neuroscience and Neurology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, 192-0392, Japan.

Pelizaeus-Merzbacher disease (PMD) is a central nervous system (CNS) demyelinating disease in human, currently known as prototypic hypomyelinating leukodystrophy 1 (HLD1). The gene responsible for HLD1 encodes proteolipid protein 1 (PLP1), which is the major myelin protein produced by oligodendrocytes. HLD9 is an autosomal recessive disorder responsible for the gene differing from the gene. Read More

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http://dx.doi.org/10.1016/j.bbrep.2019.100705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849085PMC
December 2019

Unfolded protein response in myelin disorders.

Neural Regen Res 2020 Apr;15(4):636-645

Department of Neuroscience; Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA.

Activation of the unfolded protein response in response to endoplasmic reticulum stress preserves cell viability and function under stressful conditions. Nevertheless, persistent, unresolvable activation of the unfolded protein response can trigger apoptosis to eliminate stressed cells. Recent studies show that the unfolded protein response plays an important role in the pathogenesis of various disorders of myelin, including multiples sclerosis, Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease, vanishing white matter disease, spinal cord injury, tuberous sclerosis complex, and hypoxia-induced perinatal white matter injury. Read More

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http://dx.doi.org/10.4103/1673-5374.266903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975143PMC
April 2020
1 Read

Heterozygous Variants in the Mechanosensitive Ion Channel TMEM63A Result in Transient Hypomyelination during Infancy.

Am J Hum Genet 2019 11 3;105(5):996-1004. Epub 2019 Oct 3.

Department of Child Neurology, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam and Amsterdam Neuroscience, Amsterdam 1081 HV, the Netherlands. Electronic address:

Mechanically activated (MA) ion channels convert physical forces into electrical signals. Despite the importance of this function, the involvement of mechanosensitive ion channels in human disease is poorly understood. Here we report heterozygous missense mutations in the gene encoding the MA ion channel TMEM63A that result in an infantile disorder resembling a hypomyelinating leukodystrophy. Read More

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http://dx.doi.org/10.1016/j.ajhg.2019.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848986PMC
November 2019
3 Reads

Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation.

Cell Stem Cell 2019 Oct;25(4):531-541.e6

Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy caused by mutations in Proteolipid Protein 1 (PLP1), encoding a major myelin protein, resulting in profound developmental delay and early lethality. Previous work showed involvement of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways, but poor PLP1 genotype-phenotype associations suggest additional pathogenetic mechanisms. Using induced pluripotent stem cell (iPSC) and gene-correction, we show that patient-derived oligodendrocytes can develop to the pre-myelinating stage, but subsequently undergo cell death. Read More

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http://dx.doi.org/10.1016/j.stem.2019.09.003DOI Listing
October 2019

Advantages of ddPCR in detection of duplications.

Intractable Rare Dis Res 2019 Aug;8(3):198-202

Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.

Pelizaeus-Merzbacher disease (PMD) is an X-linked, recessively inherited disorder associated with hypomyelination in the brain white matter. Mutations involving the proteolipid protein 1 gene () located on Xq22.2 are responsible for PMD. Read More

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http://dx.doi.org/10.5582/irdr.2019.01067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743437PMC
August 2019
4 Reads

Magnetic resonance imaging traits may help to differentiate Pelizaeus-Merzbacher and Pelizaeus-Merzbacher-like disease.

Arq Neuropsiquiatr 2019 09 5;77(8):594. Epub 2019 Sep 5.

Universidade Federal do Rio Grande do Norte, Departamento de Medicina Integrada, Natal RN, Brasil.

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http://dx.doi.org/10.1590/0004-282X20190081DOI Listing
September 2019

Late-onset phenotype associated with a homozygous GJC2 missense mutation in a Turkish family.

Parkinsonism Relat Disord 2019 09 31;66:228-231. Epub 2019 Jul 31.

Erasmus MC, University Medical Center, Rotterdam, the Netherlands, Department of Clinical Genetics. Electronic address:

Objective: Recessive mutations in the Gap Junction Protein Gamma 2 (GJC2) gene cause Pelizaeus-Merzbacher-like disease type 1, a severe infantile-onset hypomyelinating leukodystrophy. Milder, late-onset phenotypes including complicated spastic paraplegia in one family (SPG44), and mild tremor in one case, were reported associated to GJC2 homozygous missense mutations. Here, we report a new family with two siblings carrying a different homozygous GJC2 mutation, presenting with late-onset ataxic and pyramidal disturbances, and parkinsonism in one of them. Read More

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http://dx.doi.org/10.1016/j.parkreldis.2019.07.033DOI Listing
September 2019
2 Reads

Current Status and Use of Resources of Lysosomal Storage Diseases: Analysis of a Spanish Claims Database.

Endocr Metab Immune Disord Drug Targets 2020 ;20(2):263-270

BCN Health Economics & Outcomes Research S.L., Barcelona, Spain.

Background: The knowledge of the pathophysiology of Lysosomal Storage Disorders has gradually increased, but information on their incidence is still scarce. The objective of this study was to evaluate the status and use of resources of these disorders in Spain from 1997 to 2015.

Methods: Records from 4,999 patients diagnosed with a Lysosomal Storage Disorder were extracted from a Spanish database containing data from public and private hospitals from 1997 to 2015. Read More

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http://dx.doi.org/10.2174/1871530319666190807162344DOI Listing
January 2020

Long-Term Safety, Immunologic Response, and Imaging Outcomes following Neural Stem Cell Transplantation for Pelizaeus-Merzbacher Disease.

Stem Cell Reports 2019 08 1;13(2):254-261. Epub 2019 Aug 1.

Department of Neurological Surgery, University of California San Francisco, 550 16(th) Street, 4(th) Floor, San Francisco, CA 94143-0137, USA; Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA; Department of Paediatrics, University of Cambridge, Cambridge CB2 1TN, UK.

Four boys with Pelizaeus-Merzbacher disease, an X-linked leukodystrophy, underwent transplantation with human allogeneic central nervous system stem cells (HuCNS-SC). Subsequently, all subjects were followed for an additional 4 years in this separate follow-up study to evaluate safety, neurologic function, magnetic resonance imaging (MRI) data, and immunologic response. The neurosurgical procedure, immunosuppression, and HuCNS-SC transplantation were well tolerated and all four subjects were alive at the conclusion of the study period. Read More

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http://dx.doi.org/10.1016/j.stemcr.2019.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700500PMC
August 2019
2 Reads

Novel mutations in the GJC2 gene associated with Pelizaeus-Merzbacher-like disease.

Mol Biol Rep 2019 Aug 3;46(4):4507-4516. Epub 2019 Jul 3.

Human Genetics, Faculty of Medicine and Health Sciences, University of Oldenburg, Ammerländer Heerstr. 114-118, 26129, Oldenburg, Germany.

Inherited white matter disorders of the central nervous system frequently are degenerative and progressive clinical entities. They are classified into myelin disorders, including hypomyelination, dysmyelination, demyelination, and myelin vacuolization, but also astrocytopathies, leuko-axonopathies, microgliopathies, and leuko-vasculopathies. Hypomyelinating leukodystrophy is the main feature of Pelizaeus-Merzbacher disease (PMD) and Pelizaeus-Merzbacher-like disease (PMLD1). Read More

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http://dx.doi.org/10.1007/s11033-019-04906-4DOI Listing
August 2019
5 Reads

Allele-specific silencing as treatment for gene duplication disorders: proof-of-principle in autosomal dominant leukodystrophy.

Brain 2019 07;142(7):1905-1920

University of Torino, Department of Medical Sciences, Torino, Italy.

Allele-specific silencing by RNA interference (ASP-siRNA) holds promise as a therapeutic strategy for downregulating a single mutant allele with minimal suppression of the corresponding wild-type allele. This approach has been effectively used to target autosomal dominant mutations and single nucleotide polymorphisms linked with aberrantly expanded trinucleotide repeats. Here, we propose ASP-siRNA as a preferable choice to target duplicated disease genes, avoiding potentially harmful excessive downregulation. Read More

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http://dx.doi.org/10.1093/brain/awz139DOI Listing

Pelizaeus-Merzbacher Disease due to PLP1 Frameshift Mutation in a Female with Nonrandom Skewed X-Chromosome Inactivation.

Neuropediatrics 2019 08 28;50(4):268-270. Epub 2019 May 28.

Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Istituto Giannina Gaslini, Genoa, Italy.

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http://dx.doi.org/10.1055/s-0039-1688954DOI Listing
August 2019
5 Reads

Opening New Horizons in the Treatment of Childhood Onset Leukodystrophies.

Neuropediatrics 2019 08 21;50(4):211-218. Epub 2019 May 21.

Department of Paediatrics and Adolescent Medicine, University Medical Centre Göttingen, Georg August University Göttingen, Germany.

Leukodystrophies (LDs) predominantly affect the white matter of the central nervous system and its main component, the myelin. The majority of LDs manifests in infancy with progressive neurodegeneration. Main clinical signs are intellectual and motor function losses of already attained developmental skills. Read More

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http://dx.doi.org/10.1055/s-0039-1685529DOI Listing
August 2019
2 Reads

Drug screening for Pelizaeus-Merzbacher disease by quantifying the total levels and membrane localization of PLP1.

Mol Genet Metab Rep 2019 Sep 7;20:100474. Epub 2019 May 7.

Department of Pediatrics, Jichi Medical University, Tochigi, Japan.

Background: Pelizaeus-Merzbacher disease (PMD) is caused by point mutations or copy number changes in the proteolipid protein 1 gene (). is exclusively localized in the myelin sheath of oligodendrocytes. Amino acid-substituted PLP1 protein is unable to fold properly and is subsequently degraded and/or restrictedly translated, resulting in a decrease in the PLP1 protein level and a failure to localize to the membrane. Read More

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http://dx.doi.org/10.1016/j.ymgmr.2019.100474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510973PMC
September 2019
15 Reads

Gene suppressing therapy for Pelizaeus-Merzbacher disease using artificial microRNA.

JCI Insight 2019 05 16;4(10). Epub 2019 May 16.

Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.

Copy number increase or decrease of certain dosage-sensitive genes may cause genetic diseases with distinct phenotypes, conceptually termed genomic disorders. The most common cause of Pelizaeus-Merzbacher disease (PMD), an X-linked hypomyelinating leukodystrophy, is genomic duplication encompassing the entire proteolipid protein 1 (PLP1) gene. Although the exact molecular and cellular mechanisms underlying PLP1 duplication, which causes severe hypomyelination in the central nervous system, remain largely elusive, PLP1 overexpression is likely the fundamental cause of this devastating disease. Read More

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http://dx.doi.org/10.1172/jci.insight.125052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542614PMC
May 2019
6 Reads

Rare Case of Female with Pelizaeus Mertzbacher Disease due to deletion of Proteolipid Protein 1: A Case Report.

JNMA J Nepal Med Assoc 2018 Nov-Dec;56(214):967-969

Department of Family Medicine, Theodosia Family Medical Clinic, Theodosia, USA.

Pelizaeus Merzbacher Disease is a rare X-linked central nervous system disease involving the proteolipid protein 1 gene. Patients exhibit signs for instance nystagmus, hypotonia, ataxia. We report a three-year-old female patient with chief compliant of developmental delay. Read More

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September 2019
6 Reads

Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP1.

J Hum Genet 2019 Jul 19;64(7):665-671. Epub 2019 Apr 19.

Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, 162-8666, Japan.

Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive disorder caused by abnormalities in the gene PLP1. Most females harboring heterozygous PLP1 abnormalities are basically asymptomatic. However, as a result of abnormal patterns of X-chromosome inactivation, it is possible for some female carriers to be symptomatic. Read More

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http://dx.doi.org/10.1038/s10038-019-0600-xDOI Listing
July 2019
5 Reads

Pathogenic variants in AIMP1 cause pontocerebellar hypoplasia.

Neurogenetics 2019 05 28;20(2):103-108. Epub 2019 Mar 28.

Departments of Pediatrics, Neurology & Neurosurgery, MUHC-Research Institute, McGill University, 1001 Blvd Décarie, Montreal, H4A 3J1, Canada.

Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1) is a non-catalytic component of the multi-tRNA synthetase complex which catalyzes the ligation of amino acids to the correct tRNAs. Pathogenic variants in several aminoacyl-tRNA synthetases genes have been linked to various neurological disorders, including leukodystrophies and pontocerebellar hypoplasias (PCH). To date, loss-of-function variants in AIMP1 have been associated with hypomyelinating leukodystrophy-3 (MIM 260600). Read More

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http://link.springer.com/10.1007/s10048-019-00572-7
Publisher Site
http://dx.doi.org/10.1007/s10048-019-00572-7DOI Listing
May 2019
22 Reads

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

Acta Neuropathol 2019 07 27;138(1):147-161. Epub 2019 Mar 27.

Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075, Göttingen, Germany.

Pelizaeus-Merzbacher disease (PMD) is an untreatable and fatal leukodystrophy. In a model of PMD with perturbed blood-brain 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. Read More

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http://dx.doi.org/10.1007/s00401-019-01985-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570703PMC
July 2019
12 Reads

Genetic mimics of cerebral palsy.

Mov Disord 2019 05 26;34(5):625-636. Epub 2019 Mar 26.

Department of Neurogenetics, Kolling Institute, Royal North Shore Hospital and University of Sydney, St Leonards, NSW, Australia.

The term "cerebral palsy mimic" is used to describe a number of neurogenetic disorders that may present with motor symptoms in early childhood, resulting in a misdiagnosis of cerebral palsy. Cerebral palsy describes a heterogeneous group of neurodevelopmental disorders characterized by onset in infancy or early childhood of motor symptoms (including hypotonia, spasticity, dystonia, and chorea), often accompanied by developmental delay. The primary etiology of a cerebral palsy syndrome should always be identified if possible. Read More

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http://dx.doi.org/10.1002/mds.27655DOI Listing
May 2019
23 Reads

A novel PLP1 deletion causing classic Pelizaeus-Merzbacher disease.

J Neurol Sci 2019 Feb 23;397:135-137. Epub 2018 Dec 23.

INGEMM/IdIPAZ/CIBERER, Hospital Universitario La Paz, Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2018.12.031DOI Listing
February 2019
5 Reads

PLP1 Mutations in Patients with Multiple Sclerosis: Identification of a New Mutation and Potential Pathogenicity of the Mutations.

J Clin Med 2018 Oct 11;7(10). Epub 2018 Oct 11.

UQ Centre for Clinical Research, the University of Queensland, Brisbane, QLD 4029, Australia.

is located on the X-chromosome and encodes myelin proteolipid protein (PLP), the most abundant protein in central nervous system myelin. Generally, point mutations in result in X-linked dysmyelinating disorders, such as Pelizaeus-Merzbacher disease (PMD) or spastic paraplegia type 2 (SPG2). However, several case studies have identified patients with missense point mutations in and clinical symptoms and signs compatible with a diagnosis of multiple sclerosis (MS). Read More

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http://dx.doi.org/10.3390/jcm7100342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6210135PMC
October 2018
34 Reads

Brain Diffusion Imaging and Tractography to Distinguish Clinical Severity of Human PLP1-Related Disorders.

Dev Neurosci 2018 27;40(4):301-311. Epub 2018 Sep 27.

Service de Neurologie Pédiatrique et Maladies Métaboliques, Centre de référence des leucodystrophies et leucoencéphalopathies de cause rare, CHU-APHP Robert-Debré, Paris, France.

Aims: We performed quantitative diffusion tensor imaging and brain tractography to distinguish clinical severity in a series of 35 patients with hypomyelinating PLP1-related disorders classified using the Motor Developmental Score according to the best motor function acquired before the age of 5 years and the gross motor function measure (GMFM) at the time of magnetic resonance imaging acquisition.

Methods: We calculated fractional anisotropy and diffusivity values in 26 regions of interest and the numbers of fibers and volumes of hemisphere tractograms. Fiber bundles on tractograms were characterized according to 3 criteria: size, direction of main-stream fibers, and connectivity of bundles (extratelencephalic projections, commissural fibers, and intrahemispheric connections). Read More

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http://dx.doi.org/10.1159/000492218DOI Listing
March 2019
14 Reads
2.700 Impact Factor

Morpholino Antisense Oligomers as a Potential Therapeutic Option for the Correction of Alternative Splicing in PMD, SPG2, and HEMS.

Mol Ther Nucleic Acids 2018 Sep 5;12:420-432. Epub 2018 Jul 5.

Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA; Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA; Department of Pediatrics, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address:

DNA variants of the proteolipid protein 1 gene (PLP1) that shift PLP1/DM20 alternative splicing away from the PLP1 form toward DM20 cause the allelic X-linked leukodystrophies Pelizaeus-Merzbacher disease (PMD), spastic paraplegia 2 (SPG2), and hypomyelination of early myelinating structures (HEMS). We designed a morpholino oligomer (MO-PLP) to block use of the DM20 5' splice donor site, thereby shifting alternative splicing toward the PLP1 5' splice site. Treatment of an immature oligodendrocyte cell line with MO-PLP significantly shifted alternative splicing toward PLP1 expression from the endogenous gene and from transfected human minigene splicing constructs harboring patient variants known to reduce the amount of the PLP1 spliced product. Read More

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http://dx.doi.org/10.1016/j.omtn.2018.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036941PMC
September 2018
4 Reads

Glucose metabolism in the brain in LMNB1-related autosomal dominant leukodystrophy.

Acta Neurol Scand 2019 Feb 25;139(2):135-142. Epub 2018 Sep 25.

Radiology, Uppsala University, Uppsala, Sweden.

Objective: LMNB1-related autosomal dominant leukodystrophy is caused by an overexpression of the protein lamin B1, usually due to a duplication of the LMNB1 gene. Symptoms start in 5 to 6 decade. This slowly progressive disease terminates with death. Read More

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http://doi.wiley.com/10.1111/ane.13024
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http://dx.doi.org/10.1111/ane.13024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585974PMC
February 2019
9 Reads

Chemical Screening Identifies Enhancers of Mutant Oligodendrocyte Survival and Unmasks a Distinct Pathological Phase in Pelizaeus-Merzbacher Disease.

Stem Cell Reports 2018 09 23;11(3):711-726. Epub 2018 Aug 23.

Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Electronic address:

Pelizaeus-Merzbacher disease (PMD) is a fatal X-linked disorder caused by loss of myelinating oligodendrocytes and consequent hypomyelination. The underlying cellular and molecular dysfunctions are not fully defined, but therapeutic enhancement of oligodendrocyte survival could restore functional myelination in patients. Here we generated pure, scalable quantities of induced pluripotent stem cell-derived oligodendrocyte progenitor cells (OPCs) from a severe mouse model of PMD, Plp1. Read More

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http://dx.doi.org/10.1016/j.stemcr.2018.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135742PMC
September 2018
19 Reads

Clinical and mutational spectrum of Colombian patients with Pelizaeus Merzbacher Disease.

Colomb Med (Cali) 2018 Jun 30;49(2):182-187. Epub 2018 Jun 30.

Genetica Medica, Facultad de Medicina, Pontificia Universidad Javeriana. Bogotá, Colombia.

Case Presentation: Pelizaeus Merzbacher Disease (PMD) is an X-linked developmental defect of myelination that causes childhood chronic spastic encephalopathy. Its genetic etiology can be either a duplication (or other gene dosage alterations) or a punctual mutation at the locus. Clinically, it presents with developmental delay, nystagmus and, spasticity, supported by neuroimaging in which the defect of myelination is evident. Read More

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http://colombiamedica.univalle.edu.co/index.php/comedica/art
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http://dx.doi.org/10.25100/cm.v49i2.2522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084915PMC
June 2018
15 Reads

Novel Mutations Identified With Next-Generation Sequencing Expand the Spectrum of PLP1-Associated Leukodystrophy Clinical Phenotypes.

Child Neurol Open 2018 23;5:2329048X18789282. Epub 2018 Jul 23.

Pediatric Motor Disorders Research Program, Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA.

Next-generation sequencing was performed for 2 families with an undiagnosed neurologic disease. Analysis revealed X-linked mutations in the () gene, which is associated with X-linked Pelizaeus-Merzbacher disease and Spastic Paraplegia type 2. In family A, the novel missense mutation c. Read More

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http://dx.doi.org/10.1177/2329048X18789282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056774PMC
July 2018
24 Reads

Protective effect of 4-Phenylbutyrate against proteolipid protein mutation-induced endoplasmic reticulum stress and oligodendroglial cell death.

Neurochem Int 2018 09 22;118:185-194. Epub 2018 Jun 22.

Biopathologie de la Myéline, Neuroprotection et Stratégies Thérapeutiques, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, France. Electronic address:

Proteolipid protein (PLP) mutation causes oligodendrocyte degeneration and myelin disorders including Pelizaeus-Merzbacher Disease (PMD). As the pathophysiological mechanisms involved in PMD are poorly known, the development of therapies remains difficult. To elucidate the pathogenic pathways, an immortalized oligodendroglial cell line (158JP) expressing PLP mutation has been generated. Read More

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http://dx.doi.org/10.1016/j.neuint.2018.06.008DOI Listing
September 2018
11 Reads