scholarly journals Rare Case of Female with Pelizaeus Mertzbacher Disease Due to Deletion of Proteolipid Protein 1

2018 ◽  
Vol 56 (214) ◽  
pp. 967-969
Author(s):  
Masanosuke Kinoshita ◽  
William Roston
Keyword(s):  
Central Nervous System ◽  
Developmental Delay ◽  
Rare Case ◽  
Proteolipid Protein ◽  
Chromosomal Microarray ◽  
Radiological Imaging ◽  
Clinical Disorder ◽  
Cytogenetic Band ◽  
Plp1 Gene ◽  
Pelizaeus Merzbacher Disease

Pelizaeus Merzbacher Disease (PMD) is a rare X-linked central nervous system (CNS) disease involving the proteolipid protein 1 (PLP1) gene. Patients exhibit signs for instance nystagmus, hypotonia, ataxia. We report a three year old female patient with chief compliant of developmental delay. On physical examination, patient was alert but had poor eye contact while sitting in a stroller. Since no chromosomal evaluation was performed, a chromosomal microarray testing was performed. Review of geneticist report indicated that patient carries a deletion of at least 2.26 Mb within cytogenetic band Xq22.1 to Xq22.2 which is known to contain 39 genes. Out of the 39 genes, PLP1 is associated with known clinical disorder; PMD. Our case highlights the second only known female with PMD due to deletions of PLP1 gene. For a patient with developmental delay, the importance of performing genetic testing and/or radiological imaging early on is strongly recommended.

scholarly journals EIF2AK2-related Neurodevelopmental Disorder With Leukoencephalopathy, Developmental Delay, and Episodic Neurologic Regression Mimics Pelizaeus-Merzbacher Disease

2020 ◽  
Vol 7 (1) ◽  
pp. e539
Author(s):  
Daniel G. Calame ◽  
Meagan Hainlen ◽  
Danielle Takacs ◽  
Leah Ferrante ◽  
Kayla Pence ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Copy Number Variants ◽  
Retrospective Chart Review ◽  
Missense Variant ◽  
Chromosomal Microarray ◽  
Single Nucleotide Variants ◽  
Pelizaeus Merzbacher Disease ◽  
Delayed Myelination

ObjectiveTo demonstrate that de novo missense single nucleotide variants (SNVs) in EIF2AK2 cause a neurodevelopmental disorder with leukoencephalopathy resembling Pelizaeus-Merzbacher disease (PMD).MethodsA retrospective chart review was performed of 2 unrelated males evaluated at a single institution with de novo EIF2AK2 SNVs identified by clinical exome sequencing (ES). Clinical and radiographic data were reviewed and summarized.ResultsBoth individuals presented in the first year of life with concern for seizures and developmental delay. Common clinical findings included horizontal and/or pendular nystagmus during infancy, axial hypotonia, appendicular hypertonia, spasticity, and episodic neurologic regression with febrile viral illnesses. MRI of the brain demonstrated severely delayed myelination in infancy. A hypomyelinating pattern was confirmed on serial imaging at age 4 years for proband 1. In proband 2, repeat imaging at age 13 months confirmed persistent delayed myelination. These clinical and radiographic features led to a strong suspicion of PMD. However, neither PLP1 copy number variants nor pathogenic SNVs were detected by chromosomal microarray and trio ES, respectively. Reanalysis of trio ES identified heterozygous de novo EIF2AK2 missense variant c.290C>T (p.Ser97Phe) in proband 1 and c.326C>T (p.Ala109Val) in proband 2.ConclusionsThe autosomal dominant EIF2AK2-related leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome should be considered in the differential diagnosis for PMD and other hypomyelinating leukodystrophies (HLDs). A characteristic history of developmental regression with febrile illnesses may help distinguish it from other HLDs.

Biology of Oligodendrocyte and Myelin in the Mammalian Central Nervous System

2001 ◽  
Vol 81 (2) ◽  
pp. 871-927 ◽  
Author(s):  
Nicole Baumann ◽  
Danielle Pham-Dinh
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Proteolipid Protein ◽  
Demyelinating Diseases ◽  
Neural Cells ◽  
The Central Nervous System ◽  
Experimental Demyelination ◽  
Pelizaeus Merzbacher Disease ◽  
Spontaneous Mutants ◽  
Extracellular Environment

Oligodendrocytes, the myelin-forming cells of the central nervous system (CNS), and astrocytes constitute macroglia. This review deals with the recent progress related to the origin and differentiation of the oligodendrocytes, their relationships to other neural cells, and functional neuroglial interactions under physiological conditions and in demyelinating diseases. One of the problems in studies of the CNS is to find components, i.e., markers, for the identification of the different cells, in intact tissues or cultures. In recent years, specific biochemical, immunological, and molecular markers have been identified. Many components specific to differentiating oligodendrocytes and to myelin are now available to aid their study. Transgenic mice and spontaneous mutants have led to a better understanding of the targets of specific dys- or demyelinating diseases. The best examples are the studies concerning the effects of the mutations affecting the most abundant protein in the central nervous myelin, the proteolipid protein, which lead to dysmyelinating diseases in animals and human (jimpy mutation and Pelizaeus-Merzbacher disease or spastic paraplegia, respectively). Oligodendrocytes, as astrocytes, are able to respond to changes in the cellular and extracellular environment, possibly in relation to a glial network. There is also a remarkable plasticity of the oligodendrocyte lineage, even in the adult with a certain potentiality for myelin repair after experimental demyelination or human diseases.

scholarly journals Effects of Intron 1 Sequences on Human PLP1 Expression: Implications for PLP1-Related Disorders

ASN NEURO ◽  
2017 ◽  
Vol 9 (4) ◽  
pp. 175909141772058 ◽  
Author(s):  
Patricia A. Wight
Keyword(s):  
Potential Role ◽  
Splice Variants ◽  
Proteolipid Protein ◽  
Spastic Paraplegia ◽  
Intron 1 ◽  
Plp1 Gene ◽  
Pelizaeus Merzbacher Disease ◽  
Myelin Proteolipid ◽  
Human Specific

Alterations in the myelin proteolipid protein gene ( PLP1) may result in rare X-linked disorders in humans such as Pelizaeus–Merzbacher disease and spastic paraplegia type 2. PLP1 expression must be tightly regulated since null mutations, as well as elevated PLP1 copy number, both lead to disease. Previous studies with Plp1-lacZ transgenic mice have demonstrated that mouse Plp1 ( mPlp1) intron 1 DNA (which accounts for slightly more than half of the gene) is required for the mPlp1 promoter to drive significant levels of reporter gene expression in brain. However not much is known about the mechanisms that control expression of the human PLP1 gene ( hPLP1). Therefore this review will focus on sequences in hPLP1 intron 1 DNA deemed important for hPLP1 gene activity as well as a couple of “human-specific” supplementary exons within the first intron which are utilized to generate novel splice variants, and the potential role that these sequences may play in PLP1-linked disorders.

scholarly journals Pelizaeus Merzbacher Disease in a Female due to Proteolipid Protein 1 duplication: A Case Report

2021 ◽  
Vol 8 (1) ◽  
pp. 01-03
Author(s):  
Sulaiman Almobarak
Keyword(s):  
Motor Development ◽  
De Novo ◽  
Phenotypic Expression ◽  
Copy Number Variant ◽  
Proteolipid Protein ◽  
Central Nervous System Disease ◽  
De Novo Mutation ◽  
Chromosomal Microarray ◽  
System Disease ◽  
Pelizaeus Merzbacher Disease

Pelizaeus–Merzbacher disease (PMD) is a rare X-linked central nervous system disease involving the proteolipid protein 1 (PLP1) gene on Xq22.1. PMD patients’ commonly exhibit signs including nystagmus, hypotonia, and developmental delay. We report a female case of mild spectrum phenotypic expression of PMD attributable to a de novo Copy Number Variant (CNV) change. A two and half-year-old girl presented to our clinic with hypotonicity. She had apneic spells at birth, and was diagnosed to have nystagmus when she was 3 months old. In addition, she presented with delayed motor development including poor head control and inability to sit independently at 6 months of age, eventually standing with support at 20 months, and a prominent wide-based gait at 24 months. MRI head revealed diffuse, markedly delayed myelination, with a reduction in white matter volume. A chromosomal microarray testing indicated that patient carries an Xq22.1 q23 duplication of uncertain significance, of which the PLP1 is fully duplicated. Parental studies were normal. X-inactivation study was normal. Therefore, our case represents a phenotypic expression of PMD due to de novo mutation, a rare occurrence in a female.

scholarly journals Multiplex Ligation-Dependent Probe Amplification for Rapid Detection of Proteolipid Protein 1 Gene Duplications and Deletions in Affected Males and Carrier Females with Pelizaeus–Merzbacher Disease

2006 ◽  
Vol 52 (7) ◽  
pp. 1267-1275 ◽  
Author(s):  
Ilka Warshawsky ◽  
Olga B Chernova ◽  
Christian A Hübner ◽  
Reinhard Stindl ◽  
Marco Henneke ◽  
...  
Keyword(s):  
Quantitative Pcr ◽  
Neurodegenerative Disorder ◽  
Gene Dosage ◽  
Proteolipid Protein ◽  
Gene Duplications ◽  
Gene Deletions ◽  
Gene Copies ◽  
Plp1 Gene ◽  
Pelizaeus Merzbacher Disease ◽  
Dependent Probe

Abstract Background: Pelizaeus–Merzbacher disease is a rare X-linked neurodegenerative disorder caused by sequence variations in the proteolipid protein 1 gene (PLP1). PLP1 gene duplications account for ∼50%–75% of cases and point variations for ∼15%–20% of cases; deletions and insertions occur infrequently. We used multiplex ligation-dependent probe amplification (MLPA) to detect PLP1 gene alterations, especially gene duplications and deletions. Methods: We performed MLPA on 102 samples from individuals with diverse PLP1 gene abnormalities and from controls, including 50 samples previously characterized for the PLP1 gene by quantitative PCR but which were anonymized for prior results and sex. Results: All males with PLP1 gene duplications (n = 13), 1 male with a triplication, 2 males with whole gene deletions, and all controls (n = 72) were unambiguously assigned to their correct genotype. Of 4 female carriers tested by MLPA and quantitative PCR, 3 were duplication carriers by both methods, and 1 was a triplication carrier by MLPA and a duplication carrier by quantitative PCR. For 1 sample with a partial deletion, MLPA showed exon 3 deleted but PCR showed exons 3 and 4 deleted. Sequence analysis of 2 samples with reduced dosage for exons 3 and 5 revealed point variations overlapping the annealing site for the corresponding MLPA probe. The precision of MLPA analysis was excellent and comparable to or better than quantitative PCR, with CVs of 4.3%–9.8%. Conclusions: MLPA is a rapid and reliable method to determine PLP1 gene copies. Samples with partial PLP1 gene dosage alterations require confirmation with a non-MLPA method.

scholarly journals Murine Esophagus Expresses Glial-Derived Central Nervous System Antigens

2021 ◽  
Vol 22 (6) ◽  
pp. 3233
Author(s):  
Christopher Kapitza ◽  
Rittika Chunder ◽  
Anja Scheller ◽  
Katherine S. Given ◽  
Wendy B. Macklin ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Schwann Cells ◽  
Glial Cells ◽  
Proteolipid Protein ◽  
Pcr Analysis ◽  
Specific Expression ◽  
Enteric Glial Cells ◽  
Cell Type Specific Expression ◽  
Long Time

Multiple sclerosis (MS) has been considered to specifically affect the central nervous system (CNS) for a long time. As autonomic dysfunction including dysphagia can occur as accompanying phenomena in patients, the enteric nervous system has been attracting increasing attention over the past years. The aim of this study was to identify glial and myelin markers as potential target structures for autoimmune processes in the esophagus. RT-PCR analysis revealed glial fibrillary acidic protein (GFAP), proteolipid protein (PLP), and myelin basic protein (MBP) expression, but an absence of myelin oligodendrocyte glycoprotein (MOG) in the murine esophagus. Selected immunohistochemistry for GFAP, PLP, and MBP including transgenic mice with cell-type specific expression of PLP and GFAP supported these results by detection of (1) GFAP, PLP, and MBP in Schwann cells in skeletal muscle and esophagus; (2) GFAP, PLP, but no MBP in perisynaptic Schwann cells of skeletal and esophageal motor endplates; (3) GFAP and PLP, but no MBP in glial cells surrounding esophageal myenteric neurons; and (4) PLP, but no GFAP and MBP in enteric glial cells forming a network in the esophagus. Our results pave the way for further investigations regarding the involvement of esophageal glial cells in the pathogenesis of dysphagia in MS.

scholarly journals Clinical utility of comprehensive genomic profiling in central nervous system tumors of children and young adults

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Jianling Ji ◽  
Kristiyana Kaneva ◽  
Matthew C Hiemenz ◽  
Girish Dhall ◽  
Tom Belle Davidson ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Clinical Utility ◽  
Adolescent And Young Adult ◽  
Cns Tumors ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Genomic Profiling ◽  
Comprehensive Genomic Profiling ◽  
Clinically Significant

Abstract Background Recent large-scale genomic studies have revealed a spectrum of genetic variants associated with specific subtypes of central nervous system (CNS) tumors. The aim of this study was to determine the clinical utility of comprehensive genomic profiling of pediatric, adolescent and young adult (AYA) CNS tumors in a prospective setting, including detection of DNA sequence variants, gene fusions, copy number alterations (CNAs), and loss of heterozygosity. Methods OncoKids, a comprehensive DNA- and RNA-based next-generation sequencing (NGS) panel, in conjunction with chromosomal microarray analysis (CMA) was employed to detect diagnostic, prognostic, and therapeutic markers. NGS was performed on 222 specimens from 212 patients. Clinical CMA data were analyzed in parallel for 66% (146/222) of cases. Results NGS demonstrated clinically significant alterations in 66% (147/222) of cases. Diagnostic markers were identified in 62% (138/222) of cases. Prognostic information and targetable genomic alterations were identified in 22% (49/222) and 18% (41/222) of cases, respectively. Diagnostic or prognostic CNAs were revealed by CMA in 69% (101/146) of cases. Importantly, clinically significant CNAs were detected in 57% (34/60) of cases with noncontributory NGS results. Germline cancer predisposition testing was indicated for 27% (57/212) of patients. Follow-up germline testing was performed for 20 patients which confirmed a germline pathogenic/likely pathogenic variant in 9 cases: TP53 (2), NF1 (2), SMARCB1 (1), NF2 (1), MSH6 (1), PMS2 (1), and a patient with 47,XXY Klinefelter syndrome. Conclusions Our results demonstrate the significant clinical utility of integrating genomic profiling into routine clinical testing for pediatric and AYA patients with CNS tumors.

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