2,695 research outputs found
Clinical neurophysiology in GJA12-related hypomyelination vs Pelizaeus-Merzbacher disease
No full textBackground: Among the hypomyelinating leukoencephalopathies with onset in childhood, Pelizaeus-Merzbacher disease (PMD) and Pelizaeus-Merzbacher-like disease (PMLD) constitute a large subgroup with almost indistinguishable clinical and neuroradiologic features. Whereas PMD is due to X-linked PLP1 mutations, PMLD is genetically heterogeneous, with about 8% of patients carrying autosomal recessive GJA12/GJC2 mutations. The aim of this study was to evaluate whether neurophysiologic testing may separate PMD from GJA12/GJC2-associated PMLD. Methods: Retrospective data collection study with reevaluation of evoked potentials (EP) and nerve conduction studies (NCS) in 10 patients from 7 families with PMLD due to various GJA12/GJC2 mutations and 8 boys from 7 families with classic PMD caused by a PLP1 duplication or missense mutation. Results: In brainstem auditory EP, waves III-V were absent in all patients with PMD, but clearly recordable in 11 of 13 investigations in 8 patients with PMLD. Visual evoked potentials and somatosensory evoked potentials revealed conduction delay in both PMD and PMLD, without significant difference. NCS were normal in all patients with PMD and indicated mild peripheral neuropathy in only 2 of 10 patients with PMLD. Conclusion: In a patient with clinical and neuroradiologic features of Pelizaeus-Merzbacher disease/Pelizaeus-Merzbacher-like disease and a pedigree consistent with both conditions, brainstem auditory evoked potentials provide good selectivity between these disorders and point in the right direction for identifying the primary genetic defect. Neurology(R) 2010;74:1785-178
High frequency of GJA12/GJC2 mutations in Turkish patients with Pelizaeus-Merzbacher disease
No full textBilir B, Yapici Z, Yalcinkaya C, Baris I, Carvalho CMB, Bartnik M, Ozes B, Eraksoy M, Lupski JR, Battaloglu E. High frequency of GJA12/GJC2 mutations in Turkish patients with Pelizaeus-Merzbacher disease. Clin Genet 2013: 83: 66-72. (C) John Wiley & Sons A/S. Published by Blackwell Publishing Ltd, 2012 Pelizaeus-Merzbacher disease is an early onset dysmyelinating leukodystrophy. About 80% of PMD cases have been associated with duplications and mutations of the proteolipid protein 1 (PLP1) gene. Pelizaeus-Merzbacher-like disease is a genetically heterogeneous autosomal recessive disease and rarely caused by mutations in gap junction protein alpha 12 (GJA12/GJC2) gene. The molecular basis of the disease was investigated in a cohort of 19 Turkish families. This study identified novel chromosomal rearrangements proximal and distal to, and exclusive of the PLP1 gene, showed equal frequencies of PLP1 and GJA12/GJC2 mutations at least in our cohort, and suggested further genetic heterogeneity
Pelizaeus-Merzbacher-Like disease presentation of MCT8 mutated male subjects.
No full textPelizaeus-Merzbacher Disease is an X-linked hypomyelinatiing leukodystrophy. We
report mutations in the thyroid hormone transporter gene MCT8 in 11% of 53
families affected by hypomyelinating leukodystrophies of unknown aetiology. The
12 MCT8 mutated patients express initially a Pelizaeus-Merzbacher-Like disease
phenotype with a latter unusual improvement of magnetic resonance imaging white
matter signal despite absence of clinical progression. This observation
underlines the interest of determining both free T3 and free T4 serum
concentrations to screen for MCT8 mutations in young patients (<3 y) with a
severe Pelizaeus-Merzbacher-Like disease presentation or older severe mentally
retarded male patients with "hypomyelinated" regions
A novel deletion in the GJA12 gene causes Pelizaeus-Merzbacher-like disease
No full textPelizaeus-Merzbacher disease (PMD) and Pelizaeus-Merzbacher-like disease (PMLD) are hypomyelinating disorders of the central nervous system with a very similar phenotype. PMD is an X-linked disorder caused by mutations in PLP1. PMLD is an autosomal recessive condition caused by mutations in GJA12. We report a 5-year-old girl with a complex neurological syndrome and severe hypomyelination on brain magnetic resonance imaging. She harbored a homozygous 34-bp deletion in the coding region of GJA12. There are no distinctive features for the differential diagnosis of PMD/PMLD. GJA12 should be analyzed in all patients without PLP1 mutations but should also be considered the initial genetic test in women and in patients with consanguineous parents
Altered high-energy phosphate and membrane metabolism in Pelizaeus–Merzbacher disease using phosphorus magnetic resonance spectroscopy
No full textPelizaeus–Merzbacher disease is an X-linked recessive leucodystrophy of the central nervous system caused by mutations affecting the major myelin protein, proteolipid protein 1. The extent of the altered in vivo neurochemistry of protein, proteolipid protein 1 duplications, the most common form of Pelizaeus–Merzbacher disease, is, however, poorly understood. Phosphorus magnetic resonance spectroscopy is the only in vivo technique that can assess the biochemistry associated with high-energy phosphate and membrane phospholipid metabolism across different cortical, subcortical and white matter areas. In this cross-sectional study, whole-brain, multi-voxel phosphorus magnetic resonance spectroscopy was acquired at 3 T on 14 patients with Pelizaeus–Merzbacher disease with protein, proteolipid protein 1 duplications and 23 healthy controls (all males). Anabolic and catabolic levels of membrane phospholipids (phosphocholine and phosphoethanolamine, and glycerophosphoethanolamine and glycerophosphocholine, respectively), as well as phosphocreatine, inorganic orthophosphate and adenosine triphosphate levels relative to the total phosphorus magnetic resonance spectroscopy signal from 12 different cortical and subcortical areas were compared between the two groups. Independent of brain area, phosphocholine, glycerophosphoethanolamine and inorganic orthophosphate levels were significantly lower (P = 0.0025, P < 0.0001 and P = 0.0002) and phosphocreatine levels were significantly higher (P < 0.0001) in Pelizaeus–Merzbacher disease patients compared with controls. Additionally, there was a significant group-by-brain area interaction for phosphocreatine with post-hoc analyses demonstrating significantly higher phosphocreatine levels in patients with Pelizaeus–Merzbacher disease compared with controls across multiple brain areas (anterior and posterior white matter, superior parietal lobe, posterior cingulate cortex, hippocampus, occipital cortex, striatum and thalamus; all P ≤ 0.0042). Phosphoethanolamine, glycerophosphoethanolamine and adenosine triphosphate levels were not significantly different between groups. For the first-time, widespread alterations in phosphorus magnetic resonance spectroscopy metabolite levels of Pelizaeus–Merzbacher disease patients are being reported. Specifically, increased high-energy phosphate storage levels of phosphocreatine concomitant with decreased inorganic orthophosphate across multiple areas suggest a widespread reduction in the high-energy phosphate utilization in Pelizaeus–Merzbacher disease, and the membrane phospholipid metabolite deficits suggest a widespread degradation in the neuropil content/maintenance of patients with Pelizaeus–Merzbacher disease which includes axons, dendrites and astrocytes within cortex and the myelin microstructure and oligodendrocytes within white matter. These results provide greater insight into the neuropathology of Pelizaeus–Merzbacher disease both in terms of energy expenditure and membrane phospholipid metabolites. Future longitudinal studies are warranted to investigate the utility of phosphorus magnetic resonance spectroscopy as surrogate biomarkers in monitoring treatment intervention for Pelizaeus–Merzbacher disease
GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease.
No full textObjective: Pelizaeus-Merzbacher-like disease is a rare hypomyelinating leukodystrophy caused by autosomal recessive mutations in GJC2, encoding a gap junction protein essential for production of a mature myelin sheath. A previously identified GJC2 mutation (c.-167G > A) in the promoter region is hypothesized to disrupt a putative SOX10 binding site; however, the lack of additional mutations in this region and contradictory functional data have limited the interpretation of this variantMethods: We describe two independent Pelizaeus-Merzbacher-like disease families with a novel promoter region mutation and updated in vitro functional assays.Results: A novel GJC2 mutation (c.-170G > A) in the promoter region was identified in Pelizaeus-Merzbacher-like disease patients. In vitro functional assays using human GJC2 promoter constructs demonstrated that this mutation and the previously described c.-167G > A mutation similarly diminished the transcriptional activity driven by SOX10 and the binding affinity for SOX10.Interpretation: These findings support the role of GJC2 promoter mutations in Pelizaeus-Merzbacher-like disease. GJC2 promoter region mutation screening should be included in the evaluation of patients with unexplained hypomyelinating leukodystrophies. (C) 2013 Published by Elsevier Inc
Mutation analysis of the M6b gene in patients with Pelizaeus-Merzbacher-like syndrome
No full text"Pelizaeus-Merzbacher-like syndrome" is an undetermined leukodystrophy disorder of diffuse hypomyelination. The patients' clinical phenotype is indistinguishable from classical Pelizaeus-Merzbacher disease (PMD), but the patients lack PLP1 gene duplications or mutations. They represent about 20% of all cases with a clinical PMD phenotype. The M6b gene has been localized to Xp22.2. The encoded M6B protein is a member of a novel proteolipid family that also includes other major brain myelin components like the proteolipid protein (PLP). Recent cotransfection experiments suggest a protein-protein interaction of M6B and mutant PLP1 that may contribute to oligodendrocyte dysfunction in PMD. Therefore, M6b has been considered a good candidate gene for Pelizaeus-Merzbacher-like syndrome. However, our molecular analyses in eight thoroughly characterized patients make it unlikely that mutations in this gene are involved in this subgroup of human hypomyelination disorders
Neurogenetics of Pelizaeus-Merzbacher disease
No full textPelizaeus-Merzbacher disease (PMD) is an X-linked disorder caused by mutations in the PLP1 gene, which encodes the proteolipid protein of myelinating oligodendroglia. PMD exhibits phenotypic variability that reflects its considerable genotypic heterogeneity, but all forms of the disease result in central hypomyelination associated with early neurologic dysfunction, progressive deterioration, and ultimately death. PMD has been classified into three major subtypes, according to the age of presentation: connatal PMD, classic PMD, and transitional PMD, combining features of both connatal and classic forms. Two other less severe phenotypes were subsequently described, including the spastic paraplegia syndrome and PLP1-null disease. These disorders may be associated with duplications, as well as with point, missense, and null mutations within the PLP1 gene. A number of clinically similar Pelizaeus-Merzbacher-like disorders (PMLD) are considered in the differential diagnosis of PMD, the most prominent of which is PMLD-1, caused by misexpression of the GJC2 gene encoding connexin-47. No effective therapy for PMD exists. Yet, as a relatively pure central nervous system hypomyelinating disorder, with limited involvement of the peripheral nervous system and little attendant neuronal pathology, PMD is an attractive therapeutic target for neural stem cell and glial progenitor cell transplantation, efforts at which are now underway in a number of centers internationally.</p
Myelin-associated glycoprotein gene mutation causes Pelizaeus-Merzbacher disease-like disorder
No full textPelizaeus-Merzbacher disease is an X-linked hypomyelinating leukodystrophy. Lossos et al. describe a family with an early-onset Pelizaeus-Merzbacher disease-like phenotype that slowly evolves into complicated hereditary spastic paraplegia, affecting both the CNS and PNS. Exome sequencing reveals a causative homozygous missense mutation in MAG, which encodes myelin associated glycoprotei
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