Pelizaeus-Merzbacher disease (PMD) is a rare dysmyelination disorder, characterized by significant developmental delay, truncal hypotonia, spasticity, dysarthria, and nystagmus. Conventional magnetic resonance (MR) images demonstrate discordance of myelin maturation, while newer MR techniques, such as MR spectroscopy and diffusion tensor imaging, may be helpful in disease assessment. We report on a family of two young boys and their mother who share the same unusual 4-bp deletion of the PLP1 gene: c51_54 del TTCC, causing truncation of the PLP1 in exon 2. The brain MRI appearances in this unique deletion, using newer MR imaging, are described.
"The clinical features of PMD are variable and include nystagmus, psychomotor delay, seizure, stridor, feeding difficulties, ataxia, and hypotonia progressing to spasticity. Moreover, the degree of dysmyelination is correlated with the severity of the clinical manifestations4,9,11). "
[Show abstract][Hide abstract] ABSTRACT: Pelizaeus-Merzbacher disease (PMD) is a rare, X-linked recessive disorder characterized by dysmyelination in the central nervous system. PMD results from deletion, mutation, or duplication of the proteolipid protein gene (PLP1) located at Xq22, leading to the failure of axon myelination by oligodendrocytes in the central nervous system. PMD may be suspected when there are clinical manifestations such as nystagmus, developmental delays, and spasticity, and genetic analysis can confirm the diagnosis. Further diagnostic manifestations of the disease include a lack of myelination on brain magnetic resonance (MR) imaging and aberrant N-acetyl aspartate (NAA) and choline concentrations that reflect axonal and myelination abnormalities on phroton MR spectroscopy. We report 5 cases of PMD (in 1 girl and 4 boys). PLP1 duplication was detected in 2 patients. Brain MR analyses and MR spectroscopy were performed for all the patients. The brain MR images showed white matter abnormalities typical of PMD, and the MR spectroscopic images showed diverse patterns of NAA, creatinine, and choline concentrations. We propose that MR spectroscopic analysis of metabolic alterations can aid the PMD diagnosis and can contribute to a better understanding of the pathogenesis of the disease.
Korean Journal of Pediatrics 10/2012; 55(10):397-402. DOI:10.3345/kjp.2012.55.10.397
"Both the Po and Dr measures showed the largest relative group differences (Table 2). The increased radial diffusivity, Dr, measurements in the sh pups are consistent with studies in dysmyelination models like the shiverer mouse and the jimpy mouse (Song et al., 2002; Tyszka et al., 2006; Harsan et al., 2006, 2007), the myelin deficient (md) rat brain and spinal cord (Biton et al., 2007; Bar-Shir et al., 2009), and with abnormal diffusion anisotropy reported in humans with PMD (Ono et al., 1994 & 1997; Sener 2004; Miller et al., 2010). It is believed that Dr is a fairly specific biomarker of myelin (Song et al., 2002) although its validity in regions of complex crossing WM has been questioned (Wheeler-Kingshot and Cercignani, 2009). "
[Show abstract][Hide abstract] ABSTRACT: Recent studies in rodents have demonstrated that diffusion imaging is highly sensitive to differences in myelination. These studies suggest that demyelination/dysmyelination cause increases in the radial diffusivity from diffusion tensor imaging (DTI) measurements and decreases in the restricted diffusion component from high b-value diffusion-weighted imaging experiments. In this study, the shaking pup (sh pup), a canine model of dysmyelination, was studied on a clinical MRI scanner using a combination of conventional diffusion tensor imaging and high b-value diffusion-weighted imaging methods. Diffusion measurements were compared between control dogs and sh pups in the age range 3 months to 16 months, which is similar to the period of early childhood through adolescence in humans. The study revealed significant group differences in nearly all diffusion measures with the largest differences in the zero-displacement probability (Po) from high b-value DWI and the radial diffusivity from DTI, which are consistent with the observations from the published rodent studies. Age-related changes in Po, FA, mean diffusivity, radial diffusivity and axial diffusivity were observed in whole brain white matter for the control dogs, but not the sh pups. Regionally, age-related changes in the sh pup white matter were observed for Po, mean diffusivity and radial diffusivity in the internal capsule, which may be indicative of mild myelination. These studies demonstrate that DWI may be used to study myelin abnormalities and brain development in large animal models on clinical MRI scanners, which are more amenable to translation to human studies.
[Show abstract][Hide abstract] ABSTRACT: Diffusion tensor imaging (DTI) is a powerful technique for the noninvasive assessment of the central nervous system. To facilitate the application of this technique to in vivo studies, we characterised a mouse model of the leukodystrophy, Pelizaeus-Merzbacher disease (PMD), comparing high-resolution ex vivo DTI findings with quantitative histological analysis of selected areas of the brain. The mice used in this study (Plp1-transgenic) carry transgenic copies of the Plp1 gene and are models for PMD as a result of gene duplication. Plp1 transgenic mice display a mild ataxia and experience frequent seizures around the time at which they were imaged. Axial (λ(1) ) and radial (RD) diffusivities and fractional anisotropy (FA) data were analysed using an exploratory whole-brain voxel-based method, a voxel-based approach using tract-based spatial statistics (TBSS), and by application of conventional region of interest (ROI) analyses to selected white matter tracts. Raw t value maps and TBSS analyses indicated widespread changes throughout the brain of Plp1-transgenic mice compared with the wild-type. ROI analyses of the corpus callosum, anterior commissure and hippocampal fimbria showed that FA was reduced significantly, whereas λ(1) and RD were increased significantly, in Plp1-transgenic mice compared with the wild-type. The DTI data derived from ROI analyses were subsequently compared with histological measures taken in the same regions. These revealed an almost complete absence of myelin, preservation of axons, marked astrocytosis and increased or unchanged cell densities. These data contribute to our growing understanding of the basis of anisotropic water diffusion in the normal and diseased nervous system.
NMR in Biomedicine 12/2011; 24(10):1369-79. DOI:10.1002/nbm.1700 · 3.04 Impact Factor
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