Quantitative proton MRS of Pelizaeus-Merzbacher disease - Evidence of dys- and hypomyelination

Universitätsmedizin Göttingen, Göttingen, Lower Saxony, Germany
Neurology (Impact Factor: 8.29). 10/2005; 65(5):701-6. DOI: 10.1212/01.wnl.0000174642.32187.20
Source: PubMed


Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive neurologic disorder caused by a mutation in the proteolipid protein (PLP) gene on chromosome Xq22. The associated depletion of PLP and severe reduction of other major myelin proteins results in dysmyelination. MRI reveals loss of T1 contrast between gray and affected white matter and T2 hyperintensities of white matter due to elevated water content.
In vivo proton magnetic resonance spectroscopy (MRS) was used to determine cerebral metabolite patterns in five patients with genetically proven PMD. Absolute metabolite concentrations were obtained in cortical gray matter, affected white matter, and basal ganglia and compared to age-matched control values.
In comparison to age-matched controls, MRS of affected white matter resembled the metabolite pattern of cortical gray matter, as indicated by increased concentrations of N-acetylaspartate and N-acetylaspartylglutamate (tNAA), glutamine (Gln), myo-inositol (Ins), and creatine and phosphocreatine. Most remarkably, the concentration of choline-containing compounds was reduced. Parietal gray matter and basal ganglia appeared normal but showed a tendency for elevated tNAA, Gln, and Ins.
Magnetic resonance spectroscopy (MRS)-detected alterations are consistent with enhanced neuroaxonal density, astrogliosis, and reduction of oligodendroglia. These disturbances in cellular composition are in close agreement with the histopathologic features characteristic of dys- and hypomyelination. The proton MRS profile of Pelizaeus-Merzbacher disease (PMD) differs from the pattern commonly observed in demyelinating disorders and allows PMD to be distinguished from other leukodystrophies.

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Available from: Jens Frahm, Feb 09, 2016
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    • "The decreases in both white matter and gray matter plasmalogens we measured in PMD fibroblasts are consistent with the decreases in white matter [15] and neuronal loss [16] in PMD patients. It is not unexpected that alterations in membrane plasmalogens, which represent 85% of the myelin lipid pool, and in PLP, which represents 50% of the myelin protein pool, might alter membrane transporter function in this complex disease. "
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    ABSTRACT: Leukodystrophies are devastating diseases characterized by dys- and hypo-myelination. While there are a number of histological and imaging studies of these disorders, there are limited biochemical data available. We undertook targeted lipidomic analyses of Pelizaeus-Merzbacher disease (PMD) fibroblasts, PMD lymphocytes, and 158JP oligodendrocytes, a murine model of PMD, to define the lipid changes in these cell models. Further targeted metabolomics analyses were conducted to obtain a preliminary evaluation of the metabolic consequences of lipid changes and gene mutations in these cell models. In both PMD fibroblasts and lymphocytes, and 158JP oligodendrocytes, ethanolamine plasmalogens were significantly decreased. Labeling studies with 158JP oligodendrocytes further demonstrated a decreased rate of lipid remodeling at sn-2. Targeted metabolomics analyses of these cells revealed dramatic increases in cellular levels of myo-inositol. Further uptake studies demonstrated increased rates of myo-inositol uptake by PMD lymphocytes. Our data demonstrating PlsEtn decrements, support previous studies indicating leukodystrophy cells possess significant peroxisomal deficits. Our data for the first time also demonstrate that decrements in peroxisomal function coupled with the PLP1 gene defects of PMD, result in changes in the function of membrane myo-inositol solute carriers resulting in dramatic increases in cellular myo-inositol levels.
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    • "We are not able to estimate the extent to which impaired myelin membrane formation due to laminin a2 deficiency may account for leukoencephalopathy in MDC1A. Dominant hypomyelination, however, is asso-ciated with a distinct MRS pattern different from that reported here, i.e. increased concentrations of tNAA, tCr, and Ins together with a reduction of Cho as demonstrated in Pelizaeus–Merzbacher disease [25]. Our finding of largely normal spectra in cortical and subcortical grey matter is in line with the predominance of alterations in white matter well known from MRI studies of MDC1A. "
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    ABSTRACT: Congenital muscular dystrophy (CMD) due to merosin (laminin alpha2 chain) deficiency is an autosomal recessively inherited disorder characterized by severe muscular weakness and hypotonia from birth on. Brain involvement is the rule and characterized by variable T2 hyperintensities of white matter which appears swollen on cranial MRI. The pathophysiology of these white matter changes is not clear. In five patients with laminin alpha2 deficient CMD we performed short-echo time localized proton MRS with determination of absolute metabolite concentrations in grey and white matter. In affected white matter, a consistent pattern of metabolites was detected comprising reduced concentrations of N-acetylaspartate and N-acetylaspartylglutamate, creatine, and phosphocreatine, and to a milder degree of choline-containing compounds. In contrast, concentrations of myo-inositol were in the normal range. Spectra of cortical and subcortical grey matter were normal. The observed metabolite profile is consistent with white matter edema, that is reduced cellular density, and relative astrocytosis. This interpretation is in line with the hypothesis that laminin alpha2 deficiency results in leakage of fluids across the blood-brain barrier and a histopathological report of astrocytic proliferation in CMD.
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    • "Cho is highly concentrated in oligodendrocytes and represents contributions from precursors of membrane synthesis as well as from membrane degradation products, and is thus considered a marker of myelin turnover [16] . Reduced concentrations of Cho have been observed as a characteristic MRS feature of hypomyelination in Pelizaeus-Merzbacher dis- ease [17]. On the other hand, increased levels of Cho point to demyelinating leucodystrophies such as adrenoleucodystrophy , Krabbe disease, and metachromatic leucodystrophy [18]. "
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