Quantitative proton MRS of Pelizaeus-Merzbacher disease: evidence of dys- and hypomyelination.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Quantitative proton magnetic resonance spectroscopy of children with adrenoleukodystrophy before and after hematopoietic stem cell transplantation.

About 35-40 % of boys with X-linked adrenoleukodystrophy (ALD) develop a rapidly progressive cerebral form which leads to severe neurologic disability and death within 3-5 years after onset of clinical symptoms. Because previous proton magnetic resonance spectroscopy (MRS) studies of ALD identified metabolite patterns characteristic of demyelination, gliosis, and neuroaxonal loss, this work tested the hypothesis that MRS--apart from indicating disease progression--provides criteria for the outcome after hematopoietic stem cell transplantation (HSCT) which has been promising at an early stage of the active disease. Follow-up quantitative proton MRS was performed in frontal and occipital white matter of ALD patients (n = 12) before and up to 5 years after HSCT. The observed metabolite alterations were retrospectively correlated with the clinical outcome representing either a stable condition (n = 5), a further deterioration (n = 5), or death (n = 2). While disease progression of patients before HSCT was mainly characterized by a further increase of elevated choline-containing compounds (Cho) as an indicator of active demyelination, a positive outcome after HSCT was correlated with high N-acetylaspartate (tNAA) levels in affected white matter before HSCT yielding positive and negative predictive values for tNAA of 80 %. Although to be confirmed in a larger cohort of patients, the present findings suggest the preservation of neuroaxonal integrity as a prerequisite for an arrested course. Conversely, the combination of increased Cho with markedly reduced tNAA before HSCT apparently reflects a degree of tissue degeneration which precludes a successful therapeutic intervention.

Clinical and genetic heterogeneity in megalencephalic leukoencephalopathy with subcortical cysts (MLC).

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) was recently localized on chromosome 22q (tel) and 26 different mutations of the gene MLC1 have been found. We report three siblings of non-consanguineous parents who presented with characteristic features of MLC, but did not have MLC1 mutations. MEYHODS: Clinical, laboratory and neuro-imaging findings of the siblings are described and similar patients with MLC are reviewed. RESULTS: All three siblings suffered from ataxia, progressive severe tetraparesis, dysarthria, dysphagia and epilepsy. Generalized dystonia occurred in one patient. Mental deterioration progressed more slowly than motor deterioration. The youngest male was the most severely affected and died at the age of 23 years. The two older females are now 34 and 35 years old. Our patients are among the oldest described with this clinical entity. No mutation of the MLC1 gene was found in our siblings and linkage with the MLC1 locus was excluded. CONCLUSIONS: The genetic findings in our patients suggest at least a second gene locus for MLC.

Quantitative proton magnetic resonance spectroscopy of childhood adrenoleukodystrophy.

Cerebral metabolic disturbances in patients with childhood adrenoleukodystrophy (ALD) were assessed by quantitative localized proton MRS. Patient monitoring by follow-up MRS studies served to identify putative markers for disease onset and progression. Whereas normal-appearing white matter of neurologically asymptomatic patients is characterized by slightly elevated concentrations of choline-containing compounds (Cho), an increase of both Cho and myo-inositol (Ins) seems to indicate the onset of demyelination. Markedly elevated concentrations of Cho, Ins, and glutamine in affected white matter reflect active demyelination and glial proliferation. A simultaneous reduction of the concentrations of N-acetylaspartate and glutamate is consistent with neuronal damage or loss. The observation of elevated lactate is in line with inflammation and/or macrophage infiltration. The more severe metabolic disturbances in cerebral ALD correspond to progressive demyelination, neuroaxonal loss and gliosis leading to clinical deterioration and eventually death. The detection of MRS abnormalities before the onset of neurological symptoms may help in the selection of patients for bone marrow transplantation (BMT). Stabilization and partial reversal of metabolic abnormalities is demonstrated in a patient after BMT.

Proton magnetic resonance spectroscopy of linear nevus sebaceus syndrome.

Cerebral metabolites of a patient with linear nevus sebaceus syndrome and hemimegalencephaly were determined at 18 and 30 months of age by localized proton magnetic resonance spectroscopy. Clinically, the patient suffered from hemiparesis and epileptic seizures. At 18 months of age, spectroscopy of the enlarged hemisphere revealed decreased N-acetylaspartate mainly in parietal white matter relative to the unaffected hemisphere. One year later, white matter studies indicated both reduced N-acetylaspartate and elevated myoinositol. In insular gray matter the previously normal concentrations of creatine, choline-containing compounds, myoinositol, and glutamine were increased. The findings are consistent with mild neuroaxonal loss or damage (white matter) and glial proliferation (cortical gray and white matter) of the affected hemisphere. The metabolic disturbances indicate disease progression but are less pronounced than in older patients with hemimegalencephaly.

Cystic leukoencephalopathy in a megalencephalic child: clinical and magnetic resonance imaging/magnetic resonance spectroscopy findings.

A neurodegenerative disorder characterized by megalencephaly since early infancy and slowly progressive symptoms of cerebellar, pyramidal, and extrapyramidal dysfunction, pseudobulbar signs, and epilepsy was detected in an 8-year-old girl with severe neuromotor handicap but preservation of mental and sensory functions. Cranial computed tomography and magnetic resonance imaging revealed brain swelling as well as severe abnormalities of frontal, temporal, and parietal white matter, with an extended cystlike appearance isointense to cerebrospinal fluid. Localized proton magnetic resonance spectroscopy of affected cystic white matter showed a loss of all metabolites, in accordance with a complete disintegration of neuroaxonal and glial tissue. This case is likely a severe variant of a recently described megalencephalic leukoencephalopathy with swelling and discrepantly mild clinical course.