A new leukoencephalopathy with vanishing white matter

Abstract

Article abstract-We identified nine children with a leukoencephalopathy of similar type according to clinical and MRI findings. The patients included three affected sibling pairs. The age range was 3 to 19 years. The onset of the disease was in childhood; the course was both chronic-progressive and episodic, There were episodes of deterioration following infections and minor head traumas, and these could result in unexplained coma. In eight patients with advanced disease, MRI revealed a diffuse cerebral hemispheric leukoencephalopathy, in which increasing areas of the abnormal white matter had a signal intensity close to that of CSF on all pulse sequences. In one patient in the early stages of disease, initial MRI showed diffusely abnormal cerebral white matter, which only reached the signal characteristics of CSF at a later stage. In the patients in whom the disease was advanced, magnetic resonance spectroscopy (MRS) of the white matter showed an almost complete disappearance of all normal signals and the presence of glucose and lactate, compatible with the presence of mainly CSF and little brain tissue. Spectra of the cortex were much better preserved. However, in addition to the normal resonances, there were signals representing lactate and glucose. MRS of the white matter in the patient whose disease was at an early stage was much less abnormal. Autopsy in one patient confirmed the presence of extensive cystic degeneration of the cerebral white matter with reactive change and a preserved cortex. Typical involve ment of pontine tegmental white matter was suggested by MRI and confirmed by autopsy. The disease probably has an autosomal recessive mode of inheritance, but the basic metabolic defect is not known. NEUROLOGY 1997;48:845-855 There is a growing number of progressive encepha lopathies identified and defined by enzyme defect, gene defect, or both.1 MRI has contributed consider ably to the detection of leukoencephalopathies,2 but a significant proportion remains unclassified.3 In some cases, MRI and magnetic resonance spectroscopy (MRS) findings are sufficiently distinct to be used as criteria for a classifying diagnosis.4As part of an ongoing study of unclassified leu koencephalopathies, we identified nine patients with a distinct disorder, as defined by clinical and MRI criteria. We describe the clinical picture, metabolic investigations, and neurophysiologic studies, as well as MRI, MRS, and autopsy findings, and provide criteria for the diagnosis. Proton ^H) MRS was performed in five patients (pa tients 3, 4, 5, 7, and 9) with the standard imaging head coil. We used single-voxel spectroscopy in order to achieve a high-quality assessment of the neurochemical composi tion of white matter versus cortex. A 2 X 2 X 2 cm3 voxel was chosen in the mid-occipital area, containing mainly occipital cortex of both hemispheres and some white mat ter and CSF. Another voxel of 2 X 2 X 2 cm3 was chosen in the parieto-occipital area, containing white matter and, at most, some ventricular CSF. The spectra were acqui...

Natural History of Vanishing White Matter

“…Ovarian dysgenesis was found on ultrasound in 1 patient at 3 years and at autopsy in 2 patients at 10 months and 6 years 2, 32. Six women had offspring; none reported episodic deterioration during or shortly after pregnancy.…”

“…Vanishing white matter (VWM; Online Mendelian Inheritance in Man database 603896) 1, 2, 3 is one of the more prevalent leukodystrophies 4. It is caused by recessive mutations in any of the genes EIF2B1–5.…”

“…It is caused by recessive mutations in any of the genes EIF2B1–5. 5, 6 Patients typically have normal early development, followed by chronic neurological deterioration and additionally stress‐provoked episodes of rapid decline 2. No curative treatment is available 7.…”

“…No curative treatment is available 7. Although VWM was initially recognized as a disorder of young children,1, 2, 8 it has become apparent that disease onset and severity vary widely, from antenatal or early infantile onset disease with rapid demise9, 10, 11 to adult onset slow disease 3, 12…”

Affected astrocytes in the spinal cord of the leukodystrophy vanishing white matter

“…Subpopulations might be selectively affected and might correlate with variation in WM pathology. Indeed, the brains of various leukodystrophies show variation in vulnerability, with for instance sparing of the U‐fibres underneath the cortex (van der Knaap et al, 1997; van Rappard, Boelens, & Wolf, 2015). Microenvironmental factors may contribute to this heterogeneity in pathology, such as regions with neuronal subpopulations with distinct axonal signals, distribution of the vasculature bed, timing of myelination programs, and presence of other neural cells.…”