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We report neuropathological, biochemical and molecular studies on two patients with childhood ataxia with diffuse central nervous system hypomyelination (CACH) syndrome, a leukodystrophy recently defined according to clinical and radiological criteria. Both had severe cavitating orthochromatic leukodystrophy without atrophy, predominating in hemispheric white matter, whereas U-fibers, internal capsule, corpus callosum, anterior commissure and cerebellar white matter were relatively spared. The severity of white matter lesions contrasted with the rarity of myelin breakdown products and astroglial and microglial reactions. In the white matter, there was an increase in a homogeneous cell population with the morphological features of oligodendrocytes, in many instances presenting an abundant cytoplasm like myelination glia. These cells were negative for glial fibrillary acidic protein and antibodies PGM1 and MIB1. Some were positive for myelin basic protein, proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein, but the majority were positive for human 2'-3' cyclic nucleotide 3' phosphodiesterase and all were positive for carbonic anhydrase II, confirming that they are oligodendrocytes. Myelin protein and lipid content were reduced. The PLP gene, analyzed in one case, was not mutated or duplicated. The increased number of oligodendrocytes without mitotic activity suggests an intrinsic oligodendroglial defect or an abnormal interaction with axons or other glial cells. This neuropathological study supports the notion that CACH syndrome constitutes a specific entity.

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It has been reported that oligodendrocytes do not contain nuclear T3 receptors, which is in apparent contradiction with the well-known effects of thyroid hormones on myelination. In this study we have reexamined the presence of receptors in this cell population, using pure rat oligodendrocyte cultures. T3 binding was also studied with the use of pure rat astrocytes as well as in mixed neuronal-glial cultures. The latter are mainly neuronal during the first days in culture and essentially glial thereafter. Binding studies carried out in intact cells demonstrated the presence of high affinity-low capacity binding sites for thyroid hormones in pure cultures of oligodendrocytes. The maximal binding capacity was 50-60 fmol/100 micrograms DNA and the dissociation constant (Kd) 0.13 nM. Pure rat astrocyte cultures also contained high affinity sites for thyroid hormones, although receptor concentrations was 2-3 times lower than in oligodendrocytes or neurons. This was confirmed in pure cultures of chick astrocytes and in neuronal-glial cultures during the astroglial period. The relative affinity of the receptor for thyroid hormone analogs was triiodothyroacetic acid = T3 greater than T4 greater than tetraiodothyroacetic acid in oligodendrocyte and astrocyte nuclei, and the sedimentation coefficient of the receptor was approximately 3.8S in both cell types. These results demonstrate that nuclear T3 receptors similar to those found in neurons and astrocytes are also present in oligodendrocytes. This suggests that the effects of thyroid hormones on myelination could result from a direct action of the hormone in the oligodendrocytes.

It is generally accepted that thyroid hormones act at the genomic level through an interaction with specific nuclear receptors. Using a monoclonal antibody raised against the rat liver nuclear L-T3 receptor (NTR), we report here the immunocytochemical localization of T3 receptors in the adult rat brain. The strongest NTR immunoreactivity was found in the olfactory bulb, the hippocampus, the dentate gyrus, the amygdala areas, and the neocortex (layers III-VI). An intermediate NTR immunoreactivity was found in the hypothalamus, whereas the thalamus, the caudate-putamen, and the pallidum were weakly NTR-immunoreactive. In the cerebellum, a strong NTR immunoreactivity was found in the nuclei of Purkinje cells, in the internal granular layer, and in some nuclei of cells located in the molecular layer. In the brainstem, a strong NTR immunoreactivity was found in the lateral mamillary nucleus and the interstitial nucleus. A weak to moderate NTR immunoreactivity was observed in the central gray matter, while the substantia nigra and the interpeduncular nucleus were weakly stained. Furthermore, we also found NTR immunoreactivity in the nuclei of ependymocytes, epithelial cells of the choroid plexus, and cells located in the white matter. At the electron microscope level, we confirm that the immunoreactivity was not only localized in the nuclei of neurons but also in the nuclei of astrocytes and medium oligodendrocytes. This study provides new information concerning the distribution of NTR in the rat brain: (1) NTR are present not only in neurons but also in glial and ependymal cells, and (2) there is a regional and cellular heterogeneity in the distribution of NTR in the central nervous system.

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