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The instability of the mitochondrial genome in individuals harboring pathogenic mutations in the catalytic subunit of mitochondrial DNA (mtDNA) polymerase gamma (POLG) is well recognized, but the underlying molecular mechanisms remain to be elucidated. In 5 pediatric patients with severe myoclonic epilepsy and valproic acid-induced liver failure, we identified 1 novel and 4 previously described pathogenic mutations in the linker region of this enzyme. Although muscle biopsies in these patients showed unremarkable histologic features, postmortem liver tissue available from 1 individual exhibited large cytochrome c oxidase-negative areas. These cytochrome c oxidase-negative areas contained 4-fold less mtDNA than cytochrome c oxidase-positive areas. Decreased copy numbers of mtDNA were observed not only in the liver, skeletal muscle, and brain but also in blood samples from all patients. There were also patient-specific patterns of multiple mtDNA deletions in different tissues, and in 2 patients, there were clonally expanded mtDNA point mutations. The low amount of deleted mtDNA molecules makes it unlikely that the deletions contribute significantly to the general biochemical defect. The clonal expansion of a few individual-specific deletions and point mutations indicates an accelerated segregation of early mtDNA mutations that likely are a consequence of low mtDNA copy numbers. Moreover, these results suggest a potential diagnostic approach for identifying mtDNA depletion in patients.

A 34-year-old woman with no family history of orthochromatic leukodystrophy (OLD) developed progressive intellectual deterioration, a frontal syndrome and spastic tetraparesis. She died four years after the onset of the clinical illness. Neuropathological studies included light and electron microscopy of cerebral and nerve biopsies, and a complete postmortem examination. Light microscopy demonstrated OLD with pigmented macrophages and glial cells. Electron microscopy showed electron-dense, membrane-bound intracytoplasmic lamellar inclusions with curved or straight parallel arrangement, or fingerprint pattern, in white matter macrophages, astrocytes and oligodendrocytes. Cortical cells contained lipofuscin which was normal in type and amount. This suggests that the material in white matter glial cells and macrophages is ceroid pigment, however, the distribution is not that seen in ceroid-lipofuscinosis. Similar inclusions have been found in oligodendrocytes in other forms of OLD. Biochemical study did not show evidence of demyelination. Galactolipids were normal. Polyunsaturated fatty acids were decreased. The most striking feature was an increase in plasmalogens.

Ultrastructural and biochemical studies on the cerebral biopsy of a 3-month-old male with a clinical diagnosis of Pelizaeus-Merzbacher disease revealed normal myelin sheaths but characteristic alterations in the oligodendrocytes. They displayed unique vacuoles with concentric lamellae in the perikarya and numerous myelin balls in the terminal processes. Very few macrophages containing non-specific sudanophilic lipids were encountered. Cerebroside concentration and several acid hydrolases were normal. The above findings differed distinctly from those obtained on a previous unrelated case of Pelizaeus-Merzbacher disease (35). It remains unknown whether these differences are an expression of genetic heterogeneity.

Quantitative investigations on the glial population in the corpus callosum were carried out on 7 Jimpy mice and on 4 normal controls of the same strain and age. A statistical analysis revealed a significant (p = 0.01) increase in the relative number of all spongioblastic cell types (large glial precursors) and a decrease in the relative number of astrocytes (15.4%) and oligodendrocytes (14.1%). However the relative number of small dark cells (small glioblasts) was similar to that of controls. The present findings suggest a delay in the differentiation of glial cells of Jimpy mice. Some spontaneous mutations in laboratory animals provide models of genetically determined disorders of the central nervous system. As reported by other authors ( Sidman , 1965; Sidman et al. , 1964), Jimpy mice offer new opportunities for studying the formation and function of myelin as well as the conditions in leucodystrophy ( Sidman and Hayes , 1965). More recent studies death with ultrastructural changes in myelin sheath and myelin formation ( Hirano et al. , 1969). Neurochemical investigations suggested a serious alteration of those glial cells which are essential for myelination of the central nervous system ( Nescovic et al. , 1969). Histochemical studies ( Torii et al. , 1971) revealed the absence of myelination and the presence of sudanophilic material in the cerebellum at 12 to 15 days after birth, which increased after three weeks of age. Glial cell changes were mentioned by Frakas et al. (1970) and Torii et al. (1971). In an attempt to obtain further information on morphological changes in the neuroglial cell population of the Jimpy mutant mouse, the properties of the different glial cell types were studied quantitatively in the corpus callosum and compared with normal controls.

Chemical studies were done on cerebral white matter, gray matter, and myelin of a case of subacute sclerosing leukoencephalitis. Myelin was obtained in one-third the normal yield and was found to have an abnormal lipid composition but a normal lipid-protein ratio, normal solubility properties in CHCl3-CH3OH and normal morphology. The myelin cholesterol was increased by 50 per cent with a concomitant decrease of cerebrosides, sulfatides and ethanolamine phosphatides. The white matter showed a pattern typical of severe demyelination, whereas the gray matter was relatively normal. Total solids of white matter were 50 per cent of normal; the cholesterol ester was 27 per cent of total lipid with large decreases in proteolipid protein, cerebrosides and ethanolamine phosphatides and smaller decreases in other lipids. During the myelin isolation a light, abnormal fraction was found which was 57 per cent cholesterol ester and presumably represents the sudanophilic material. A ganglioside abnormality was found only in the white matter. The total amount of gangliosides were twice normal on a dry weight basis and were found to have greatly increased amounts of the usually minor gangliosides, G2A, G3A, G5 and G6. These 4 gangliosides accounted for 57 per cent of the total lipid neuraminic acid.

The clinical and pathologic changes manifested by a young female patient with subacute sclerosing leukoencephalitis have been described. Clinical features included early psychological changes and visual abnormalities, followed by progressive dementia, myoclonus, rigidity, and death. Laboratory findings were: a periodic EEG abnormality and an elevated cerebrospinal fluid gamma globulin. Pathological changes included subacute inflammatory changes, gliosis, and extensive demyelination. Virus-like particles, 600 to 800 A in diameter, were found in the cytoplasm of astrocytes. No infectious agent was recovered from rodents or tissue culture cell lines inoculated with brain material.