A. Jirásek

Neuroaxonal Dystrophy in Man: Character and Natural History

A short correlative review is given of the light and electron microscopical features and histochemical reactions of dystrophic axons in the mature human CNS. Their ultrastruc- tural similarities to axonal changes in the disease entity of the neuroaxonal dystrophies and various experimental conditions are confirmed. The incidence of axonal spheroids in the gracile and cuneate nuclei and in the reticular zone of the substantia nigra was studied in 1450 consecutive autopsies and correlated with age and underlying disease process. Axonal dystrophy of posterior column nuclei and substantia nigra showed a significant age-dependancy without predilection for either sex. The incidence of dystrophic axons in the globus pallidus and other sites was also examined. No clear relationship of the severity and frequency of the involvement of gracile nucleus with any underlying disease was established, while axonal dystrophy in substantia nigra showed significant correlations to alcoholic encephalopathies and Parkinson’s syndrome, and a trend to negative relationship with presenile cerebral atrophies. In addition to the natural occurrence of dystrophic axons as a physiological, age-dependant phenomenon, these lesions may arise prematurely and to excess in a variety of natural and experimental disorders. The reported findings suggest that some metabolic factors are involved in the pathogenesis of dystrophic axonal changes. Relations to axonal dying-back processes are discussed.

Niemann-Pick disease type C

SummaryA complex neuropathological study of two cases of Niemann-Pick disease (NPD) type C (NPDC) revealed some novel features in the chemical pathology of the neuronal storage. Lipid histochemistry showed the presence of a lipid which met the criteria of a neuronal glycosphingolipid. Sphingomyelin (SM) was not detected in the neurones in any of the regions examined. Lipid chemical analysis of total extracts and of partially purified lysosomal fraction of the brain cortex showed markedly increased levels of neutral ceramide hexosides especially of glucosylceramide and ceramide dihexoside (mostly of its slower band). Phospholipids were not significantly increased. Monosialogangliosides GM2 and GM3 were increased only slightly. The storage process displayed the well known fine structure and was accompanied by a marked secondary increase in some lysosomal enzyme activities. There was neuroaxonal dystrophy (NAD) of considerable intensity and extent. Many spheroids contianed masses of degenerated organelles and neurofilaments in various proportions and displayed variable activities of acid phosphatase, nonspecific esterase and dehydrogenases. There was marked brain atrophy accompanied in one case by severe demyelination. Enzyme studies revealed partial decrease of sphingomyelinase (SMase) and betaglucosidase activities in cultured fibroblasts, as well as lack of cathodic SMase activity on isoelectric focusing. No defects of these enzymes were found in the brain samples. The findings are regarded as significant since they indicate a biochemical defect in which SM is not primarily involved and which may thus be fundamentally different from that in type A of NPD.

Neuropathology of Various Types of Niemann-Pick Disease

A comparative neuropathological and histochemical study was performed on the brains of seven cases of NPD. In type A (two cases), besides the neuronal storage of SM, a widespread endothelial storage of a neutral glycosphingolipid was found. In one case a pseudosystemic lesion of the pallido-nigral system was observed. In type B (one case) the only finding was the endothelial storage of SM. In type C (four cases) the degree of neuronal storage distension contrasted considerably with a very low amount of lipid demonstrable histochemically in fixed brains. Only in one case, focal neuronal storage of a phosphoglyceride could be proved. However, in peripheral neurons (of unfixed appendix) the phosphoglycerides were clearly predominating (one case). A remarkable and constant finding in each case of the series was a widespread neuroaxonal dystrophy with various topical maxima (thalamus, dentate nuclei). The significance of the findings are discussed in relation to the present status of knowledge of this type.

Niemann-Pick disease type C with enhanced glycolipid storage

A case of infantile neurovisceral disease was classified according to the morphological and chemical analysis of fixed tissue as a chemically different type of Niemann-Pick disease (NPD) type C, with glycolipids dominating the storage process. The diagnosis was reached on the basis of massive accumulation of neutral glycolipids in visceral storage elements (hepatocytes and macrophages) as an outstanding feature of lipid histochemistry. Chemical lipid analysis corroborated the findings by detecting a manyfold increase of glucosyl ceramide, lactosyl ceramide, ceramide trihexoside and GM3 ganglioside. In addition, macrophages contained variable quantities of sphingomyelin. The brain showed slightly increased quantities of lactosylceramide (Slower fraction) and glucosyl ceramide. Apart from the classical neuronal storage changes there was also marked neuroaxonal dystrophy. In terms of quality, the glycolipid spectrum was comparable to that of NPD type C, in terms of quantity, the changes were consistent with those in so-called lactosyl-ceramidosis, which, however, was reclassified as NPD type C only recently. In our view, the present case is the second published observation of lactosylceramidosis classifiable as a glycolipid (GL) variety of NPD type C in which the normally considerable tendency to glycolipid storage is further enhanced while the storage of sphingomyelin is less expressed.

Niemann-Pick disease (Crocker's type C)

SummaryA histochemical study is reported of regional differences of the lipid storage in a case of Niemann-Pick disease (NPD) type C. Besides tissues known to be affected (reticuloendothelium, hepatocytes, nervous system), storage was demonstrated in adrenal cortical spongiocytes, sweat glands, renal glomerular and tubular cells, smooth muscle, excretory tubules of some salivary glands, ependyma and in choroid plexus. In most tissues were stored sphingomyelin, cholesterol and a small amount of a glycosphingolipid. In the endothelium of cerebral and spinal vessels the main stored lipid was a glycosphingolipid. The significance of these regional differences are discussed and their study is recommended as a useful counterpart to the biochemical investigation.

An unusual case of phospholipidosis.

We present the results of a structural, histochemical and lipid-chromatographic study of tissues obtained at postmortem from an unusual case of phospholipidosis. A previous biopsy of the appendix and liver (Elleder et al., 1975a) had revealed a predominance of phosphoglyceride storage, principally of lysobisphosphatidic acid (LBPA) postmortem material showed that this lipid was stored exclusively in central neurons. In the spleen and the lymph node, however, sphingomyelin (SP) was shown, histochemically and chromatographically, to be the main lipid stored. Total sphingomyelinase (SPase) activity in the appendix was reduced to about 50% of normal. Neuroaxonal dystrophy (NAD) and a conspicuous discrepancy between the degree of distension of some neurons and their lipid content deserve special mention. The case is contrasted with classical sphingomyelinosis; the complexity of the Niemann-Pick group of diseases is discussed as an indication of the difficulties of classification of any atypical case.

New enzymatic findings in infantile neuroaxonal dystrophy

SummaryTwo siblings with infantile neuroaxonal dystrophy (INAD) exhibited highly increased activity of nonspecific esterase (resistant to physostigmine and sensitive to organophosphates) topically correlating with the morphological manifestations of the disease (spheroids), confined in those two particular cases to the central nervous system (CNS). This is demonstrated for the first time. NADH tetrazolium reductase was another enzyme noted with increased activity and similar topography. The lesions were devoid of any marked activity of typical mitochondrial (succinate and alpha-glycerolphosphate) dehydrogenases and lysosomal (acid phosphatase and beta-glucuronidase) enzymes. The diagnostic significance of monitoring nonspecific esterase and NADH tetrazolium reductase activities in the diagnosis of INAD is discussed in particular.

Peripheral nervous system affection in experimental lipidosis induced by 4,4′-diethylaminoethoxyhexesterol

SummaryA picture of generalized phosphoglyceride and cholesterol storage was induced, in keeping with literary data, by the experimental administration of 4,4′-diethylaminoethoxyhexesterol to rats. An asset of this model lies in the discovery that considerable storage occurs in the peripheral nervous system in contrast to the CNS, whose resistance to hexesterol is generally known. The siginificance of this finding is briefly discussed.