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P426L and I179S are the two most frequent mutations in juvenile and adult metachromatic leukodystrophy (late-onset MLD), which, in contrast to infantile MLD, show marked phenotypic heterogeneity.

To improve diagnostic criteria for sporadic Creutzfeldt–Jakob disease (CJD).

Objectives: To study the occurrence of cross-reactivities of antibodies against infectious agents with human nervous tissue.

We studied serum antibodies against gangliosides GQ1b and GM1 in 13 patients with Miller Fisher syndrome (MFS) and in 18 patients with Guillain-Barré syndrome (GBS) with cranial nerve involvement. Anti-GQ1b titers were elevated in all patients with MFS cases (immunoglobulin G [IgG] > IgA, IgM), and in 8 of the 18 with GBS. Lower frequencies of increased anti-GM1 titers were observed in MFS patients (3 of 13), as well as in GBS patients (5 of 18). During the course of MFS, anti-GQ1b titers of all Ig classes decreased within 3 weeks after onset. By contrast, anti-GM1 titers (mainly IgM) transiently increased during the course of MFS in five of six patients, suggesting a nonspecific secondary immune response. In patients with MFS following respiratory infections, IgG was the major anti-GQ1b Ig class (six of six patients) and IgG3 was the major subclass (five of six). In contrast, four of five patients with MFS following gastrointestinal infections showed predominance of anti-GQ1b IgA or IgM over IgG and predominance of the IgG2 subclass; anti-GQ1b IgG (IgG3) prevailed in one patient only. These distinct Ig patterns strongly suggest that different infections may trigger different mechanisms of anti-GQ1b production, such as via T-cell-dependent as opposed to T-cell-independent pathways. Thus, the origin of antibodies against GQ1b in MFS may be determined by the type of infectious agent that precipitates the disease.

Seven patients with Miller Fisher syndrome (MFS), six in the acute phase and one in the recovery phase, were investigated for serum antibodies against gangliosides and purified lipopolysaccharides (LPS) from different strains of Campylobacter jejuni, including the MFS-associated serotypes O:2 and O:23. Immunoglobulin G antibodies against gangliosides GT1a and GQ1b were found in five of six patients in the acute phase of disease. Three of these patients also displayed antibodies to ganglioside GD2, a finding not previously reported for MFS. All anti-GT1a- and anti-GQ1b-seropositive patients showed antibody binding to C. jejuni LPS, predominantly to O:2 and O:23 LPS. Antibody cross-reactivity between gangliosides GT1a and GQ1b and O:2 and O:23 LPS was demonstrated by adsorption studies. This cross-reactivity between gangliosides and C.jejuni LPS, which is obviously due to oligosaccharide homologies, may be an important pathogenetic factor in the development of MFS after C. jejuni infection.

The function responsible for discrimination among markers (point mutations) in Pneumococcus (hex) was traced back to the early strains used to demonstrate the chemical basis of transformation in the early 1940s. Those currently used laboratory strains failing to manifest this function arose from a single subline of the original strain. The function was also evident in other independently isolated strains including a number of different serological types. The hex function was not evident in transformation between heterologous pneumococcal strains probably as a result of the sensitivity of the function to saturation in the presence of deoxyribonucleic acid from closely related but nonisogenic strains.

Ganglioside-antisera, the ganglioside GM1-ligands, cholera toxin (CT), and CT subunit B, respectively, were injected into the lumbosacral subarachnoid space of normal rats. The cytotoxic effects of the injected compounds on the peripheral and central nervous system were investigated by light and electron microscopy; the severity of CNS lesions was evaluated by quantitation of macrophages containing debris. In contrast to control sera and GM2-antiserum, antisera against a mixture of the major brain gangliosides GM1, GD1a, GD1b, and GT1b (MaBG) or against GM1 induced demyelination in spinal roots and spinal cord, as well as alterations of astroglia. CT induced the same cytotoxic effects as MaBG- and GM1-antisera, whereas CT subunit B was without effect. The ineffectiveness of GM2-antiserum is obviously due to the very low concentration of the specific binding target, GM2, on cell surfaces; that of CT subunit B to the lack of the cytotoxic operator, subunit A. Our results indicate that a similar pattern of neuropathological lesions may be effected by different cytotoxic mechanisms through attachment of the cytotoxic agent onto the cell surface via a common target molecule, and further substantiate the role of GM1-antibodies in the pathogenesis of demyelination.

Immunoglobulin (Ig) concentrations were investigated in white matter samples of two adrenoleukodystrophy (ALD), threee multiple sclerosis (MS), two systemic lupus erythematosus (SLE), one rheumatoid arthritis, and three control brains obtained at autopsy. “Free” Igs were extracted at pH 7.4; subsequently, bound Igs were extracted at pH 2.5 and 10.8, respectively. Igs were quantified by radial immunodiffusion. In ALD material there was an increase of free IgG and IgA, in one sample also of IgM, as compared to controls. No significant amounts of Igs were detected in the pH 2.5 and 10.8 extracts of ALD brain. Similarly to ALD, an increase of free IgG and IgA was a characteristic finding in MS brain; in contrast to ALD and control material, significant amounts of bound Igs (IgG) extractable at acid or alkaline pH, respectively, were present in MS tissue. In both SLE brains increase of free IgM was conspicuous. Preliminary studies on binding of Igs extracted at pH 7.4 from brain to frozen sections of normal human and bovine brain tissue revealed different binding properties of Igs from ALD, MS, SLE, and control brains. Immunochemical findings in ALD indicating pathologic accumulation of Igs in brain tissue were paralleled by immunocytochemical observations demonstrating accumulation of lymphoid cells staining for IgG, IgA, and IgM, respectively, mainly in areas of recent demyelination. Participation of Igs in the pathogenesis of ALD lesions may be considered but needs further confirmation.

The ganglioside concentrations and the ganglioside patterns were investigated in 18 meningiomas of different histological type and in the meninges. The ganglioside concentration in the meningiomas ranged from 0.16 to 1.63 mg ganglioside N-acetylneuraminic acid per gram dry weight (mean 0.68 mg/g). The gangliosides GM3, GD3 and GD1a were found to be the major ganglioside fractions of the meningiomas. In the endotheliomatous meningiomas, on teh average, the percentage of GM3 was higher, and the percentage of GD3 lower than in the endotheliomatous-fibromatous tumours. However, none of the individual ganglioside patterns observed seemed to be specific of a certain histological type.

A 43-year-old female with adrenoleukodystrophy (ALD) is described, who developed spastic tetraparesis, suffered grand mal seizures, and became stuporous and demented during the last 5 years of her life. Computed tomography revealed symmetrical hypodense lesions in the peritrigonal regions. Adrenal insufficiency was not evident except for skin pigmentation. The ultrastructure of a rectal biopsy specimen showed inclusions with lamellae and interspersed clefts in macrophages of the submucosal layer. At autopsy, the adrenals were found to contain large foam cells filled with similar inclusions. The brain cortex and the spinal cord were histologically normal. However, cerebral white matter exhibited widespread demyelination which spared only the arcuate fibres. In regions of less severe demyelination scattered inflammatory cells were seen. On electron microscopy, aggregates of typical paired leaflets with distinct intermediate lines were demonstrated in perivascular macrophages. Histochemical study showed these cells to contain free as well as esterified cholesterol. Gas chromatographic analysis of very long chain fatty acids (VLFA) from the demyelinated cerebral white matter showed a marked increase of C26:0 fatty acid in cholesterol esters and above-normal values for C24:0 and C24:1 in gangliosides. It is suggested that the condition was a heterozygote form of X-linked ALD. Patients with neurodegenerative symptoms with or without adrenal insufficiency can easily be screened for X-linked ALD by VLFA analysis in blood or cultured fibroblasts.

About half of pneumococci recovered from pediatric patients and one-third of isolates from adult patients yielded bacteriophages active against one or more of four noncapsulated indicator strains of pneumococcus. Strains of capsular types most frequently causing pediatric infections were associated with lysogeny. Classical restriction-modification phenomena have been demonstrated in vivo with some of the temperate phages, and correlation of restriction with the presence of one or the other of the two known pneumococcal restriction endonucleases has been established. The temperate phages differ serologically and in several other characteristics from virulent pneumococcal phages previously described. All pneumococcal phages so far studied can be classified into a minimum of three serological groups.

An autopsy case of adult metachromatic leukodystrophy (MLD) manifested clinically as schizophrenic psychosis is reported. A 50-year-old man developed progressive mental changes 10 years before his death, and later manifested a schizophrenic syndrome without neurologic deficits or EEG changes. After his death from uremia neuropathology disclosed MLD with demyelination accentuated in the frontal lobes and abundant metachromatic deposits in the preserved areas of cerebral white matter. Neurochemical examination of the demyelinated frontal area showed reduced concentration of cerebrosides and sulfatides, decreased amounts of total lipids in the tissue, and an increase of sulfatides, and particularly of their cerebron fractions in lipid extract. The problems of adult forms of MLD with prolonged course are discussed with special reference to cases showing mainly psychiatric syndromes.

IgM, IgG, IgA, and IgG subclass anti-GM1, anti-GQ1b, and anti-asialo-GM1 (anti-GA1) antibodies, respectively, were investigated by ELISA in serum from neurological and other patients. Increased anti-GM1 occurred mostly in ?35-15 of the cases without statistical differences; high percentages were found in Guillain-Barré syndrome (GBS) preceded by gastrointestinal infection and multifocal motor neuropathy. Roughly, IgM anti-GM1 was most frequent; however, distinct IgG and IgA reactions were found i.a. in GBS. A particular IgM anti-mono- and disialoganglioside pattern occurred in a patient with sensorimotor neuropathy and paraproteinemia. Anti-GQ1b was elevated in all Miller-Fisher patients, with some prevalence of IgG2 among IgG subclasses. Cross-reactivity of anti-GQ1b was demonstrated with Campylobacter jejunilipopolysaccharides. Increased anti-GM1 andor anti-GA1 was more frequent in systemic lupus erythematosus with central nervous system involvement than without. Incidence of anti-GM1 and anti-GA1 in X-adrenoleukodystrophy was relatively high.

Fragments of the adrenoleukodystrophy (ALD) cDNA from a patient with adolescent ALD were amplified by polymerase chain reaction and subcloned. Bidirectional sequencing of the entire coding ALD gene disclosed a cytosine to guanine transversion at nucleotide 1451 in exon five, resulting in substitution of proline 484 by arginine. Five of nine siblings of the patient, comprising two cerebral ALD, one adrenomyeloneuropathy, one Addison only as well as the symptomatic mother (all accumulating very long chain fatty acids) carried this mutation, which was not found in the unaffected persons, in five unrelated ALD patients, and in twenty controls. We propose that this missense mutation generated the disease per se as well as the metabolic defect; the different phenotypes, however, must have originated by means of additional pathogenetic factors.Copyright 1994, 1999 Academic Press, Inc.

Inflammatory demyelination in the central nervous system in the childhood cerebral phenotype of X-linked adrenoleukodystrophy (X-ALD) bears resemblance to that of multiple sclerosis. With a view to an association of HLA class II genes, specifically HLA-DRB1 subtype DRB1*15 to multiple sclerosis we investigated the HLA class II DR haplotype in 29 unrelated X-ALD patients including 17 childhood cerebral phenotype patients. Our results did not show an association of DRB1*15 and X-ALD, but disclosed a significant association of HLA DRB1*16 alleles and X-ALD in general. This finding suggests that in addition to the X-chromosomal ALD gene an autosomal gene linked to the HLA class II region is involved in the pathogenesis of X-ALD This gene should affect a pathomechanism common to all ALD variants, such as defective peroxisomal metabolism of very long chain fatty acids.

Ganglioside-antibodies produced subsequent to Campylobacter jejuniinfection may play a role in the pathogenesis of the neurological disorder Guillain-Barré syndrome (GBS). Since lipopolysaccharides (LPS) of certain C. jejuniserotypes associated with GBS (O:2, O:4, O:19) exhibit structural mimicry of gangliosides in their core oligosaccharides, we investigated antibody and ligand cross-reactivities between gangliosides and LPS of these C. jejuniserotypes. GM1-antibody reacted with O:19 LPS reflecting GM1 mimicry by the O:19 core oligosaccharide. On the other hand, asialoGM1-antibody bound to O:2 and O:19 LPS indicating a shared epitope not dependent on ganglioside mimicry. Serum IgA from GBS patients after C. jejuniinfection reacted with gangliosides, predominantly GM1, and LPS of all three serotypes. Cholera toxin (GM1 ligand) recognized O:4 and O:19 LPS, whereas peanut agglutinin (Galβ1-3GalNAc ligand) recognized LPS of all three serotypes, thereby confirming structural mimicry. These results suggest that LPS from certain C. jejunistrains may function as cross-reactive antigens for anti-ganglioside B cells.

Ganglioside and DNA levels were estimated in the striatum of rats 10 days and 6 weeks after lesioning by intrastriatal injection of kainic acid. There was a moderate, 21–24% decrease of the ganglioside concentration per unit protein on the side of the lesion, which can be ascribed to the loss of the intrinsic striatal neurons following the injection of kainic acid. On the other hand, there was a 131 and 60% increase of DNA per unit protein in the kainate injected side 10 days and 6 weeks after the lesions, respectively; these changes apparently reflected the gliotic reaction brought about by the neurotoxin. Qualitatively similar findings — a decrease of ganglioside and an increase of DNA levels per unit protein — were also found in the brain of patients with Huntington's disease; however, as compared with the corresponding control material, the decrease of the ganglioside concentration was more pronounced in the striatum of Huntington's disease (by 38% in the caudate nucleus and by 46% in the putamen) than in the kainate lesioned rat striatum. This difference could be due to the different proportions of the intrinsic and extrinsic neuronal plasma membranes in the striatum of the two species; however, the possibility of a more generalized affection of neuronal plasma membranes in Huntington's disease may also be envisaged.

Seven patients with Miller Fisher syndrome (MFS), six in the acute phase and one in the recovery phase, were investigated for serum antibodies against gangliosides and purified lipopolysaccharides (LPS) from different strains of Campylobacter jejuni, including the MFS-associated serotypes O:2 and O:23. Immunoglobulin G antibodies against gangliosides GT1a and GQ1b were found in five of six patients in the acute phase of disease. Three of these patients also displayed antibodies to ganglioside GD2, a finding not previously reported for MFS. All anti-GT1a- and anti-GQ1b-seropositive patients showed antibody binding to C. jejuni LPS, predominantly to O:2 and O:23 LPS. Antibody cross-reactivity between gangliosides GT1a and GQ1b and O:2 and O:23 LPS was demonstrated by adsorption studies. This cross-reactivity between gangliosides and C.jejuni LPS, which is obviously due to oligosaccharide homologies, may be an important pathogenetic factor in the development of MFS after C. jejuni infection.

The urinary excretion of epinephrine, norepinephrine metanephrine and normetanephrine was investigated in rats with and without pretreatment with iproniacide and i.p. administration of epinephrine, norepinephrine, metanephrine and normetanephrine. The following results could be obtained: In normal rats no detectable urinary excretion of metanephrine (MN) and normetanephrine (NMN) was found (below 15–20 µg/kg/24 hrs). In rats pretreated with iproniacide no MN but 46 µg/kg/24 hrs NMN was excreted in the urine. The i.p. administration of 400 µg/kg epinephrine or 800 µg/kg MN lead concordantly to an urinary output of MN with a yield of 11% of the given dose. Pretreatment with iproniacide increased the MN excretion following the administration of epinephrine and MN to 29% and beside caused a significant rise in the urinary NMN output. Following the i.p. administration of 400 µg/kg norepinephrine 7% and after the i.p. injection of 800 µg/kg NMN 13% were recovered as NMN in untreated animals and 11% and 19% in rats pretreated with iproniacide. There was a linear positive correlation between the amount of i.p. given MN and the urinary output of NMN within a dose range of 400–1600 µg/kg MN in rats pretreated with iproniacide, indicating a competitive displacement of NMN from specific tissue stores by MN. No such increased NMN urinary output could be detected following the i.p. administration of adrenalone and noradrealone.

Morphological and neurochemical findings are reported in dogs with two types of amaurotic idiocy.

Zusammenfassung Liquor cerebrospinalis von einem Patienten mit Tay-Sachsscher Erkrankung (infantile Form der amaurotischen Idiotie) und von acht „normalen“ Vergleichsfällen wurde dünnschichtchromatographisch auf das Vorkommen von Gangliosiden untersucht. Die erhaltenen Ergebnisse weisen darauf hin, daß Ganglioside vom Tetrasaccharidtyp normale Liquorbestandteile sind. Im Liquor des Tay-Sachs-Patienten wurde Tay-Sachs-Gangliosid (Gangliosid G0) aufgefunden. Auf die mögliche diagnostische Bedeutung einer Gangliosidbestimmung im Liquor bei Erkrankungen mit Störungen im Gangliosidstoffwechsel wird hingewiesen.

Zusammenfassung 1. Es wurde die Verteilung des 5-Hydroxytryptamins (5-HT) im normalen Gehirn des Menschen untersucht. In den 5-HT-reichen Regionen nahm die Konzentration dieses Amins in der folgenden Reihenfolge ab: Formatio reticularis — Substantia nigra — zentrales Höhlengrau des Mittelhirnes — Nucleus caudatus — Putamen — Hypothalamus — Thalmus — Pallidum.

Zusammenfassung Mittels Ätherextraktion und papierchromatographischer Trennung wurden im Harn eine Reihe von Phenolsäuren nachgewiesen, von denen die 3-Methoxy-4-Hydroxymandelsäure (VMS), die mund p-Hydroxyhippursäure (m-, p-HHS) sowie die p-Hydroxybenzoesäure (p-HBS) quantitativ durch Elution und kolorimetrische Messung der Farbstoffe auf den Chromatogrammen nachgewiesen wurden. Die Mittelwerte dieserSäuren in vier normalen und vier klinischen Harnen mit unbestätigtem Phäochromocytomverdacht betrugen für die VMS 0,5 mg/24 Std, die p-HHS 2,5 mg/24 Std, die m-HHS 2,9 mg/24 Std und für die p-HBS 0,5 mg/24 Std. Bei einem Fall eines durch Operation verifizierten Phäochromocytoms trat neben einer starken Vermehrung der Katecholaminausscheidung in den Anfallsperioden auch eine starke Vermehrung der Ausscheidung der VMS, m-HHS und p-HHS in Erscheinung. Eine signifikante Vermehrung der Ausscheidung dieser Säuren war auch in einem Harn einer anfallsfreien Periode nachweisbar, bei dem die Katecholaminausscheidung im Bereich der Norm lag. In den Anfallsharnen trat nach salzsaurer Hydrolyse eine unbekannte Säure auf, die in keinem der Normalharne zu finden war und deren Charakterisierung durch einen violetten Azofarbstoff und durch dieRf-Werte in zwei Phasen erfolgte. Die diagnostische Bedeutung der vermehrten Phenolsäureausscheidung beim Phäochromocytom sowie der Weg des Abbaues zu den Hydroxyhippursäuren werden diskutiert.

1. The occurrence and distribution of catecholamines in the ocular tissue of the calf has been investigated by a fluorimetric method.

Zusammenfassung 1. Die früheren Befunde über eine Abnahme des Noradrenalins im Hypothalamus und des Dopamingehaltes im Neostriatum parkinsonkranker Patienten wurden an sechs weiteren Fällen bestätigt.

Es wurde das Verhalten des Dopaminmetaboliten Homovanillinsäure (HVS) in verschiedenen Gehirnregionen von insgesamt 13 parkinsonkranken Menschen untersucht. Bei den Parkinsonkranken war die HVS-Konzentration in Nucleus caudatus, Putamen, Substantia nigra und Globus pallidus gegenüber der Norm im Mittel um 68–82% herabgesetzt; die Dopaminkonzentration in Nucleus caudatus und Putamen dieser Fälle war im Mittel um 85 bzw. 94% gegenüber der Norm erniedrigt. Diese Befunde sprechen für einen herabgesetzten Umsatz des Gehirn-Dopamins und machen das Bestehen einer Störung in der Bildung von Dopamin wahrscheinlich. Der herabgesetzte HVS-Gehalt im Globus pallidus von Parkinsonkranken ergibt den ersten sicheren Hinweis darauf, daß auch in dieser Gehirnregion eine Störung des Dopaminstoffwechsels vorliegt. Der Befund, daß das Verhältnis der molaren Konzentrationen HVS: Dopamin in manchen Gehirnregionen parkinsonkranker Menschen gegenüber der Norm verändert zu sein scheint, wird diskutiert.

1. An Katzen in Chloralose-Narkose wurde die Wirkung von zentral verabreichtem Reserpin auf Blutdruck, Carotissinus-Reflexe [Carotissinus-Entlastungsreflex (CSER), seine Baro- und Chemoreceptorkomponente sowie Chemoreceptorreflex] und auf den Katecholamingehalt in Gehirn, Herz und Aorta untersucht. Die Zufuhr von Reserpin erfolgte in die A. vertebralis über einen A. brachialis- bzw. A. subclavia-Katheter.

Very long chain fatty acids (VLCFA) were found to be markedly increased and phytanic acid was borderline above normal in formalin-fixed brain white matter of case with an unusual type of familial leukodystrophy with epitheloid cells as described previously by Gullotta et al. [Neuropädiatrie (1970) 2: 173–186]. Increased VLCFA in brain clearly demonstrate that the patient had suffered from a peroxisomal disease. This diagnosis is corroborated by ultrastructural findings in brain showing typical lamellar inclusions. The particular type of peroxisomal disorder present in case (heterozygote of X-linked adrenoleukodystrophy?) remains speculative.

Zusammenfassung „Normaler“ Liquor cerebrospinalis des Menschen wurde auf das Vorkommen von Gangliosiden untersucht. Die Identifizierung der Ganglioside erfolgte dünnschichtchromatographisch sowie enzymatisch durch Abbau mit Neuraminidase. Die Ganglioside GII, GIII und GIV stellen die Hauptfraktionen der Liquorganglioside dar. Die Gangliosidkonzentration im Liquor liegt grob geschätzt in einer Größenordnung von etwa 1 µg/ml. Zumindest der Hauptanteil der „normalen“ Liquorganglioside ist nicht auf die im Liquor befindlichen Zellen zurückzuführen.

HOMOVANILLIC acid (3-methoxy-4-hydroxyphenylacetic acid, HVA) is formed by the action of the enzymes monoamine oxidase and catechol-O-methyl-transferase as a final product of dopamine metabolism, and its occurrence in urine has been described1–6. From other investigations7,8it may be concluded that in experimental conditions the HVA level in the brain tissue reflects the dopamine turnover, although with a certain delay. It also seems likely that for the normal brain tissue a similar statement may be made. The actual HVA concentration in the normal brain tissue, therefore, might be a suitable index in the evaluation of the local dopamine turnover. Sharman9has recently demonstrated the presence of HVA in the caudate nucleus of animals of several species. This seems consistent with the high dopamine concentration in this brain area10. Detailed investigations have been performed on the local distribution of dopamine in the human brain11–15. This account describes the occurrence and local distribution of HVA in the human brain.

Ohne Zusammenfassung:

Zusammenfassung Es wurde das Vorkommen des 5-Hydroxytryptamin-Metaboliten 5-Hydroxyindolessigsäure (5-HIES) im Gehirn des Menschen untersucht. Signifikante 5-HIES-Konzentrationen wurden in einer Reihe von Gehirnregionen aufgefunden; innerhalb des Gehirnes zeigte sich, ähnlich dem Verhalten des 5-Hydroxytryptamins, ein Anstieg der Konzentrationen nach caudal zu. Die 5-HIES-Konzentrationen vermitteln möglicherweise ein Bild des 5-Hydroxytryptamin-Umsatzes.