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Biomedical subjects

B Molzer

Publications and source records attributed to B Molzer.

At least 37 records · Page 2Linked to original sources
PubMed1993

Unusual orthochromatic leukodystrophy with epitheloid cells (Norman-Gullotta): increase of very long chain fatty acids in brain discloses a peroxisomal disorder.

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.

Adrenoleukodystrophy↗
PubMed1993

Simultaneous detection of the two most frequent metachromatic leukodystrophy mutations.

Metachromatic leukodystrophy (MLD) is an autosomal recessive neurometabolic disorder caused by deficiency of arylsulfatase A (ASA). To detect ASA mutations E2S609 and E8P2382, the two most frequent MLD mutations, a non-radioactive polymerase chain reaction (PCR)-based assay was developed. This assay is a multiple "mutated primer-modulated PCR restriction fragment length polymorphism". The primers related to each mutation mismatch to create an XbaI or PstI restriction site in mutation E2S609 or E8P2382, respectively. The assay was designed to give four fragments of 160, 130, 100, and 70 bp, easy to distinguish. An internal control fragment is not necessary since both primer pairs amplify different regions of the ASA gene and fragments will be obtained in all allelic possibilities. This technique produced clear-cut results when genomic DNA, isolated either from leukocytes, cultured human fibroblasts, or paraffin-embedded autopsy material, was used as template. The assay will be of help in comparative studies on the relation between MLD genotype and phenotype, a problem not yet fully understood. Since our method was shown to work also on DNA from paraffin-embedded autopsy material, genotype/phenotype studies would not be restricted to in vivo investigations but could be done also on post mortem material, thus including investigations on a large group of cases and also studies on the relation between genotype and neuropathological features.

Base Sequence↗
PubMed1993

Multiple sclerosis-like syndrome in a woman heterozygous for adrenoleukodystrophy.

A 28-year-old asymptomatic woman was diagnosed to be heterozygous for adrenoleukodystrophy (ALD) by elevated very long-chain fatty acids in serum and fibroblasts after ADL had been diagnosed in her son. A year later she had transient unilateral blurred vision. Evoked potentials and brain magnetic resonance imaging showed further separate cerebral white matter lesions suggesting multiple sclerosis (MS). MS-like syndromes in women heterozygous for ALD may be more frequent than previously recognized.

Adrenoleukodystrophy↗
PubMed1993

[Zellweger syndrome, neonatal adrenoleukodystrophy or infantile Refsum's disease in a case with generalized peroxisome defect?].

An eleven month-old boy presented clinically with craniofacial dysmorphia, severe psychomotor retardation, neurological deterioration, no response to visual and acoustic stimuli, failure to thrive, hepatomegaly and adrenal insufficiency. Specific biochemical markers for a peroxisomal deficiency disorder (Zellweger's syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease) revealed pathological results for very long chain fatty acids, phytanic acid, pristanic acid, plasmalogen biosynthesis and catalase, thus confirming the clinical diagnosis. Comparison of clinical and biochemical findings in the patient with the characteristics of the three peroxisomal deficiency disorders showed overlapping with each of these disorders, which corresponds to the current view that these three peroxisomal disorders differ only with respect to onset and severity of the clinical manifestations, but not with regard to the biochemical defects.

Adrenoleukodystrophy↗
PubMed1993

Diagnosis of peroxisomal disorders with neurological involvement.

Peroxisomal disorders are a group of inherited metabolic diseases caused by impairment of one or more peroxisomal functions. Ten disorders with neurological involvement have been recognized. Diagnosis and differentiation of these disorders is based on a number of important biochemical markers. For all disorders elevated values of very long chain fatty acids (VLCFA) and/or phytanic acid (PHYT) are important primary diagnostic parameters. Our results with regard to these two diagnostic markers are presented. VLCFA determined by gaschromatography in 414 samples (plasma, leukocytes or fibroblasts respectively) revealed increased values of hexacosanoic acid in 30 hemizygotes and 10 heterozygotes of adrenoleukodystrophy/adrenomyeloneuropathy and in eight infants with Zellweger disease or neonatal adrenoleukodystrophy. 15 cases with peroxisomal disorders were detected by VLCFA analysis in autopsy material. Gaschromatographic analysis of PHYT in plasma showed in some patients with Zellweger disease or neonatal adrenoleukodystrophy increase. In seven Refsum patients beside gaschromatographic demonstration of PHYT accumulation in plasma, analysis of plasma phytanyltriglycerides by thin-layer chromatography proved to be a rapid and reliable method for detection of patients and monitoring dietary treatment.

Adrenoleukodystrophy↗
PubMed1992

Elevated sulfatide excretion in heterozygotes of metachromatic leukodystrophy: dependence on reduction of arylsulfatase A activity.

Sulfatide excretion in urine and arylsulfatase A (ASA) activity in leukocytes were determined in 10 homozygotes of metachromatic leukodystrophy (MLD), 7 obligate and 5 facultative MLD heterozygotes, 6 low ASA subjects (not related to MLD homozygotes), and in 9 controls. As compared to controls (sulfatides: 0-2 nmol/mg lipid; ASA: 101-287 nmol p-nitrocatechol/mg protein/hr), MLD homozygotes displayed highly increased sulfatide excretions (27-280 nmol) and low residual ASA activities (0-13 nmol). Of 12 MLD heterozygotes (ASA: 18-87 nmol) 10 showed increased sulfatides (3-24 nmol). All heterozygotes with ASA activity < 60 nmol (n = 8) had elevated sulfatide excretions (4-24 nmol). Thus, reduction of ASA activity below 40% of the mean value of controls seems to be the critical threshold for elevated sulfatide excretion in MLD heterozygotes. The low ASA subjects (ASA in the heterozygote range) excreted sulfatides in the control range, even those with ASA activities < 60 nmoles (n = 3; including a definite homozygote for ASA-pseudodeficiency; ASA:25 nmol). Statistical evaluation of sulfatide excretion and ASA activity in all subjects (n = 37) revealed a significant inverse relation (Spearman rank correlation; R = 0.8278, P < 0.001). The finding of elevated sulfatide excretion in certain MLD heterozygotes might point to increase of sulfatides also in the nervous system.

Adult↗
PubMed1992

[Peroxisomal neurologic diseases and Refsum disease: very long chain fatty acids and phytanic acid as diagnostic markers].

Peroxisomal disorders are genetic metabolic diseases with generalized, multiple, or single functional disturbances of the peroxisome. According to the extent of the functional disturbances 3 groups of diseases can be differentiated: disorders with generalized loss of peroxisomal functions (Zellweger syndrome, ZS; neonatal adrenoleukodystrophy, NALD; infantile Refsum's disease), disorders with multiple enzymatic defects (e.g. rhizomelic chondrodysplasia punctata), and disorders with a single enzymatic defect in the peroxisome, the most important being adrenoleukodystrophy/adrenomyeloneuropathy (ALD/AMN). Adult Refsum's disease, a genetic neurological disorder with phytanic acid accumulation, is due to a mitochondrial enzyme deficiency, but is often considered together with peroxisomal diseases because of phytanic acid (PHYT) accumulation in most peroxisomal diseases. The main clinical and pathological criteria of the major disorders and the biochemical parameters of their differentiation are presented. Elevated levels of very long chain fatty acids (VLCFA) and/or PHYT are the primary diagnostic markers for all peroxisomal disorders and adult Refsum's disease, respectively. Our investigations disclosed 30 ALD/AMN hemizygotes, 16 ALD/AMN heterozygotes, 8 cases of ZS/NALD and 7 patients with adult Refsum's disease. In addition, 15 cases of peroxisomal disorders were confirmed by biochemical investigations in autopsy material. With regard to peroxisomal disorders, therapeutic concepts exist only for ALD/AMN: corticosteroid substitution for adrenal insufficiency, dietary treatment, and bone marrow transplantation (BMT). Adult Refsum's disease can be treated successfully by dietary therapy. In case of dietary treatment and BMT, assay of VLCFA and/or PHYT is important for the biochemical evaluation of these therapies.

Adolescent↗
PubMed1989

Phytanic acid and very long chain fatty acids in genetic peroxisomal disorders.

1. Phytanic acid, phytanyl-triacylglycerols, and very long chain fatty acids were analysed by gas chromatography or thin-layer chromatography in blood and tissues of patients with different genetic peroxisomal disorders (Refsum's disease, X-linked adrenoleukodystrophy, neonatal adrenoleukodystrophy, Zellweger syndrome). 2. We evaluated these analyses in the detection of patients with Refsum's disease, X-linked adrenoleukodystrophy, neonatal adrenoleukodystrophy, and Zellweger syndrome, and of carriers of X-linked adrenoleukodystrophy. In particular, the analysis of phytanyl-triacylglycerols by thin-layer chromatography proved to be a rapid and reliable method for the detection of patients and the monitoring of their dietary treatment in Refsum's disease. In X-linked adrenoleukodystrophy, carrier detection may depend on very long chain fatty acid analysis in more than one material (e.g. plasma and fibroblasts). 3. Analysis of phytanic acid showed that in patients with multiple impairments of peroxisomal functions (Zellweger syndrome, neonatal adrenoleukodystrophy) phytanic acid levels may be increased not only in serum, but also in the tissue (e.g. brain, adrenals, kidney). 4. Analysis of very long chain fatty acids in cholesterol esters from the brain, adrenals, kidney, and liver of patients with peroxisomal disorders revealed four different types of very long chain fatty acid patterns according to the behaviour of C 26:0 and of other saturated and monounsaturated very long chain fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1987

Adrenoleukodystrophy in an adult female. A clinical, morphological, and neurochemical study.

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.

Adrenal Glands↗
PubMed1986

Very long chain fatty acids in genetic peroxisomal disease fibroblasts: differences between the cerebro-hepato-renal (Zellweger) syndrome and adrenoleukodystrophy variants.

Very long chain fatty acids were investigated by gas chromatography in fibroblasts of patients with genetic peroxisomal diseases (cerebro-hepato-renal (Zellweger) syndrome, childhood adrenoleukodystrophy, adrenomyeloneuropathy, neonatal adrenoleukodystrophy) and of controls. Concentrations of C 26:0 were increased to about the same extent in all disorders investigated. C 26:1 concentrations, on the other hand, were considerably elevated only in the cerebro-hepato-renal syndrome. In all control, adrenoleukodystrophy, and adrenomyeloneuropathy cases the C 22:0 concentration was higher than the respective C 26:0 concentration; the reverse was found in the cerebro-hepato-renal syndrome. These differences seem to reflect different impairment of peroxisomes in the cerebro-hepato-renal syndrome and adrenoleukodystrophy variants, respectively. Additional experiments to characterize C 26:1 by thin layer chromatography, gas chromatography and mass spectrometry revealed the presence of two straight-chain C 26:1 isomers with similar fragmentation patterns.

Abnormalities, Multiple↗
PubMed1985

The cerebrohepatorenal (Zellweger) syndrome: an improved method for the biochemical diagnosis and its potential value for prenatal detection.

The sequence of reactions involved in plasmalogen biosynthesis has been evaluated in cultured fibroblasts of patients with the cerebrohepatorenal syndrome. A double-label, double-substrate incubation using [1-14C] hexadecanol and 1-0-[9', 10'-3H]hexadecylglycerol was performed to monitor the relative rates of peroxisomal and microsomal biosynthesic steps. [14C] radioactivity associated with 1'-alkenyl groups of plasmalogens was found to be drastically reduced in fibroblasts of affected patients whereas [3H] incorporation was apparently normal. This finding is specific for cerebrohepatorenal syndrome fibroblasts since cell lines of patients with childhood adrenoleukodystrophy and neuronal ceroidlipofuscinosis utilized the lipid precursors of plasmalogen biosynthesis at normal rates. The results show that the defect in plasmalogen synthesis in the cerebro-hepato-renal syndrome is restricted to the peroxisomal steps. The finding of normal microsomal biosynthetic steps was exploited to devise a novel diagnostic assay in fibroblasts and amniocytes based on the comparison of [3H/14C] isotope ratios within aldehydes released from plasmalogens by acid hydrolysis. The procedure can be completed with a minimal amount of cells since it renders quantitative analyses unnecessary. Therefore, this technique appears ideally suited for the sensitive and safe prenatal diagnosis of the cerebro-hepato-renal syndrome.

Abnormalities, Multiple↗
PubMed1982

Detection of adrenoleukodystrophy by increased C26:0 fatty acid levels in leukocytes.

Very long chain fatty acids of peripheral blood leukocytes were analyzed by gas chromatography in nine members of a family including two hemizygotes and one obligate heterozygote for adrenoleukodystrophy (ALD), as well as in twelve controls. Comparative investigations were done in cultured fibroblasts. Elevated C26:0 levels were observed in leukocytes and fibroblasts of ALD hemizygotes. The obligate heterozygote displayed a clear-cut increase of C26:0 concentration in leukocytes but not in fibroblasts. Determination of C26:0 in leukocytes may serve as diagnostic tool in the detection of ALD gene carriers.

Adolescent↗
PubMed1981

Fatty acid patterns in brain, fibroblast, leukocyte and body fluid lipids in adrenoleukodystrophy.

Fatty acid patterns of certain tissue and body fluid lipids of ALD and control cases were investigated by thin layer and gas chromatography. A high percentage (55.2%) of VLFA was found in the ALD brain white matter cholesterol esters; this was mainly due to increased proportions of 26:0, 25:0, 26:1 and greater than 26 C fatty acids. The percentage of VLFA in the white matter cholesterol esters of pathological controls with myelin breakdown of different etiology was low (0.4-7.1%). In the fibroblast total lipids of an ALD patient an increase of 26:0 and 25:0 fatty acids was found. Moderately increased proportions of hexacosanoic acid were observed in the leukocyte total lipids of 2 severely affected ALD patients, but not in a slightly as well as in a possible affected case. No accumulation of VLFA was detected in cholesterol ester, triglyceride and free fatty acid fractions in the CSF of an ALD patient and in ALD serum sphingomyelin. Our results substantiate the specificity of VLFA accumulation in the white matter cholesterol esters of ALD brain and lend some further evidence to the view that a generalized impairment of VLFA metabolism seems to be present in this disease.

Adolescent↗
PubMed1981

Accumulation of very long chain fatty acids is common to 3 variants of adrenoleukodystrophy (ALD). "Classical" ALD, atypical ALD (female patient) and adrenomyeloneuropathy.

Fatty acids of cholesterol esters were analyzed by gas chromatography in affected CNS white matter of 3 variants of ALD ("classical" ALD, atypical ALD (adult female) and AMN) and of 10 controls with myelin breakdown of an etiology other than ALD. In all 3 ALD variants a marked accumulation of very long chain fatty acids (VLFA) as compared to control material was observed. This was due to the accumulation mainly of saturated C24-C32 fatty acids, particularly of C26:0, C25:0 and, to a lesser extent, C24:0 and C27:0 fatty acids. Our results demonstrate for the first time an accumulation of VLFA in an adult female patient (atypical ALD), who probably is an ALD heterozygote rather than a variant of AMN, and confirm and extend earlier findings in classical ALD and AMN, respectively. It appears that ALD may be a single nosological entity with clinically and morphologically different variants sharing specific ultrastructural (accumulation of paired leaflets) and neuro-biochemical (accumulation of VLFA) diagnostic markers.

Addison Disease↗
PubMed1979

Di-, mono- and nonphytanyl triglycerides in the serum: a sensitive parameter of the phytanic acid accumulation in Refsum's disease.

The relative proportions of the diphytanyl, monophytanyl and nonphytanyl triglycerides ("triglyceride pattern"), the phytanic acid content of the triglycerides and the phytanic acid levels in the serum of 3 patients with Refsum's disease (heredopathia atactica polyneuritiformis, phytanic acid storage disease) were estimated by thin-layer chromatography, densitometry and gas chromatography, respectively. The individual triglyceride patterns were clearly dependent on the phytanic acid content of the triglycerides: the more phytanic acid in the triglycerides, the higher the percentage of the diphytanyl and the lower the percentage of the nonphytanyl triglycerides. The monophytanyl triglycerides were also related to the phytanic acid content of the triglycerides, although in a complex manner. The triglyceride pattern can be taken as a parameter of the phytanic acid accumulation in Refsum's disease to be at least as sensitive as the serum phytanic acid level in the biochemical evaluation of the efficiency of the dietary treatment.

Eicosanoic Acids↗
PubMed1979

[Clinical and biochemical follow up of Refsum's disease (author's transl)].

Within a family refered here, two sisters are presenting heredopathia atactica polyneuritiformis (Morbus Refsum) with the complete clinical, electromyographical and serological findings (increased phytanic acid level, accumulation of mono- and diphytanyl, triglycerides). In addition, some symptoms of Refsum's disease are clinically apparent in the eight year old daughter of one of the patients, but significant principal characteristics are absent (dissociation of the spinal fluid, retinopathia pigmentosa, increased phytanic acid level). The phytanic acid level in the serum of ten clinically normal blood relations (three of which are also obligatory heterozygotes) is normal. In both patients with manifest illness we found not only the usual spinal fluid changes with highly increased protein levels (gammaglobulin, IgA- and IgG-fraction) but also a remarkably large number of macrophages with vacuoles. Within almost two years of keeping to a strict diet with low phytanic acid and phytol content, both patients showed a distinct clinical improvement in parallel with a decrease of the phytanic acid level. Even a temporary increase of the phytanic acid level in one of the patients did not cause clinical relapse. Regarding the biochemical control of the course of the disease, the phytanic acid containing triglycerides proved to be a highly sensitive parameter.

Adult↗