Biomedical subjects
Publications and source records attributed to F Hanefeld.
Combined MRI/MRS studies were performed in 9 girls with Rett syndrome of different ages. NAA, as marker of neuronal tissue, was found to decrease with increasing age. There was no evidence for a defective energy metabolism. The data point towards a probably secondary degenerative process in the pathogenesis of Rett syndrome.
Two children with hemimegalencephaly were examined by magnetic resonance imaging (MRI) and localized proton MR spectroscopy (MRS). In both cases, structural changes in the enlarged hemisphere included pachy- or polymicrogyria and gliosis of white matter. Associated metabolic disturbances included a dramatic reduction of glutamate and N-acetylaspartate (NAA) in white matter. Less severe or no alterations were noted in cortical gray matter, basal ganglia, and cerebellum. The older child (13 years) showed increased myoinositol in both gray and white matter as well as markedly increased choline-containing compounds in gray matter. Both children also had mildly decreased NAA levels in the white matter of the contralateral hemisphere. The spectroscopic findings indicate loss of vital neuroaxonal tissue and glial cell proliferation. Metabolic disturbances were more pronounced in the older child. The normal-appearing hemisphere was mildly affected in both cases.
Morphologic and metabolic abnormalities in six children aged 2-9 years with carbohydrate-deficient glycoprotein (CDG) syndrome were assessed by magnetic resonance imaging (MRI) and localized proton magnetic resonance spectroscopy (MRS). In all patients, MRI revealed pronounced cerebellar atrophy. Follow-up examinations in two patients suggested early onset and rapid progression in the first years of life. Further pathologies comprised Dandy-Walker malformation, atrophy of the pons, brain stem and olives, supratentorial frontotemporal cortical atrophy, slightly dilated ventricles and a small corpus callosum. Two patients presented with small cysts in the white matter. The prominent metabolic abnormality detected by proton MRS in five patients was a reduction in N-acetylaspartate in white matter by more than 20%, indicating loss of vital neuroaxonal tissue. Further findings in white matter were glutamine and gamma-aminobutyrate increases by a factor of 2. One patient with type III CDG syndrome showed the most severe alterations of metabolite concentrations.
The syndrome of autosomal recessive pontocerebellar hypoplasia, microcephaly, severely impaired mental and motor development, and extrapyramidal dyskinesia is a distinct system degeneration, previously designated pontocerebellar hypoplasia type 2 (PCH-2). To further characterize its clinical and neuroimaging features, we compiled data from 10 nonrelated pedigrees. Six pedigrees were Dutch, two Swedish, and two German. All 16 patients showed an identical profile of virtually absent developmental milestones, early-onset severe chorea, and microcephaly together with pontocerebellar hypoplasia. Family distribution supports autosomal recessive transmission. The present data support the PCH-2 phenotype as a distinct neurogenetic entity.
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We report an application of multiprimed polymerase chain reaction (PCR) which allows a rapid, nonradioactive detection of deletions in mitochondrial DNA using EDTA-blood and muscle samples. The use of two primer sets consisting of three forward and five reverse primers, respectively, allows a competitive PCR resulting in significant amplification products only in the presence of deletion-harbouring DNA species. Under the conditions described, deletions causing Kearns-Sayre syndrome (KSS) and progressive external ophthalmoplegia (PEO) have been successfully detected. The location of the primers on mitochondrial DNA used in this study should allow identification and localization of most of the large-scale deletions (i.e. more than 1 kb) of mitochondrial DNA reported so far.
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Giant axonal neuropathy (GAN) is a generalized neurological disorder with accumulation of intermediate filaments in different cell populations. The hallmark are enormous axonal swellings containing densely packed neurofilaments. Clinical symptoms reported so far are mainly limited to the nervous system. We report on a four-year-old girl with clinical and sural nerve biopsy findings typical of GAN. In addition, scanning electron microscopy (SEM) showed longitudinal grooves in the hairs of our patient. This peculiarity so far has only been described in two other patients with GAN. Scanning electron microscopy of hairs therefore may serve as a method of screening in patients suspected of suffering from GAN.
Two patients with DiGeorge syndrome (DGS), one with and one without characteristic dysmorphic facial features, were studied by high resolution banding, fluorescence in situ hybridization (FISH) and quantitative Southern blotting. In both patients, even in the one with no typical facial stigmata, a microdeletion within 22q11.2 was detected. FISH analysis, in particular, is most useful in screening for 22q11.2 segmental monosomy in patients with DGS and DGS-related features.
In a patient with extrapyramidal movement disorder and extremely low creatinine concentrations in serum and urine, in vivo proton magnetic resonance spectroscopy disclosed a generalized depletion of creatinine in the brain. Oral substitution of arginine, a substrate for creatine synthesis, resulted in an increase of brain guanidinoacetate as the immediate precursor of creatine but did not elevate cerebral creatine levels. In contrast, oral substitution of creatine-monohydrate led to a significant increase of brain creatine, a decrease of brain guanidinoacetate, and a normalization of creatinine in serum and urine. Phosphorus magnetic resonance spectroscopy of the brain revealed no detectable creatine-phosphate before oral substitution of creatine and a significant increase afterward. Partial restoration of cerebral creatine concentrations was accompanied by improvement of the patient's neurologic symptoms. This is the first report of a patient with complete creatine deficiency in the brain. Magnetic resonance spectroscopy during arginine and creatine treatment point to an inborn error of creatine biosynthesis at the level of guanidinoacetete-methyltransferase.
Carbohydrate-deficient glycoprotein syndrome type I is a multisystem disease with early severe nervous system involvement. The disease, which is inherited as an autosomal recessive trait, is biochemically characterized by complex defects in the terminal carbohydrate residues of a number of serum glycoproteins. This can be most readily detected in transferrin. A whole genome scan was initiated in order to localize the gene (CDG1) with linkage techniques. We analyzed individuals from 25 CDG1 pedigrees with several highly polymorphic microsatellite markers and after exclusion of about 30% of the genome linkage was detected with markers located in chromosome region 16p. The lod score (Zmax) was above 8 (theta max = 0.00) for several markers in this region. In order to further localize the CDG1 gene, recombination and linkage disequilibrium analyses were performed. Recombination events in some pedigrees indicated that the CDG1 gene is located in a 13 cM interval between microsatellite markers D16S406 and D16S500. Furthermore, allelic association was shown for marker D16S406 indicating that the CDG1 gene is located close to this. No heterogeneity could be detected in the European family material tested by us. The positions of cytogenetically localized flanking markers suggest that the location of the CDG1 gene is in chromosome region 16p13.3-p13.12.
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Morphologic appearance and metabolic disturbances of the brain of a patient with L-2-hydroxyglutaric acidemia were investigated with use of magnetic resonance imaging and localized proton magnetic resonance spectroscopy in vivo. Whereas magnetic resonance imaging revealed increased internal and external cerebrospinal fluid spaces as well as patchy white matter lesions, metabolic deviations included a 50% decrease of N-acetylaspartate (neuronal marker), a 75% increase of myo-inositol (glial marker), and a 40% decrease of choline-containing compounds in white matter relative to age-matched controls. A clinical deterioration of the patient was clearly reflected in a follow-up examination 22 mo later, resulting in a further reduction of N-acetylaspartate and a more pronounced enhancement of myo-inositol. No elevation of lactate was observed. The magnetic resonance spectroscopy findings are in line with a generalized neurodegenerative process in L-2-hydroxyglutaric acidemia but also suggest a defect in phosphatidyl inositol metabolism of glial cells.
Quantitative reference values for the concentrations of organic acids in cerebrospinal fluid (CSF) and plasma, as well as ratios of individual organic acids between CSF and plasma, were determined in twenty-three pairs of samples from pediatric patients. Twenty-six organic acids were present and quantifiable in all or the majority of plasma and CSF specimens (limit of detection 1 mumol/l). There were substantial differences between subgroups of organic acids, best reflected by the ratios of individual acids between CSF and plasma. Metabolites related to fatty acid oxidation were present in CSF in substantially lower amounts than in plasma. Organic acids related to carbohydrate and energy metabolism and to amino acid degradation were present in CSF in equal or slightly lower amounts than in plasma. Finally, some organic acids were found in substantially higher amounts in CSF than in plasma, e.g. glycolate, glycerate, 2,4-dihydroxybutyrate, citrate and isocitrate. Quantitation of organic acids in CSF and plasma should aid diagnosis and monitoring of treatment of patients with organic acid disorders.
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L-2-Hydroxyglutaric acidaemia represents a newly defined inborn error of metabolism, with increased levels of L-2-hydroxyglutaric acid in urine, plasma and cerebrospinal fluid. The concentration in cerebrospinal fluid is higher than in plasma. The other consistent biochemical finding is an increase of lysine in blood and cerebrospinal fluid, but lysine loading does not increase L-2-hydroxyglutaric acid concentration in plasma. This autosomal recessively inherited disease is expressed as progressive ataxia, mental deficiency with subcortical leukoencephalopathy and cerebellar atrophy on magnetic resonance imaging. Since these features were described in 8 patients by Barth and co-workers in 1992, 4 more patients with similar findings have been diagnosed and added to the present series. L-2-Hydroxyglutaric acid is found in only trace amounts on routine gas chromatographic screening in normal persons, and its origin, its fate and even its relevance to normal metabolism are unknown. Therefore its catabolism was studied in normal liver. Incubation of rat liver with L-2-hydroxyglutaric acid did not produce H2O2, which excluded (peroxisomal) L-2-hydroxyacid oxidase as the main route of catabolism. However, L-2-hydroxyglutaric acid is rapidly dehydrogenated if NAD+ is added as a co-factor to the standard reaction medium. This could also be demonstrated in human liver. The preliminary evidence for this enzyme activity in rats and humans, L-2-hydroxyglutaric acid dehydrogenase, is given. Further investigations are required to clarify the possible relevance to the metabolic defect in L-2-hydroxyglutaric acidaemia.