[Inflammatory stage of incontinentia pigmenti (Bloch-Sulzberger syndrome)].
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Biopsy↗
Biomedical subjects
B Assmann
Publications and source records attributed to B Assmann.
Clinical findings and a therapeutic trial in the first patient with beta-ureidopropionase deficiency.
The clinical, neurophysiological and neuroradiological work-up as well as the results of a specific treatment trial are presented of the first patient diagnosed with beta-ureidopropionase deficiency (E.C. 3.5.1.6, McKusick 606673). The patient presented with an early-onset dystonic movement disorder, severe developmental delay with marked impairment of visual responsiveness in combination with severely delayed myelination in magnetic resonance imaging studies. In addition, there were partial optic atrophy, pigmentary retinopathy and mild cerebellar hypoplasia. The enzyme defect was expected to lead to intracerebral deficiency of beta-alanine which seems to be a neuromodulator at inhibitory synapses. Therefore, a therapeutic trial with supplementation of beta-alanine was undertaken over 1.5 years with no convincing clinical improvement.
Amidohydrolases↗
Improvement of CDG diagnosis by combined examination of several glycoproteins.
Congenital disorders of glycosylation (CDG) represent a family of genetic diseases with broad clinical presentation. Initial diagnosis is currently mainly based on the identification of hyposialylated serum transferrin (TF) by isoelectric focusing (IEF). To improve the diagnosis of known CDG types and to identify so far unknown CDG cases, additional glycoproteins, alpha1-antitrypsin titrypsin (alpha1-AT) and alpha1-antichymotrypsin (alpha1-ACT), were studied. According to the patterns of transferrin, enzyme assays and mutation analysis, 16 patients with various clinical symptoms suspicious for CDG were divided into three groups: group A (n = 6) with confirmed CDG; group B (n = 4) with clear abnormal TF-IEF patterns of unknown origin (all known CDG types were excluded) and group C (n = 6) with borderline TF-IEF patterns; 164 samples served as a control group. Automated IEF of TF, alpha1-AT and alpha1-ACT was carried out using a PhastSystem. CDG patients with glycosylation defects of known origin (group A) and patients with abnormal TF-IEF patterns due to glycosylation defects of as yet unknown origin (group B) showed abnormal IEF patterns of all three glycoproteins. These results confirmed generalized defects of glycosylation. Furthermore, the IEF pattern of alpha1-ACT seems to allow a differentiation between CDG Ia and CDG Ic. However, patients with borderline TF-IEF pattern (group C) showed a normal alpha1-AT-IEF pattern. Four of these six patients also showed a normal alpha1-ACT-IEF pattern; this constellation suggests that CDG can most likely be excluded. In the two remaining patients of group C with a borderline TF-IEF pattern an abnormal pattern of alpha1-ACT-IEF was obtained which needs further investigations. We conclude that the combined investigation of three glycoproteins provides additional information in the diagnostic work-up of patients with possible CDG. The suspicion of CDG in patients with apparent glycosylation defects of unknown origin or borderline TF-IEF pattern can be either substantiated or weakened.
Adolescent↗
Looking forward--an evidence-based approach to glutaryl-CoA dehydrogenase deficiency.
Three decades after the first description of glutaryl-CoA dehydrogenase deficiency, major progress has been achieved in the prevention of acute striatal necrosis and neurological sequelae in affected children, if diagnosis is made early and treatment is started before manifestation of acute encephalopathic crises. However, all concepts for diagnostic work-up, monitoring, and treatment are solely experience-based, and 10-35% of early-diagnosed children do not or only incompletely benefit from the current management. They still develop neurological deterioration and sequelae despite early implementation of dietary treatment, carnitine supplementation and emergency treatment during acute intercurrent illnesses. International efforts should be made to move management of affected children from experience-based to evidence-based medicine. Major tools for this optimization are the establishment of an international patients' database, the implementation of an international prospective clinical study, and the development of international guidelines for diagnostic work-up, monitoring and therapy.
Amino Acid Metabolism, Inborn Errors↗
A new case of CDG-x with stereotyped dystonic hand movements and optic atrophy.
We report the clinical findings and the diagnostic work-up of a 17-month-old girl with CDG-x. Predominant clinical signs were, besides psychomotor retardation and truncal hypotonia, stereotyped dystonic hand movements and ophthalmological abnormalities such as optic atrophy, nystagmus and strabismus. Other symptoms that are often found in patients with CDG were not present, such as seizures, microcephaly, cerebellar hypoplasia, dysmorphic features, hepatointestinal disease, coagulopathy or multiorgan involvement. Isoelectric focusing (IEF) of the patient's serum showed a marked elevation of disialotransferrin, thus confirming an IEF type 1 pattern. A generalized glycosylation defect was confirmed also by IEF of a further glycoprotein (alpha1-antitrypsin), an increased carbohydrate deficient transferrin (CDT) serum concentration and an increased CDT/transferrin ratio. All known types of CDG-I, secondary glycosylation abnormalities and variants of amino acid sequence were excluded.
Dystonia↗
Congenital disorder of glycosylation IId (CDG-IId) -- a new entity: clinical presentation with Dandy-Walker malformation and myopathy.
A 1.5-year-old boy with macrocephaly due to a Dandy-Walker malformation presented with progressive hydrocephalus, extensive muscular hypotonia, transient cholestatic syndrome, extensive coagulation abnormalities and elevated creatine kinase indicating myopathy. Diagnostic work-up indicated a congenital disorder of glycosylation (CDG, formerly carbohydrate deficient glycoprotein syndrome). The serum transferrin pattern obtained by automated isoelectric focusing (IEF) showed an hitherto unreported pattern with strongly elevated tri-, di-, mono- and asialotransferrin bands, increasing in this order together with markedly decreased tetrasialotransferrin. Investigation of two additional glycoproteins, alpha(1)-antitrypsin and alpha(1)-antichymotrypsin, confirmed a generalised defect of glycosylation. All known glycosylation defects could be ruled out by enzymatic analyses in either leukocytes or fibroblasts or by the results obtained by IEF. SDS-electrophoresis demonstrated a marked difference in the molecular weight of transferrin, suggesting the lack of parts or of all oligosaccharide chains. The defect could be delineated to a deficiency of beta-1,4-galactosyltransferase (E.C.2.4.1.38) due to a homozygous insertion (1031 - 1032 insC). Details of the biochemical and molecular findings will be described elsewhere.
Adolescent↗
3-Ureidopropionate contributes to the neuropathology of 3-ureidopropionase deficiency and severe propionic aciduria: a hypothesis.
3-Ureidopropionate (3-UPA) is a physiologic metabolite in pyrimidine degradation. Pathological accumulation of 3-UPA in body fluids is found in 3-ureidopropionase deficiency and severe forms of propionic aciduria. Both diseases clinically present with a severe neuropathology involving gray and white matter as well as with a dystonic dyskinetic movement disorder. To date nothing is known about the toxic nature of this metabolite. The aim of the present study was to elucidate whether 3-UPA may act as endogenous neurotoxin. Exposure of cultured chick neurons to 3-UPA induced a concentration- and time-dependent neurodegeneration. Neuronal damage was reduced by the antioxidant alpha-tocopherol and the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. In contrast, the non-NMDA receptor antagonist CNQX, the metabotropic glutamate receptor antagonist L-AP3, and succinate showed no protective effect. Furthermore, 3-UPA elicited an increased production of reactive oxygen species followed by a delayed increase in intracellular calcium concentrations. Activity measurement of single respiratory chain complexes I-V revealed an inhibition of complex V activity, but not of the electron-transferring complexes I-IV by 3-UPA. In contrast, 3-UPA did not affect the mitochondrial beta-oxidation of fatty acids. In conclusion, our results provide strong evidence that 3-UPA acts as endogenous neurotoxin via inhibition of mitochondrial energy metabolism, resulting in the initiation of secondary, energy-dependent excitotoxic mechanisms.
Animals↗
Deficits in haptic perception and right parietal theta power changes in patients with anorexia nervosa before and after weight gain.
OBJECTIVE: Our goal was to investigate whether patients with anorexia nervosa (AN) show deficits in haptic exploration tasks before and after weight gain. METHOD: The haptic exploration tasks consisted of palpating the structure of six sunken reliefs in sequence with both hands, eyes closed. After each exploration, the structure was reproduced on a piece of paper. A 19-channel digital electroencephalogram (EEG; linked ears) was continuously recorded during rest and haptic tasks for 10 AN patients (females, mean age: 15.90) and 10 healthy controls (CO; females, mean age: 16.14). Mean spectral power density was calculated as the mean amplitude of the spectral lines of the theta band (4-8 Hz). The AN patients were examined again after weight gain (T(0) and T(1)). RESULTS: The reproductions submitted by the AN patients were of notably poorer quality than those of the CO. Reproduction quality was unchanged after weight gain and independent of body mass index and intelligence. Mean exploration time was similiar in AN patients and CO. The analysis of spectral EEG power of both groups showed significant decrease in power data in the theta frequency band during haptic exploration compared with the rest intervals. The comparison of the theta power between CO and AN patients during haptic exploration showed major differences between the groups in both T(0) and T(1). Theta power was lower in AN patients than in the CO over the right hemisphere and right parietal regions. DISCUSSION: The quality of reproduction of the haptic stimuli and the theta-power changes indicate a cortical dysfunction and deficits in somatosensory integration processing of the right parietal cortex in AN patients even after weight gain.
Adolescent↗
Detection of beta-ureidopropionase deficiency with HPLC-electrospray tandem mass spectrometry and confirmation of the defect at the enzyme level.
The pyrimidine bases uracil and thymine are degraded via the consecutive action of three enzymes to beta-alanine and beta-aminoisobutyric acid, respectively. To date, a number of patients have been described with a deficiency of dihydropyrimidine dehydrogenase and dihydropyrimidinase, the first two enzymes of the pyrimidine degradation pathway. In this study, we demonstrate that the first patient presenting with N-carbamyl-beta-amino aciduria, due to a deficiency of beta-ureidopropionase, was easily diagnosed at the metabolite level using HPLC-tandem mass spectrometry. Urinary analysis showed strongly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid, with normal or moderately increased levels of the pyrimidine bases and the dihydropyrimidines, respectively. The deficiency of beta-ureidopropionase was confirmed by measuring all three enzymes of the pyrimidine degradation pathway. No activity of beta-ureidopropionase could be detected in a liver biopsy of the patient, while a normal activity of dihydropyrimidine dehydrogenase and dihydropyrimidinase was present. Thus, HPLC-tandem mass specrometry proved to be a powerful tool for the initial diagnosis of patients with deficiency of beta-ureidopropionase.
Amidohydrolases↗
A new subtype of a congenital disorder of glycosylation (CDG) with mild clinical manifestations.
A boy with an unspecific symptomatology consisting of mental retardation, strabismus, hypotonia and mild ataxia was diagnosed with a congenital disorder of glycosylation (CDG). Neither cerebellar atrophy nor dysmorphic features were present. The serum transferrin band pattern obtained by isoelectric focusing(IEF) showed a strongly elevated disialotransferrin band together with only slightly elevated asialotransferrin, thus a type I pattern. This is a new CDG classified CDG-x since CDG-la, -b, -c, -d and -e were excluded. Quantitative differences to the type 1 pattern of a CDG-la patient with a moderate to severe course were confirmed by densitometric evaluation of the gels and by SDS gel electrophoresis. Liver biopsy showed lysosomal inclusions suggesting a pre-Golgi defect. This patient's case supports the approach to include isoelectric focusing of serum transferrin in the diagnostic work-up of patients with unexplained symptoms.
Asialoglycoproteins↗
Haptic perception in anorexia nervosa before and after weight gain.
Haptic perception of patients with anorexia nervosa (n = 10) was analyzed in a longitudinal study (T0-T1). The haptic explorations consisted of palpating the structure of 12 sunken reliefs in sequence with both hands, eyes closed. After each exploration the structure was reproduced on a piece of paper. In the anorexia group, mean exploration time was significantly shorter than in healthy control subjects. However, the reproductions of complex stimuli submitted by the anorexia group were of notably poorer quality than those of the healthy controls. This was also observed after weight gain (T1). The results of the haptic explorations can be interpreted as a cortical dysfunction and deficits in somatosensorical integration processing in patients with anorexia nervosa. This may be due to a disorder of tactual-spatial processing in the right parieto-occipital regions.
Adult↗
Confirmation of the enzyme defect in the first case of beta-ureidopropionase deficiency. Beta-alanine deficiency.
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Abnormalities, Multiple↗
Increased carbohydrate-deficient transferrin concentration and abnormal protein glycosylation of unknown etiology in a patient with achondroplasia.
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Achondroplasia↗
[Haptic perception and EEG changes in anorexia nervosa].
OBJECTIVES: We predicted that due to diminished somatosensory integrative ability, the anorectic patients would have problems reproducing haptic stimuli. In addition we sought to determine whether EEGs from anorectic patients (AN) and the healthy controls (CO) would show discrepancies between the two groups during haptic explorations in theta-power over the right parietal region. METHOD: EEG power (theta-power) data of AN (n = 13) and CO (n = 13) were analyzed during haptic exploration tasks and rest intervals. The haptic explorations consisted of palpating the structure of six sunken reliefs in sequence with both hands, eyes closed. After each exploration the structure was drawn on a piece of paper. RESULTS: The reproductions of haptic stimuli submitted by the anorectic patients were of notably poorer quality than those of the healthy controls. During rest intervals and haptic explorations, spectral power was generally lower in the AN group in comparison to the healthy controls. Significant theta-power differences between groups showed over the right parietal cortex during haptic explorations. The decrease in EEG power in the anorectic patients in the theta bands across the right parietal region during haptic exploration tasks could be interpreted as a minor activation of visuo-spatial regions. The results of the haptic explorations as well as the EEG-power changes indicate a cortical dysfunction and deficits in somatosensory integration processing in anorexia nervosa patients.
Adolescent↗
Adenylosuccinase deficiency: possibly underdiagnosed encephalopathy with variable clinical features.
Adenylosuccinase deficiency is an autosomal recessive inherited defect of purine synthesis. In enzyme deficient patients, two normally undetectable compounds, succinylaminoimidazole carboxamide riboside and succinyladenosine, accumulate in urine, cerebrospinal fluid and, to a minor extent, in plasma. Analysing 150 highly selected urine specimens from patients with unidentified neurogenerative disorders we discovered the first two German cases of adenylosuccinase deficiency. The deficiency causes moderate to severe mental retardation, often accompanied by epileptic seizures and/or autistic features, and is occasionally associated with growth retardation and muscular hypotonia. Of the two German cases we present here, one patient fits into the clinical picture outlined by previous reports. The other patient, however, shows a pattern of symptoms so far undescribed: severe early infantile epileptic encephalopathy with reduced myelination. On mutation analysis this patient is the first to reveal a 39 base pair deletion in the adenylosuccinase gene in contrast to the point mutations detected in previous cases. Adenylosuccinase deficiency may be an underdiagnosed metabolic disorder with variable expression. This should be taken into consideration in patients with unclassified neurological conditions.
Adenylosuccinate Lyase↗
Phosphomannomutase deficiency is the main cause of carbohydrate-deficient glycoprotein syndrome with type I isoelectrofocusing pattern of serum sialotransferrins.
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Congenital Disorders of Glycosylation↗
Dihydropyrimidinase deficiency and congenital microvillous atrophy: coincidence or genetic relation?
We describe a boy of consanguineous parents who suffered from intractable diarrhoea due to congenital microvillous atrophy, a recessively inherited autosomal disorder. He developed severe cholestatis starting at 2 weeks of age and leading to liver cirrhosis. His psychomotor development appeared only slightly delayed. At the age of 7 months he died due to septicaemia. In addition to disturbances of electrolyte balance and renal tubular function, which could be attributed to microvillous atrophy, marked elevations of dihydrouracil and dihydrothymine as well as moderately elevated excretion of uracil and thymine in urine were repeatedly demonstrated, suggesting a disorder of pyrimidine degradation. An enzymatic defect of 5,6-dihydropyrimidine amidohydrolase (EC 3.5.2.2, dihydropyrimidinase, DHP) was demonstrated in liver biopsy. As both of these recessive disorders seem to be extremely rare, it remains speculative, whether he suffered from two independently inherited metabolic diseases or whether this represents a hitherto undescribed contiguous gene syndrome.
Amidohydrolases↗
Determination of creatinine-related urinary uracil excretion in children by high-performance liquid chromatography.
Excretion rates of uracil and thymine in children (n = 140) and circadian rhythms of urinary uracil excretion (n = 9) were investigated by reversed-phase high-performance liquid chromatography with ultraviolet detection. Excretion values were related to urinary creatinine determined by Jaffé's method. Creatinine-related uracil excretion was not dependent on age or sex. The values seemed to be distributed according to a Gaussian graph in both school children and those in hospital. The intra-individual range was 1.32-23.70 mg uracil per g creatinine over a four-day period in one subject. Uracil excretion seems to be somewhat lower during the night.
Adolescent↗