Smith-Lemli-Opitz syndrome: treatment with cholesterol and bile acids.
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Bile Acids and Salts↗
Biomedical subjects
K Ullrich
Publications and source records attributed to K Ullrich.
Sustained attention in untreated non-PKU-hyperphenylalaninemia.
Twenty-four untreated adolescent and adult patients with non-PKU hyperphenylalaninemia (HPA) (serum Phe levels < 600 mumol/L) and 24 healthy controls matched for age, sex, and IQ were investigated for simple motor reaction time and sustained attention, which are prolonged in patients with mild or classical phenylketonuria (PKU). Patients with HPA were of normal intelligence and did not differ significantly from healthy controls in their test results. For HPA patients, reaction times and sustained attention were not significantly influenced by serum phenylalanine concentrations. We conclude that dietary treatment is not necessary in patients with non-PKU HPA.
Adolescent↗
No fine motor deficits in patients with untreated non-phenylketonuria hyperphenylalaninaemia.
Twenty-four untreated adolescent and adult patients with non-phenylketonuria (PKU) hyperphenylalaninaemia (HPA) (serum phenylalanine levels < 600 mumol l-1) and 24 healthy controls matched for age, sex and IQ were investigated for their neurological outcome, especially for fine motor abilities by the Motor Performance Task. No pathological findings could be revealed by clinical neurological examination. Patients with HPA and healthy controls did not significantly differ in their fine motor performances. These performances were not significantly influenced by serum phenylalanine concentrations. Our results indicate that untreated patients with non-PKU HPA are not at clinically significant risk for developing fine motor deficits and severe neurological impairment. From this point of view a dietary treatment is not necessary in patients with HPA, as recommended most recently.
Adolescent↗
Survival after early treatment for carbamyl phosphate synthetase (CPS) I deficiency associated with increase of intramitochondrial CPS I.
The basis for the benefit of early treatment in urea-cycle defects might be an increase in intramitochondrial mutant enzyme in hepatocytes in the postnatal period. In two siblings with carbamyl phosphate synthetase I (CPS I) deficiency, immunoreactive CPS I was greatly reduced in the liver and no residual enzyme activity was detectable. The elder child died at age 4 days, before the diagnosis of CPS I deficiency was established, but in the younger child, age 9 months, treatment was initiated on the 2nd day of life when ammonia concentration was moderately increased, and she has survived. Intramitochondrial CPS I was substantially higher in this sibling than in the elder sister. The different outcome in the younger patient was probably attributable to prompt treatment after early diagnosis.
Amino Acid Metabolism, Inborn Errors↗
A novel point mutation at codon 269 of the ornithine transcarbamylase (OTC) gene causing neonatal onset of OTC deficiency.
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Codon↗
In vivo study of brain metabolism in galactosemia by 1H and 31P magnetic resonance spectroscopy.
In order to further evaluate different hypotheses concerning brain metabolism in galactosemia, six adult patients aged 18-29 years with classical galactosemia under dietary treatment underwent localized 1H and 31P magnetic resonance spectroscopy (MRS) in addition to conventional T1- and T2-weighted MRI. Galactose-1-phosphate levels in erythrocytes were 1.1-3.7 mg/dl, plasma concentrations of galactitol ranged from 8.4-14.2 mumol/l. Imaging revealed abnormal peripheral myelination in five and enlargement of lateral ventricles in two patients. Brain galactitol in parieto-occipital white matter was below detectability of 1H MRS leading to the assumption that brain concentrations of the free metabolite was well below 1 mmol/kg. Signal intensities of free myo-inositol, which was postulated to be indicative of changes in the second messenger pathway, were within the normal range. MRS data revealed a normal energy status of the brain. In summary 1H and 31P MRS indicated normal metabolite concentrations as compared to healthy controls.
Adolescent↗
In-vivo NMR spectroscopy in patients with phenylketonuria: changes of cerebral phenylalanine levels under dietary treatment.
Localized proton magnetic resonance spectroscopy at short echo times was used to measure phenylalanine (Phe) in parieto-occipital periventricular brain. Six treated adult patients with phenylketonuria were investigated repeatedly following reinstitution of a Phe-restricted diet. Difference spectroscopy clearly enabled the identification of elevated cerebral Phe levels by subtracting spectra obtained from healthy volunteers. Estimates of absolute brain concentrations always yielded values well below the serum levels with ratios [Phe]brain/[Phe]serum ranging from 0.27 to 0.63. A plot of [Phe]brain versus [Phe]serum could be fitted to a straight line (R = 0.90) if [Phe]serum was below 1.3 mM. Measurements at higher serum levels could only be performed in one patient and yielded brain Phe concentrations of 0.63 +/- 0.10 mM suggesting a saturation of the carrier systems. The feasibility to quantify Phe transport across the blood-brain barrier in humans non-invasively employing in-vivo proton spectroscopy can effectively improve the prognostic significance of serum data.
Adolescent↗
Neurological findings in early treated phenylketonuria.
Twenty early treated, normal intelligent patients (IQ: mean 101.4, SD 10.0; age: mean 10.11, SD 1.3 years) with classical phenylketonuria and 20 age-, sex- and IQ-matched healthy controls were investigated for neurological outcome, especially with regard to fine motor ability using the motor performance task ("Motorische Leistungsserie"). No pathological findings were seen on clinical neurological examination. The patient group had significantly poorer results in a concentration task (Test-d-2) as well as in some subtests of the motor performance task. Patients had difficulties in tasks which needed speed and precision of arm-hand-finger movements. High serum phenylalanine concentrations were significantly correlated with these deficiencies in fine motor ability. Our data demonstrated mild neurological impairment even in early and relatively strictly treated patients with phenylketonuria.
Attention↗
Ultrastructural, immunocytochemical and stereological investigation of hepatocytes in a patient with the mutation of the ornithine transcarbamylase gene.
We studied a male newborn suffering from deficiency of ornithine transcarbamylase (OTC) that is due to a G-to-A substitution in codon 269 of the OTC gene. This study intends to define the cell biological mechanisms in this naturally occurring OTC mutation which may explain the mild clinical course in spite of the very low residual enzyme activity. Using immunogold labeling of thawed thin frozen sections of liver from this patient and a control liver, we analyzed the quantitative distribution of several mitochondrial proteins in the cytosol and the mitochondria of hepatocytes. In addition, the absolute volumes and surface densities of mitochondria and peroxisomes were determined. Our results show that the absolute volume of mitochondria in the patient's hepatocytes was increased to 141% (P < 0.001) without any change in the surface density indicating an increased number of mitochondria. In the patient's hepatocytes the peroxisomes were increased in size but not in number. The concentration of OTC was elevated in the cytosol (P < 0.001) and to a lesser extent in mitochondria (P < 0.01) of the patient's hepatocytes thus indicating a doubling of OTC relative to control liver cells. The quantity of OTC in mitochondria was 63% higher in diseased liver cells. By conventional thin section electron microscopy, mitochondria-like structures with poorly defined cristae and an electron-dense matrix were observed in the cytoplasm of the diseased hepatocytes. By immunoelectron microscopy, they contained the cytochrome c oxidase II subunit as well as DNA but lacked OTC, carbamylphosphate synthetase, F1-ATPase beta subunit and catalase. Thus it appears that these structures represent defective and probably degenerating mitochondria. Our data indicate that the reduced enzyme activity of the mutant OTC is partly compensated by an increased amount of enzyme molecules in the cytosol as well as mitochondria combined with an increase in the biogenesis of mitochondria.
Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzin↗
Smith-Lemli-Opitz syndrome diagnosed by using time-of-flight secondary-ion mass spectrometry.
We describe a rapid and sensitive method involving time-of-flight secondary-ion mass spectrometry (TOF-SIMS) for specific laboratory diagnosis of the Smith-Lemli-Opitz syndrome, which is characterized by massive (approximately 1000-fold) accumulation of the biosynthetic cholesterol precursor 7-dehydrocholesterol. Minute amounts of blood (1-50 microL) were extracted with n-hexane, and aliquots were analyzed by TOF-SIMS. 7-Dehydrocholesterol and its isomers were detected at 491.3 mass units ([M + 107Ag]+) and cholesterol at 495.3 mass units ([M + 109Ag]+). Quantitation of 7-dehydrocholesterol and cholesterol was achieved after saponification and addition of stigmasterol as internal standard. Whereas 7-dehydrocholesterol and isomeric dehydrocholesterol were not detectable in controls, the patients revealed concentrations ranging between 0.84 and 1.25 mmol/L. Comparison with results obtained by gas chromatography indicated that quantitation by TOF-SIMS yielded the sum of 7-dehydrocholesterol, isomeric dehydrocholesterol II, and sterol III, the latter two also being increased in the patients. Consistent with quantitation by gas chromatography, the cholesterol concentrations in the patients ranged between 1.54 and 2.12 mmol/L (controls: 6.10 +/- 1.37 mmol/L).
Cholesterol↗
Carbohydrate-deficient glycoprotein syndrome (CDGS)--glycosylation, folding and intracellular transport of newly synthesized glycoproteins.
Carbohydrate-deficient glycoprotein syndrome (CDGS) is a hereditary glycosylation disorder of unknown origin. In this study we used skin fibroblasts from patients with CDGS to study the glycosylation of three well characterized glycoproteins using gel mobility analysis, endoglycosidase treatments and protein folding studies. We show that glycoprotein transport along the secretory pathway was delayed. Dilation of the rough endoplasmic reticulum indicated a retention phenomenon for selected glycoproteins. However, for all examined glycoproteins cotranslational glycosylation in CDGS fibroblasts was normal.
Abnormalities, Multiple↗
Ifosfamide-induced subclinical nephrotoxicity and its potentiation by cisplatinum.
Renal function was assessed in 72 children and adolescents 3.5 to 123 months after completion of chemotherapy employing ifosfamide (n = 39) or ifosfamide plus cisplatinum (n = 33). No patient had preexisting renal parenchymal disease. Whereas reduction in glomerular filtration rate was present in six of 69 patients (8.7%), impairment of tubular transport for phosphate, glucose, and amino acids was more frequent: 32.8% of the patients showed reduction in phosphate reabsorption, and glucose and amino acid reabsorption was lowered in 16.4% and 55.0%, respectively. Elevated sodium excretion was found only occasionally, and there was no evidence of renal tubular acidosis. Proximal tubular damage is related to ifosfamide chemotherapy, but correlation between ifosfamide dose and phosphate reabsorption was not linear. The most severe depletion of phosphate reabsorption was seen in patients treated with both ifosfamide and cisplatinum. On reexamination of phosphate reabsorption after a median interval of 8 months, the majority of patients with initially reduced values showed further deterioration of this function.
Adolescent↗
Effect of L-dopa on pattern visual evoked potentials (P-100) and neuropsychological tests in untreated adult patients with phenylketonuria.
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Adult↗
No white matter abnormalities in untreated patients with persistent hyperphenylalaninaemia: findings in magnetic resonance imaging. German PKU Collaborative Study.
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Adolescent↗
Growth in patients with phenylketonuria.
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Adolescent↗
Screening for lysosomal disorders.
Patients at any age who develop regression of learned skills, onset of dementia, loss of motor control and organ enlargement should be considered for lysosomal screening. Morphological and biochemical screening methods may reinforce the clinical suspicion, but they are not diagnostic. A widespread use of enzyme assays that appear to be related to the clinical problems is recommended.
Humans↗
The use of dichloroacetate in the treatment of overwhelming hypoxic acidosis.
Overwhelming hypoxic acidosis due to poor tissue oxygen delivery from low cardiac output, pulmonary failure, and other causes has devastating effects postoperatively on patient outcome. Whereas conventional therapeutics often can not reverse the downward spiral of these patients, dichloroacetate (DCA) has been shown to be beneficial. This study investigated the metabolic and hemodynamic effects of DCA given after the onset of overwhelming hypoxic acidosis in a canine model. A hypoxically ventilated canine model of severe induced acidosis was established and dogs surviving the development of acidosis were randomized to receive DCA or sodium chloride (NaCl) treatment. Dogs receiving DCA after development of hypoxic lactic acidosis showed no further change in metabolic parameters during the 90-minute treatment period (pH, 7.24 to 7.23; HCO3, 17.7 to 18 mmol/L; lactate, 2.04 to 1.05 mM/L); whereas animals receiving an equivalent sodium load showed progressive, significant deterioration in all parameters (pH, 7.24 to 7.12; HCO3, 16.8 to 13.2 mM/L; lactate, 2.05 to 3.55 mM/L). Myocardial blood flow was significantly increased by hypoxia in all dogs. Finally, cardiac output and stroke volume were significantly increased at 90 minutes by DCA versus control. Myocardial oxygen utilization efficiency (LV work/M VO2) was improved during DCA treatment. DCA, a carboxylic acid, increases pyruvate dehydrogenase activity, thereby enhancing lactate use a metabolic substrate. DCA had an ameliorative metabolic effect, and benefitted myocardial performance without a direct inotropic effect. DCA treatment appears to enhance myocardial performance on a metabolic and not primarily inotropic basis, does not increase the "cost" of myocardial work, and warrants further study.
Acidosis, Lactic↗
Cranial MRI in PKU: evaluation of a critical threshold for blood phenylalanine.
A group of 15 adolescent patients with PKU and good life time blood phenylalanine control was tested for white matter abnormalities on MRI. Five of the patients presented mild to moderate abnormalities in association with blood phenylalanine levels above 5.0 mg/dl. Patients with and without MRI changes could statistically not be discriminated by blood phenylalanine concentrations at the time of investigation as well as by phenylalanine levels of different time periods prior to MRI examination.
Adolescent↗