Familial association of intracranial aneurysms and multiple congenital anomalies.

The familial occurrence of intracranial aneurysms and the possible relationship with connective tissue disease are discussed. We studied a large family in which seven members presented with aneurysms. Another family member presented with a subarachnoidal hemorrhage. Two other family members each presented with Marfan's syndrome and an unclassified multiple congenital anomalies syndrome, respectively. The multiplicity of the aneurysms in four members is in excess of that found in sporadic or familial cases with intracranial aneurysms. We suggest a common cause, eg, a connective tissue disorder for both the intracranial aneurysms, the Marfan's syndrome, and the unclassified syndrome.

Red blood cell enzymes in the diagnosis of genetic disease.

Erythrocytes are uniform cells which contain only those proteins that are synthesized during the reticulocyte stage. The relationship of red cell enzymes to gene dosage and gene expression enables the use of red cell enzyme assays to determine the presence or absence of gene defects causing enzyme deficiencies leading to various metabolic diseases; in addition, the mode of inheritance of these defects can frequently be ascertained by analyzing red cell enzymes. However, indirect evidence favoring other enzyme deficiency states can sometimes be obtained from a study of red cell enzyme activities, because apparent enzyme deficiencies may result from the accumulation of inhibitory metabolites formed due to an enzyme deficiency in other tissues. The polymorphic expression of many red cell enzymes lends itself to biochemical analysis which can produce highly accurate and specific diagnostic information.

Simultaneous occurrence of xanthine oxidase and sulfite oxidase deficiency. A molybdenum dependent inborn error of metabolism?

In a 3-week old female child with clinical features including neurologic abnormalities and lens dislocation, xanthinuria co-existed with increased excretion of sulfur compounds (sulfite, S-sulfocysteine, taurine and thio-sulfate). Low xanthine oxidase and absent sulfite oxidase activities were found on liver biopsy. No abnormality was detected in either parent. Both the above enzymes are molybdenum-flavoproteins. Normal serum molybdenum concentration seemed to rule out dietary deficiency or impaired absorption. A defect in the incorporation of the metal into flavoproteins is postulated in this case.

Some kinetic properites of liver ornithine carbamoyl transferase (OCT) in a patient with OCT deficiency.

Some kinetic properties of liver OCT from a patient with OCT deficiency were studied. Contrary to controls, in which two pH optima were observed (pH 7.7 and pH 8.5), only the pH optimum of 8.5 could be demonstrated in our patient. From KM studies at pH 7.7 and pH 8.5, the most striking abnormalities in comparison with human controls were (a) a strongly increased KM (ornithine) at pH 7.7, but less pronounced at pH 8.5, (b) a higher VMAX at pH 8.5 compared with the VMAX at pH 7.7 and (c) the absence of substate inhibition at pH 8.5 to ornithine was elevated up to a concentration above approximately 1.5 mM.

Esterase D: evaluation of a potential derived gene marker for hereditary retinoblastoma.

The gene locus of esterase D is closely linked to that coding for retinoblastoma. When the occurrence of retinoblastoma is based on a chromosome deletion, red cell esterase D might be a potential tumor marker for diagnosing retinoblastoma. This diagnostic utility was tested by measuring total esterase D and differentiating esterase D to its different phenotypes in red cells of patients with bilateral retinoblastoma, unilateral retinoblastoma having a positive family history and unilateral sporadic retinoblastoma. These results are compared with the findings within a group of first degree relatives of these patients and of a reference group of apparently healthy controls. A poor sensitivity and a low positive predictive value were found. So, the conclusion might be drawn that screening of all retinoblastoma patients for esterase D in order to get insight in the weighting of risk of retinoblastoma is very much open to question and due to high cost efficiency ratio might not be recommended.

Tyrosinemia and tyrosyluria in healthy prematures: time courses not vitamin C-dependent.

Tyrosyluria and for a part also tyrosinemia were studied in 60 healthy prematures of various birth weights and gestational ages. The first analyses were performed between the 6th and the 14th day after birth. A normal milk diet was given and the protein-intake was between 3 and 4 g/kg. After the first collection of urine half the patients received extra ascorbic acid, 100 mg/kg daily. Urinary analyses of tyrosine and p-hydroxyphenyl metabolites were performed once a week, until the excretion of p-hydroxyphenylpyruvic plus p-hydroxyphenyllactic acids was lower than 5 mmoles per gram creatinine. In 22 out of the 60 prematures (or 37%) a tyrosyluria of more than 5 mmoles/g creatinine and in 19 out of 44 (43%) patients analysed serum tyrosine was higher than 5 mg/100 ml at first analysis. No inverse correlation between tyrosyluria and tyrosinemia on the one hand and birth weight and gestational age on the other hand existed. But in children with a delayed intra-uterine development the incidence of tyrosyluria was higher as prematurity was more pronounced. Ascorbic acid had no effect on the rate of disappearance of tyrosyluria. It was concluded that the addition of extra vitamin C to the diet of prematures is not useful for the normalization of tyrosine metabolism.

Permanent chemical phenylketonuria and a normal phenylalanine tolerance in two sisters with a normal mental development.

A positive ferric chloride reaction was found at routine examination of the urine of a 14 year old mentally normal girl, admitted for complaints of headache and other meningitis-like symptoms. It turned out that she excreted permanently increased amounts of phenylpyruvic, phenyllactic and o-hydroxyphenylacetic acids, but phenylacetic acid (free plus conjugated) was normal. Fasting serum phenylalanine was not increased nor was urinary phenylalanine. On loading with L-phenylalanine (100 mg/kg) a normal serum phenylalanine response followed, but urinary phenylpyruvic, phenyllactic and o-hydroxyphenylacetic acids increased further. Phenylacetic acid responded too, but remained in the normal range. In addition to the above-mentioned abnormalities the urine contained a still unidentified abnormal acid, which also increased after loading with phenylalanine. Her 12 year old healthy sister showed the same chemical abnormality. Two older brothers and the parents had normal excretions. The enzyme defect has not been identified. As a possibility the defective decarboxylation of phenylpyruvic acid is proposed.

Determination of remifentanil in human heparinised whole blood by tandem mass spectrometry with short-column separation.

For the use in pharmacokinetic studies, a fast and sensitive assay method was developed for the determination of remifentanil in human heparinised whole blood samples of 0.5 ml. The assay method is based on tandem mass spectrometry detection (LC-MS/MS). The limit of quantification is 0.1 ng/ml and linear up to 50 ng/ml. The precision, accuracy, recovery and applicability were found to be adequate for pharmacokinetic studies.