Studies on the genotype-phenotype relation in the hph-1 mouse mutant deficient in guanosine triphosphate (GTP) cyclohydrolase I activity.

The guanosine triphosphate (GTP) cyclohydrolase I (GTP-CHI) catalyses the rate-limiting step in the de novo synthesis of tetrahydrobiopterin, a cofactor of three aromatic amino acid hydroxylases, one of which is phenylalanine hydroxylase. The hph-1 mouse mutant deficient in GTP-CHI activity exhibits hyperphenylalaninemia which peculiarly disappears at 3 weeks of age, thus corresponding to the increase in liver GTP-CHI activity. The present gas chromatographic-mass spectrometric analysis of the phenylalanine and catecholamine metabolisms demonstrated the former metabolism to remain disturbed even in adult hph-1, which demonstrated a metabolic basis for sensitivity to the phenylalanine challenge in adult hph-1. A Northern blot analysis showed the hepatic GTP-CHI RNA expression in hph-1 at 2, 3 and 4 weeks of age to parallel the peculiar time course of the enzyme activity previously reported. No mutation was detected in either the coding region or the 5' flanking region (nt.-1 to -746) of the GTP-CHI gene of the hph-1. Further molecular genetic analyses are therefore required to elucidate the mechanism of the peculiar phenotype of hph-1.

Ehlers-Danlos syndrome and congenital heart anomalies.

Two sisters with Ehlers-Danlos syndrome, inherited as an autosomal recessive trait, and congenital heart disease are herein reported. One was a 20-year-old woman with Ehlers-Danlos syndrome and multiple aphthous stomatitis, bronchial asthma, an emphysematous lung, a ventricular septal defect and a bilateral inguinal hernia due to hyperextensibility and joint hypermobility. The other was a 17-year-old girl with the same syndrome and an atrial septal defect, a ventricular septal defect and patent ductus arteriosus. The combination of Ehlers-Danlos syndrome and congenital heart anomalies in these siblings suggest a common genetic defect to be the cause of these diseases.

Primary hypoparathyroidism in Turner's syndrome.

A case of hypoparathyroidism accompanied with Turner's syndrome is reported. On admission, a 44-year-old woman had facial dystonia, deafness, and primary amenorrhea. Laboratory examinations showed a decrease in serum PTH and mosaicism of 45,X and 46,XX(6:34). A brain CT revealed marked calcification in the basal ganglia, cerebellum and periventricular area. Antiparkinsonian drugs were found to be effective for the dystonia. This case therefore suggests that some relationship may exist between intracranial calcification and Turner's syndrome.

Neurosteroids in cerebrospinal fluid in neurologic disorders.

In order to investigate the role of "neurosteroids" in the central nervous system (CNS), cerebrospinal fluid (CSF) levels of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were determined by radioimmunoassay in 57 patients with various neurologic disorders and 26 patients with non-neurologic disorders. The content of CSF DHEA and DHEAS in patients with Guillain-Barré syndrome (GBS), and the content of CSF DHEAS in patients with carcinomatous meningitis were significantly higher as compared to non-neurological control patients. These changes may be explained by the breakdown of blood-nerve barrier in these disorders. A significant positive correlation was observed between DHEAS and total protein in CSF. In males but not females, a negative correlation was observed between CSF DHEAS and aging. The level of CSF DHEAS, but not DHEA, was significantly higher in males than in females.