Nobuyuki Mizoguchi

Potential interaction between ritonavir and carbamazepine

Ritonavir (RTV), a protease inhibitor, and carbamazepine (CBZ), an anticonvulsant, were administered concurrently to a patient who had human immunodeficiency virus infection and epilepsy. The combination resulted in elevated serum concentrations of CBZ, with accompanying vomiting, vertigo, and transient liver dysfunction. After discontinuing RTV and reducing the dosage of CBZ, the serum concentration of CBZ returned to the optimal range, symptoms subsided, and liver function returned to baseline. Carbamazepine is metabolized in the liver to a large extent by the cytochrome P450 (CYP) system, especially CYP3A4, 2C8, and 1A2, whereas RTV is metabolized primarily by CYP3A and is a potent inhibitor of this enzyme. Careful clinical monitoring may help prevent adverse drug interactions when these drugs are administered concurrently.

The C677T mutation in the methylenetetrahydrofolate reductase gene contributes to hyperhomocysteinemia in patients taking anticonvulsants

Hyperhomocysteinemia, a possible risk factor for vascular disease can result from folate deficiency due to anticonvulsant therapy. A reaction catalyzed by 5,10-methylenetetrahydrofolate reductase (MTHFR) supplies 5-methyltetrahydrofolate, needed to remethylate homocysteine to methionine. MTHFR gene mutation (C677T) also can lead to hyperhomocysteinemia. We examined interaction between anticonvulsant therapy, C677T homozygosity, serum folate concentration, and plasma total homocysteine (tHcy) concentration in 81 epileptic patients. Patients receiving monotherapy showed no difference in occurrence of hyperhomocysteinemia (tHcy>90th percentile for controls) between homozygotes for C677T and heterozygotes or patients with no mutant MTHFR. No monotherapy patient was folate deficient (<3 ng/ml). Among patients receiving multidrug therapy, hyperhomocysteinemia in homozygotes for C677T occured significantly more often than in heterozygotes or patients with no mutant enzyme (88.9 vs. 21.1%). The same was true for folate deficiency (44.4 vs. 0%). The C677T mutation is closely related to hyperhomocysteinemia and folate deficiency in epileptic patients taking multiple anticonvulsants.

Clinical features and outcome of eight infants with intrahepatic porto-venous shunts detected in neonatal screening for galactosaemia

Of 18 newborn infants found to have persistent galactosaemia and without enzyme deficiencies, intrahepatic porto‐venous (P‐V) shunts were the cause in 8 cases. We retrospectively analysed the clinical and biochemical features of the eight infants. Four patients received prednisolone, one of whom with heart failure owing to arteriovenous shunts also underwent hepatic arterial embolization. The other four patients were merely observed without receiving drug therapy. Regardless of treatment, the P‐V shunts disappeared in five infants before the age of 1 y and persisted in three others. All infants showed mild or moderate abnormalities in liver function tests. None exhibited hyperammonemia or neuropsychiatric symptoms related to the shunts. The data indicated that the prognosis of infants with intrahepatic P‐V shunts is generally good. In the absence of complications related to the P‐V shunts, no treatment other than galactose elimination diet is indicated.

Manganese elevations in blood of children with congenital portosystemic shunts

Abstract Magnetic response imaging has demonstrated increased signal intensities within the basal ganglia in patients with hepatic encephalopathy; the densities are considered to represent manganese deposition. We measured whole blood manganese concentrations in nine children with congenital portosystemic venous shunts detected by screening tests for galactosaemia. Beyond 1 year of age, these patients showed significantly higher manganese concentrations than controls (2.40 ± 0.43 versus 1.48 ± 0.38 μg/dl; P=0.0001). Four of the nine patients were studied by magnetic response imaging. T1-weighted images showed increased signal intensities in the basal ganglia of those four patients, suggesting manganese accumulation. Conclusion Children with congenital portosystemic venous shunts showed manganese elevations in blood and magnetic response imaging changes in the basal ganglia. These children should avoid excessive manganese intake.

Spontaneous disappearance of a middle cranial fossa arachnoid cyst after suppurative meningitis

BACKGROUND Spontaneous disappearance of an arachnoid cyst is very rare, particularly after suppurative meningitis. CASE REPORT A 2-month-old boy with a high fever was diagnosed with suppurative meningitis by cerebrospinal fluid examination. Computed tomography disclosed a large arachnoid cyst in the left middle cranial fossa. Two months later, the meningitis was cured. The arachnoid cyst disappeared with long-term antibiotic therapy alone. CONCLUSION Although an infected arachnoid cyst may disappear with antibiotic treatment alone, careful observation and individualized patient management are essential.

Congenital porto–left renal venous shunt as a cause of galactosaemia

Congenital porto–left renal venous (PRV) shunt was found to be the cause of galactosaemia in four galactosaemic neonates detected by mass screening (Paigen method). The patients did not have hereditary galactosaemias and were diagnosed as having galactosaemia of unknown cause, because porto–systemic venous (PS) shunts had not been recognized. At the time of diagnosis, hypergalactosaemia was not severe (0.44–0.55 mmol/L; 8–10 mg/dl) and plasma concentration of total bile acids (TBA) did not suggest a PS shunt (46–50 μmol/L). However, slightly but consistently increased concentrations of galactose and TBA strongly suggested the presence of a PS shunt, and careful ultrasonographic investigation revealed PRV shunt. We conclude that PRV shunt should be suspected in patients with hypergalactosaemia of unknown cause.

Elevated plasma bile acids in hypergalactosaemic neonates : a diagnostic clue to portosystemic shunts

Abstract To determine whether plasma levels of total bile acids may provide a useful index for hypergalactosaemia due to porto-systemic shunts, these levels were determined in hypergalactosaemic neonates. Increased levels were found in all cases with portohepatic venous or portocaval shunts. The levels of both total bile acids and galactose were normalized when the shunts disappeared on the echograms. Both bile acids and galactose are almost completely absorbed by the liver via the first portal blood passage. Portosystemic shunts contribute to elevated levels of bile acids and galactose. Conclusion Increased plasma levels of total bile acids serve as a diagnostic clue to the presence of porto systemic shunts in neonates with hypergalactosaemia.

Methylenetetrahydrofolate reductase 677C>T mutation and epilepsy

Homocysteine is a sulphur-containing amino acid formed during the metabolism of methionine. Mild to moderate homocysteinaemia has been demonstrated to be a risk factor for vascular thromboembolic disease. Recent studies have demonstrated a common 677C[T mutation in the 5,10methylenetetrahydrofolate reductase (MTHFR) (EC 1.5.1.20) gene, the key enzyme in the transmethylation of homocysteine to methionine (Rozen 1996). This mutation causes thermolability of the reductase enzyme and reduces the activity. Homozygotes for the 677C[T mutation make up 5E18% of di†erent populations and homozygosity predisposes to hyperhomocysteinaemia, especially in the presence of a low plasma folate (Rozen 1996). Although a relationship between severe MTHFR deÐciency and seizures has been reported, there are no reports of a relationship between impaired remethylation of homocysteine due to the 677C[T mutation and epilepsy. We investigated this association in Japanese individuals. We compared the genotypic distribution and prevalence of the mutated MTHFR allele in 90 epileptic patients (mean age 14.8 years ; range 1E40) and 97 healthy adult control subjects without epilepsy (mean age 25 years ; range 20E30). We divided patients into two groups according to the presence of predisposing factors for epilepsy. Idiopathic epileptic patients were considered as a group without predisposing factor. Symptomatic or cryptogenic epileptic patients were considered as the other group with predisposing factors including known central nervous system defect or some developmental delay. Informed consent was obtained from all subjects prior to their participation in the study. After venous blood samples were drawn, genomic DNA was extracted from white blood cells. The presence of the 677C[T MTHFR gene mutation was investigated by ampliÐcation by polymerase chain reaction and digestion of the fragment by endonuclease Hinf I (Frosst et al 1995). FisherIs exact probability test was used to analyse the data. The frequency of the 677C[T mutation in MTHFR was signiÐcantly higher (p \ 0.05) in the symptomatic or cryptogenic epileptic patients than in controls. There was no di†erence in allele frequency between idiopathic epileptic patients and controls (Table 1). Our results suggest that the MTHFR 677C[T mutation might be associated

Galactose metabolites in blood from neonates with and without hypergalactosaemia detected by mass screening

Abstract Concentrations of galactose (Gal) in plasma and galactose metabolites in red blood cells (RBC) were determined in 18 normal neonates and 249 others with hypergalactosaemia according to the Paigen method. Normal neonatal values for plasma Gal, RBC galactose-1-phosphate (Gal-1-P), RBC uridine diphosphate glucose (UDP-Glc), and RBC uridine diphosphate galactose (UDP-Gal) were 0.96 ± 0.71 mg/dl, 1.69 ± 1.45 mg/dl of packed RBC, 1.00 ± 0.45 mg/dl of packed RBC, and 1.44 ± 0.45 mg/dl of packed RBC, respectively. The UDP-Gal concentration was higher and the UDP-Glc concentration lower than previously reported in normal children. Of the 249 cases with excessive Gal in whole blood, 23 showed high Gal concentrations in plasma; among these, four portacaval shunts and one case of congenital biliary atresia were diagnosed. In subjects homozygous or heterozygous for UDP-Gal-4 epimerase deficiency, concentrations of UDP-Gal and Gal-1-P were elevated only in RBC, corresponding to restriction of the metabolic abnormality to these cells. Most cases of hypergalactosaemia detected by the Paigen method have large excesses of Gal-1-P in RBC. Although a specific diagnosis based solely on blood Gal metabolites is difficult, individual concentrations reflect underlying conditions to some extent. Conclusion In neonates, uridine diphosphate galactose concentrations were higher and uridine diphosphate glucose concentrations were lower than previously reported paediatric values. Patients with high plasma galactose concentrations should be investigated by hepatic imaging.

Betaine and homocysteine concentrations in infant formulae and breast milk

Abstract Background : Early diagnosis and treatment of homocystinuria with methionine‐free or low methionine formulae significantly improve prognosis in children found by newborn screening and treated soon after birth. Betaine (Bet) supplementation is also an effective strategy for dietary treatment of homocystinuria. However, previous reports on diet therapy have only examined methionine and cysteine concentrations but not those of Bet and homocysteine (Hcy) in infant diets.