Sustaining hypercitrullinemia, hypercholesterolemia and augmented oxidative stress in Japanese children with aspartate/glutamate carrier isoform 2-citrin-deficiency even during the silent period.

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) shows diverse metabolic abnormalities such as urea cycle dysfunction together with citrullinemia, galactosemia, and suppressed gluconeogenesis. Such abnormalities apparently resolve during the first year of life. However, metabolic profiles of the silent period remain unknown. We analyzed oxidative stress markers and profiles of amino acids, carbohydrates, and lipids in 20 asymptomatic children with aspartate/glutamate carrier isoform 2-citrin-deficiency aged 1-10 years, for whom tests showed normal liver function. Despite normal plasma ammonia levels, the affected children showed higher blood levels of ornithine (p<0.001) and citrulline (p<0.01)--amino acids involved in the urea cycle--than healthy children. Blood levels of nitrite/nitrate, metabolites of nitric oxide (NO), and asymmetric dimethylarginine inhibiting NO production from arginine were not different between these two groups. Blood glucose, galactose, pyruvate, and lactate levels after 4-5h fasting were not different between these groups, but the affected group showed a significantly higher lactate to pyruvate ratio. Low-density and high-density lipoprotein cholesterol levels in the affected group were 1.5 times higher than those in the controls. Plasma oxidized low-density lipoprotein apparently increased in the affected children; their levels of urinary oxidative stress markers such as 8-hydroxy-2'-deoxyguanosine and acrolein-lysine were significantly higher than those in the controls. Results of this study showed, even during the silent period, sustained hypercitrullinemia, hypercholesterolemia, and augmented oxidative stress in children with citrin deficiency.

Craniotabes in normal newborns: the earliest sign of subclinical vitamin D deficiency.

CONTEXT: Craniotabes in otherwise normal neonates has been regarded as physiological and left untreated. OBJECTIVE: Our objective was to investigate the role of vitamin D deficiency in the development of craniotabes in normal neonates. DESIGN AND SETTING: Newborn screening of craniotabes was conducted at the single largest obstetrical facility in Kyoto, Japan. Follow-up study at 1 month was conducted at Kyoto University Hospital. SUBJECTS: A total of 1120 consecutive normal Japanese neonates born in May, 2006, through April, 2007, were included in the study. MAIN OUTCOME MEASURES: The incidence of craniotabes was scored each month. Neonates with craniotabes were followed up at 1 month with measurements of serum calcium, phosphorus, alkaline phosphatase (ALP), intact PTH, 25-OH vitamin D (25-OHD), urinary calcium, phosphorus, creatinine, and hand x-rays. RESULTS: Craniotabes was present in 246 (22.0%) neonates, and the incidence had obvious seasonal variations, highest in April-May and lowest in November. At 1 month, infants with craniotabes had significantly higher serum ALP compared with normal neonates; 6.9% of them had elevated intact PTH over 60 pg/ml, and 37.3% had 25-OHD less than 10 ng/ml. When separately analyzed according to the method of feeding, 56.9% of breast-fed infants showed 25-OHD less than 10 ng/ml, whereas none of formula/mixed-fed infants did, and breast-fed infants had significantly higher serum PTH and ALP compared with formula/mixed-fed infants. SUMMARY: These results suggest that craniotabes in normal neonates is associated with vitamin D deficiency in utero, and the deficiency persists at 1 month in many of them, especially when breast-fed.

Lipoprotein profiles in children with two common cholesteryl ester transfer protein gene mutations, D442G and I14A, during the first year of life.

BACKGROUND: Hyperalphalipoproteinemia is associated with cholesteryl ester transfer protein (CETP) deficiency in adults but has unclear associations in children. METHODS: We measured lipoproteins in 19 heterozygotes (D442G, n=17; I14A, n=2), one D442G/I14A compound heterozygote, 13 non-affected siblings, and 30 healthy controls at birth, 3-4 months, and 12 months. RESULTS: CETP mass was 32-70% lower in heterozygotes than in controls throughout the year. Low-density lipoprotein-cholesterol (LDL-C) was lower in heterozygotes than in controls by 30, 20, and 15% at birth, 3-4 months, and 12 months, respectively. High-density lipoprotein-cholesterol (HDL-C) was similar among the groups at birth, but was 10% higher in heterozygotes compared with controls at 3-4 and 12 months. ApoE-rich HDL-C was similar between the two groups at birth, but was 50% higher in heterozygotes than in controls at 3-4 and 12 months. These lipoprotein profile characteristics were prominent in the compound heterozygote but were not found in non-affected siblings. In heterozygotes, CETP mass correlated positively with LDL-C but negatively with HDL-C at 3-4 and 12 months. CONCLUSION: CETP is a determinant for LDL-C and HDL-C in CETP-deficient individuals in the first year of life.

Fibrillin I gene polymorphism is associated with tall stature of normal individuals.

In order to test the hypothesis that polymorphisms of the Marfan syndrome gene (FBN1) might affect the stature (height) of normal individuals, we genotyped three exonic SNPs on 428 males, 219 with tall stature (>2 SD) and 209 with normal stature (within +/-1 SD). One of the SNPs, rs8033037, in exon 15 showed a significant correlation (P = 0.0061) with the adult height, suggesting that FBN1 is one of the 'stature genes' of normal individuals.