Patient with neonatal-onset chronic hepatitis presenting with mevalonate kinase deficiency with a novel MVK gene mutation.

A Japanese girl with neonatal-onset chronic hepatitis and systemic inflammation was diagnosed with hyper-immunoglobulinemia D and periodic fever syndrome (HIDS). However, she lacked the typical HIDS features until the age of 32 months. She had compound heterozygous MVK mutations, H380R and A262P, the latter of which was novel. These findings suggest that HIDS patients could lack typical episodes of recurrent fever at the onset and that HIDS should be considered as a possible cause of neonatal-onset chronic hepatitis.

Fluctuating liver functions in siblings with MPV17 mutations and possible improvement associated with dietary and pharmaceutical treatments targeting respiratory chain complex II.

BACKGROUND/AIMS: To describe the clinical and biological findings of two Japanese siblings with novel MPV17 gene mutations (c.451insC/c.509C > T) manifesting hepatic mitochondrial DNA depletion syndrome. METHODS: We observed these brothers and sought to determine the efficacy of treatment targeting respiratory chain complex II for the younger brother. RESULTS: A 3-month-old boy had presented with profound liver dysfunction, failure to thrive, and watery diarrhea. Although he was then placed on a carbohydrate-rich diet, his liver function thereafter fluctuated greatly in association with viral infections, and rapidly deteriorated to liver failure. He underwent liver transplantation at 17 months of age but died at 22 months of age. The younger brother, aged 47 months at the time of this writing, presented with liver dysfunction from 8 months of age. His transaminase levels also fluctuated considerably fluctuations in association with viral infections. At 31 months of age, treatment with succinate and ubiquinone was initiated together with a lipid-rich diet using ketone milk. Thereafter, his transaminase levels normalized and never fluctuated, and the liver histology improved. CONCLUSIONS: These cases suggested that the clinical courses of patients with MPV17 mutations are greatly influenced by viral infections and that dietary and pharmaceutical treatments targeting the mitochondrial respiratory chain complex II may be beneficial in the clinical management of MPV17 mutant patients.

Live birth prevalence of Down syndrome in Tottori, Japan, 1980-1999.

One hundred sixty-four patients with Down syndrome (DS) were confirmed in Tottori Prefecture, Japan, from 1980 to 1999. The sex ratio of 1.52 (99 males and 65 females) was comparable to that reported in previous studies. The live birth prevalence per 1,000 was 1.52 (95% CI: 1.29-1.75) from 1980 to 1999, with a prevalence of 1.34 (95% CI: 1.05-1.63) recorded between 1980 and 1989, and 1.74 (95% CI: 1.37-2.11) between 1990 and 1999. There was no statistically significant change between these two decades (chi(2)-test). Live birth prevalence in these two decades showed a significant increase (chi(2)-test, P < 0.005) compared with that recorded in 1969-1978 in Tottori Prefecture (0.803, 95% CI: 0.677-0.929). Mean ages of mothers at the birth of a DS patient were 31.0 years in 1980-1989 and 32.4 years in 1990-1999 (t-test, no significant difference). Dispersion analysis on the mean age of mothers at birth for patients born between 1969-1978, 1980-1989, and 1990-1999 showed a significant difference (t-test, P < 0.005), while comparing the mean age of mothers in 1969-1978 to those in 1990-1999 also revealed a significant difference (t-test, P < 0.001). Live birth prevalence has increased due to the rise in fertility rates among older women, although maternal age-specific risk rates remain unchanged. The widespread introduction of induced abortion following prenatal diagnosis decreased live birth prevalence of DS largely in European (and a few Asian) countries after 1990, or kept prevalence steady, despite increasing fertility rates among women aged 30 and over. In contrast, all published studies have reported an increase in live birth prevalence of this syndrome in Japan, probably resulting from the fact that prenatal diagnoses are used only exceptionally in this country (due to the negative attitude toward selection of life in Japanese culture).

Cutis laxa with frontoparietal cortical malformation: a novel type of congenital disorder of glycosylation.

This report describes a female infant with cutis laxa, short stature, microcephaly, wide anterior fontanel and bifrontal cortical malformation. Isoelectrofocusing of plasma transferrin and apolipoprotein C-III showed abnormal patterns suggesting defective N- and O-glycosylation. Together with recently reported patients, this patient represents a novel type of congenital disorder of glycosylation.

A possible mechanism of neonatal intrahepatic cholestasis caused by citrin deficiency.

For this study, we investigated why cholestasis develops into neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), and concluded that primary mitochondrial impairment associated with the delayed maturity of bile acid metabolism may contribute to the occurrence of NICCD.

Myocerebrohepatopathy spectrum disorder due to POLG mutations: A clinicopathological report.

We report on the clinical, neuropathological, and genetic findings of a Japanese case with myocerebrohepatopathy spectrum (MCHS) disorder due to polymerase gamma (POLG) mutations. A girl manifested poor sucking and failure to thrive since 4 months of age and had frequent vomiting and developmental regression at 5 months of age. She showed significant hypotonia and hepatomegaly. Laboratory tests showed hepatocellular dysfunction and elevated protein and lactate levels in the cerebrospinal fluid. Her liver function and neurologic condition exacerbated, and she died at 8 months of age. At autopsy, fatty degeneration and fibrosis were observed in the liver. Neuropathological examination revealed white matter-predominant spongy changes with Alzheimer type II glia and loss of myelin. Enzyme activities of the respiratory chain complex I, III, and IV relative to citrate synthase in the muscle were normal in the biopsied muscle tissue, but they were reduced in the liver to 0%, 10%, and 14% of normal values, respectively. In the liver, the copy number of mitochondrial DNA compared to nuclear DNA was reduced to 3.3% of normal values as evaluated by quantitative polymerase chain reaction. Genetic analysis revealed compound heterozygous mutations for POLG (I1185T/A957V). This case represents the differential involvement of multiple organs and phenotype-specific distribution of brain lesions in mitochondrial DNA depletion disorders.

Risk factors for mother-to-child transmission of hepatitis C virus: Maternal high viral load and fetal exposure in the birth canal.

AIM: Mother-to-child transmission (MTCT) is the major transmission pathway of hepatitis C virus (HCV) in children. However, its risk factors remain unsettled for introduction of putative intervention. METHODS: Pregnant women screened for HCV and MTCT in children born to antibody-positive mothers were prospectively studied in Tottori, Japan. RESULTS: Among 41 856 screened women, 188 (0.45%) were HCV antibody-positive, of whom 61% had detectable HCV RNA. While 10 of the 34 children (29%) born to high viral load (HVL: ≥6.0 × 10(5) IU/mL) mothers were infected, none born to RNA-detectable but non-HVL mothers were infected (P < 0.001). MTCT among vaginally delivered children born to HVL mothers was analyzed. Children delivered after 4 h or more of labor were more frequently infected than were those born within 4 h of labor (P = 0.019). Premature rupture of fetal membranes was significantly more common in infected children than in uninfected children (P < 0.001). Durations of membrane rupture and labor were longer in infected children than in uninfected children (P = 0.008 and P = 0.040, respectively). Elective cesarean section that eliminates these risk factors, other than HVL, significantly reduced MTCT from nine of 22 (41%) to none of nine children (0%) (P = 0.032). CONCLUSION: Our data suggest that contamination of the fetus in the birth canal with infected maternal blood is a major risk factor for HCV MTCT, in addition to maternal HVL. To rationalize intervention by elective cesarean section, the natural history of infected children should be carefully evaluated.

Efficacy of pegylated interferon-α2a monotherapy in Japanese children with chronic hepatitis C.

AIM: There is little information available on the efficacy of pegylated interferon (PEG IFN) therapy for children with chronic hepatitis C. The aim of this study was to evaluate the efficacy and tolerability of PEG IFN-α2a monotherapy for children infected by chronic hepatitis C virus (HCV). METHODS: From 2004-2006, we conducted a prospective, open-label, multicenter study of 22 patients aged 4-18 years, including eight with genotype 1 and 14 with genotype 2. None had previously received IFN. The patients were treated with s.c. PEG IFN-α2a at a dose of 3 µg/kg once a week for 48 weeks. Rapid virological response (RVR) was defined as: undetectable serum HCV RNA at week 4; early viral response (EVR) as a 2 or more log reduction or undetectable serum HCV RNA at week 12; and sustained viral response (SVR) as undetectable serum HCV RNA at 24 weeks after the cessation of treatment. RESULTS: SVR was achieved in 10 (45%) of the 22 patients (three with genotype 1, seven with genotype 2). Retrospectively, the patients with SVR included five with RVR (one with genotype 1, four with genotype 2) and five with EVR (two with genotype 1, three with genotype 2). PEG IFN-α2a monotherapy was well tolerated, except in one patient in whom alanine aminotransferase activity flared (>500 IU/L) during treatment. CONCLUSION: The efficacy of PEG IFN-α2a monotherapy in children is similar to that for adults, while tolerability seems to be better in children than in adults.

Epidemiological survey of Japanese children infected with hepatitis B and C viruses.

AIM: The lack of a nationwide survey on hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in Japan led us to investigate the epidemiological profiles of these infections among Japanese children. METHODS: We conducted a questionnaire survey of children (<20 years of age) infected with either HBV (n = 136) or HCV (n = 114), who visited 636 pediatric institutions in Japan from 2003 through 2005. Most HBV-infected subjects (94%) were born in 1986 or after when a nationwide immunization program for infants born to HBe antigen-positive carriers was initiated. The transmission routes were divided into five groups: maternal, horizontal (subdivided into intrafamilial, iatrogenic and other horizontal), and unknown transmission. RESULTS: Comparison of subjects born in 1990 or after and those born in 1989 or before, when anti-HBc and anti-HCV (c100-3) screening tests of blood donors began, showed a shift in the relative proportions of maternal, intrafamilial, iatrogenic, other horizontal, and unknown transmission from 52%, 19%, 4%, 7% and 19% to 70%, 14%, 6%, 1% and 9%, respectively, for HBV, which was statistically insignificant (P = 0.120), and from 14%, 0%, 76%, 4% and 7% to 89%, 2%, 4%, 0% and 5%, respectively, for HCV, which was statistically significant (P < 0.001). HBV horizontal transmission did not decrease in proportion. No transfusion-acquired HCV infection was reported in subjects born in 1993 or after. CONCLUSION: Maternal transmission is a prominent source of HCV infection among Japanese children. The implementation of measures to prevent HBV horizontal infection is also essential, and the present system of selective vaccination should be expanded to universal vaccination.

Histological findings in the livers of patients with neonatal intrahepatic cholestasis caused by citrin deficiency.

AIM: To characterize the histological features of the livers of patients with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), we studied specimens from 30 patients diagnosed with NICCD by genetically analyzing the SLC25A13 gene. METHODS: Liver biopsy specimens were subjected to hematoxylin-eosin, Azan, and Berlin-blue staining. RESULTS: Most specimens showed varying degrees of fibrosis. The degree of inflammation varied among the specimens, with half showing moderate or severe inflammatory changes. Fat deposition in hepatocytes was observed in almost all of the specimens, and severe fatty liver was noted in 20 (67%) of them. There was a mixture of two types of hepatocytes with macrovesicular or microvesicular fat droplets, and cholestasis was observed at a rate of 77%. Hemosiderin deposition, mostly mild and localized in periportal hepatocytes and macrophages in portal areas, was observed in 57% of the specimens. CONCLUSION: A combination of mixed macrovesicular and microvesicular fatty hepatocytes and the above-described findings, such as fatty liver, cholestasis, necroinflammatory reaction and iron deposition, are almost never observed in other liver diseases in infants and adults. We believe that NICCD is a disease with characteristic hepatopathological features.

Associated factors in neonatal hypoglycemic brain injury.

Although associated factors are important for the occurrence of neural damage in neonatal hypoglycemia, they are not fully understood. Sixty patients with neonatal hypoglycemia were studied through a review of their medical records in Tottori University Hospital. The patients were classified into two main groups: Group I were patients who had mental retardation, developmental delay, cerebral palsy or epilepsy while Group II were those who were normal in their follow-up. Group I consisted of 12 patients while Group II consisted of 48 patients. The median gestational age was 38 weeks in Group I and 36.7 weeks in Group II. The frequencies of small for gestational age were similar in both groups. Blood glucose levels less than 15 mg/dl were more frequent in Group 1 (50.0%) than in Group 2 (14.6%) (P=0.015). Duration of hypoglycemia was longer in Group I (median, 14 h) than in Group II (median, 1.75 h) (p<0.001). The following factors were more frequent in Group I than in Group II: toxemia (33.3% and 8.3%, p=0.043), fetal distress (58.3% and 14.5%, p=0.004), an Apgar score of less than 5 at 1 min (33.3% and 6.4%, p=0.025), neonatal seizure (53.8% and 4.3%, p<0.001) and pathological jaundice (41.7% and 6.4%, p=0.006). Cranial CT or MRI revealed cerebral lesions in 8 of the 9 Group I patients in follow-up examinations. This study indicates that severe and prolonged neonatal hypoglycemia can cause cerebral lesions and other perinatal risk factors, such as hypoxia, neonatal seizure and pathological jaundice, would exacerbate hypoglycemic brain injuries.

Clinical heterogeneity of neonatal intrahepatic cholestasis caused by citrin deficiency: case reports from 16 patients.

A deficiency of citrin, which is encoded by the SLC25A13 gene, causes both adult-onset type II citrullinemia (CTLN2) and neonatal intrahepatic cholestasis (NICCD). We analyzed 16 patients with NICCD to clarify the clinical features of the disease. Severe intrahepatic cholestasis with fatty liver was the most common symptom, but the accompanying clinical features were variable, namely; suspected cases of neonatal hepatitis or biliary atresia, positive results from newborn screening, tyrosinemia, failure to thrive, hemolytic anemia, bleeding tendencies and ketotic hypoglycemia. Laboratory data showed elevated serum bile acid levels, hypoproteinemia, low levels of vitamin K-dependent coagulation factors, and hypergalactosemia. Hypercitrullinemia was detected in 11 out of 15 patients examined. Most of the patients were given a lactose-free and/or medium chain triglycerides-enriched formula and lipid-soluble vitamins. The prognosis of the 16 patients is going fairy well at present, but we should observe these patients carefully to see if they manifest any symptom of CTLN2 in the future.