Clinical and molecular basis of hepatocerebral mitochondrial DNA depletion syndrome in Japan: evaluation of outcomes after liver transplantation.

BACKGROUND: Hepatocerebral mitochondrial DNA depletion syndrome (MTDPS) is a disease caused by defects in mitochondrial DNA maintenance and leads to liver failure and neurological complications during infancy. Liver transplantation (LT) remains controversial due to poor outcomes associated with extrahepatic symptoms. The purposes of this study were to clarify the current clinical and molecular features of hepatocerebral MTDPS and to evaluate the outcomes of LT in MTDPS patients in Japan. RESULTS: We retrospectively assessed the clinical and genetic findings, as well as the clinical courses, of 23 hepatocerebral MTDPS patients from a pool of 999 patients who were diagnosed with mitochondrial diseases between 2007 and 2019. Causative genes were identified in 18 of 23 patients: MPV17 (n = 13), DGUOK (n = 3), POLG (n = 1), and MICOS13 (n = 1). Eight MPV17-deficient patients harbored c.451dupC and all three DGUOK-deficient patients harbored c.143-307_170del335. The most common initial manifestation was failure to thrive (n = 13, 56.5%). The most frequent liver symptom was cholestasis (n = 21, 91.3%). LT was performed on 12 patients, including nine MPV17-deficient and two DGUOK-deficient patients. Among the 12 transplanted patients, five, including one with mild intellectual disability, survived; while seven who had remarkable neurological symptoms before LT died. Five of the MPV17-deficient survivors had either c.149G > A or c.293C > T. CONCLUSIONS: MPV17 was the most common genetic cause of hepatocerebral MTDPS. The outcome of LT for MTDPS was not favorable, as previously reported, however, patients harboring MPV17 mutations associated with mild phenotypes such as c.149G > A or c.293C > T, and exhibiting no marked neurologic manifestations before LT, had a better prognosis after LT.

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.

Fat areas on the extremities in normal weight and overweight children and adolescents: Comparison between age-related and weight-related changes in adiposity.

The purpose of the study was to compare changes in fat distribution in association with obesity and puberty in adolescent boys and girls. Fat areas at the ulnar, triceps, thigh, and calf regions were measured in normal weight prepubertal children (P) and adolescents (N), and overweight adolescents (O). There were significant differences in fat areas at the four sites between N and O of both sexes, especially in the proximal extremities (triceps, thigh) in boys. On the other hand, fat areas on the extremities of N boys and girls were not significantly different from those of P children except for thigh fat area in girls. It is suggested that pubertal maturation in girls, but not in boys, is associated with increased adiposity on the legs, particularly in the proximal regions, and that there are sex differences between changes in fat distribution associated with puberty and obesity. © 1996 Wiley-Liss, Inc.

Usefulness of a stature-based standard of skinfold thickness, especially for short children.

Skinfold thicknessess (SFT) were measured at ulnar, triceps, subscapular and suprailiac sites in 730 boys and 724 girls (age 3-12 years) whose stature ranged from 100 to 150 cm and whose weight was within ±20% of the average. Means and standard deviation (SD) were calculated after logarithmic transformation of the original skinfold readings to demonstrate stature-based standards of SFT in Japanese children. The means of SFT exhibited nadirs (boys/ girls: ulnar 5.1/5.9 mm, triceps 7.9/9.5 mm, subscapular 4.9/6.1 mm, suprailiac 4.5/6.2 mm) in subjects 110-115 cm tall except for ulnar SFT in girls. SFT values increased as children increased in stature. Standard deviations of SFT at the four sites in short children (staturte < mean -1 SD) were estimated using the stature-based standard as well as an age-based standard. Susms of the SDs assessed by the age-based standard were significantly smaller than those assessed by the stature-based standard in boys (P < 0.05) and girls (P < 0.01) with short stature, suggesting that SFT in short children was falsely understimated by the age-based standard. Thus, the stature-based standard is beneficial for the assessment of SFT, especially in children whose stature is below the mean --1 SD. © 1995 Wiley-Liss, Inc.

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.

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.

Five- and 10-year survival rates after surgery for biliary atresia: a report from the Japanese Biliary Atresia Registry.

PURPOSE: The aim of this study was to elucidate the epidemiology and short- and long-term results of biliary atresia in Japan analyzing the data of the Japanese Biliary Atresia Registry (JBAR). METHODS: In 1989, the Japanese Biliary Atresia Society started a nationwide registry, JBAR, to investigate all aspects of biliary atresia. A total of 1,381 patients, 863 girls, 507 boys, and 11 unknown, were registered between 1989 and 1999. JBAR includes an initial and follow-up questionnaires. Using these patients' data, the incidence, sex distribution, associated anomalies, the type of obstruction, the type of operation, and the surgical results were evaluated. The 5- and the 10-year results of 735 patients who were registered initially in or before 1994 also were analyzed. RESULTS: The incidence of biliary atresia was 1 in 9,640 live births. One hundred sixty-four patients (11.9%) had type I atresia of the common bile duct, 34 (2.5%) had type II atresia of the hepatic ducts, and 1,162 (84.1%) had type III atresia at the porta hepatis. Congenital associated anomalies were found in 19.6% of the patients including 33 cases associated with polysplenia. Impact of the age at operation on bile flow was not clear until 90 days of age, and after 90 days the bile flow rate worsened. The original Roux-en-Y procedure had been used in more than 50% of the patients since 1995. In 1999, 96% of the patients underwent the original Roux-en-Y procedure or the Roux-en-Y with an intestinal valve, and only 3 patients (3.5%) underwent other modifications. There were no significant differences in either the rate of disappearance of jaundice or the incidence of cholangitis among these 3 procedures. Of the 735 patients registered in or before 1994, 19 patients (2.6%) were lost to follow-up. The 5-year survival rates of patients registered in 1989, 1990, 1991, 1992, 1993, and 1994 were 62%, 64.5%, 61.3%, 59.0%, 58.7%, and 52.7% without liver transplantation (LTx), and 69.4%, 74.2%, 75.2%, 79.5%, 78%, and 78.3% with LTx, respectively. Although the overall 5-year survival rate changed from 69.4% to 78.3%, the difference was not statistically significant. According to the 10-year follow-up results of the 108 patients initially registered in 1989, 72 (66.7%) and 57 (52.8%) survived with and without the aid of LTx, respectively. CONCLUSIONS: The overall 5- and 10-year survival rates were 75.3% (553 of 734) and 66.7% (72 of 108), respectively. In spite of the increasing number of survivors after LTx, there was no significant improvement in the 5-year survival rate. It was shown that the JBAR system was functioning well with only 19 patients lost to follow-up among the 743 patients registered from 1989 to 1994.