Incidence of menstrual cycle abnormalities and polycystic ovary syndrome in female Japanese patients with type 1 diabetes mellitus. The role of androgens.

Type 1 diabetes mellitus (T1DM) adversely affects gonadal function. This study aimed to define the characteristics and factors associated with menstrual cycle abnormalities and polycystic ovary syndrome (PCOS) in Japanese patients with T1DM. Our study enrolled 157 patients, including 55 with oligomenorrhea (prolonged menstrual cycle) and 102 without oligomenorrhea. LH/FSH ratio (p = 0.04) and total testosterone levels (p = 0.03) were significantly higher in the oligomenorrhea group than in the non-oligomenorrhea group. No significant differences were found between the two groups regarding age at menarche, age at T1DM diagnosis, treatment, glycated hemoglobin, or total daily insulin dose. Of the 55 patients in the oligomenorrhea group, 27 were diagnosed with PCOS based on the Rotterdam criteria. We concluded that female patients with T1DM, as well as abnormal menstrual cycles and hyperandrogenism, may suffer from undiagnosed PCOS and should be referred to a gynecologist for full assessment, diagnosis, and treatment.

Changes in FeNO, d-ROMs, and BH4 by Intravenous L-Arginine in Children and Its Putative Role in Asthma Treatment.

Purpose: Pteridines are metabolites of tetrahydrobiopterin (BH4), being coenzymes for nitric oxide synthase (NOS). No study has clarified the relationship among pteridines and NOS, fractional exhaled nitric oxide (FeNO) generated by pteridines, and reactive oxygen species. In this study, we administered arginine, a precursor of NO, and confirmed changes in the levels of pteridines, FeNO, and reactive oxygen species and their relationship to clarify the pathogenesis of airway inflammation in which oxidative stress is involved, such as bronchial asthma. Patients and Methods: This is a prospective, randomized open-label study. Children, aged 2 to 15 years, who were scheduled for growth hormone stimulation tests and were able to undergo a respiratory function test were recruited. They were randomly divided into two groups: arginine-administered and control groups. In the former, L-arginine hydrochloride was intravenously administered. After administration, the levels of diacron-reactive oxygen metabolites (d-ROMs), serum pteridines, serum amino acids, and fractional exhaled NO (FeNO) were measured. Results: We analyzed 15 children aged 4 to 14 years. In the arginine-administered group, there was an increase in the FeNO level and a decrease in the d-ROMs level, reaching a peak 30 min after administration, compared with the control group. In addition, there was a decrease in the serum biopterin level and an increase in the d-ROMs level, reaching peak 60 min after administration. Conclusion: The administration of L-arginine increased the NO level and decreased the d-ROMs level. Due to this, biopterin may be consumed and decreased, leading to an increase in the d-ROMs level. As a reduction in reactive oxygen species leads to the relief of inflammation, arginine and biopterin may be useful for inhibiting inflammation.

α-L-iduronidase fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa) for mucopolysaccharidosis type I: A phase 1/2 trial.

Mucopolysaccharidosis type I (MPS I) causes systemic accumulation of glycosaminoglycans due to a genetic deficiency of α-L-iduronidase (IDUA), which results in progressive systemic symptoms affecting multiple organs, including the central nervous system (CNS). Because the blood-brain barrier (BBB) prevents enzymes from reaching the brain, enzyme replacement therapy is effective only against the somatic symptoms. Hematopoietic stem cell transplantation can address the CNS symptoms, but the risk of complications limits its applicability. We have developed a novel genetically modified protein consisting of IDUA fused with humanized anti-human transferrin receptor antibody (lepunafusp alfa; JR-171), which has been shown in nonclinical studies to be distributed to major organs, including the brain, bringing about systemic reductions in heparan sulfate (HS) and dermatan sulfate concentrations. Subsequently, a first-in-human study was conducted to evaluate the safety, pharmacokinetics, and exploratory efficacy of JR-171 in 18 patients with MPS I. No notable safety issues were observed. Plasma drug concentration increased dose dependently and reached its maximum approximately 4 h after the end of drug administration. Decreased HS in the cerebrospinal fluid suggested successful delivery of JR-171 across the BBB, while suppressed urine and serum concentrations of the substrates indicated that its somatic efficacy was comparable to that of laronidase.

Intracerebroventricular enzyme replacement therapy in patients with neuronopathic mucopolysaccharidosis type II: Final report of 5-year results from a Japanese open-label phase 1/2 study.

Intravenous idursulfase is standard treatment for mucopolysaccharidosis II (MPS II) in Japan. In the interim analysis of this open-label, phase 1/2 study (Center for Clinical Trials, Japan Medical Association: JMA-IIA00350), intracerebroventricular (ICV) idursulfase beta was well tolerated, suppressed cerebrospinal fluid (CSF) heparan sulfate (HS) levels, and stabilized developmental decline over 100 weeks in Japanese children with MPS II. Here, we report the final study results, representing 5 years of ICV idursulfase beta treatment. Six male patients with MPS II and developmental delay were enrolled starting in June 2016 and followed until March 2021. Patients received up to 30 mg ICV idursulfase beta every 4 weeks. Outcomes included CSF HS levels, developmental age (DA) (assessed by the Kyoto Scale of Psychological Development), and safety (adverse events). Monitoring by laboratory biochemistry tests, urinary uronic tests, immunogenicity tests, and head computed tomography or magnetic resonance imaging were also conducted regularly. Following ICV idursulfase beta administration, mean CSF HS concentrations decreased from 7.75 µg/mL at baseline to 2.15 µg/mL at final injection (72.3% reduction). Mean DA increased from 23.2 months at screening to 36.0 months at final observation. In five patients with null mutations, mean DA at the final observation was higher than or did not regress compared with that of historical controls receiving intravenous idursulfase only, and the change in DA was greater in patients who started administration aged ≤3 years than in those aged >3 years (+28.7 vs -6.5 months). The difference in DA change versus historical controls in individual patients was +39.5, +40.8, +17.8, +10.5, +7.6 and - 4.5 (mean + 18.6). Common ICV idursulfase beta-related adverse events were vomiting, pyrexia, gastroenteritis, and upper respiratory tract infection (most mild/moderate). These results suggest that long-term ICV idursulfase beta treatment improved neurological symptoms in Japanese children with neuronopathic MPS II.

Treatment strategy for maturity-onset diabetes of the young 3 (MODY3): Experience with two sisters and their mother.

Maturity onset diabetes of the young (MODY) is a relatively young-onset diabetes mellitus with an autosomal dominant inheritance. Among these phenotypes, MODY3, caused by mutations in HNF1A, is one of the most frequent. Although MODY3 is known to respond markedly to sulfonylureas (SU), many cases require insulin therapy. However, there are no clear guidelines for factors to consider when introducing antidiabetic drugs and insulin. This report describes a familial case in which an older sister was diagnosed with diabetes and subsequently with MODY3, followed by the onset of diabetes in the younger sister and mother. The elder sister initially denied insulin treatment and exhibited a suboptimal response to SU but finally agreed to insulin use. The mother initially selected insulin therapy because of the challenges associated with adherence to strict dietary therapy. Conversely, the younger sister responded positively to SU and maintained effective glycemic control. The management of MODY3, even though they have the same single-gene mutation and similar residual insulin secretion at diagnosis, should be flexibly individualized for each family member to ensure long-term adherence and appropriate glycemic control.

Two-year interim safety and efficacy of pegvaliase in Japanese adults with phenylketonuria.

Phenylketonuria (PKU) is an inborn error of metabolism caused by deficiency of phenylalanine hydroxylase, resulting in high blood phenylalanine (Phe) concentrations with potential for impaired neurocognition. Pegvaliase, a pegylated recombinant phenylalanine ammonia lyase that metabolizes Phe, is approved for use in adults with PKU and high blood Phe despite prior management. In the Phase 3 PRISM studies conducted in the United States, pegvaliase induction/titration/maintenance dosing led to clinically meaningful and statistically significant blood Phe reductions versus placebo, with a manageable safety profile. Here we report the primary endpoint, change in blood Phe levels from baseline to Week 52, and 2-year interim efficacy and safety results (to Week 144; data cut-off March 31, 2022) of an ongoing, open-label study in a Japanese PKU population (JapicCTI-194,642). Participants were 12 adults with PKU from Japan aged 18-70 years with blood Phe levels >600 µmol/L. In Part 1, participants received subcutaneous 2.5 mg pegvaliase once weekly for 4 weeks (induction), followed by titration up to 20 mg/day, then dose adjustment to a maximum 40 mg/day to achieve blood Phe efficacy (≤360 µmol/L); this maintenance dose was continued to Week 52. In Part 2, participants continued pegvaliase with dose adjustments up to a maximum 60 mg/day for up to 168 weeks. Among 11 participants evaluable for efficacy, mean (standard deviation) blood Phe concentration decreased from 1025.9 (172.7) µmol/L at baseline to 448.3 (458.8) µmol/L at Week 52 (mean 57.5% decrease). Up to Week 104, all 11 (100%) efficacy-evaluable participants achieved blood Phe levels ≤600 µmol/L, 9 (81.8%) achieved ≤360 µmol/L, and 8 (72.7%) achieved ≤120 µmol/L. All 12 participants reported ≥1 adverse event (AE), most commonly injection site erythema and injection site swelling (n = 10, 83.3% each). The pegvaliase exposure-adjusted AE rate was 23.5 per person-years overall, 41.2 per person-years during induction/titration, and 13.5 per person-years during maintenance. All participants developed pegvaliase-induced antibody responses. There were no AEs leading to discontinuation, no deaths, and no anaphylaxis events. Although interim, these results support the use of pegvaliase in Japanese adults with PKU with elevated blood Phe levels and are consistent with results from the Phase 3 PRISM studies.

Oculofaciocardiodental syndrome caused by a novel BCOR variant.

Oculofaciocardiodental syndrome is caused by variants in the BCL6 corepressor (BCOR) gene. We identified a novel heterozygous frameshift variant, NM_001123385.2(BCOR):c.2326del, that arose de novo in a Japanese girl with characteristic facial features, congenital heart disease, bilateral syndactyly of toes 2 and 3, congenital cataracts, dental abnormalities, and mild intellectual disability. Reports of BCOR variants are rare, and further case accumulation is warranted.

Blood glucose trends in glycogen storage disease type Ia: A cross-sectional study.

BACKGROUND: Glycogen storage disease type Ia (GSDIa) is caused by biallelic pathogenic variants in the glucose-6-phosphatase gene (G6PC) and mainly characterized by hypoglycemia, hepatomegaly, and renal insufficiency. Although its symptoms are reportedly mild in patients carrying the G6PC c.648G>T variant, the predominant variant in Japanese patients, details remain unclear. Therefore, we examined continuous glucose monitoring (CGM) data and daily nutritional intake to clarify their associations in Japanese patients with GSDIa with G6PC c.648G>T. METHODS: This cross-sectional study enrolled 32 patients across 10 hospitals. CGM was performed for 14 days, and nutritional intake was recorded using electronic diaries. Patients were divided according to genotype (homozygous/compound heterozygous) and age. The durations of biochemical hypoglycemia and corresponding nutritional intake were analyzed. Multiple regression analysis was performed to identify factors associated with the duration of biochemical hypoglycemia. RESULTS: Data were analyzed for 30 patients. The mean daily duration of hypoglycemia (<4.0 mmol/L) in the homozygous group increased with age (2-11 years [N = 8]: 79.8 min; 12-18 years [5]: 84.8 min; ≥19 years [10]: 131.5 min). No severe hypoglycemic symptoms were recorded in the patients' diaries. The mean frequency of snack intake was approximately three times greater in patients aged 2-11 years (7.1 times/day) than in those aged 12-18 years (1.9 times/day) or ≥19 years (2.2 times/day). Total cholesterol and lactate were independently associated with the duration of biochemical hypoglycemia. CONCLUSION: Although nutritional therapy prevents severe hypoglycemia in patients with GSDIa with G6PC c.648G>T, patients often experience asymptomatic hypoglycemia.

Delayed recognition of autism spectrum disorder and attention-deficit/hyperactivity disorder in a girl with ornithine transcarbamylase deficiency: A case report.

RATIONALE: Ornithine transcarbamylase (OTC) deficiency, a urea cycle disorder, is a rare congenital metabolic error that leads to hyperammonemia. Psychiatric symptoms of hyperammonemia are nonspecific and can cause autism spectrum disorder (ASD)-like symptoms and attention-deficit/hyperactivity disorder (ADHD)-like symptoms. Some studies report that OTC deficiency is often initially diagnosed as ASD or ADHD. However, there are no reports of OTC deficiency comorbid with ASD and ADHD. PATIENT CONCERNS: The patient is 17-year-old girl diagnosed with OTC deficiency at 3 years of age. She had behavioral problems since childhood, including depressed mood, irritability, and impulsive behavior; however, they were considered OTC-mediated nonspecific psychiatric symptoms. Therefore, the patient had not been appropriately assessed for ASD and ADHD. She presented with depressed mood and self-harm at 17 years of age. DIAGNOSES: We diagnosed her with ASD and ADHD based on her medical history and semistructured interviews. INTERVENTIONS: We focused her ASD and ADHD traits and discussed strategies with her for better adaptive living. OUTCOMES: Our interventions resulted in her better social adjustment. LESSONS: Physicians should consider the possibility of comorbid ASD and ADHD in individuals with OTC, facilitating appropriate and intervention for better outcomes.

A favorable impression of vaccination leads to a better vaccination rate for the human papillomavirus vaccine: A Japanese questionnaire survey investigation.

Background: The Japanese vaccination rate for infants and children is seemingly excellent, except for the human papillomavirus (HPV) vaccine. Regardless of its efficacy, the inoculation rate in Japan has dropped to approximately 1 % since 2013 because of negative information about vaccine side effects. We aimed to demonstrate the factors that lead to low vaccine acceptance rates (e.g., caregiver attitudes, popular misconceptions) to inform the relevant target demographic of a stronger intention to immunize and to facilitate recovery of HPV vaccine coverage. Methods: We conducted this study using data from two questionnaire surveys. Statistical analyses of factors affecting vaccine impressions and mediation effects of HPV vaccine impressions were performed. The difference in the knowledge about each vaccine was evaluated. Results: Of the respondents, 95.9 % reported their intent to vaccinate their infants, whereas 58.2-78.3 % felt that they sufficiently understood the aims, efficacy, and risks of vaccination and 66.6 % had a positive impression of vaccines. Overall, 21.3 % of parents responded that they planned to have their child vaccinated against HPV, and 25.8 % had a favorable impression of this vaccine. Among factors affecting vaccine impressions, we found that parents had anxiety about vaccines when they felt that their knowledge of vaccines was insufficient. Additionally, impressions of the HPV vaccine had a mediating effect on the association between the impressions of infant vaccines and parents' intent to provide the vaccine to their children. Conclusion: These findings show that as a society, we need to improve impressions and knowledge regarding vaccines, including but not exclusively the HPV vaccine. Moreover, although the recovery of HPV vaccine coverage is strongly desired for improving public health, simply improving impressions about the HPV vaccine or educating parents with substantive knowledge is insufficient. Instead, improving impressions and understanding of the vaccination itself is necessary.

Child Neurology: Pathologically Confirmed Thrombotic Microangiopathy Caused by Onasemnogene Abeparvovec Treatment for SMA.

Onasemnogene abeparvovec is an adeno-associated virus vector-based gene therapy for spinal muscular atrophy (SMA). Although several cases of drug-induced thrombotic microangiopathy due to onasemnogene abeparvovec have been reported, none has been confirmed pathologically. Here, we present renal histopathologic findings of TMA due to onasemnogene abeparvovec. On day 5 after receiving onasemnogene abeparvovec, a 23-month-old girl with SMA type 1 developed thrombocytopenia, microangiopathic hemolytic anemia, liver dysfunction, acute kidney injury, and hypertension. She was diagnosed with TMA and received an increased dose of prednisolone, antihypertensives, diuretics, packed red blood cell and platelet transfusion, a single dose of eculizumab, 4 cycles of plasmapheresis, and intermittent and continuous hemodialysis. Her TMA resolved by day 30. On day 49, renal biopsy was performed. Light microscopy revealed proliferation of glomerular mesangial cells and matrix, with mesangiolysis, endothelial cell swelling, and partial double contours of the glomerular basement membrane. Electron microscopy showed endothelial injury, with edematous changes of the subendothelial spaces and neoformation of the basement membrane, without electron-dense depositions. These findings are compatible with the recovery phase of TMA. One year after drug administration, her motor function is improved. She can hold her posture against gravity and has neither dysphagia nor respiratory disturbance, but mild hypertension persists. Physicians should be vigilant regarding TMA as a severe side effect of onasemnogene abeparvovec treatment, especially when thrombocytopenia, hemolytic anemia, increased lactate dehydrogenase, or acute kidney injury is present.

Severity estimation of very-long-chain acyl-CoA dehydrogenase deficiency via 13C-fatty acid loading test.

BACKGROUND: The clinical severity of very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is difficult to predict using conventional diagnostic methods. METHODS: Peripheral blood mononuclear cells obtained from 14 VLCAD deficiency patients and 23 healthy adults were loaded with carbon-13-universally labeled (U-13C-) fatty acids. Differences in acylcarnitine ratios between the patients and healthy groups and correlations between acylcarnitine ratios and a newly established clinical severity score (CSS) in the patient group were statistically examined. RESULTS: There was a significant decrease in the 13C-C2/13C-C18 and 13C-C12/13C-C14 ratios in the U-13C-stearic acid loading test and in the 13C-C2/13C-C18:1 and 13C-C12:1/13C-C14:1 ratios in the U-13C-oleic acid loading test in the patient group. The values of each ratio were significantly correlated with the CSS, suggesting that they could predict disease severity. Additionally, patients with a higher 13C-C16/13C-C18 ratio than the 13C-C14/13C-C18 ratio in the U-13C-stearic acid loading test had a significantly higher CSS and were presumed to have more severe disease. CONCLUSIONS: Our data indicated that this method could be used to predict the clinical severity of VLCAD deficiency, and identify patients at a risk of severe disease. IMPACT: We established a novel method to predict the severity of VLCAD deficiency by performing a loading test with carbon-13-labeled fatty acids on peripheral blood mononuclear cells. The U-13C-oleic acid loading test was useful for comparing the patient group with the control group in terms of disease severity. The U-13C-stearic acid loading test was useful for identifying the more severely affected patients. These methods are relatively less invasive and enable rapid evaluation of the clinical severity.

Age at menarche in Japanese patients with type 1 diabetes mellitus: a look at changes since 1960s.

Menarche is delayed in patients with type 1 diabetic mellitus (T1DM) compared to non-diabetics. The purpose of this survey study was to define the age of onset of menarche in Japanese patients with T1DM, as well the secular trends in menarcheal age across the period of 1976-2020 and determine the effects of T1DM and disease management on that age. The study subjects (n = 155) were recruited from among Japanese T1DM patients who visited the outpatient clinic of the Department of Pediatrics, Osaka City University Hospital. The study subjects experienced menarche during 1976-2020. They were divided into the menarche-post-T1DM group (n = 117) and the menarche-pre-T1DM group (n = 38), in whom menarche occurred after or before the diagnosis of T1DM, respectively. The time of birth was also stratified into five decade/time bins extending from 1960s to 2000s. The subjects filled a questionnaire on menarche. Other clinical information was obtained from the medical records. The median age at menarche was 12.5 years (11.3-13.4) (25th-75th percentile) for the menarche-post-T1DM group and 11.8 years (10.9-13.0) for the menarche-pre-T1DM group (p = 0.024). Menarche occurred at a significantly younger age in recent years in the menarche-post-T1DM group (r = -0.209, p = 0.023), but no such trend was found in the control group. Analysis of data of subjects born after 1990 still showed significant delay associated with T1DM [post-T1DM group: 12.3 years (11.3-13.2), pre-T1DM group: 11.8 years (11.0-12.2), p = 0.045]. The results suggest that recent advances in insulin therapy seem to improve metabolism under T1DM but might have not enough impact on menarche in Japanese girls.

Real world long-term outcomes in patients with mucopolysaccharidosis type II: A retrospective cohort study.

We investigated the decline of activities of daily living with symptomatic progression in patients with mucopolysaccharidosis type II (MPS II) and investigated the associated factors. Clinical data were retrospectively collected from the medical records of 28 patients with MPS II who visited our hospital between October 2007 and August 2019. Activities of daily living were assessed over time using a 5-point scale (from stage 1, indicating independent, to stage 5, indicating total assistance + medical care); the relationships of the interval years from stage 2 (mild symptoms) to stage 4 (total assistance) with therapeutic intervention, anti-drug antibodies (ADA), urinary glycosaminoglycans (uGAG), and genotypes were analyzed. Eight are attenuated types, and 20 are severe types. Further, 20 underwent enzyme replacement therapy (ERT) alone, 5 underwent hematopoietic stem cell transplantation (HSCT) alone, and 3 underwent both therapy. The mean interval years (standard deviation) from stage 2 to 4 was 3.5 (0.7) and 7.3 (3.3) in patients who started undergoing ERT (n = 6) and HSCT (n = 3) at stage 2, respectively, whereas it was 3.1 (1.5) in patients who received no treatment until they reached stage 4 (n = 8). The study findings revealed the process of changes in the activities of daily living over a long duration in patients with MPS II undergoing different treatments. In severe type, the activity deteriorated regardless of the stage at which ERT was initiated. The activity declined slower in patients who received HSCT at an early stage.

Divergent developmental trajectories in two siblings with neuropathic mucopolysaccharidosis type II (Hunter syndrome) receiving conventional and novel enzyme replacement therapies: A case report.

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked recessive lysosomal storage disease caused by a mutation in the IDS gene and characterized by systemic accumulations of glycosaminoglycans. Its somatic symptoms can be relieved by enzyme replacement therapy (ERT) with idursulfase, but because the enzyme cannot cross the blood-brain-barrier (BBB), it does not address the progressive neurodegeneration and subsequent central nervous system (CNS) manifestations seen in patients with neuropathic MPS-II. However, pabinafusp alfa, a human iduronate-2-sulfatase (IDS) fused with a BBB-crossing anti-transferrin receptor antibody, has been shown to be efficacious against both the somatic and CNS symptoms of MPS II. We report two cases of MPS-II in Japanese siblings sharing the same G140V mutation in the IDS gene, who showed markedly contrasting developmental trajectories following enzyme replacement therapy (ERT). Sibling 1 was diagnosed at 2 years of age, started undergoing conventional ERT shortly afterward, and scored a developmental quotient (DQ) of 53 on the Kyoto Scale of Psychological Development (KSPD) at 4 years of age. Sibling 2 was diagnosed prenatally and received conventional ERT from the age of 1 month through 1 year and 11 months, when he switched to pabinafusp alpha. He attained a DQ of 104 at age 3 years and 11 months, along with significant declines in heparan sulfate concentrations in the cerebrospinal fluid. This marked difference in neurocognitive development highlights the importance of early initiation of ERT with a BBB-penetrating enzyme in patients with neuropathic MPS-II.

Relationship Between Bedside Ketone Levels and Time to Resolution of Diabetic Ketoacidosis: A Retrospective Cohort Study.

INTRODUCTION: There is no information on the factors that influence the time required to induce resolution of diabetic ketoacidosis (DKA). New methods are currently available for bedside measurement of serum 3-hydroxybutyrate (3HB). The aim of this study was to determine the relationship between serum 3HB and the time to DKA resolution. METHODS: We reviewed the medical records of patients with type 1 diabetes (T1D) and a history of DKA who were admitted to the Department of Pediatrics, Osaka City University Hospital, between November 2008 and October 2018. DKA resolution was defined as 3HB below 1.0 mmol/L as measured by a bedside ketone meter. RESULTS: Data of 52 T1D-DKA episodes were analyzed (median age, 8.0 years; 20 male patients; 32 female patients; new T1D diagnosis, n = 13; established diagnosis, n = 39). In all cases, correction of serum 3HB was an important aspect of T1D management. The median time to DKA resolution (defined as the time from the start of insulin infusion until the fall of 3HB level to below 1.0 mmol/L) was 11 and 10 h in new and established T1D cases, respectively. 3HB on admission and the required insulin infusion dose per body weight, but not blood pH level on admission, correlated with time to DKA resolution. There was no relationship between blood pH level and 3HB on admission. CONCLUSIONS: Our results showed that DKA resolution could be achieved within 10-11 h when DKA treatment is guided by bedside 3HB monitoring without any severe complications. Blood 3HB level is a potentially suitable marker for the severity and resolution of DKA.

Platelet count and abdominal dynamic CT are useful in predicting and screening for gastroesophageal varices after Fontan surgery.

OBJECTIVE: Patients who undergo Fontan surgery for complex cardiac anomalies are prone to developing liver and gastrointestinal complications. In particular, gastroesophageal varices (GEVs) can occur, but their prevalence is unknown. We aimed to elucidate the occurrence of GEVs and the predicting parameters of GEVs in these patients. MATERIALS AND METHODS: Twenty-seven patients (median age, 14.8 years; median time since surgery, 12.9 years) who had undergone the Fontan surgery and were examined by abdominal dynamic computed tomography (CT) for the routine follow-up were included in the study. Radiological findings including GEVs and extraintestinal complications were retrospectively evaluated by experienced radiologists in a blinded manner. Relationships between blood-biochemical and demographic parameters and the presence of GEVs were statistically analyzed. RESULTS: Dynamic CT revealed gastric varices (n = 3, 11.1%), esophageal varices (n = 1, 3.7%), and gastrorenal shunts (n = 5, 18.5%). All patients with gastric varices had gastrorenal shunts. All gastric varices were endoscopically confirmed as being isolated and enlarged, with indications for preventive interventional therapy. A platelet count lower than 119 × 109 /L was identified as a predictor of GEV (area under the receiver operating curve, 0.946; sensitivity, 100%; and specificity, 87%). CONCLUSIONS: GEVs are important complications that should not be ignored in patients who have undergone a Fontan procedure. Platelet counts lower than 119 × 109 /L may help to prompt patient screening by using abdominal dynamic CT to identify GEVs and their draining collateral veins in these patients.

Factors associated with high care burden of primary caregivers of children with medical complexity after completing a discharge-support program in a recovery center.

INTRODUCTION: Recently, many seriously ill children requiring medical equipment are being recommended to transition from hospital to home care in Japan. Since 2011, our recovery center has provided a support program for the transfer process from hospital to home for ill children and their families. The purpose of this study was to evaluate the factors related to high care burden after completing the discharge-support program. METHODS: A questionnaire-based cross-sectional study was conducted on all primary caregivers whose children received the program in our center and moved from hospital to home (30 children and 29 families) from May 2011 to May 2018. Fifteen children came from the neonatal intensive care unit. The questionnaire consisted of three parts: characteristics of children and families and life after the program; the Zarit Burden Interview (ZBI); and the Positive and Negative Affect Schedule (PANAS). RESULTS: Twenty-three primary caregivers responded (79% response rate). All children received tracheostomy and 71% received home mechanical ventilation. Primary caregivers were all mothers. High ZBI score was not related to the severity and type of medical equipment. There were relationships between high ZBI score and following factors: 'unimproved relationship between patients and family members without primary caregivers' and 'additional medical equipment after discharge'. The result of PANAS showed that positive attitude was not different between those with high and low ZBI scores. CONCLUSION: It is crucial to reach out to family members without a primary caregiver. Additional medical care/equipment after the program is related to the care burden of primary caregivers.

Spinal Muscular Atrophy: Diagnosis, Incidence, and Newborn Screening in Japan.

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder that causes degeneration of anterior horn cells in the human spinal cord and subsequent loss of motor neurons. The severe form of SMA is among the genetic diseases with the highest infant mortality. Although SMA has been considered incurable, newly developed drugs-nusinersen and onasemnogene abeparvovec-improve the life prognoses and motor functions of affected infants. To maximize the efficacy of these drugs, treatments should be started at the pre-symptomatic stage of SMA. Thus, newborn screening for SMA is now strongly recommended. Herein, we provide some data based on our experience of SMA diagnosis by genetic testing in Japan. A total of 515 patients suspected of having SMA or another lower motor neuron disease were tested. Among these patients, 228 were diagnosed as having SMA with survival motor neuron 1 (SMN1) deletion. We analyzed the distribution of clinical subtypes and ages at genetic testing in the SMN1-deleted patients, and estimated the SMA incidence based on data from Osaka and Hyogo prefectures, Japan. Our data showed that confirmed diagnosis by genetic testing was notably delayed, and the estimated incidence was 1 in 30,000-40,000 live births, which seemed notably lower than in other countries. These findings suggest that many diagnosis-delayed or undiagnosed cases may be present in Japan. To prevent this, newborn screening programs for SMA (SMA-NBS) need to be implemented in all Japanese prefectures. In this article, we also introduce our pilot study for SMA-NBS in Osaka Prefecture.

Clinical and Genetic Characteristics of Patients with Mild Hyperphenylalaninemia Identified by Newborn Screening Program in Japan.

Phenylketonuria (PKU) and hyperphenylalaninemia (HPA), both identified in newborn screening, are attributable to variants in PAH. Reportedly, the p.R53H(c.158G>A) variant is common in patients with HPA in East Asia. Here, we aimed to define the association between p.R53H and HPA phenotype, and study the long-term outcome of patients with HPA carrying p.R53H. We retrospectively reviewed the genotype in 370 patients detected by newborn screening, and identified the phenotype in 280 (117, HPA; 163, PKU). p.R413P(c.1238G>C) was the most frequently found (n = 117, 31.6%) variant, followed by p.R53H (n = 89, 24.1%). The odds ratio for heterozygous p.R53H to cause HPA was 48.3 (95% CI 19.410-120.004). Furthermore, we assessed the non-linear association between the phenylalanine (Phe) value and elapsed time using the follow-up data of the blood Phe levels of 73 patients with HPA carrying p.R53H. The predicted levels peaked at 161.9 µmol (95% CI 152.088-172.343) at 50-60 months of age and did not exceed 360 µmol/L during the 210-month long observation period. The findings suggest that patients with HPA, carrying p.R53H, do not need frequent Phe monitoring as against those with PKU. Our study provides convincing evidence to determine clinical management of patients detected through newborn screening in Japan.