中島 葉子

Mucopolysaccharidosis type II (MPS II) results from iduronate-2-sulfatase (IDS) enzyme deficiency due to IDS gene mutations. Most patients with neuronopathic MPS II experience progressive neurological decline; however, effectiveness of standard treatment, intravenous idursulfase, is limited by blood-brain barrier transfer. Intracerebroventricular (ICV) idursulfase beta, approved in Japan in 2021, directly delivers idursulfase beta into cerebral ventricles. This post-marketing surveillance reports long-term effectiveness and safety of ICV idursulfase beta (30 mg every 4 weeks) in all treated patients from April 2021 through August 2024. Outcomes included cerebrospinal fluid (CSF) heparan sulfate (HS) levels (quarterly), developmental age (DA; Kyoto Scale of Psychological Development, annually), and safety. Thirty-seven Japanese male patients across 21 sites were enrolled (safety population n = 36; effectiveness population n = 35). Mean CSF HS concentrations decreased from 7.36 to 3.19 μg/mL from baseline to week 24, with reduction sustained through week 100. Patients who initiated treatment within 3 years of age had DA progression aligned with healthy cohorts, regardless of mutation type; however, those starting later had no comparable benefit. Adverse events (AEs) occurred in 20 patients (55.6%). Procedure-related serious AEs (SAEs) occurred in 2 patients (bacterial meningitis, device-related infection, pyrexia). Treatment-related AEs affected 14 patients (38.9%), mainly pyrexia (27.8%, including one SAE). One SAE (membranous glomerulonephritis) was not intervention related. No deaths, anaphylaxis, or anti-IDS antibodies in CSF were detected. ICV idursulfase beta demonstrated sustained CSF HS reduction with no new safety signals. Earlier treatment initiation (≤3 years) was associated with improved neurodevelopmental outcomes, regardless of mutation type.

BACKGROUND: Urea cycle disorders (UCD) are rare, nutrition-dependent inborn errors of metabolism in which outcomes depend on pharmacological treatment and sustained access to specialized formulas, low-protein medical foods, and dietary counseling. System-level support for dietary management varies across countries, yet comparative analyses are scarce. METHODS: We conducted a structured comparative analysis of dietary management systems for UCD in Japan and the United States (US) using clinical guidelines, policy documents, industry information, and professional reports. The review examined four domains: pharmacological and nutritional resources, availability of specialized formulas and low-protein medical foods, healthcare delivery and insurance, and the role of metabolic dietitians. RESULTS: In the US, individuals with UCD generally have access to multiple nitrogen-scavenging agents, UCD-specific or functionally equivalent formulas, and diverse low-protein staple foods, with care coordinated through specialized metabolic clinics and dietitians. Coverage for medical foods and formulas varies widely, leading to substantial out-of-pocket costs and inequities. In Japan, universal health insurance, pediatric subsidy schemes, and rare disease programs provide coverage for approved pharmacological treatments and hospital-based care. However, essential amino acids (EAA)-enriched, UCD-specific formulas are unavailable, EAA preparations are prescribed off-label, low-protein foods are limited, and most dietary products are not reimbursed. CONCLUSIONS: The US model emphasizes product diversity and multidisciplinary care within a fragmented insurance framework, whereas Japan offers universal coverage and continuity of medical care but limited structural support for dietary therapy. Integrating strengths from both systems may improve nutritional management and quality of life for individuals with UCD.

Hyperammonemic crisis (HAC) remains a major risk factor for urea cycle disorders (UCD), and practical outpatient predictors are limited. We tested whether short-term changes in plasma glutamine (ΔGln) and ammonia (ΔNH3) predict HAC and whether effects differ by onset type. In a retrospective cohort (2014-2024) of 18 patients with UCD (neonatal-onset [NO] nine; late-onset [LO] nine), HAC was defined as ammonia (NH3) > 150 μg/dL (88.1 μmol/L). For each patient, ΔGln and ΔNH3 were calculated between sequential outpatient samples. Investigation 1 compared the changes observed between 31-60 days and 8-30 days before HAC, with stable period changes. Investigation 2 compared changes at 61-90 and 31-60 days before HAC with stable period changes. Associations were evaluated using generalized linear mixed-effects models with onset-specific effects. In NO, larger ΔGln during Investigation 1 was associated with higher HAC risk (p < 0.001) whereas ΔNH3 was not associated with HAC (p = 0.361). The probability of HAC in NO was estimated to reach 67.1% at ΔGln +500 μmol/L. In LO, neither ΔGln nor ΔNH3 during Investigation 1 showed a significant association with HAC, and the estimated probabilities remained low across the observed ranges. During Investigation 2, no significant associations between biomarkers and HAC were observed in either group. Progressive increases in plasma glutamine levels within the 31-60 and 8-30 days pre-HAC window may serve as early markers of HAC risk in NO-UCD, supporting the utility of longitudinal monitoring. These trends were not associated with LO-UCD, suggesting the need for alternative surveillance strategies tailored to the onset phenotype.

Propionic acidemia is a rare autosomal recessive disorder caused by mutations in the PCCA or PCCB gene, resulting in deficient propionyl-CoA carboxylase activity. We identified a unique homozygous deep-intronic PCCA variant, NM_000282.4:c.1285-1358C>G, in an individual with neonate-onset propionic acidemia. Fibroblasts from this individual expressed only PCCA mRNA containing an 84-bp pseudoexon, which is present at low levels in healthy controls, leading to the loss of PCCA and PCCB proteins and severely reduced propionyl-CoA carboxylase activity. Transfection of fibroblasts with chemically synthesized antisense oligonucleotides (ASOs) designed to skip the pseudoexon restored productive PCCA splicing, rescued PCCA protein expression, and markedly increased propionyl-CoA carboxylase activity above wild-type levels. The efficacy of the ASOs was further evaluated in fibroblasts from 7 additional individuals with propionic acidemia carrying mutations in PCCA or PCCB. ASO treatment successfully restored enzymatic activity, particularly in fibroblast lines, with residual activity exceeding 1% of normal. These findings suggest that ASO-mediated splicing correction targeting the 84-bp pseudoexon can restore mRNA, protein, and enzymatic function in individuals with deep intronic mutations, as well as in other individuals with propionic acidemia, indicating the feasibility of ASO therapy as a molecular treatment strategy for a subset of individuals with propionic acidemia.

PURPOSE: Anticancer therapy for patients with gastric cancer on hemodialysis is challenging owing to varying pharmacokinetics and a lack of clinical trial data. This study aimed to evaluate the efficacy and safety of the capecitabine plus oxaliplatin (CapeOX) regimen in a 73-year-old male Japanese patient with stage IV gastric cancer (human epidermal growth factor receptor 2 negative) undergoing hemodialysis. METHODS: The selected chemotherapy regimen was approximately 50% dose of CapeOX (capecitabine 1500 mg/day on days 1-14 and oxaliplatin 100 mg/day 2-h infusion on day 1) every 3 weeks. Data on plasma drug concentrations, metabolic enzyme genetic polymorphisms, and clinical outcomes were analyzed. RESULTS: Anticancer therapy initially controlled the tumor; however, disease progression and cumulative peripheral neuropathy led to discontinuation after 17 cycles (approximately 12 months of treatment). Oxaliplatin exhibited a rebound increase after each dialysis session (dialyzer clearance [CLdial]: median, 44.12 [interquartile range {IQR}: 24.89 - 70.08] mL/min; hemodialysis removal rate: median, 35.98% [IQR: 19.63 - 54.45]. α-fluoro-β-alanine, the final metabolite of capecitabine, accumulated substantially, although approximately half of them was removed by hemodialysis (CLdial: median, 61.32 [IQR: 24.89 - 70.08] mL/min; hemodialysis removal rate: median, 47.98% [IQR: 44.74 - 50.29]). The UPB1 intronic variant and a DPYD missense mutation (1627 A > G) were detected. The DPYD variant likely influenced 5-fluorouracil metabolism, as its area under the concentration-time curve from 0 to 12 h was comparable to the standard dosage. CONCLUSION: These findings suggest that appropriate dose reduction and genetic screening might be considered part of chemotherapy guidance to improve safety and effectiveness for patients with advanced gastric cancer undergoing hemodialysis.