Phenylketonuria (PKU) is an inborn error of metabolism leading to phenylalanine (Phe) accumulation and consequent neurological, neurocognitive, and psychiatric symptoms. Pegvaliase, a pegylated recombinant phenylalanine ammonia lyase that metabolizes Phe, effectively reduced blood Phe in phase III studies in the United States. This multicenter, open-label, phase III study (jRCT2080224573) evaluated efficacy and safety of up to 4 years of pegvaliase treatment in 12 adult Japanese participants with PKU (blood Phe > 600 μmol/L). Subcutaneous pegvaliase followed an induction/titration/maintenance dosing regimen up to a maximum of 60 mg/day. After Week 52, diet and pegvaliase dose could be adjusted if blood Phe was ≤ 360 μmol/L. Mean (standard deviation [SD]) treatment duration was 166.4 (66.5) weeks. At Week 192 (n = 10), mean (SD) blood Phe was 296.2 (430.7) μmol/L, a 71.2% decrease from baseline, and daily protein intake from intact and medical food was 49.9 (21.4) g (68.0% increase) and 7.6 (16.2) g (64.2% decrease), respectively. All participants had ≥ 1 treatment-emergent adverse event (TEAE) during induction/titration, most commonly injection site erythema and injection site swelling (83.3% each); nine of 10 had a TEAE during maintenance. Of 395 TEAEs recorded during maintenance, 82 occurred between the 2-year interim analysis and the 4-year final analysis. One serious TEAE (allergic arthritis) was considered pegvaliase related. The exposure-adjusted rate of pegvaliase-related events was 17.0 per person-year (41.2 during induction/titration, 8.9 during maintenance). Pegvaliase effectively lowered blood Phe in Japanese participants with PKU, with no new safety issues with long-term treatment, and many participants were able to liberalize their diet.

PURPOSE:To report interim results from the ongoing, open-label, phase 3 APHENITY Extension Study (NCT05166161), evaluating long-term treatment with sepiapterin in patients with phenylketonuria. METHODS:Participants received an age-based dose of oral sepiapterin daily; those with mean blood phenylalanine (Phe) levels <360 μmol/L (<5.95 mg/dL) after 2 weeks underwent a 26-week dietary Phe tolerance assessment, wherein dietary Phe intake was adjusted and blood Phe levels monitored. Other participants continued treatment with optional diet liberalization. Primary endpoints included change from baseline to week 26 in dietary Phe intake and treatment-emergent adverse events (TEAEs). RESULTS:As of September 2, 2024, 169 participants received sepiapterin (median [minimum, maximum] age: 14.0 [0.2, 55.0] years, median exposure: 72.9 weeks); 102 participants underwent dietary Phe tolerance assessments. Mean (SD) dietary Phe intake increased from 27.6 (18.0) mg/kg/day at baseline to 62.5 (41.5) mg/kg/day at week 26 (least-squares mean change [SE]: 36.4 [2.8] mg/kg/day from baseline) (P < .0001 from post hoc analysis). The incidence of treatment-related TEAEs was 29.0%; 3 participants (1.8%) discontinued treatment owing to treatment-related TEAEs. There were no treatment-related serious TEAEs or deaths. CONCLUSION:Interim results support the long-term safety of sepiapterin and demonstrate the potential for diet liberalization in adults and children with phenylketonuria. CLINICALTRIALS: GOV IDENTIFIER:NCT05166161 (https://www. CLINICALTRIALS:gov/study/NCT05166161; date of registration, December 8, 2021).

Mucopolysaccharidoses (MPS) are a group of lysosomal disorders characterized by pathological accumulation of glycosaminoglycans (GAGs). Enzyme-based newborn screening (NBS) for MPS often yields high false-positive rates because of carriers and pseudodeficient newborns. To improve screening specificity, we developed an LC-MS/MS-based enzymatic method to quantify GAG-derived disaccharides in dried blood spots (DBSs) and evaluated its utility as a second-tier test. Using DBS samples MPS-positive newborns, we quantified dermatan sulfate- (DS), heparan sulfate- (HS), and keratan sulfate-derived disaccharides. Under the primary positivity rule (DS or HS ≥ the 95th percentile cutoff), the method achieved 100% sensitivity and specificity for MPS I, completely eliminating false-positive results among MPS I carriers. For MPS II, the same rule yielded 100% sensitivity and 84.3% specificity. Reanalysis using a stricter rule requiring both DS and HS to exceed the cutoff improved specificity for MPS II to 100% without loss of sensitivity (100%). All confirmed MPS I and II patients exceeded both DS and HS cutoffs, whereas HS-only values above the cutoff occurred exclusively in MPS II pseudodeficiency, reflecting analytical and cutoff-related overlap rather than pathological GAG accumulation. Based on these findings, we recommend the stricter dual-marker rule for laboratory implementation, particularly for improving specificity in MPS II. Implementation of this approach as a second-tier test may substantially reduce false-positive referrals, eliminating all false positives for MPS I carriers and improving specificity for MPS II pseudodeficiency from 84.3% to 100%. This method may serve as a practical complementary screening tool within expanded NBS programs.

AimsWe previously identified a strong association between seven rare DPYD variants (Ser199Asn, Ile245Phe, Thr305Lys, Glu386Ter, Ser556Arg, Ala571Asp, and Trp621Cys) and fluoropyrimidine-related toxicity in Japanese cancer patients. Herein, we reported clinical and molecular functional analyses of these seven rare DPYD variants.MethodsMutant dihydropyrimidine dehydrogenase (DPD) enzymes were expressed in HEK293 cells. DPD activity was measured by quantifying dihydro-5-FU using high-performance liquid chromatography-tandem mass spectrometry. DPD levels and dimerization were analyzed via western blotting and blue native PAGE. In addition, three-dimensional (3D) structural modeling was performed to evaluate the effects of these mutations on enzyme structure and function.ResultsTransient expression of DPD variant enzymes in HEK293 cells showed that the Ser199Asn, Ala571Asp, and Glu386Ter variants caused profound reductions in activity compared to the wild type (27%, 5.0%, and undetectable, respectively), while Thr305Lys, Trp621Cys, Ile245Phe, and Ser556Arg retained partial to normal activity (49%, 58%, 118%, and 113%). The results of 3D structural analysis supported the functional findings from HEK293 cell experiments. Clinical evaluation revealed that carriers with the five variants (Ser199Asn, Ile245Phe, Glu386Ter, Ala571Asp, and Trp621Cys) presented with adverse reactions Graded 3 or higher according to the Common Terminology Criteria for Adverse Events. Retrospective assessment of DPD activity in peripheral blood mononuclear cells revealed that patients carrying Ser199Asn, Ala571Asp, or Glu386Ter exhibited reduced DPD activity, correlating with findings from HEK293 cell experiments.ConclusionsExpression studies demonstrated that the rare DPYD variants Ser199Asn, Ala571Asp, and Glu386Ter were associated with decreased DPD enzyme activity and 5-FU toxicity, even in the heterozygous state.

INTRODUCTION:Factor XIII deficiency (FXIIID) is a rare coagulation disorder that can cause severe or delayed bleeding and impair wound healing despite normal routine coagulation test results. Congenital FXIIID is caused by homozygous germline pathogenic variants of F13A or F13B. Herein, we report the successful treatment of a patient with FXIIID who underwent surgery for juvenile polyposis syndrome (JPS)-associated early gastric cancer. CASE PRESENTATION:A 44-year-old woman was admitted to the hospital with anemia secondary to menorrhagia. Gastrointestinal examination revealed polyposis throughout the stomach and type 0-Is early gastric cancer, which was consistent with the histological diagnosis of the biopsy specimens. Investigation into her family history revealed that her mother and maternal aunt had gastric polyposis. Preoperative laboratory tests were almost normal, except for low levels of hemoglobin (6.0 g/dL) and Factor XIII (FXIII) activity (31%). Robot-assisted total gastrectomy with D1-level lymph node dissection, followed by Roux-en-Y reconstruction, was successfully performed, with an operative time of 347 min and estimated blood loss of 26 mL. To prevent surgery-related bleeding, preoperative and postoperative administration of FXIII concentrate (30 IU/kg) was planned. The postoperative course was uneventful, and the patient was discharged on POD 9. Genetic testing identified a germline pathogenic frameshift variant in SMAD4 (c.96delT [p.Ser32fs*13]), which was consistent with the phenotype of JPS, and a heterozygous missense variant of uncertain significance in F13A1 (c.308A>T [p.Glu103Val]). Nine months postoperatively, FXIII activity was re-evaluated and remained low at 59%, although it was higher than the preoperative level. CONCLUSIONS:Recognition of FXIIID and appropriate perioperative management may help prevent unexpected bleeding and enable safe gastrectomy in patients with FXIIID.

OBJECTIVE:A phase III, double-blind, placebo-controlled, randomized withdrawal trial of SPP‑004 (5‑aminolevulinic acid hydrochloride and sodium ferrous citrate) was conducted to confirm the efficacy and safety of SPP-004 for maintenance of clinical response in patients diagnosed with Leigh syndrome (LS) showing central nervous system disorders. METHODS:Fifty-four patients entered a 24-week open-label period of SPP-004 administration. Among them, 28 patients who showed improvement on the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) for cranial nervous symptoms and myopathy symptoms proceeded to a 48-week double-blind (DB) period, where they were randomized (1:1) to receive SPP‑004 or placebo (n = 14 each). Efficacy was evaluated using NPMDS for the full analysis set (FAS) during the DB‑period (SPP-004 n = 13, Placebo n = 14) and the entire study period (n = 54). Safety evaluation focused on adverse events (AEs) in all 54 patients administered SPP-004. RESULTS:The primary endpoint, the proportion of patients who discontinued due to inadequate efficacy at 48 weeks, was lower in the SPP-004 group (15.4% [95% CI: 1.9-45.4%]) compared to the placebo group (50.0% [23.0-77.0%]). Over 80% of the SPP-004 group showed maintained efficacy (p = 0.0486). All adverse drug reactions were mild, with no notable differences in AEs between groups. CONCLUSION:These findings suggest that SPP-004 is safe and may provide therapeutic effect for LS patients who achieved an initial clinical response.

ABSTRACT 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 (ΔNH 3 ) 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 (NH 3 ) > 150 μg/dL (88.1 μmol/L). For each patient, ΔGln and ΔNH 3 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 ΔNH 3 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 ΔNH 3 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.

Newborn screening (NBS) for Fabry disease (FD) is an effective way to identify individuals with FD before the onset of symptoms, enabling early therapeutic treatment. The classic form of FD typically begins in early childhood or later, but the late-onset form often develops in adulthood. However, FD-NBS identifies positive cases regardless of the expected timing of symptom onset. Consequently, concerns have been raised about prolonged uncertainty, medicalization, and caregivers' hypervigilance throughout the asymptomatic period. These issues are particularly salient for mothers, who are often heterozygous carriers and primary caregivers. Despite the growing implementation of FD-NBS in some countries, the perspectives of parents, especially mothers, have not been adequately explored. This study explores the experiences, emotions, and needs of five mothers whose children were diagnosed with FD through NBS, aiming to uncover the psychological impact and support required during the asymptomatic period. Semistructured interviews were conducted and analyzed using the KJ (Kawakita Jiro) method, a kind of bottom-up qualitative approach. The findings revealed that mothers experienced a psychological burden related to monitoring for disease onset. However, this burden was reduced by several factors, including an understanding of the timing of onset, the attending physician's opinions, the passage of time, and personalized coping strategies. Needs were identified for support in understanding the disease, as well as for spaces that facilitate empathy and information exchange. Opinions regarding FD-NBS were generally positive; however, negative feelings were also expressed, including views that they did not have to discover their child's FD through NBS. These findings suggest that understanding the experiences of mothers of asymptomatic children and providing support, such as genetic counseling and peer support, could enhance the effectiveness of FD-NBS.

Recently, Newborn screening (NBS) has been expanded worldwide to include lysosomal storage diseases (LSDs) and adrenoleukodystrophy (ALD) due to the importance of early diagnosis and early treatment. In Japan, NBS for LSDs, termed expanded NBS, was first implemented in Kumamoto prefecture in 2006 as pilot study. NBS for ALD was subsequently introduced in Aichi prefecture and Gifu prefecture in 2021. Expanded NBS for LSDs and ALD has become more widespread in Japan. In light of this current situation, we considered it is necessary to clarify the usefulness of expanded NBS, prevalence of each disease, challenges encountered. Therefore, we reported the current implementation status of expanded NBS in Japan. A survey was conducted among physicians responsible for expanded NBS in each target region Japan. The target regions were those that implemented NBS for LSDs and/or ALD for more than one year. The survey items included: the entity conducting expanded NBS, the facilities conducting the tests, the target areas, medical institutions for close examination such as detailed biochemical analysis and/or genetic sequencing, and treatments, types of target diseases, fee for NBS, sample collection methods, testing method, and quantitative data on expanded NBS, retesting, and diagnoses in each area. Responses were received from nine regions and an organization (CReARID). The total number of 733,838 newborns were screening, with 101 diagnoses: 75 cases of Fabry disease, 10 of mucopolysaccharidosis (MPS) II, 8 of Pompe disease, 5 of Gaucher disease, 2 of MPS I, 1 of ALD, respectively) were diagnosed. More cases were diagnosed with the target disease than the estimated prevalence. In contrast, the positive predictive value was low and false-positive rates was elevated, particularly for PD, MPS II, and ALD, have been attributed to pseudodeficiency alleles and methodological differences. Moreover, variant of unknown significance (VUS) in the ABCD1 gene was detected in many of the patients with suspected ALD. In Japan, Expanded NBS for LSDs and ALD has become more widespread. Since its implementation, some patients have been diagnosed and received treatment. However, challenges such as pseudodeficiency, indications, testing methods, and VUS that require improvement.

A phase III, double-blind, placebo-controlled, randomized withdrawal trial of SPP-004 (5-aminolevulinic acid hydrochloride and sodium ferrous citrate) in patients diagnosed as Leigh syndrome (LS) was conducted to confirm the efficacy and safety of SPP-004 in patients with LS showing central nervous system disorders. Fifty-four patients entered a 24-week open-label period of SPP-004 administration. Among them, 28 patients showing improved scores on the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) for cranial nervous symptoms and myopathy symptoms proceeded to a 48-week double-blind (DB) period, where they were randomized (1:1) to receive SPP-004 or placebo ( n =14 each). Efficacy was evaluated using NPMDS for the full analysis set (FAS) during the DB-period (SPP-004 n =13, Placebo n =14) and the entire study period ( n =54). Safety evaluation focused on adverse events (AEs) in all 54 patients administered SPP-004. The primary endpoint, the proportion of patients who discontinued due to inadequate efficacy at 48 weeks, was lower in the SPP-004 group (15.4% [95% CI: 1.9-45.4%]) compared to the placebo group (50.0% [23.0-77.0%]). Over 80% of the SPP-004 group maintained efficacy (p=0.0486). All adverse drug reactions were mild, with no notable differences in AEs between groups. These findings suggest that SPP-004 is safe and may provide therapeutic effect for LS symptoms.

Pancreaticoduodenectomy(PD)has been increasingly performed as conversion surgery for advanced gastric cancer. We report 6 cases of gastric cancer in which PD was performed following chemotherapy. The reasons for requiring PD were pancreatic head invasion in 3 cases, common bile duct invasion in 1 case, and lymph node recurrence in the hepatic hilum after distal gastrectomy in 2 cases. Preoperative chemotherapy regimens included S-1+oxaliplatin in 3 cases, S-1+oxaliplatin+ trastuzumab in 1 case, capecitabine+oxaliplatin in 1 case, and S-1+cisplatin in 1 case. One patient died during hospitalization due to sepsis caused by postoperative cholangitis. A pancreatic fistula classified as Clavien-Dindo classification Grade Ⅲa occurred in 1 case. The 1-year and 2-year overall survival rates were 83.3% and 66.7%, respectively. The 1-year and 2- year recurrence-free survival rates were both 75.0%. Although the number of cases is limited, PD as conversion surgery for gastric cancer is considered an effective treatment option.

Intraoperative nerve monitoring (IONM) during esophageal cancer surgery can help to identify and preserve the recurrent laryngeal nerve (RLN). To devise a useful parameter for prediction of left vocal cord palsy (VCP), we measured the electromyographic (EMG) amplitude of the left RLN and vagus nerve (VN) using intermittent IONM. We studied 35 consecutive patients who underwent esophagectomy with lymph node dissection around the left RLN. After lymph node dissection, the left RLN and left VN were stimulated, and the EMG amplitude was measured using IONM. The VN/RLN ratio (V/R ratio) was calculated, and the presence of left VCP, diagnosed by laryngoscopy on the first postoperative day, was compared among the patients. Ten of the 35 patients (28.6

Propionic acidemia (PA) is a known cause of secondary dilated cardiomyopathy (DCM). However, little is known about how diet and heart failure treatment impact long-term cardiac outcomes in adult PA patients. We report the successful treatment of metabolic disease and secondary DCM-associated heart failure in a 20-year-old male patient with neonatal-onset PA and intellectual disability. At age 19 years, echocardiography had revealed DCM without impaired cardiac contractility. At age 20 years, he developed heart failure, presumably from a common cold infection, and was hospitalized. Acute heart failure treatment improved his symptoms, leading to discharge, but they worsened again, necessitating re-admission. He then was discharged only after successfully adding carvedilol and pimobendan to his medication. Six weeks later, however, he developed hyperammonemia with elevated serum propionyl carnitine and decreased free carnitine levels. He received acute phase treatment for this metabolic crisis and his diet therapy was readjusted, including by reducing natural protein. In the following 5 years, while continuing and slightly adapting heart failure medication and dietary regimens, the patient's cardiac function stably improved and his diuretic dose could be reduced. Our findings support that careful diet therapy and modulation of heart failure medication can improve cardiac function in PA patients with DCM. Learning objective:Neonatal-onset propionic acidemia (PA) tends to be the most severe form of PA and life-threatening metabolic disease. Even if the impact of the disease can be ameliorated by adapting the diet, later in life these patients often develop symptoms such as intellectual disability, metabolic crises, and dilated cardiomyopathy (DCM), as observed in this case. This case demonstrates that heart failure medication and dietary therapy can help protect against metabolic disease and DCM-associated heart failure in an adult patient with neonatal-onset PA.

PURPOSE:This retrospective study was performed to investigate the recent trend of occurrence of cancer of the remnant colorectal segment(RCRS)after ileal-pouch anal anastomosis(IPAA)/ileorectal anastomosis(IRA)and to consider the optimal surveillance methods in patients with familial adenomatous polyposis(FAP)undergoing(procto)colectomy.PATIENTS AND METHODS:The subject was a total of patients with FAP undergoing IPAA or IRA between 2005 and 2022. Clinicopathological data were extracted from medical charts and analyzed. Cumulative incidence of cancer in the RCRS and overall survival after treatment of such tumors were calculated by the Kaplan-Meier method.RESULTS:There were 45 male and 56 female. IPAA was performed in 49 patients(hand-sewn; n=33, stapled; n=16)and IRA was performed in 52 patients. The median age at initial colorectal surgery was 32 years old(range, 13-66 years old). Median postoperative follow-up was 11 years(range, 1-48 years). Eighty-one patients were confirmed to have pathogenic variant of APC by genetic test. The cumulative incidence of cancer of the RCRS did not differ between patients undergoing IPAA and those undergoing IRA(p= 0.73, 4.1% versus 1.9% at 10 years). The cumulative 5-year overall survival rate after additional surgery for the tumor of RCRS was 82%.CONCLUSION:This study has several limitations due to single institutional retrospective study with small cases and non-standardized postoperative endoscopic surveillance. However, our results seem to show satisfactory oncological outcomes of patients with FAP in terms of the control of cancer of the RCRS under postoperative periodic surveillance, regardless of the type of colorectal resection.

BACKGROUND:Based on molecular characteristics, deficient DNA mismatch repair (dMMR) solid tumors are largely divided into three categories: somatically MLH1-hypermethylated tumors, Lynch syndrome (LS)-associated tumors, and Lynch-like syndrome (LLS)-associated tumors. The incidence of each of these conditions and the corresponding pathogenic genes related to LLS remain elusive. METHODS:We identified dMMR tumors in 3609 tumors from 9 different solid organs, including colorectal cancer, gastric cancer, small-bowel cancer, endometrial cancer, ovarian cancer, upper urinary tract cancer, urinary bladder cancer, prostate cancer, and sebaceous tumor, and comprehensively summarized the characterization of dMMR tumors. Characterization of dMMR tumors were performed as loss of at least one of MMR proteins (MLH1, MSH2, MSH6, and PMS2), by immunohistochemistry, followed by MLH1 promotor methylation analysis and genetic testing for MMR genes where appropriate. Somatic variant analysis of MMR genes and whole exome sequencing (WES) were performed in patients with LLS. RESULTS:In total, the incidence of dMMR tumors was 5.9% (24/3609). The incidence of dMMR tumors and the proportion of the three categorized dMMR tumors varied considerably with different tumor types. One to three likely pathogenic/pathogenic somatic MMR gene variants were detected in 15 out of the 16 available LLS tumors. One patient each from 12 patients who gave consent to WES demonstrated non-MMR germline variants affect function (POLQ or BRCA1). CONCLUSIONS:Our data regarding the LS to LLS ratio would be useful for genetic counseling in patients who are suspected to have LS, though the genetic backgrounds for the pathogenesis of LLS need further investigation.

Muir-Torre syndrome(MTS)is a disease characterized by the simultaneous occurrence of sebaceous tumors and visceral malignant tumors. This syndrome is now considered to be a phenotypic variant of Lynch syndrome(LS). Our patient was a 58-year-old woman with a history of endometrioid adenocarcinoma of the uterine isthmus at the age of 40 years and left-sided triple negative breast cancer at the age of 44 years. At the age of 52 years, a multigene panel testing revealed a pathogenic variant in MSH2, and the patient was diagnosed with LS. During surveillance for LS in our department, a 2-mm sized intradermal nodule was found on the patient's left shoulder, at the age of 58 years. Histopathological examination of the resected intradermal nodule revealed a sebaceous adenoma. LS can present as MTS, and it is, therefore, important to conduct surveillance not only for visceral malignant tumors but also for skin tumors.

The proband is a 47-year-old woman who underwent a posterior total pelvic exenteration for Stage Ⅲb rectal cancer. Microsatellite instability(MSI)test and immunohistochemistry(IHC)for mismatch repair(MMR)proteins using the resected tumor tissue showed MSI-High and loss of MLH1/PMS2 expression. In addition, although BRAF V600E variant was not identified, MLH1 methylation was detected. Therefore, this patient was diagnosed as having sporadic deficient MMR(MSI-High) rectal cancer. However, the possibility of Lynch syndrome could not be ruled out because of her family history and young age of onset, then we performed a multigene panel testing including MMR genes. Subsequently, a likely pathogenic variant of MSH2(c.2260A>G)was identified. This case suggests that MLH1-methylated rectal cancer can develop in patients with Lynch syndrome and that multigene panel test using next-generation technology would be useful for searching hereditary cancer predisposition syndromes such as Lynch syndrome even in patients with sporadic dMMR colorectal cancer.