JIMD reports最新文献_第3页

Pregnancy in Lysinuric Protein Intolerance Complicated by Immune Dysregulation and Severe Thrombocytopenia 赖氨酸尿酸蛋白不耐受合并免疫失调和严重血小板减少症的妊娠

IF 1.8

JIMD reports Pub Date : 2026-07-03 DOI: 10.1002/jmd2.70109

Eamon P. McCarron, Melanie Hill, Adam Lomas, Victoria Elliott, Emma Walkinshaw, Tessa Bonnett, Kar-Ping Kuet, Rachel Tattersall, Claire Mapplebeck

{"title":"Pregnancy in Lysinuric Protein Intolerance Complicated by Immune Dysregulation and Severe Thrombocytopenia","authors":"Eamon P. McCarron, Melanie Hill, Adam Lomas, Victoria Elliott, Emma Walkinshaw, Tessa Bonnett, Kar-Ping Kuet, Rachel Tattersall, Claire Mapplebeck","doi":"10.1002/jmd2.70109","DOIUrl":"10.1002/jmd2.70109","url":null,"abstract":"Lysinuric protein intolerance (LPI) is a rare disorder of dibasic amino acid transport associated with secondary urea cycle defects and immune dysregulation. Pregnancy in LPI is seldom reported and presents significant management challenges. We report a 25-year-old woman with genetically confirmed LPI complicated by prior hemophagocytic lymphohistiocytosis (HLH) and systemic lupus erythematosus (SLE) who presented with an unplanned pregnancy. Early gestation was characterised by metabolic instability, including transient hyperammonaemia and elevated orotic acid, which improved with optimisation of nitrogen scavenger therapy and nutritional support. Progressive severe thrombocytopenia and anaemia developed during the second trimester and were managed as presumed immune thrombocytopenia with corticosteroids and intravenous immunoglobulin. Delivery by caesarean section at 35 weeks resulted in favourable maternal and neonatal outcomes. To our knowledge, this represents the first reported case of pregnancy in LPI complicated by established immune dysregulation (HLH and SLE) and severe thrombocytopenia, defining a previously uncharacterised high-risk phenotype with a favourable outcome.","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Impaired Fat Metabolism During Exercise in Patients With Methylmalonic and Propionic Acidemia 甲基丙二酸和丙酸血症患者运动时脂肪代谢受损

IF 1.8

JIMD reports Pub Date : 2026-07-01 DOI: 10.1002/jmd2.70101

S. Myrup, A. Høj, M. M. Naume, N. Løkken, G. Van Hall, A. Lund, M. Duno, J. Vissing, M. C. Ørngreen

{"title":"Impaired Fat Metabolism During Exercise in Patients With Methylmalonic and Propionic Acidemia","authors":"S. Myrup, A. Høj, M. M. Naume, N. Løkken, G. Van Hall, A. Lund, M. Duno, J. Vissing, M. C. Ørngreen","doi":"10.1002/jmd2.70101","DOIUrl":"10.1002/jmd2.70101","url":null,"abstract":"Methylmalonic acidemia (MMA) and propionic acidemia (PA) are inherited metabolic diseases causing deficiency in the catabolism of amino acids, cholesterol, and odd-chain fatty acids. Both patient groups report exercise intolerance and fatigue. We recently reported findings of impaired lipolysis and blunted fat oxidation during exercise in a patient with PA, suggesting a metabolic myopathy phenotype. To further investigate this phenomenon, we conducted a new study to investigate fat and glucose metabolism during exercise in patients with PA and MMA. We included two patients with MMA and two with PA. The patients performed a low-intensity exercise test on a cycle ergometer, working at a workload corresponding to 50% of their maximal oxygen capacity. Fat and glucose metabolism were quantified at rest and during exercise via continuous infusion of stable isotope-labeled glucose and palmitate, and indirect calorimetry. The results were compared to those of matched healthy controls. Lipolysis and fatty acid oxidation were close to normal at rest, but impaired during exercise in the patients vs. healthy controls exercising at the same absolute workload: Lipolytic rate (1.5 ± 0.6 vs. 4.0 ± 1.4 μmol kg−1 min−1, p = 0.001) and palmitate oxidation (0.8 ± 0.6 vs. 2.1 ± 1.0 μmol kg−1 min−1, p = 0.018). To compensate, the patients increased carbohydrate oxidation (68.2 ± 18.1 vs. 44.9 ± 16.4 μmol kg−1 min−1). Our findings indicate that both PA and MMA should be considered metabolic myopathies, which may explain the reported exercise intolerance and fatigue.","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

JAK Inhibition in PNPT1-Related Mitochondrial Interferonopathy: A Case Report and Review of Mitochondrial–Immune Crosstalk JAK抑制与pnpt1相关的线粒体干扰素病：一个线粒体-免疫串扰的病例报告和综述。

IF 1.8

JIMD reports Pub Date : 2026-06-29 DOI: 10.1002/jmd2.70096

Dan Ross Brooks, Hyun Yong Koh, Taylor Martin Kerrins, Steven Lang, Emily Bland, Rui Yang, Sarah Kogan Nicholas, Stephanie Jean Sikkink, Stephen Kralik, Christine Eng, Chaya Nautiyal Murali, Seema Lalani, Pilar Lenglet Magoulas, Lisa Emrick, Kristen Sydney Fisher, Fernando Scaglia

{"title":"JAK Inhibition in PNPT1-Related Mitochondrial Interferonopathy: A Case Report and Review of Mitochondrial–Immune Crosstalk","authors":"Dan Ross Brooks, Hyun Yong Koh, Taylor Martin Kerrins, Steven Lang, Emily Bland, Rui Yang, Sarah Kogan Nicholas, Stephanie Jean Sikkink, Stephen Kralik, Christine Eng, Chaya Nautiyal Murali, Seema Lalani, Pilar Lenglet Magoulas, Lisa Emrick, Kristen Sydney Fisher, Fernando Scaglia","doi":"10.1002/jmd2.70096","DOIUrl":"10.1002/jmd2.70096","url":null,"abstract":"Biallelic pathogenic variants in PNPT1 cause combined oxidative phosphorylation deficiency 13 (COXPD13) (MIM #614932), linking mitochondrial dysfunction to type I interferon (IFN) activation through cytosolic leakage of mitochondrial double-stranded RNA (mt-dsRNA). This mechanism connects mitochondrial disease to interferonopathies such as Aicardi–Goutières syndrome (AGS). We describe a 7-month-old female infant with compound heterozygous PNPT1 variants presenting with severe hypotonia, feeding difficulties necessitating gastrostomy, dystonia, and elevated serum lactate. Brain magnetic resonance imaging (MRI) demonstrated marked cerebellar, brainstem, and basal ganglia atrophy, with a lactate peak on MR spectroscopy (consistent with an inverted doublet). Serum immune profiling revealed a mild but elevated type I IFN signature. Given the mechanistic overlap with AGS, off-label tofacitinib, a Janus kinase (JAK) inhibitor that blocks IFN-driven JAK/STAT signaling, was initiated following pediatric interferonopathy dosing protocols. Tofacitinib was associated with normalization of serum type I IFN biomarkers, reduction in lactate and transaminases, improvement in dystonic movements, ventilatory stability, and improved growth/nutrition without treatment-limiting adverse events. To our knowledge, this represents the first reported use of JAK inhibition in COXPD13. The observed clinical and biochemical stabilization supports defining COXPD13 as a “mitochondrial interferonopathy” and suggests that IFN-signature screening may identify mitochondrial disease patients who could benefit from targeted immunomodulation.","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13312033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148351946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Long-Term Follow-Up of Patients With Mitochondrial Carbonic Anhydrase VA Deficiency. A Case Report and Literature Review 线粒体碳酸酐酶VA缺乏症患者的长期随访。1例报告及文献回顾。

IF 1.8

JIMD reports Pub Date : 2026-06-28 DOI: 10.1002/jmd2.70102

Shaymaa Shurrab, Amira Mobarak, Gabriella Horvath, Sylvia Stocker-Ipsiroglu, Clara van Karnebeek, Ramona Salvarinova-Zivkovic

{"title":"Long-Term Follow-Up of Patients With Mitochondrial Carbonic Anhydrase VA Deficiency. A Case Report and Literature Review","authors":"Shaymaa Shurrab, Amira Mobarak, Gabriella Horvath, Sylvia Stocker-Ipsiroglu, Clara van Karnebeek, Ramona Salvarinova-Zivkovic","doi":"10.1002/jmd2.70102","DOIUrl":"10.1002/jmd2.70102","url":null,"abstract":"Mitochondrial carbonic anhydrase VA (CA-VA) deficiency is a rare inherited metabolic disorder caused by biallelic variants of the CA5A gene. It presents with hyperammonemia, lactic acidosis, and ketonuria, with or without hypoglycemia. We report the long-term follow-up of the first two reported cases of CA-VA deficiency: a 16-year-old female (case 1) and her 14-year-old brother (case 2), both of whom presented with neonatal hyperammonemic encephalopathy, hypoglycemia, elevated lactate, ketonuria, and compensated metabolic acidosis. The diagnosis was made in both cases through the TIDEX study, which identified a homozygous pathogenic variant in the CA5A gene (c.697T>C, (p.Ser233Pro)). The clinical course of the index patient revealed three additional metabolic decompensation episodes (MDEs) triggered by intercurrent illnesses, with the last episode occurring at 8 years of age, highlighting the unusual timing of her MDEs compared to previously reported cases. Case 2 remained metabolically stable without any additional MDEs. These episodes were successfully treated with parenteral dextrose, a single dose of enteral carglumic acid, and occasionally parenteral lipids. Management of intercurrent illness included a sick-day formula high in carbohydrates and fats. Currently, both cases show normal growth, development, and neurological outcomes, suggesting a favorable prognosis, and in keeping with previously reported cases. Early diagnosis of CA-VA deficiency allows prompt treatment and prevents severe complications. With proper management, long-term outcomes are favorable, although severe and fatal outcomes have been reported. The impact on longevity needs to be assessed over longer durations. The development of consensus management for CA-VA deficiency is warranted.","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13310582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148345464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Clinical Characteristics of 19 Patients With Acid Sphingomyelinase Deficiency: A Case Series From Multiple Centers in Argentina 19例酸性鞘磷脂酶缺乏症患者的临床特征：来自阿根廷多个中心的病例系列

IF 1.8

JIMD reports Pub Date : 2026-06-28 DOI: 10.1002/jmd2.70104

Maria Cristina Robin, Consuelo Durand, Guillermo Guelbert, Norberto Guelbert, Mariana Leguizamon, Mariana Nuñez Miñana, Maria Alejandra Cédola, Maria Gabriela de Lourdes Pacheco, Evangelina Gonzalez, Marisa Spallina, Sandra Quijano

{"title":"Clinical Characteristics of 19 Patients With Acid Sphingomyelinase Deficiency: A Case Series From Multiple Centers in Argentina","authors":"Maria Cristina Robin, Consuelo Durand, Guillermo Guelbert, Norberto Guelbert, Mariana Leguizamon, Mariana Nuñez Miñana, Maria Alejandra Cédola, Maria Gabriela de Lourdes Pacheco, Evangelina Gonzalez, Marisa Spallina, Sandra Quijano","doi":"10.1002/jmd2.70104","DOIUrl":"10.1002/jmd2.70104","url":null,"abstract":"Acid sphingomyelinase deficiency (ASMD), historically known as Niemann-Pick disease, is a rare and potentially fatal lysosomal storage disease caused by pathogenic variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene, which encodes acid sphingomyelinase (ASM). Deficient ASM activity results in dysregulation of cellular membrane homeostasis and accumulation of sphingomyelin in multiple organs. ASMD spans a broad clinical spectrum, with symptoms varying at presentation depending on age at onset and degree and type of organ/systemic involvement. To describe the diagnostic experience and clinical manifestations of ASMD in Argentina, a national retrospective case series was conducted across seven centers in patients diagnosed between 1988 and 2022. Diagnosis was confirmed by reduced ASM activity, with SMPD1 sequencing performed when possible. Nineteen patients (8 females/11 males; 0–76 years) were identified: Type A (4, 21%), Type B (12, 63%), Type A/B (2, 11%), and one unknown. Average age at symptom onset was 3.9 years, and average age at diagnosis was 11.4 years, corresponding to a diagnostic delay of 7.5 years. All patients presented with hepatosplenomegaly. Anemia (79%), pulmonary involvement (79%), thrombocytopenia (79%), and osteopenia (56%) were also reported in a majority of patients. Two patients were initially misdiagnosed with Gaucher disease. This series highlights the variety of clinical presentations and substantial diagnostic delays associated with ASMD in Argentina. Increasing awareness across specialties is essential to improve disease recognition, reduce time to diagnosis, and prevent misdiagnosis.","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13310959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148351917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cardiac Manifestation in Wilson Disease: Results of a 9-Year Prospective Cohort 威尔逊病的心脏表现：一项9年前瞻性队列研究结果

IF 1.8

JIMD reports Pub Date : 2026-06-25 DOI: 10.1002/jmd2.70106

S. Quick, M. Cybularz-Bednarek, L. Wiegand, K. Zhang, K. Ibrahim, M. Christoph, J. Hamann, A. Linke, F. M. Heidrich

{"title":"Cardiac Manifestation in Wilson Disease: Results of a 9-Year Prospective Cohort","authors":"S. Quick, M. Cybularz-Bednarek, L. Wiegand, K. Zhang, K. Ibrahim, M. Christoph, J. Hamann, A. Linke, F. M. Heidrich","doi":"10.1002/jmd2.70106","DOIUrl":"https://doi.org/10.1002/jmd2.70106","url":null,"abstract":"Wilson disease (WD) is a rare autosomal recessive disorder. Although hepatic and neurologic manifestations are characterized, long-term cardiac outcomes remain poorly defined. We report the first longitudinal study systematically assessing cardiac symptoms and events over nearly a decade in WD. In 2016, 61 WD patients underwent prospective cardiac evaluation including echocardiography, MRI and 24-h ECG. Nine years later, we re-contacted all surviving participants by telephone and emailed standardized questionnaires. Baseline characteristics of respondents and non-respondents were compared to assess selection bias; mortality data were obtained from family interviews and medical records. Outcomes were available for 31 of 61 patients (27 interviewed, 4 deceased; no cardiac-related deaths) after a mean follow-up of 9.1 years. Respondents did not differ from those lost to follow-up, except for fewer disease exacerbations. General and cardiac health remained unchanged in about half (48% and 52%), worsened in ~40%, and improved in ≤ 15%. Palpitations were frequent (70%), whereas dizziness (26%), syncope (7%), and leg oedema (15%) were infrequent and comparable to general-population estimates. Daily activity was unrestricted in 44%, mildly to moderately restricted in 52% and severely restricted in 4%. Only six patients (22%) remained in routine cardiology care. Baseline imaging, strain, autonomic and laboratory parameters did not predict symptoms at follow-up. Over 9 years, cardiac symptoms in WD were common but mostly mild to moderate. These findings support a symptom-guided cardiological assessment within interdisciplinary care. Whether systematic screening of asymptomatic patients is warranted remains uncertain and requires dedicated prospective study.","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70106","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148324376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cardiac Manifestation in Wilson Disease: Results of a 9-Year Prospective Cohort 威尔逊病的心脏表现：一项9年前瞻性队列研究结果

IF 1.8

JIMD reports Pub Date : 2026-06-25 DOI: 10.1002/jmd2.70106

S. Quick, M. Cybularz-Bednarek, L. Wiegand, K. Zhang, K. Ibrahim, M. Christoph, J. Hamann, A. Linke, F. M. Heidrich

{"title":"Cardiac Manifestation in Wilson Disease: Results of a 9-Year Prospective Cohort","authors":"S. Quick, M. Cybularz-Bednarek, L. Wiegand, K. Zhang, K. Ibrahim, M. Christoph, J. Hamann, A. Linke, F. M. Heidrich","doi":"10.1002/jmd2.70106","DOIUrl":"https://doi.org/10.1002/jmd2.70106","url":null,"abstract":"Wilson disease (WD) is a rare autosomal recessive disorder. Although hepatic and neurologic manifestations are characterized, long-term cardiac outcomes remain poorly defined. We report the first longitudinal study systematically assessing cardiac symptoms and events over nearly a decade in WD. In 2016, 61 WD patients underwent prospective cardiac evaluation including echocardiography, MRI and 24-h ECG. Nine years later, we re-contacted all surviving participants by telephone and emailed standardized questionnaires. Baseline characteristics of respondents and non-respondents were compared to assess selection bias; mortality data were obtained from family interviews and medical records. Outcomes were available for 31 of 61 patients (27 interviewed, 4 deceased; no cardiac-related deaths) after a mean follow-up of 9.1 years. Respondents did not differ from those lost to follow-up, except for fewer disease exacerbations. General and cardiac health remained unchanged in about half (48% and 52%), worsened in ~40%, and improved in ≤ 15%. Palpitations were frequent (70%), whereas dizziness (26%), syncope (7%), and leg oedema (15%) were infrequent and comparable to general-population estimates. Daily activity was unrestricted in 44%, mildly to moderately restricted in 52% and severely restricted in 4%. Only six patients (22%) remained in routine cardiology care. Baseline imaging, strain, autonomic and laboratory parameters did not predict symptoms at follow-up. Over 9 years, cardiac symptoms in WD were common but mostly mild to moderate. These findings support a symptom-guided cardiological assessment within interdisciplinary care. Whether systematic screening of asymptomatic patients is warranted remains uncertain and requires dedicated prospective study.","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70106","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148324729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Longitudinal Changes in Glutamine and Ammonia in Relation to Hyperammonemic Crisis in Urea Cycle Disorders 谷氨酰胺和氨的纵向变化与尿素循环紊乱中的高氨血症危象有关

IF 1.8

JIMD reports Pub Date : 2026-06-18 DOI: 10.1002/jmd2.70105

Yasuaki Yasuda, Yoko Nakajima, Yuta Sudo, Takuma Ishihara, Tetsuya Ito

{"title":"Longitudinal Changes in Glutamine and Ammonia in Relation to Hyperammonemic Crisis in Urea Cycle Disorders","authors":"Yasuaki Yasuda, Yoko Nakajima, Yuta Sudo, Takuma Ishihara, Tetsuya Ito","doi":"10.1002/jmd2.70105","DOIUrl":"https://doi.org/10.1002/jmd2.70105","url":null,"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 (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.","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70105","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148282371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Longitudinal Changes in Glutamine and Ammonia in Relation to Hyperammonemic Crisis in Urea Cycle Disorders 谷氨酰胺和氨的纵向变化与尿素循环紊乱中的高氨血症危象有关

IF 1.8

JIMD reports Pub Date : 2026-06-18 DOI: 10.1002/jmd2.70105

Yasuaki Yasuda, Yoko Nakajima, Yuta Sudo, Takuma Ishihara, Tetsuya Ito

{"title":"Longitudinal Changes in Glutamine and Ammonia in Relation to Hyperammonemic Crisis in Urea Cycle Disorders","authors":"Yasuaki Yasuda, Yoko Nakajima, Yuta Sudo, Takuma Ishihara, Tetsuya Ito","doi":"10.1002/jmd2.70105","DOIUrl":"https://doi.org/10.1002/jmd2.70105","url":null,"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 (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.","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70105","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148282370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Long-Term Efficacy and Safety of Glycerol Phenylbutyrate in Japanese Patients With Urea Cycle Disorders: Results From a Phase 3 Switch-Over and 12-Month Extension Study 苯丁酸甘油治疗日本尿素循环障碍患者的长期疗效和安全性：来自3期转换和12个月延长研究的结果

IF 1.8

JIMD reports Pub Date : 2026-06-14 DOI: 10.1002/jmd2.70082

Yoichi Wada, Mahoko Furujo, Kenichi Kashimada, Takashi Hamazaki, Hiromi Nyuzuki, Keiko Ichimoto, Toshihiko Kakiuchi, Shirou Matsumoto, Yoriko Watanabe, Chiho Ono, Takako Shimizu, Hiroiku Furukawa, Kimitoshi Nakamura

{"title":"Long-Term Efficacy and Safety of Glycerol Phenylbutyrate in Japanese Patients With Urea Cycle Disorders: Results From a Phase 3 Switch-Over and 12-Month Extension Study","authors":"Yoichi Wada, Mahoko Furujo, Kenichi Kashimada, Takashi Hamazaki, Hiromi Nyuzuki, Keiko Ichimoto, Toshihiko Kakiuchi, Shirou Matsumoto, Yoriko Watanabe, Chiho Ono, Takako Shimizu, Hiroiku Furukawa, Kimitoshi Nakamura","doi":"10.1002/jmd2.70082","DOIUrl":"10.1002/jmd2.70082","url":null,"abstract":"Sodium phenylbutyrate (NaPBA) is used for nitrogen scavenging in urea cycle disorders (UCDs), but its volume, palatability, and sodium load affect adherence and ammonia control. Glycerol phenylbutyrate (GPB) offers an alternative option with demonstrated improvements in metabolic control and palatability. For a Japanese perspective, we undertook an open-label, multicentre, prospective Phase 3 study of efficacy, pharmacokinetics (PK), and safety. In a switch-over, 15 patients received NaPBA for 7 days, then GPB for 7 days. Primary endpoint: 24-h blood ammonia AUC (AUCNH3,0–24). Secondary endpoints: blood ammonia and glutamine concentration; PK of scavenger metabolites in blood and urine; safety. Patients then received GPB for up to 12 months. For GPB and NaPBA, respectively, mean (SD) AUCNH3,0–24 was 627 (198) and 757 (307) μmol·h/L (ratio 0.849; 95% CI 0.723–0.997). Mean peak and mean blood ammonia were 37 and 26 μmol/L versus 52 and 32 μmol/L. Mean plasma AUC0–24 for phenylbutyrate (PBA), phenylacetate (PAA), and phenylacetylglutamine (PAGN) were 470, 1420, and 836 versus 425, 984, and 741 μg·h/mL. Mean PBA metabolite fluctuation was 297% versus 366%. One adverse event (hyperammonaemia) led to discontinuation in each treatment arm. In the extension (n = 14), mean (SD) blood ammonia at Month 12 was 21 (8) μmol/L. No new safety findings were observed. GPB demonstrated effective control of blood ammonia with a favourable safety profile. It offers a practical and clinically advantageous alternative to NaPBA, extending previous evidence to Japanese individuals with UCDs. Trial registration: jRCT2071220110.","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13265243/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148264367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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