JIMD reports最新文献

{"title":"Re: Pegvaliase Treatment for Adolescents With Phenylketonuria: A Multi-Site Study","authors":"Patricia L. Hall, Coleman Turgeon, Dietrich Matern","doi":"10.1002/jmd2.70085","DOIUrl":"10.1002/jmd2.70085","url":null,"abstract":"<p>In the recent paper “Pegavaliase Treatment for Adolescents With Phenylketonuria: A Multi-Site Study,” Hollander et al. use “blood” phenylalanine (Phe) levels as indicator of pegvaliase response [<span>1</span>]. While that is an obvious choice, we believe that any report that associates Phe concentrations to pegvaliase treatment should indicate the blood collection procedure, temperature during transport to the laboratory, and specimen type analyzed (i.e., plasma or dried blood spots). The reason is that the accuracy of Phe measurements in patients taking pegvaliase is dependent on all these factors. As we reported previously Phe can decrease in a blood specimen prior to analysis when the patient is treated with pegvaliase [<span>2</span>]. In plasma specimens, even during the short time needed to prepare a sample at room temperature for analysis, pegvaliase present in the specimen still degrades Phe resulting in a discrepancy of the in vitro versus in vivo concentration. The study's Phe decrease (50% reduction compared to before treatment was initiated) described to indicate achievement of treatment efficacy could easily be mimicked by routine sample handling at room temperature. The lowest Phe values observed (range 7–1418 μmol/L) in this study may be evidence of this phenomenon, as opposed to true Phe deficiency under treatment. If blood measurements are used as guide points to liberalize intact protein intake, understanding these preanalytical factors is key.</p><p>Of course, if the study adhered to the manufacturer's clinical trial manual, which recommends spinning down blood and freezing plasma within 30 min of collection, the reported Phe concentrations may be valid. But even under ideal conditions it is unlikely that a specimen will remain unfrozen for less than an hour when accounting for the above-mentioned factors. It is likely that only a point-of-care Phe measurement could prevent these preanalytical effects, unless rigorous procedures were followed on the collection and the laboratory sides. From the laboratory perspective, such specimens would have to be marked to ensure the shortest processing time possible.</p><p>It is important to note that we do not believe that the lack of detailed blood collection and processing descriptions alters the overall findings and conclusions drawn from this study. However, those who treat patients with pegvaliase should be aware of the continued activity of pegvaliase in blood specimens after collection and consult with laboratories performing plasma amino acid analyses for their patients to ensure processes are in place to provide reliable Phe measurements. This is also important because sometimes specimens are exposed to longer times at room temperature due to unanticipated delays caused by assay failures or equipment access. Pegvaliase is an important new treatment option for patients with PKU; however, this medication has fundamental implications for accurate measurement and interpretation of","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/PMC13265135/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258261","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}

{"title":"Heterozygous OGDH Variants Are Involved in Peripheral Neuropathy With Ataxia and Optical Atrophy","authors":"Liedewei Van de Vondel,&nbsp;Gyu S. Lee,&nbsp;Jonathan De Winter,&nbsp;Satoshi Matsuzaki,&nbsp;Abigail Sandoval,&nbsp;Juan Felipe Ramirez,&nbsp;Alice Monticelli,&nbsp;Sukyeong Lee,&nbsp;Rita Horvath,&nbsp;Jan de Bleecker,&nbsp;Stephan Züchner,&nbsp;Kenneth M. Humphries,&nbsp;Jonathan Baets,&nbsp;Wan Hee Yoon","doi":"10.1002/jmd2.70103","DOIUrl":"10.1002/jmd2.70103","url":null,"abstract":"<p><i>2-oxyglutarate dehydrogenase</i> (<i>OGDH</i>) encodes an E1 component of α-ketoglutarate dehydrogenase complex that plays a pivotal role in the Krebs cycle. Biallelic variants in <i>OGDH</i> have been reported to cause an early-onset neurodevelopmental and mitochondrial disorder. However, monoallelic <i>OGDH</i> variants have not been associated with human disease. Here, we identified <i>de novo</i> c.1909C&gt;T (p.Arg637Trp) and heterozygous c.162T&gt;G (p.Ser54Arg) variants in <i>OGDH</i> in unrelated individuals exhibiting late-onset neurological phenotypes, characterized by cerebellar ataxia, peripheral neuropathy and optic atrophy. In silico protein structure predictions suggest that the p.Arg637Trp mutation might influence protein function. To determine the functional effects of the <i>OGDH</i> variants in vivo, we generated <i>Drosophila</i> models harboring <i>UAS-dOgdh</i> (<i>p.Arg639Trp</i>) and <i>UAS-dOgdh</i> (<i>p.Thr58Arg</i>) mutations, homologous to the human variants. While the mutant <i>OGDH</i> expression did not lead to defects in development, it did lead to age-dependent locomotion defects. Further, we found that p.Arg639Trp mutant leads to defective OGDH activity, while p.Thr58Arg causes abnormal proteolytic cleavage and impaired mitochondrial import. These findings suggest that the variants act as dominant-negative and toxic gain-of-function mutations, respectively. Our data provide evidence that monoallelic <i>OGDH</i> variants are involved in late-onset neurological disease in humans.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13244069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148211344","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}

{"title":"Expanding the MRPS34 Genotype–Phenotype Correlation: Two Novel Cases and a Cohort Review","authors":"Alberte Aspaas Lundquist,&nbsp;Sumit Parikh,&nbsp;Thomas van Overeem Hansen,&nbsp;Flemming Wibrand,&nbsp;Elsebet Østergaard","doi":"10.1002/jmd2.70089","DOIUrl":"10.1002/jmd2.70089","url":null,"abstract":"<p><i>MRPS34</i> encodes a mitoribosomal protein essential for mitochondrial translation. Biallelic pathogenic variants in <i>MRPS34</i> cause Combined Oxidative Phosphorylation Deficiency 32 (COXPD32), a rare mitochondrial disorder within the Leigh syndrome spectrum (LSS), ranging from fatal in infancy to adult survival. The objective is to describe two new individuals with <i>MRPS34</i>-related disease and expand the clinical, genetic, and phenotypic spectrum of COXPD32. Clinical, radiological, biochemical, and molecular evaluations were conducted in two individuals with Leigh Syndrome (LS). Exome and genome sequencing identified presumed biallelic <i>MRPS34</i> variants. A systematic review of all previously reported cases was performed to assess possible genotype–phenotype correlations (<i>n</i> = 11). Individual 1, who died in infancy with LS, was presumed compound heterozygous for a novel splice-site variant (c.364 + 2 T&gt;C, p.(?)) and a nonsense variant (c.94C&gt;T, p.(Gln32*)). Individual 2 survived into mid childhood and was homozygous for the hypomorphic variant c.322-10G&gt;A, p.(?). Among 11 individuals, key features included developmental delay (100%), lactic acidosis (91%), brainstem lesions (91%), and metabolic acidosis (83%). Homozygosity for c.322-10G&gt;A, p.(?) correlated with longer survival. <i>MRPS34</i>-related disease presents with multisystemic features and genotype-dependent severity. Accurate genetic diagnosis is essential for prognosis and therapeutic strategies.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13243876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148211364","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}

{"title":"Delay in Diagnosis of Classical Homocystinuria","authors":"Subadra Wanninayake,&nbsp;Reena Sharma,&nbsp;Diane Green,&nbsp;John Bassett,&nbsp;Tarekegn Geberhiwot,&nbsp;Charlotte Dawson","doi":"10.1002/jmd2.70087","DOIUrl":"https://doi.org/10.1002/jmd2.70087","url":null,"abstract":"<p>Classical homocystinuria (HCU) is an autosomal recessive disorder of methionine metabolism with a wide spectrum of severity and clinical presentation. Timely diagnosis facilitates prompt initiation of treatment, which reduces complications. Our aim was to identify the nature of the first clinical manifestation and time to subsequent diagnosis in our cohort of adults with HCU. This retrospective cross-sectional study was conducted in two tertiary referral centres for adult inherited metabolic disorders in the United Kingdom. Fifty-nine patients with sufficient clinical data for detailed analysis were included. 13/59 patients were detected asymptomatically through newborn or family screening and 46/59 were diagnosed on initial presentation with a clinical manifestation of HCU. For 15/54 (27.8%), the median time between initial presentation and diagnosis was 7 years (IQR, 2–11.9), the commonest first manifestation in the delayed group was lens subluxation (6/15, 40%) followed by venous thromboembolism (5/15, 33.3%) and skeletal deformities (2/15, 13.3%). 15/46 (32.6%) had two or more complications by the time of diagnosis. Lens subluxation is the commonest first manifestation of HCU in the group with delayed diagnosis. Early recognition, expanded screening and enhanced clinician awareness are essential for timely diagnosis and improved outcomes.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70087","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148174055","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}

{"title":"Delay in Diagnosis of Classical Homocystinuria","authors":"Subadra Wanninayake,&nbsp;Reena Sharma,&nbsp;Diane Green,&nbsp;John Bassett,&nbsp;Tarekegn Geberhiwot,&nbsp;Charlotte Dawson","doi":"10.1002/jmd2.70087","DOIUrl":"https://doi.org/10.1002/jmd2.70087","url":null,"abstract":"<p>Classical homocystinuria (HCU) is an autosomal recessive disorder of methionine metabolism with a wide spectrum of severity and clinical presentation. Timely diagnosis facilitates prompt initiation of treatment, which reduces complications. Our aim was to identify the nature of the first clinical manifestation and time to subsequent diagnosis in our cohort of adults with HCU. This retrospective cross-sectional study was conducted in two tertiary referral centres for adult inherited metabolic disorders in the United Kingdom. Fifty-nine patients with sufficient clinical data for detailed analysis were included. 13/59 patients were detected asymptomatically through newborn or family screening and 46/59 were diagnosed on initial presentation with a clinical manifestation of HCU. For 15/54 (27.8%), the median time between initial presentation and diagnosis was 7 years (IQR, 2–11.9), the commonest first manifestation in the delayed group was lens subluxation (6/15, 40%) followed by venous thromboembolism (5/15, 33.3%) and skeletal deformities (2/15, 13.3%). 15/46 (32.6%) had two or more complications by the time of diagnosis. Lens subluxation is the commonest first manifestation of HCU in the group with delayed diagnosis. Early recognition, expanded screening and enhanced clinician awareness are essential for timely diagnosis and improved outcomes.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70087","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148174054","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}

{"title":"Patient Preferences in Neuromuscular Diseases: Insights for Future Drug Development","authors":"Aura Cecilia Jimenez-Moreno,&nbsp;Alasdair Blain,&nbsp;Cathy Anne Pinto,&nbsp;Vikas Soekhai,&nbsp;Jennifer Viberg Johansson,&nbsp;Christine Dyer,&nbsp;Kate Adcock,&nbsp;Esther W. de Bekker-Grob,&nbsp;G. Ardine de Wit,&nbsp;Jane Newman,&nbsp;Gráinne S. Gorman","doi":"10.1002/jmd2.70100","DOIUrl":"https://doi.org/10.1002/jmd2.70100","url":null,"abstract":"<p>Incorporating patient preferences into drug development is crucial, particularly, for rare diseases with significant unmet needs. This study used Best-Worst Scaling type 2 (BWS-2) to explore benefit–risk trade-offs for patients and caregivers in two rare neuromuscular diseases (NMDs), myotonic dystrophy type 1 (DM1), and mitochondrial myopathy (MM). Patients with DM1 and MM, along with caregivers, completed a BWS-2 survey assessing four treatment benefits (muscle strength, energy and endurance, balance, cognition) and two risks (permanent liver damage, temporary blurring of vision). Participants were stratified by disease group and age of onset (&lt; 20, ≥ 20 years). A latent class analysis was used to calculate the relative importance of each treatment attribute. Sociodemographic and disease-related data were also collected. A total of 270 participants (DM1 <i>n</i> = 143, MM <i>n</i> = 127, including 37 caregivers) were included. BWS-2 results revealed a priority for improvements in muscle strength (24%), and energy and endurance (23%) across all groups, with caregivers placing a higher priority on cognition improvements (17%) compared to patients. There were no significant differences between disease groups or by age of onset. This study underscores the importance of patient preferences in drug development for rare NMDs. The consensus on treatment priorities across both diseases suggests that overlapping clinical features can inform and expedite future NMD or rare disease drug development.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70100","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148103170","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}

{"title":"Patient Preferences in Neuromuscular Diseases: Insights for Future Drug Development","authors":"Aura Cecilia Jimenez-Moreno,&nbsp;Alasdair Blain,&nbsp;Cathy Anne Pinto,&nbsp;Vikas Soekhai,&nbsp;Jennifer Viberg Johansson,&nbsp;Christine Dyer,&nbsp;Kate Adcock,&nbsp;Esther W. de Bekker-Grob,&nbsp;G. Ardine de Wit,&nbsp;Jane Newman,&nbsp;Gráinne S. Gorman","doi":"10.1002/jmd2.70100","DOIUrl":"https://doi.org/10.1002/jmd2.70100","url":null,"abstract":"<p>Incorporating patient preferences into drug development is crucial, particularly, for rare diseases with significant unmet needs. This study used Best-Worst Scaling type 2 (BWS-2) to explore benefit–risk trade-offs for patients and caregivers in two rare neuromuscular diseases (NMDs), myotonic dystrophy type 1 (DM1), and mitochondrial myopathy (MM). Patients with DM1 and MM, along with caregivers, completed a BWS-2 survey assessing four treatment benefits (muscle strength, energy and endurance, balance, cognition) and two risks (permanent liver damage, temporary blurring of vision). Participants were stratified by disease group and age of onset (&lt; 20, ≥ 20 years). A latent class analysis was used to calculate the relative importance of each treatment attribute. Sociodemographic and disease-related data were also collected. A total of 270 participants (DM1 <i>n</i> = 143, MM <i>n</i> = 127, including 37 caregivers) were included. BWS-2 results revealed a priority for improvements in muscle strength (24%), and energy and endurance (23%) across all groups, with caregivers placing a higher priority on cognition improvements (17%) compared to patients. There were no significant differences between disease groups or by age of onset. This study underscores the importance of patient preferences in drug development for rare NMDs. The consensus on treatment priorities across both diseases suggests that overlapping clinical features can inform and expedite future NMD or rare disease drug development.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 4","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70100","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148103163","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}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148083307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurological Outcomes of Newborn Screening-Identified Isovaleric Acidemia: A Case Series Exploring Initial C5 Acylcarnitine Levels.","authors":"Sharmila Kiss, Gary Lazarovski, Maureen Evans","doi":"10.1002/jmd2.70094","DOIUrl":"10.1002/jmd2.70094","url":null,"abstract":"<p><p>Isovaleric acidemia (IVA) is a rare autosomal recessive disorder caused by isovaleryl-CoA dehydrogenase deficiency, leading to toxic metabolite accumulation and potentially life-threatening metabolic crises. Newborn screening (NBS) has enabled early detection through elevated C5 acylcarnitine levels, yet the prognostic value of initial C5 concentrations remains unclear. This single-center retrospective study examined 10 Australian patients diagnosed with IVA via NBS between 2004 and 2025. Patients were stratified as \"mild\" or \"classic\" based on initial C5 levels and clinical severity. Developmental outcomes were assessed using standardized tools and clinical evaluations. Despite biochemical evidence of metabolic instability, including hyperammonemia, acidosis, and hospitalizations, no patients demonstrated neurological impairment on follow-up. Notably, individuals with markedly elevated C5 levels (up to 63.6 μmol/L) remained neurologically intact, suggesting that early diagnosis and timely metabolic management (protein restriction, carnitine/glycine supplementation, emergency protocols) may mitigate long-term CNS involvement. Dietary practices varied, with some patients maintaining protein restriction due to self-limited intake. Our findings reveal substantial heterogeneity in biochemical profiles and clinical trajectories, with minimal correlation between initial C5 levels and neurodevelopmental outcomes. These results align with prior studies questioning the predictive value of isolated NBS markers and support a more nuanced, individualized approach to IVA management. Limitations include small sample size, retrospective design, and incomplete standardized neurocognitive testing. Further prospective studies incorporating genotype data and formal assessments are needed to refine risk stratification and optimize long-term care strategies.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 ","pages":"e70094"},"PeriodicalIF":1.8,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13184167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147981597","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}

{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 3","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148083304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}