JIMD reports最新文献

{"title":"Antenatal and Neonatal Management of Siblings With Carbonic Anhydrase VA Deficiency","authors":"Sophie Manoy,&nbsp;Tahlee Minto,&nbsp;Kalliope Demetriou,&nbsp;Matthew Lynch,&nbsp;Arthavan Selvanathan,&nbsp;Luke Jardine,&nbsp;Michelle Lipke,&nbsp;Carolyn Bursle,&nbsp;Anita Inwood,&nbsp;Jim McGill,&nbsp;David Coman","doi":"10.1002/jmd2.70076","DOIUrl":"10.1002/jmd2.70076","url":null,"abstract":"<p>Carbonic anhydrase VA (CAVA) deficiency (OMIM 114761) is an ultra-rare inborn error of metabolism with fewer than 20 cases described. Affected infants present in the first days of life with hyperammonaemia, lactic acidosis, ketonaemia and encephalopathy. Prenatal genetic testing can facilitate the diagnosis of subsequent affected pregnancies and permit proactive clinical management to prevent metabolic decompensation. Here we describe the clinical course of two sibling infants antenatally diagnosed with CAVA deficiency who were monitored and managed in the newborn period without decompensation. The proband, their older brother, had presented on day four of life with marked lactic acidosis, hyperammonaemia and encephalopathy requiring haemofiltration due to CAVA deficiency. His brothers were each born in a tertiary neonatal setting. They were managed with regular 3–4 hourly breastfeeds with supplementary expressed breast milk and formula top-ups to ensure optimal nutrition. In addition, they received carglumic acid (100 mg/kg daily) for 5 days. Regular biochemical monitoring was undertaken with measurement of acid–base status and ammonia levels. In contrast to their older brother, these male siblings had unremarkable neonatal periods with no significant clinical or biochemical concerns, demonstrating that in a neonate known to be affected with CAVA deficiency, early intervention can be instituted to minimise the risk of metabolic decompensation in the neonatal period.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12928768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283712","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":"Intrathecal idursulfase-IT in children younger than 3 years with neuronopathic mucopolysaccharidosis II in a single-arm, open-label, phase 2/3 substudy and extension","authors":"Joseph Muenzer,&nbsp;Barbara K. Burton,&nbsp;Paul Harmatz,&nbsp;Luis González Gutiérrez-Solana,&nbsp;Matilde Ruiz-Garcia,&nbsp;Simon A. Jones,&nbsp;Nathalie Guffon,&nbsp;Michal Inbar-Feigenberg,&nbsp;Drago Bratkovic,&nbsp;Stewart Rust,&nbsp;Michael Hale,&nbsp;Yuna Wu,&nbsp;Karen S. Yee,&nbsp;David A. H. Whiteman,&nbsp;David Alexanderian","doi":"10.1002/jmd2.12443","DOIUrl":"10.1002/jmd2.12443","url":null,"abstract":"<p>Data from a phase 2/3, randomized, controlled, open-label, multicenter trial in children with neuronopathic mucopolysaccharidosis II (MPS II; Hunter syndrome) older than 3 years suggested a benefit of intrathecal idursulfase-IT on cognitive functioning in some patients. We describe a separate, parallel, open-label, single-arm, 52-week substudy of the same trial (NCT02055118) that investigated idursulfase-IT in children with MPS II younger than 3 years at enrollment and Bayley Scales of Infant and Toddler Development (BSID-III) quotient 55–85. This report describes a prespecified analysis of nine patients (aged 1.4–3.0 years) who had received 3-years' treatment with idursulfase-IT. BSID-III cognitive composite scores generally remained relatively stable over time. At the last available assessment, scores were “high average” (110; <i>n</i> = 1), “average” (100–90; <i>n</i> = 4), and “low average” (85–80; <i>n</i> = 4). Eight patients transitioned to the Differential Ability Scales (DAS-II) after ages ≥42 months, and scores decreased for all patients when the instrument for assessing cognitive function changed. However, DAS-II General Conceptual Ability scores were relatively stable for the remainder of the follow-up. At the last available assessment, scores were “average” (106; <i>n</i> = 1), “low average” (85–80; <i>n</i> = 3), and “very low” (69–43; <i>n</i> = 4). Cerebrospinal fluid concentrations of total glycosaminoglycans were markedly reduced from baseline levels (mean [range] 1278 [429–2660] ng/mL) by week 16 and remained low thereafter. Data suggest early enzyme replacement therapy may stabilize cognitive development or slow the progression of cognitive impairment in young patients with neuronopathic MPS II.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12928010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283624","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":"Clinical Profiles, Genetic Variants, and Neurodevelopmental Outcomes Following Liver Transplantation in Maple Syrup Urine Disease: A Study From Palestine","authors":"Reham Khalaf-Nazzal,&nbsp;Huthaifa Haj-Ahmad,&nbsp;Jana Zaid,&nbsp;Mohammed AbuShamleh,&nbsp;Imad Dweikat","doi":"10.1002/jmd2.70077","DOIUrl":"10.1002/jmd2.70077","url":null,"abstract":"<p>Maple syrup urine disease (MSUD) is a rare, autosomal recessive metabolic disorder resulting from a deficiency of the branched-chain α-ketoacid dehydrogenase complex. This leads to the accumulation of branched-chain amino acids and their corresponding ketoacids, causing acute metabolic crises and progressive neurological damage if untreated. The impact of founder variants, high consanguinity, and limited access to metabolic care pose challenges in medically underserved populations, such as in Palestine. We conducted a retrospective analysis of 11 patients from eight Palestinian families referred to the main Metabolic Unit in the West Bank. Clinical data, biochemical profiles, and molecular findings were reviewed to characterize the presentation and outcomes of MSUD. Management strategies, including dietary intervention and liver transplantation, were also evaluated. Acute metabolic crises were the initial presentation in 91% of cases, typically within the first days of life. Diagnostic delay averaged 47 days in families without prior MSUD history, compared to 2.3 days in those with affected siblings. Founder pathogenic variants were identified in multiple unrelated families, reflecting genetic homogeneity due to community structure; novel variants were also detected. Timely diagnosis facilitated early referral and improved outcomes. Patients who underwent liver transplantation, especially when performed early, exhibited favorable developmental trajectories, increased leucine tolerance, and fewer hospitalizations. One participant diagnosed prenatally remained free of metabolic crises until transplantation at age six, with excellent neurocognitive outcomes. This study highlights the importance of integrating prenatal screening and early diagnosis, timely dietary intervention, and liver transplantation to improve MSUD outcomes in resource-limited settings.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12928098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283656","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":"Pegvaliase Treatment for Adolescents With Phenylketonuria: A Multi-Site Study","authors":"Suzanne Hollander,&nbsp;Briana Valli,&nbsp;Erika Vucko,&nbsp;Melissa Lah,&nbsp;Amarilis Sanchez-Valle,&nbsp;Brittany M. Murray,&nbsp;Amy Kritzer,&nbsp;Stephanie Sacharow","doi":"10.1002/jmd2.70070","DOIUrl":"10.1002/jmd2.70070","url":null,"abstract":"<p>Phenylketonuria (PKU) is an inherited metabolic disorder causing elevated phenylalanine (Phe) levels and neurocognitive impairment if left untreated. While dietary therapy remains the treatment standard, adherence declines during adolescence. Pegvaliase, an injectable enzyme therapy approved for adults &gt; 18 years in the United States, lowers Phe levels while allowing dietary flexibility. This study examines pegvaliase use in adolescents, focusing on efficacy, discontinuation patterns, and predictors of success. We conducted a retrospective chart review from four metabolic centers with 53 individuals with PKU (age 14–22 years) who initiated pegvaliase through March 2025. Data included demographics, treatment response, side effects, and discontinuation reasons. Mean pretreatment Phe was 716 μmol/L, which decreased by 44% post-treatment initiation. Sixty-four percent of individuals achieved efficacy with a mean Phe of 231 μmol/L (60% decrease) after 14 months at mean dose of 37.4 mg/day. Common side effects included injection site reactions in 77%, joint pain in 64%, rash in 45%, headaches in 26%, fatigue in 19%, fever and/or chills in 13%, GI symptoms in 13%, and anaphylaxis in 9%. Discontinuation occurred in 24.5% of this cohort, with rates significantly higher in 12th graders (40%) and college students (32%) versus 9th–11th graders (5.5%). Pegvaliase may lower Phe levels in adolescents, reaching target blood Phe goals (≤ 360 μmol/L) once efficacy is achieved. Treatment showed better sustainability when initiated earlier in adolescence. The higher discontinuation during transitional years (12th grade/college) suggests treatment challenges increase during these periods. Earlier initiation, when family support is typically stronger, may improve outcomes. These findings support reconsidering current age restrictions for pegvaliase therapy.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12912880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146226649","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":"Mitochondrial Dysfunction in Propionic Acidemia: A Case-Report and Review of the Literature","authors":"Brandon K. Walther,&nbsp;Brittany M. Murray,&nbsp;Poornima Pandiyan,&nbsp;Randall Ray,&nbsp;Laura Yeoh,&nbsp;Amy Kritzer","doi":"10.1002/jmd2.70073","DOIUrl":"10.1002/jmd2.70073","url":null,"abstract":"<p>Propionic acidemia is an inborn error of metabolism involving an enzymatic defect of propionyl-CoA carboxylase that results in the build-up of toxic metabolites which can induce metabolic decompensation. Secondary mitochondrial dysfunction in propionic acidemia has been commonly recognized; however, its clinical presentation and management are not well represented in literature. Here, we present a case of profound hyperglycemia and lactic acidosis without hyperammonemia in a propionic acidemia patient, where medical management incorporated mitochondrial dysfunction via a brief reduction in glucose infusion rate. We review the literature on propionic acidemia and mitochondrial dysfunction in an effort to provide a tangible clinical case where considerations of mitochondrial dysfunction were made to guide further decision making in taking care of this patient population.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12872281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146124982","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":"Metabolic Stroke: Atypical Presentation of Succinic Semialdehyde Dehydrogenase Deficiency","authors":"Sharmila Kiss,&nbsp;Richard J. Leventer,&nbsp;Cormac Duff,&nbsp;Emma Macdonald-Laurs,&nbsp;Olivia-Paris Quinn,&nbsp;Fahaz Nazer,&nbsp;Michelle Cao,&nbsp;Abisha Srikumar,&nbsp;Jenzen Dalina,&nbsp;Mary Eggington,&nbsp;Joy Yaplito- Lee","doi":"10.1002/jmd2.70071","DOIUrl":"10.1002/jmd2.70071","url":null,"abstract":"<p>Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive neurometabolic disorder caused by biallelic pathogenic variants in <i>ALDH5A1</i>, encoding the mitochondrial enzyme SSADH. This enzyme catalyses the conversion of succinic semialdehyde to succinic acid in the γ-aminobutyric acid (GABA) degradation pathway. SSADH deficiency leads to the accumulation of neurotoxic metabolites, including γ-hydroxybutyrate (GHB), and presents with developmental delay, hypotonia, ataxia, seizures, behavioral disturbances, and intellectual disability. We report a 10-month-old Caucasian male with global developmental delay, central hypotonia, and delayed motor milestones. He presented acutely with left-sided hemiplegia following irritability and vomiting. Brain MRI showed bilateral (right &gt; left) T2 hyperintensities and diffusion restriction in the globus pallidus. Urine organic acid analysis via gas chromatography–mass spectrometry revealed markedly elevated 4-hydroxybutyric acid and 4,5-dihydroxyhexanoic lactone, pathognomonic for SSADH deficiency. Molecular testing identified compound heterozygous <i>ALDH5A1</i> variants: c.278G&gt;T p.(Cys93Phe) and c.612G&gt;A p.(Trp204*), both previously reported as pathogenic. Parental segregation confirmed trans configuration. Three weeks postillness, he developed focal seizures, which have remained well controlled on levetiracetam. His seizure onset in infancy is notably earlier than the typical early childhood onset (~9 years) reported in SSADH deficiency. This case expands the phenotypic spectrum of SSADH deficiency to include metabolic stroke as a presenting feature in infancy and highlights the importance of early recognition and molecular confirmation to guide management and emerging therapeutic strategies.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146105573","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":"Epilepsy Phenotype and EEG Finding of Rhythmic High-Amplitude Delta With Superimposed Spikes (RHADS) in Succinate Dehydrogenase Deficiency","authors":"Aaron B. Bowen,&nbsp;Chiadika Nwanze,&nbsp;Cesar Alves,&nbsp;Lance Rodan,&nbsp;Anna Lecticia Pinto,&nbsp;Melissa A. Walker,&nbsp;Irina Anselm,&nbsp;Phillip L. Pearl","doi":"10.1002/jmd2.70072","DOIUrl":"10.1002/jmd2.70072","url":null,"abstract":"<p>Succinate dehydrogenase (SDH) serves a dual function as complex II of the electron transport chain and an enzyme of the tricarboxylic acid cycle. Pathogenic variants in subunits of SDH result in diverse clinical presentations, including typically autosomal recessive neurodegenerative disorders. Biallelic variants in the SDHA subunit most often cause Leigh syndrome. However, epilepsy phenotypes of these patients are ill-defined and there is only one prior report of epilepsy in a patient with SDHA deficiency. Here we report the seizure and EEG phenotypes of three autosomal recessive SDHA patients with refractory epilepsy, two of whom are siblings. These patients exhibit multiple seizure types and a variety of EEG findings, including a patient with rhythmic high-amplitude delta with superimposed spikes (RHADS), a finding closely associated with polymerase gamma (POLG)-related disorders.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 2","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12861999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146113246","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":"A Novel PCK1 Gene Variant Associated With Cytosolic Phosphoenolpyruvate Carboxykinase Deficiency: Two Siblings With Different Clinical Presentations","authors":"Lauma Vasiļevska,&nbsp;Ieva Puķīte,&nbsp;Madara Auzenbaha,&nbsp;Dmitrijs Rots,&nbsp;Ieva Grīnfelde,&nbsp;Andžela Lazdāne,&nbsp;Sebastian Schulz-Jürgensen","doi":"10.1002/jmd2.70065","DOIUrl":"10.1002/jmd2.70065","url":null,"abstract":"<p>Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) deficiency is a rare autosomal recessive gluconeogenesis disorder caused by variants in the <i>PCK1</i> gene. Clinically, PEPCK-C deficiency is characterized by recurrent episodes of fasting-induced hypoglycemia, liver dysfunction, and seizures, with the first hypoglycemic episode typically occurring in the neonatal period or in early childhood. We report a case of PEPCK-C deficiency in an 8-year-old who presented with transient severe acute liver and kidney failure, accompanied by markedly elevated glutamine levels as the initial manifestation of the disease. The acute liver failure was reversible following continuous glucose infusion. Next-generation sequencing identified two variants in the <i>PCK1</i> gene: one previously known pathogenic variant, c.925G&gt;A p.(Gly309Arg), and a second previously unreported variant, c.1833_1834del p.(Glu611AspfsTer16). These variants were confirmed to be in a compound heterozygous state. Based on the patient's clinical presentation, the second variant was classified as likely pathogenic. Subsequent genetic testing of family members revealed that the patient's 12-year-old sister has the same <i>PCK1</i> variants but remains asymptomatic to date. Given the clinical findings, we propose that the c.1833_1834del p.(Glu611AspfsTer16) variant in the <i>PCK1</i> gene should be classified as likely pathogenic. We recommend considering molecular diagnostics for PEPCK-C deficiency in patients presenting with severe acute liver failure and elevated glutamine levels, as early diagnosis and intervention may lead to a reversible outcome.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12834696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093095","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":"Early Initiation of Enzyme Replacement Therapy in Infantile Onset Pompe Disease Improves Cardiac Outcomes: A Longitudinal Analysis","authors":"Jennifer L. Cohen,&nbsp;M. Makenzie Beaman,&nbsp;Eleanor Rodriguez-Rassi,&nbsp;V. Grace Stafford,&nbsp;P. Brian Smith,&nbsp;Andrew P. Landstrom,&nbsp;Priya S. Kishnani","doi":"10.1002/jmd2.70060","DOIUrl":"10.1002/jmd2.70060","url":null,"abstract":"<p>The objective of this study is to evaluate whether early enzyme replacement therapy (ERT) initiation is associated with a lower incidence of echocardiogram abnormalities and cardiac conduction abnormalities compared to later ERT initiation. We identified a cohort of patients treated with ERT for infantile onset Pompe disease (IOPD) and evaluated their cardiac outcomes by comparing clinically collected longitudinal functional echocardiogram and electrocardiogram (EKG) data. Longitudinal mixed-effects analysis was used to compare cardiac outcomes among the cohort based on timing of ERT initiation as a continuous variable (months of age) and accounted for repeated measures in an individual patient. Time-to-event analysis and Cox regression were performed to evaluate the time to achievement of normal left ventricular mass index (LVMI) based on ERT initiation as a dichotomous variable (≤ 1 month versus &gt; 1 month of age). Early treatment was associated with significant improvements in cardiac remodeling as demonstrated by multiple cardiac parameters with better outcomes based on earlier treatment such as interventricular septum thickness in diastole and systole, left ventricular posterior wall thickness in diastole and systole, and biventricular hypertrophy. The early-treated cohort (those started on ERT ≤ 1 month of age) achieved a normal LVMI faster compared to late-treated patients. Early treatment with ERT in patients with IOPD leads to improved cardiac chamber dimension parameters. Treatment initiation ≤ 1 month of age can shorten the time to achieve a normal LVMI. Our findings were limited by the nature of the data collection, which was retrospective and clinically driven; the results presented in this study, however, support the clinical importance of early therapeutic intervention in IOPD. Early initiation with ERT in patients with IOPD can shorten the time to achieve a normal LVMI and can improve cardiac chamber dimension parameters.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12828348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046654","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":"Drivers of Diagnostic Delay in Mitochondrial Disease: Missed Recognition of Canonical Features","authors":"Rory J. Tinker,&nbsp;Neil Jacob,&nbsp;Mohammad Ghouse Syed,&nbsp;Janhawi Kelkar,&nbsp;Colleen Donnelly,&nbsp;Ibrahim Elsharkawi,&nbsp;Jaya Ganesh,&nbsp;Bruce D. Gelb,&nbsp;Vikas Pejaver,&nbsp;Tamas Kozicz,&nbsp;Eva Morava","doi":"10.1002/jmd2.70068","DOIUrl":"10.1002/jmd2.70068","url":null,"abstract":"<p>Diagnostic delay is common in mitochondrial disease, and its drivers remain unclear despite advances in molecular diagnostics. We retrospectively analyzed 61 individuals with molecularly confirmed mitochondrial disease at the Mount Sinai Mitochondrial Disease Clinic, diagnosed after 2016. Diagnostic delay was partitioned into intervals from symptom onset to clinical suspicion, and from suspicion to molecular diagnosis. Demographic, phenotypic, and genetic data were abstracted from health records, and Human Phenotype Ontology terms were compared before and after diagnosis using ClinPhen. Most delays occurred between symptom onset and clinical suspicion (mean 8.17 years) rather than after suspicion (mean 1.28 years), yielding a mean total delay of 8.22 years (median 3.0). Delay decreased sharply by year of birth (<i>r</i> = −0.99, <i>p</i> &lt; 49.92 × 10⁻³⁹) and symptom onset (<i>r</i> = −0.96, <i>p</i> &lt; 8.14 × 10⁻²⁷), but showed no meaningful trend with year of diagnosis. Canonical features such as seizures, hypotonia, and stroke were frequently documented years before suspicion, underscoring missed opportunities. Diagnostic delay may reflect missed recognition rather than testing limitations. Systematic capture of early phenotypes and AI/NLP-based mining of electronic health records could proactively flag patients for reflexive sequencing, shortening diagnostic delay.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 1","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12827488/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146052155","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}