JIMD reports最新文献

{"title":"Fatty Acid Oxidation Disorders Detected by Newborn Screening: Clinical, Biochemical and Genetic Spectrum in a Single-Center Cohort","authors":"Elena Martín-Hernández,&nbsp;Delia Barrio-Carreras,&nbsp;María Martín-Cazaña,&nbsp;Luis Miguel García-Cárdaba,&nbsp;Carmen Martín-Fernández,&nbsp;Patricia Pérez-Mohand,&nbsp;Teresa Hernández Chamorro,&nbsp;Berta Zamora Crespo,&nbsp;Pedro Ruiz-Sala,&nbsp;Patricia Alcaide Alonso,&nbsp;Pilar Quijada-Fraile","doi":"10.1002/jmd2.70132","DOIUrl":"10.1002/jmd2.70132","url":null,"abstract":"<p>Newborn screening (NBS) has significantly improved early detection and survival in fatty acid oxidation disorders (FAODs). However, the expanding phenotypic spectrum challenges prognostic stratification, and long-term morbidity remains incompletely characterized. We conducted an observational, retrospective, single-center study of patients with FAODs identified through NBS and followed between 2011 and 2024. Clinical, biochemical, genetic, and nutritional data were extracted from medical records. Correlations between biochemical markers, enzymatic activity, and clinical outcomes were analyzed. The study was approved by the Research Committee of the Instituto de Investigación, Hospital 12 de Octubre (Madrid). Sixty-five patients were included: 42 MCADD, 11 VLCADD, 5 LCHADD, 2 CPT1D, 3 CPT2D, 1 CACTD, and 1 MADD. Median age at last follow-up was 7.2 years (range 0.4–13.6). Two patients died during follow-up (overall mortality 3.1%). In MCADD, confirmatory C8 concentrations correlated with residual enzyme activity and metabolic decompensations. In VLCADD, NBS and confirmatory C14:1 levels correlated with enzyme activity but not with clinical severity. VLCADD showed marked clinical heterogeneity, whereas LCHADD patients had the highest disease burden and required the most intensive nutritional management. Overall, 40% of patients experienced at least one metabolic decompensation, occurring significantly more frequently in LC-FAOD than in MCADD. Neuropsychological manifestations were observed in 16.9% of patients. In summary, NBS markedly improves survival in FAODs, but morbidity remains substantial, particularly in LC-FAOD. Current biochemical markers are useful for early risk stratification but remain insufficient to predict long-term clinical severity. These findings support individualized multidisciplinary follow-up, including specialized nutritional care and systematic neuropsychological assessment.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 6","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13662738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149193833","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":"Impacting Rare Diseases Healthcare by Case-Based Telelearning: Description of the Dutch Pilot Metabolic Diseases ECHO","authors":"Tirza Boschma,&nbsp;Désirée Y. van Haaften-Visser,&nbsp;Maaike C. de Vries,&nbsp;Roos Dijkstra,&nbsp;Amaya Zinck,&nbsp;Esmeralda Oussoren,&nbsp;Terry G. J. Derks,&nbsp;Andrea B. Haijer-Schreuder","doi":"10.1002/jmd2.70121","DOIUrl":"10.1002/jmd2.70121","url":null,"abstract":"<p>Inherited metabolic diseases (IMDs) are individually (ultra)rare but collectively relatively common. The Extension for Community Healthcare Outcomes (ECHO) model has been used worldwide since 2003 to disseminate knowledge and best practices in chronic diseases. In 2024, the Dutch Society for Inborn Errors of Metabolism (ESN) launched a pilot Metabolic Diseases ECHO Program. We aimed to evaluate whether ECHO is a feasible model for IMD knowledge dissemination. We conducted a retrospective review of the design, implementation, and impact of the program. Since February 2025, two ECHO hubs have been established in two Dutch medical education and training regions (ETRs). Data have been prospectively collected through the iECHO platform. Program impact was assessed using Moore's Expanded Outcomes Framework, covering seven levels ranging from participation and satisfaction to competence development and population outcomes. The Metabolic Diseases ECHO Program has achieved broad geographic reach and strong engagement among healthcare professionals. To date, 15 sessions have been completed and 10 additional sessions are scheduled. A total of 208 professionals from diverse disciplines, including pediatrics, clinical genetics, clinical chemistry, and nursing, have participated, representing 10 of the 12 Dutch provinces. The program has stimulated the development of two regional treatment protocols and integrates all core academic tasks: patient care, education, and research. The ECHO model is a feasible and sustainable approach for disseminating expertise on IMDs. Our program demonstrates meaningful impact across the first four levels of Moore's framework. Long-term continuation and expansion to other Dutch-speaking regions are under consideration. Future work will focus on assessing the direct benefits for IMD patients.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 6","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13647106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136939","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":"Dual Urea Cycle Dysfunction Caused by Coexisting Argininosuccinic Aciduria and Citrin Deficiency: Clinical, Biochemical, and Molecular Insights From an Exceptional Case","authors":"Mouna Zribi,&nbsp;Mariem Bhouri,&nbsp;Safa Khatrouch,&nbsp;Hela Boudabous,&nbsp;Johannes Häberle,&nbsp;Mohamed Slim Abdelmoula,&nbsp;Amel Ben Chehida","doi":"10.1002/jmd2.70129","DOIUrl":"https://doi.org/10.1002/jmd2.70129","url":null,"abstract":"<p>Dual inherited defects affecting urea cycle function are exceptionally rare. We report the first case, to our knowledge, of the coexistence of argininosuccinic aciduria (ASA) and citrin deficiency (CD). A girl born to consanguineous Tunisian parents presented at 6 months of age with recurrent seizures, vomiting, developmental delay, and severe hyperammonemic encephalopathy. Laboratory investigations revealed hyperammonemia, respiratory alkalosis, transaminitis, dyslipidemia, hyperglutaminemia, and mild hypercitrullinemia. Brain imaging showed delayed myelination and basal ganglia abnormalities. Management involved arginine supplementation, ammonia scavengers, protein restriction and antiepileptic drugs. The patient died at 33 months of age from severe hyperammonemia and lactic acidosis. Next-generation sequencing identified two homozygous variants affecting distinct urea cycle–related genes: <i>The known pathogenic ASL</i> variant c.1153C&gt;T p.(Arg385Cys), responsible for ASA, and a previously unreported likely pathogenic <i>SLC25A13</i> variant, c.1474C&gt;T, p.(Arg492Trp), consistent with CD. Segregation analysis confirmed biallelic inheritance of both variants. This unique association illustrates how multilocus pathogenic variation can generate an atypical phenotype. From a pathophysiological perspective, CD may aggravate urea cycle dysfunction by reducing cytosolic aspartate availability and ASS1 activity, while ASL deficiency blocks the downstream conversion of argininosuccinate, resulting in a profound impairment of ureagenesis. This dual defect creates diagnostic and therapeutic challenges, highlighting the importance of integrating comprehensive biochemical investigations with molecular testing to enable accurate diagnosis and personalized metabolic management.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 6","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70129","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149099809","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":"Utility of Exogenous Ketones and Modified Atkins Diet in a Child With GSD VII (Tarui Disease)","authors":"Kiera Batten,&nbsp;Nancy Van Doorn,&nbsp;Ji Hyun Moon,&nbsp;David Simar,&nbsp;Carolyn Broderick,&nbsp;Kaustuv Bhattacharya","doi":"10.1002/jmd2.70123","DOIUrl":"10.1002/jmd2.70123","url":null,"abstract":"<p>Glycogen storage disease VII (GSD VII), also known as Tarui disease, is caused by a deficiency of the skeletal muscle enzyme, phosphofructokinase (PFK). Classical GSD VII is characterised by reduced exercise capacity and exercise-induced myopathic symptoms, exacerbated with carbohydrate intake. No recommended medical or dietary therapy currently exists to improve exercise symptomology in GSD VII. An 11-year-old female was recommended four trial dietary therapies for 8 weeks each: (1) usual diet, (2) 150 mg/kg exogenous ketones pre-exercise, (3) modified Atkins diet (MAD), (4) MAD and pre-exercise ketones. Clinical assessments comprised cardiopulmonary exercise test, anthropometry, biochemical tests including creatine kinase (CK), quality of life (QoL), heart rate (HR) monitoring and subjective symptom reports. Exogenous ketones improved exercise capacity demonstrated by reduced HR for equivalent exercise workload, and participation in higher intensity exercise for longer duration. MAD improved QoL physical domain score by 29%, normalised CK and halved the number of symptoms reported per ‘physically active day’. Dissatisfaction with MAD resulted in unintentional weight loss, and a 20% reduction in QoL emotional domain score, leading to the patient declining the fourth study phase. This study is the first to demonstrate a beneficial effect of exogenous ketones, and separately, MAD, in a child with GSD VII. Exogenous ketones or MAD could be recommended under medical and dietetic supervision in GSD VII. However, consideration must be given to the potential negative impact of MAD on weight and emotional health. Further interventional studies are warranted in this condition.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 5","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149038753","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 Variant in Abhydrolase Domain Containing 14A (ABHD14A) and the Suspicion of Aminoacylase 1 (ACY1) Deficiency","authors":"Lil Klaas,&nbsp;Estrella López-Martín,&nbsp;Beatriz Martinez-Delgado,&nbsp;Manuel Posada de la Paz,&nbsp;Antonia Ribes,&nbsp;Jörn Oliver Sass","doi":"10.1002/jmd2.70124","DOIUrl":"https://doi.org/10.1002/jmd2.70124","url":null,"abstract":"<p>Aminoacylase 1 (ACY1) deficiency is a rare autosomal recessive inborn error of metabolism, characterised by accumulation of <i>N</i>-acetyl-<span>l</span>-amino acids in urine and highly variable clinical presentations. In contrast, the abhydrolase domain containing 14A (<i>ABHD14A</i>) has been suggested to play a role in various metabolic processes and may be linked to diseases, although its precise function remains unclear. Importantly, ABHD14A is known to form a read-through transcript with ACY1, indicating the possibility that variants in ABHD14A may influence ACY1-related phenotypes. Here, we report a patient with suspected ACY1 deficiency, carrying a heterozygous variant in the <i>ACY1</i> gene (c.1178G&gt;A) together with a variant in <i>ABHD14A</i> (c.95G&gt;A). The aim of this study was to functionally assess ACY1 activity and to investigate whether the <i>ABHD14A</i> variant affects ACY1 expression or enzyme activity. To this end, ACY1 enzyme activity was measured in patient-derived lymphocytes, and overexpression experiments in HEK293 cells were performed to analyse ACY1 enzyme activity as well as mRNA and protein levels of the patient-specific variants. We show that the patient-derived variant in <i>ABHD14A</i> does not affect ACY1 expression or enzyme activity. In addition, our report provides the first experimental evidence that the <i>ABHD14A</i>–<i>ACY1</i> read-through does not lead to a functional detectable protein, supporting the hypothesis of nonsense-mediated RNA decay.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 5","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmd2.70124","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148994574","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":"Asparagine Synthetase Deficiency: Neuropathological Evidence of Disrupted Cortical Development","authors":"Mihaela Bobić,&nbsp;Goran Sedmak,&nbsp;Ema Bokulić,&nbsp;Tila Medenica,&nbsp;Tamara Žigman,&nbsp;Bernarda Medlobi Vinković,&nbsp;Viktorija Antolović,&nbsp;Nenad Kešin,&nbsp;Ivan Lehman,&nbsp;Ana Škaričić,&nbsp;Mirjana Novoselec,&nbsp;Josipa Mateševac,&nbsp;Monica Kirigin Kalamar,&nbsp;Sanda Huljev Frković,&nbsp;Ivo Barić,&nbsp;Danijela Petković Ramadža","doi":"10.1002/jmd2.70126","DOIUrl":"10.1002/jmd2.70126","url":null,"abstract":"<p>Asparagine synthetase deficiency (ASNSD) is a rare metabolic disease causing congenital microcephaly, severe developmental delay, and spastic quadriplegia. Although the central nervous system is severely affected, other organ systems appear unaffected by asparagine deficiency. We present an infant homozygous for the mutation c.904-1G&gt;A in the <i>ASNS</i> gene, whose clinical presentation and radiological findings were typical for ASNSD. Following the patient's death at the age of 6 months, histological and immunohistochemical examination of the telencephalon revealed a vast disturbance of migration of neuronal subpopulations, consequently severe disorganization of cortical layers, and thinning of the cerebral cortex. These findings provide novel insights into disease pathogenesis and may explain the hallmark features of ASNSD, including microcephaly and epilepsy.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 5","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13572816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148968754","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":"Acute and Chronic Pancreatitis in Mitochondrial Disease: A Systematic Review","authors":"Olivia Hahl,&nbsp;Mika H. Martikainen","doi":"10.1002/jmd2.70125","DOIUrl":"10.1002/jmd2.70125","url":null,"abstract":"<p>Mitochondrial disease is a common inherited multisystem neurometabolic disorder. Pancreatic dysfunction is a recognised manifestation, most frequently presenting as mitochondrial diabetes. Although pancreatitis cases have been reported in association with mitochondrial disease, acute and chronic pancreatitis in this context remain poorly characterised. Following the PRISMA framework, we performed a systematic literature review to identify all published cases in which acute or chronic pancreatitis occurred in individuals with a genetically confirmed mitochondrial disease. Literature search yielded 604 publications, of which 19 fit the inclusion criteria. During revision two additional publications were identified, one of which fit the inclusion criteria. These 20 reports described 24 individuals with mitochondrial disease and documented history of acute or chronic pancreatitis. Mean age at first recorded pancreatitis was 13 years, with median age 10 years (range 3 months to 53 years). Pancreatitis was recurrent or chronic in 63% of cases. The most reported presenting symptoms were abdominal pain (38%) and vomiting (33%). None had established pancreatitis risk factors such as gallstones or alcohol misuse. In those who underwent imaging, no structural abnormalities of the pancreas or biliary tree were identified. Most frequent genetic aetiologies were large-scale mitochondrial DNA (mtDNA) deletions and the m.3243A&gt;G mtDNA variant (29% each). Six patients (25%) died shortly after hospital admission with pancreatitis. Pancreatitis associated with mitochondrial disease often presents in childhood and is frequently recurrent or chronic. Although uncommon, it represents a clinically significant and potentially life-threatening complication that warrants increased awareness.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 5","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13549923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148911904","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":"Unmasking Mucopolysaccharidosis Type I in a Patient With Wolf–Hirschhorn Syndrome: Diagnostic Overshadowing","authors":"Karla Cifuentes-Uribe,&nbsp;Sandrine Girard,&nbsp;Roseline Froissart,&nbsp;Magali Pettazzoni,&nbsp;Nathalie Guffon","doi":"10.1002/jmd2.70117","DOIUrl":"10.1002/jmd2.70117","url":null,"abstract":"<p>Mucopolysaccharidosis Type I (MPS I) is a rare lysosomal storage disorder caused by α-<span>l</span>-iduronidase deficiency, leading to glycosaminoglycan accumulation and multisystem involvement. Wolf–Hirschhorn Syndrome (WHS) is a chromosomal disorder characterized by growth delay, dysmorphism, and developmental impairment. Because the <i>IDUA</i> gene is located within the 4p16.3 region, the coexistence of WHS and MPS I is biologically plausible but rarely documented. We describe a 2-year-old child of North African origin presenting with dysmorphic features, developmental delay, and thoracolumbar kyphosis. Chromosomal microarray analysis identified a 5.8 Mb deletion at 4p16.3–p16.2, confirming WHS at 17 months. However, additional clinical features remained unexplained. Incidentally, during a routine blood test, a blood smear revealed lymphocytes with metachromatic inclusions, raising suspicion of a lysosomal storage disorder. An enzymatic assay confirmed α-<span>l</span>-iduronidase deficiency, and molecular analysis identified biallelic pathogenic alterations in the <i>IDUA</i> gene located on chromosome 4p16.3, establishing the diagnosis of MPS I at 18 months. Enzyme replacement therapy was initiated at 19 months and was associated with stabilization of the somatic manifestations of MPS I, including improvement in respiratory symptoms. This observation highlights the risk of diagnostic overshadowing in rare diseases. A confirmed genetic diagnosis should not preclude further investigations when clinical features are discordant.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 5","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906283","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":"Plasma Lactate Response to a 12-Min Walk Test Is a Poor Diagnostic Biomarker for Mitochondrial Myopathy","authors":"Christine Lando,&nbsp;Tahmina Khawajazada,&nbsp;Jesper Helbo Storgaard,&nbsp;Nanna Scharff Poulsen,&nbsp;John Vissing,&nbsp;Nicoline Løkken","doi":"10.1002/jmd2.70112","DOIUrl":"10.1002/jmd2.70112","url":null,"abstract":"<p>Mitochondrial myopathy (MM) represents a group with a broad phenotypic spectrum which complicates the diagnostic process. This study investigated whether plasma lactate changes following a 12-min walk test (12MWT) and 20-min recovery could be a diagnostic screening tool for MM. Thirty patients with MM and 19 healthy controls (HC) participated. Total walking distance and heart rate during the test were measured, along with plasma lactate at rest, after exercise, and during recovery. For the latter, we calculated the area under the curve (AUC). The results were compared between groups. MM patients walked shorter (1082 m [994–1143] m vs. 1349 m [1149–1435], <i>p</i> = 0.0005) and had higher resting lactate (1.7 ± 1.2 mmol/L vs. 0.9 ± 0.3 mmol/L, <i>p</i> = 0.003). No significant difference in plasma lactate was observed after exercise. Plasma lactate AUC during recovery was similar between groups. Thus, the 12MWT is not a reliable screening tool for MM as changes in plasma lactate during exercise and recovery did not differentiate MM from HC.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 5","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148840220","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":"Glucose Transporter Deficiency Syndrome Type 1 (Glut1-DS): New Insights From a Brazilian Cohort of Patients","authors":"Lívia Maria Ferreira Sobrinho,&nbsp;Juliana Cristine Fontana,&nbsp;Claudia F. Lorea,&nbsp;Helio van der Linden Júnior,&nbsp;Andréa C. S. Leite,&nbsp;Rayana Elias Maia,&nbsp;Lilia Farret,&nbsp;Carolina F. Moura de Souza,&nbsp;Soraia Poloni,&nbsp;Fabiano O. Poswar,&nbsp;Ida Vanessa D. Schwartz,&nbsp;Fernanda Sperb-Ludwig","doi":"10.1002/jmd2.70113","DOIUrl":"10.1002/jmd2.70113","url":null,"abstract":"<p>Glucose transporter deficiency syndrome type 1 (Glut1-DS) is a rare neurometabolic disorder caused by pathogenic variants in <i>SLC2A1</i>, characterized by epilepsy, neurodevelopmental delay, movement disorders, dysarthria, intellectual disability, and postnatal microcephaly. We aimed to characterize the natural history of a Brazilian cohort of patients with Glut1-DS. Brazilian patients of all ages were included if they presented with clinical features consistent with Glut1-DS and carried a pathogenic or likely pathogenic <i>SLC2A1</i> variant. Forty patients were included (21 males; median age 9.1 years [IQR: 6.0–12.9]; median age at diagnosis 5.0 years [IQR: 3.0–9.9]), of whom 32 had the classical phenotype. The most frequent manifestations at inclusion were seizures (37/40), speech delay (34/40), and movement disorders (29/35). Thirty-four patients (85%) were receiving ketogenic dietary therapy (27 classical ketogenic diet and 7 modified Atkins diet). Cerebrospinal fluid analysis was performed in 10 patients (27.5%), all of whom had hypoglycorrhachia. Genetic testing identified 31 distinct <i>SLC2A1</i> variants, including 15 novel variants. Intrafamilial phenotypic variability was observed in one of four families with recurrent disease, and reduced penetrance was identified in one affected parent. Missense variants were generally associated with milder phenotypes than truncating variants. These findings expand the phenotypic and genotypic spectrum of Glut1-DS, highlight the high proportion of previously unreported <i>SLC2A1</i> variants in the Brazilian population, and reinforce the importance of comprehensive genetic evaluation and counseling for affected families.</p>","PeriodicalId":14930,"journal":{"name":"JIMD reports","volume":"67 5","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13500214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148813172","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}