Journal of Inherited Metabolic Disease最新文献

{"title":"Epidemiology of Gaucher Disease in France: Trends in Incidence, Mortality, Management, and Complications Over Three Decades","authors":"Yann Nguyen,&nbsp;Maxime Beydon,&nbsp;Karima Yousfi,&nbsp;Samira Zebiche,&nbsp;Dalil Hamroun,&nbsp;Anaïs Brassier,&nbsp;Samia Pichard,&nbsp;Laure Swiader,&nbsp;Thierry Billette de Villemeur,&nbsp;Bénédicte Héron,&nbsp;Florence Dalbies,&nbsp;Bérengère Cador,&nbsp;Anne-Sophie Guemann,&nbsp;Francis Gaches,&nbsp;Bénédicte Hivert,&nbsp;Vanessa Leguy-Seguin,&nbsp;Agathe Masseau,&nbsp;Robin Deshayes,&nbsp;Yves-Marie Pers,&nbsp;Magali Pettazzoni,&nbsp;Soumeya Bekri,&nbsp;Catherine Caillaud,&nbsp;Edouard Le Guillou,&nbsp;Marie Szymanowski,&nbsp;Leonardo Astudillo,&nbsp;Wladimir Mauhin,&nbsp;Yann Nadjar,&nbsp;Christine Serratrice,&nbsp;Marc G. Berger,&nbsp;Fabrice Camou,&nbsp;Nadia Belmatoug,&nbsp;Jérôme Stirnemann,&nbsp;French Evaluation of Gaucher Disease Treatment Committee","doi":"10.1002/jimd.70037","DOIUrl":"https://doi.org/10.1002/jimd.70037","url":null,"abstract":"<p>Gaucher disease (GD) is a rare autosomal-recessive lysosomal disorder caused by glucocerebrosidase deficiency. In this study, we described the epidemiology of GD in France over more than three decades. The French GD registry (FGDR) includes all known patients with GD in France. We described patients' characteristics, and estimated the incidence, prevalence, and standardized mortality ratios of GD. We compared the evolution of diagnostic methods, diagnosis delays, and treatment over time, and assessed the incidence of bone events, malignancies, and Parkinson's disease. Between 1980 and 2024, 706 confirmed GD were included. In 2024, 447 patients were alive (413 type 1, 34 type 3). GD incidence was 0.21/1 000 000 PY, and GD prevalence was 0.61 and 0.05/100 000 inhabitants for type 1 and 3, respectively. The standardized mortality ratio was 0.70 for type 1 GD and 16.23 for type 3 GD. Over time, we observed a decrease in the delay between first symptoms and diagnosis (5.4 years before 2000; 0.8 after 2020; <i>p</i> = 0.001), with enzyme assays becoming the primary diagnostic method, a reduction in splenectomies, and a gradual increase in the use of substrate reduction therapy in type 1 GD. The incidences of bone events, malignancies, and Parkinson's disease were 23, 2.7, and 1.07 per 1000 person-years, respectively. This study provides updated epidemiological data on GD in France, showing improvements in disease knowledge, faster and less invasive diagnoses, and reassuring outcomes for type 1 GD, with lower mortality and a relatively low incidence of malignancies and Parkinson's disease.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blood Biomarkers Reflecting Brain Pathology—From Common Grounds to Rare Frontiers","authors":"Isabelle Weinhofer,&nbsp;Paulus Rommer,&nbsp;Johannes Berger","doi":"10.1002/jimd.70032","DOIUrl":"https://doi.org/10.1002/jimd.70032","url":null,"abstract":"<p>Understanding pathological changes in the brain is essential for guiding treatment decisions in brain injuries and diseases. Despite significant advances in brain imaging techniques, clinical practice still faces challenges due to infrastructure reliance and high resource demands. This review explores the current knowledge on blood-based biomarkers that indicate brain pathology, which can assist in identifying at-risk patients, diagnosing patients, predicting disease progression, and treatment response. We focus on the inherited metabolic disorders X-linked adrenoleukodystrophy (X-ALD) and metachromatic leukodystrophy (MLD) which share remarkable phenotypic variability. Disease-specific increases in the lipid metabolites lyso-PC26:0 in X-ALD and sulfatides in MLD might contribute to predicting clinical manifestation. Disease-unspecific biomarkers for axonal damage (neurofilament light chain protein, NfL) and glial degeneration (glial fibrillary acidic protein, GFAP) are able to distinguish X-ALD and MLD phenotypes at the group level. The implementation of X-ALD into newborn screening programs in various countries, including several U.S. states, has increased the demand for predictive blood-based biomarkers capable of detecting the early conversion from the pre-symptomatic to the early neuroinflammatory cerebral form of X-ALD. Among different biomarkers, NfL has proven most effective in reflecting neuroinflammation and correlating with brain lesion volume and the magnetic resonance imaging (MRI)-based severity scores. We discuss how NfL has moved from initial proof-of-principle towards proof-of-concept studies in brain disorders such as multiple sclerosis and how this knowledge could be applied for the clinical implementation of NfL in rare inherited metabolic disorders such as X-ALD.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143909112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Consensus of Expert Opinion for the Diagnosis and Management of Hypermanganesaemia With Dystonia 1 and 2","authors":"Sherry Fang,&nbsp;Peter T. Clayton,&nbsp;Divyani Garg,&nbsp;Sangeetha Yoganathan,&nbsp;Maha S. Zaki,&nbsp;Elin A. Helgadottir,&nbsp;Vala K. Palmadottir,&nbsp;Maude Landry,&nbsp;Sidney M. Gospe Jr,&nbsp;Kshitij Mankad,&nbsp;Vincenzo Bonifati,&nbsp;Suvasini Sharma,&nbsp;Karin Tuschl","doi":"10.1002/jimd.70031","DOIUrl":"https://doi.org/10.1002/jimd.70031","url":null,"abstract":"<p>Hypermanganesaemia with Dystonia 1 and 2 (HMNDYT1 and 2) are inherited, autosomal recessive disorders caused by pathogenic variants in the genes encoding the manganese transporters SLC30A10 and SLC39A14, respectively. Impaired hepatic and enterocytic manganese uptake (SLC39A14) and excretion (SLC30A10) lead to deposition of manganese in the basal ganglia resulting in childhood-onset dystonia-parkinsonism. HMNDYT1 is characterized by additional features due to manganese accumulation in the liver causing cirrhosis, polycythaemia, and depleted iron stores. High blood manganese levels and pathognomonic MRI brain appearances of manganese deposition resulting in T1 hyperintensity of the basal ganglia are diagnostic clues. Treatment is limited to chelation therapy and iron supplementation that can prevent disease progression. Due to their rarity, the awareness of the inherited manganese transporter defects is limited. Here, we provide consensus expert recommendations for the diagnosis and treatment of patients with HMNDYT1 and 2 in order to facilitate early diagnosis and optimize clinical outcome. These recommendations were developed through an evidence and consensus-based process led by a group of 13 international experts across the disciplines of metabolic medicine, neurology, hematology, genetics, and radiology, and address the clinical presentation, diagnostic investigations, principles of treatment, and monitoring of patients with HMNDYT1 and 2.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70031","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Propionic Acidemia-Induced Proarrhythmic Electrophysiological Alterations in Human iPSC-Derived Cardiomyocytes","authors":"Anabel Cámara-Checa,&nbsp;Mar Álvarez,&nbsp;Josu Rapún,&nbsp;Sara Pérez-Martín,&nbsp;Roberto Núñez-Fernández,&nbsp;Marcos Rubio-Alarcón,&nbsp;Teresa Crespo-García,&nbsp;Lourdes R. Desviat,&nbsp;Eva Delpón,&nbsp;Ricardo Caballero,&nbsp;Eva Richard","doi":"10.1002/jimd.70030","DOIUrl":"https://doi.org/10.1002/jimd.70030","url":null,"abstract":"<p>Propionic acidemia (PA) is a metabolic disorder caused by a deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC) due to mutations in the <i>PCCA</i> or <i>PCCB</i> genes, which encode the two PCC subunits. PA may lead to several types of cardiomyopathy and has been linked to cardiac electrical abnormalities such as QT interval prolongation, life-threatening arrhythmias, and sudden cardiac death. To gain insights into the mechanisms underlying PA-induced proarrhythmia, we recorded action potentials (APs) and ion currents using whole-cell patch-clamp in ventricular-like induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) from a PA patient carrying two pathogenic mutations in the <i>PCCA</i> gene (p.Cys616_Val633del and p.Gly477Glufs*9) (PCCA cells) and from a healthy subject (healthy cells). In cells driven at 1 Hz, PCC deficiency increased the latency and prolonged the AP duration (APD) measured at 20% of repolarization, without modifying resting membrane potential or AP amplitude. Moreover, delayed afterdepolarizations appeared at the end of the repolarization phase in unstimulated and paced PCCA cells. PCC deficiency significantly reduced peak sodium current (<i>I</i>_Na) but increased the late <i>I</i>_Na (<i>I</i>_NaL) component. In addition, L-type Ca²⁺ current (<i>I</i>_CaL) density was reduced, while the inward and outward density of the Na⁺/Ca²⁺ exchanger current (<i>I</i>_NCX) was increased in PCCA cells compared to healthy ones. In conclusion, our results demonstrate that at the cellular level, PCC deficiency can modify the ion currents controlling cardiac excitability, APD, and intracellular Ca²⁺ handling, increasing the risk of arrhythmias independently of the progressive late-onset cardiomyopathy induced by PA disease.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Biomarkers in Diagnosing Disease, Assessing the Severity and Progression of Disease, and Evaluating the Efficacy of Therapies","authors":"Raphael Schiffmann","doi":"10.1002/jimd.70034","DOIUrl":"https://doi.org/10.1002/jimd.70034","url":null,"abstract":"<p>This paper reviews biomarkers in lysosomal disease according to their categories and definitions. There are numerous biomarkers in lysosomal diseases. Some are disease or organ-specific, but most are not. Organ-specific biomarkers are especially useful, but most biomarkers help with diagnosis, assessing disease severity, prognosis, and pharmacodynamic response. There are as yet no truly validated biomarkers in lysosomal diseases by the Prentice, Fleming, and DeMets criteria. None so far can serve as surrogate endpoints in clinical trials, or as substitutes for clinically meaningful endpoints that evaluate how patients feel, function, or survive. The US Food and Drug Administration has thus far used surrogate biomarkers to license therapy only for 3 lysosomal diseases—Gaucher disease, Fabry disease, and lysosomal lipase deficiency. The paucity of surrogate biomarkers reflects success in using clinically important endpoints for the licensing of therapies for Pompe disease, mucopolysaccharidosis IVA, VI, and VII, Niemann-Pick type C, and CLN2. In conclusion, biomarkers in lysosomal diseases are best used for diagnosis, patient categorization, pharmacodynamic response, and sometimes for patient prognosis and risk. Thus far, they have been less useful as surrogate biomarkers in pivotal clinical trials.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70034","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143861891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"YME1L1 Dysfunction Associated With 3-Methylglutaconic Aciduria","authors":"Anthi Demetriadou,&nbsp;Olga Grafakou,&nbsp;Theodoros Georgiou,&nbsp;Daniela Burska,&nbsp;Anna Malekkou,&nbsp;Jana Krizova,&nbsp;Efstathia Paramera,&nbsp;Gavriella Mavrikiou,&nbsp;Maria Dionysiou,&nbsp;Athina Theodosiou,&nbsp;Carolina Sismani,&nbsp;Violetta Anastasiadou,&nbsp;Ioannis Ioannou,&nbsp;Evangelos Papakonstantinou,&nbsp;Hana Hansikova,&nbsp;Anthi Drousiotou,&nbsp;Petros P. Petrou","doi":"10.1002/jimd.70029","DOIUrl":"https://doi.org/10.1002/jimd.70029","url":null,"abstract":"<p>3-methylglutaconic aciduria (3-MGCA) is a biochemical finding in a diverse group of inherited metabolic disorders. Conditions manifesting 3-MGCA are classified into two major categories, primary and secondary. Primary 3-MGCAs involve two inherited enzymatic deficiencies affecting leucine catabolism, whereas secondary 3-MGCAs comprise a larger heterogeneous group of conditions that have in common compromised mitochondrial energy metabolism. Here, we report 3-MGCA in two siblings presenting with sensorineural hearing loss and neurological abnormalities associated with a novel, homozygous missense variant (c.1999C&gt;G, p.Leu667Val) in the <i>YME1L1</i> gene which encodes a mitochondrial ATP-dependent metalloprotease. We show that the identified variant results in compromised YME1L1 function, as evidenced by abnormal proteolytic processing of substrate proteins, such as OPA1 and PRELID1. Consistent with the aberrant processing of the mitochondrial fusion protein OPA1, we demonstrate enhanced mitochondrial fission and fragmentation of the mitochondrial network in patient-derived fibroblasts. Furthermore, our results indicate that YME1L1^L667V is associated with attenuated activity of rate-limiting Krebs cycle enzymes and reduced mitochondrial respiration, which may explain the build-up of 3-methylglutaconic and 3-methylglutaric acid due to the diversion of acetyl-CoA, not efficiently processed in the Krebs cycle, towards the formation of 3-methylglutaconyl-CoA, the precursor of these metabolites. In summary, our findings classify YME1L1 deficiency as a new type of secondary 3-MGCA, thus expanding the genetic landscape and facilitating the diagnosis of inherited metabolic disorders featuring this biochemical phenotype.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70029","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143853063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"iPSC-Derived Liver Organoids as a Tool to Study Medium Chain Acyl-CoA Dehydrogenase Deficiency","authors":"Ligia A. Kiyuna,&nbsp;José M. Horcas-Nieto,&nbsp;Christoff Odendaal,&nbsp;Miriam Langelaar-Makkinje,&nbsp;Albert Gerding,&nbsp;Mathilde J. C. Broekhuis,&nbsp;Flavio Bonanini,&nbsp;Madhulika Singh,&nbsp;Dorota Kurek,&nbsp;Amy C. Harms,&nbsp;Thomas Hankemeier,&nbsp;Floris Foijer,&nbsp;Terry G. J. Derks,&nbsp;Barbara M. Bakker","doi":"10.1002/jimd.70028","DOIUrl":"https://doi.org/10.1002/jimd.70028","url":null,"abstract":"<p>Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is an inherited metabolic disease, characterized by biallelic variants in the <i>ACADM</i> gene. Interestingly, even with the same genotype, patients often present with very heterogeneous symptoms, ranging from fully asymptomatic to life-threatening hypoketotic hypoglycemia. The mechanisms underlying this heterogeneity remain unclear. Therefore, there is a need for in vitro models of MCADD that recapitulate the clinical phenotype as a tool to study the pathophysiology of the disease. Fibroblasts of control and symptomatic MCADD patients with the c.985A&gt;G (p.K329E) were reprogrammed into induced pluripotent stem cells (iPSCs). iPSCs were then differentiated into hepatic expandable organoids (EHOs), further matured to Mat-EHOs, and functionally characterized. EHOs and Mat-EHOs performed typical hepatic metabolic functions, such as albumin and urea production. The organoids metabolized fatty acids, as confirmed by acyl-carnitine profiling and high-resolution respirometry. MCAD protein was fully ablated in MCADD organoids, in agreement with the instability of the mutated MCAD protein. MCADD organoids accumulated medium-chain acyl-carnitines, with a strongly elevated C8/C10 ratio, characteristic of the biochemical phenotype of the disease. Notably, C2 and C14 acyl-carnitines were found decreased in MCADD Mat-EHOs. Finally, MCADD organoids exhibited differential expression of genes involved in ω-oxidation, mitochondrial β-oxidation, TCA cycle, and peroxisomal coenzyme A metabolism, particularly upregulation of <i>NUDT7</i>. iPSC-derived organoids of MCADD patients recapitulated the major biochemical phenotype of the disease. Mat-EHOs expressed relevant pathways involved in putative compensatory mechanisms, notably CoA metabolism and the TCA cycle. The upregulation of <i>NUDT7</i> expression may play a role in preventing excessive accumulation of dicarboxylic acids in MCADD. This patient-specific hepatic organoid system is a promising platform to study the phenotypic heterogeneity between MCADD patients.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143801847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inborn Errors of Cell Trafficking and Complex Lipids: A Further Step in Redefining Hereditary Metabolic Disorders","authors":"Angeles García-Cazorla,&nbsp;Carlo Dionisi-Vici,&nbsp;Jean-Marie Saudubray","doi":"10.1002/jimd.70027","DOIUrl":"https://doi.org/10.1002/jimd.70027","url":null,"abstract":"&lt;p&gt;This special issue on Trafficking and Complex Lipid Metabolism represents a milestone in the evolution of Inherited Metabolic Disorders (IMD) as defined in the &lt;i&gt;Journal of Inherited Metabolic Disease&lt;/i&gt; (JIMD). Following the 2015 redefinition of IMD (Quo Vadis 2015), the last 10 years have brought a revolution in our understanding of IMD, reshaping definitions, concepts, paradigms, and classifications. This issue underscores the ubiquity of biochemical reactions in cellular processes, showing that many human genetic disorders, traditionally not classified as metabolic diseases, are rooted in biochemical disturbances.&lt;/p&gt;&lt;p&gt;Before 2015, JIMD primarily focused on disorders of intermediary metabolism and organelles, diagnosed using metabolic markers. In contrast, this special issue on trafficking disorders addresses disturbances in cellular machinery, diagnosed through molecular techniques that may lack measurable metabolic markers. Within each cell, biochemical functions are compartmentalized into organelles that work interdependently, forming a complex network where metabolites and biochemical pathways interact seamlessly. This “solidarity” between organelles—where changes in one impact others—is regulated by cellular trafficking, which facilitates the exchange of signals and metabolites between compartments.&lt;/p&gt;&lt;p&gt;This evolving understanding challenges metabolic physicians and clinical geneticists, who traditionally categorize genetic patients into inborn errors of metabolism (IEM) and dysmorphology cases. Practically, patients are often referred to separate genetic clinics based on this dual categorization. IEM is typically associated with metabolic markers (e.g., intoxication disorders, mitochondrial disorders), while dysmorphology patients are usually seen as those with congenital anomalies or intellectual disabilities. However, a holistic, integrative approach is increasingly essential to unravel the complexity of IMD mechanisms and phenotypes.&lt;/p&gt;&lt;p&gt;Today, the dual approach of IEM/dysmorphology in clinical genetics feels outdated. As many new monogenic genetic diseases emerge across specialties, notably in neurodevelopmental and neurodegenerative diseases, a broader framework is required. Cellular trafficking disorders exemplify how IMD can integrate diseases across various medical fields, offering a transversal discipline that connects cell trafficking mechanisms with biochemistry and symptomology. This integrative metabolic insight lays the groundwork for common treatments across different trafficking genes, similar to how mitochondrial disorders are managed with vitamins, cofactors, and specific diets, irrespective of the specific gene involved.&lt;/p&gt;&lt;p&gt;About 400 disorders, many of which present with multisystem phenotypes, are described in this special issue. Up to 85% of IMDs impact neurodevelopment or are responsible for neurodegeneration. Acute, chronic, or progressive neurological syndromes, psychiatric presentations, development","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143793366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CLPB Deficiency, a Mitochondrial Chaperonopathy With Neutropenia and Neurological Presentation","authors":"D. Mróz,&nbsp;J. Jagłowska,&nbsp;R. A. Wevers,&nbsp;S. Ziętkiewicz","doi":"10.1002/jimd.70025","DOIUrl":"https://doi.org/10.1002/jimd.70025","url":null,"abstract":"&lt;p&gt;Human CLPB protein, a mitochondrial disaggregase, gained recognition in 2015, when four independent studies identified pathogenic variants in &lt;i&gt;CLPB&lt;/i&gt; as the underlying cause of a novel autosomal recessive multiorgan disorder presenting distinct laboratory findings, namely neutropenia and 3-methylglutaconic aciduria (ORPHA:445038; MIM #616271) [&lt;span&gt;1-4&lt;/span&gt;]. Biallelic &lt;i&gt;CLPB&lt;/i&gt; deficiency is a neurodevelopmental disorder with neutropenia and cataracts. More recently, certain monoallelic disease-causing germline variants were further identified as the cause of autosomal dominant &lt;span&gt;s&lt;/span&gt;evere &lt;span&gt;c&lt;/span&gt;ongenital &lt;span&gt;n&lt;/span&gt;eutropenia (CLPB-SCN; ORPHA:486; MIM #619813) [&lt;span&gt;5-7&lt;/span&gt;]. Newest in the field is the discovery that also a few monoallelic variants cause the same phenotype as in biallelic &lt;i&gt;CLPB&lt;/i&gt; defect with the exception of cataracts [&lt;span&gt;5&lt;/span&gt;] (MIM #619835).&lt;/p&gt;&lt;p&gt;The &lt;i&gt;CLPB&lt;/i&gt; gene is located on chromosome 11 (11q13.4) and consists of 19 exons. Four isoforms have been reported at the mRNA level, with two major isoforms reported at the protein level. The protein was named CLPB due to the surprising similarity between its AAA+ domain and the second AAA+ domain of bacterial ClpB (itself misnamed ‘Caseinolytic protease type B’ for similarity to ClpA protease, before it was characterised as a disaggregase without proteolytic activity) and its yeast orthologues Hsp104 and Hsp78 [&lt;span&gt;4&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Though the study of the human protein gained momentum only recently, a mammalian CLPB orthologue was first described by Périer et al. [&lt;span&gt;8&lt;/span&gt;], where the expression of cDNA of the mouse CLPB homologue rescued the phenotype of the potassium-dependent yeast Trk- growth defect. The protein was thus named Skd3 (suppressor of K+ transport growth defect 3).&lt;/p&gt;&lt;p&gt;CLPB is a mitochondrial AAA+ (&lt;span&gt;&lt;i&gt;A&lt;/i&gt;&lt;/span&gt;TPases &lt;span&gt;&lt;i&gt;A&lt;/i&gt;&lt;/span&gt;ssociated with diverse cellular &lt;span&gt;&lt;i&gt;A&lt;/i&gt;&lt;/span&gt;ctivities) ATPase containing an HCLR-type (&lt;span&gt;&lt;i&gt;H&lt;/i&gt;&lt;/span&gt;slU, &lt;span&gt;&lt;i&gt;C&lt;/i&gt;&lt;/span&gt;lp-D2, &lt;span&gt;&lt;i&gt;L&lt;/i&gt;&lt;/span&gt;on and &lt;span&gt;&lt;i&gt;R&lt;/i&gt;&lt;/span&gt;uvB) ATPase domain characteristic for Hsp100 disaggregases. Similarly to those disaggregases, human CLPB in vitro solubilises aggregated luciferase, a model substrate and refolds it into enzymatically active form, implying a mitochondrial chaperone function [&lt;span&gt;9&lt;/span&gt;]. The ATPase domain is, however, preceded by a series of ankyrin repeats (Figure 1) which is an unprecedented feature in this group.&lt;/p&gt;&lt;p&gt;AAA+ proteins are involved in a wide variety of cellular processes, including proteolysis, DNA replication and repair, membrane fusion and protein unfolding and disaggregation. The proteins from this group usually form homohexameric rings and utilise the energy from ATP hydrolysis to thread their substrates through the central pore formed by the subunits. The characteristic feature of the ATPase domain of AAA+ proteins is the presence of Walker A (P-loop) and Walker","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.70025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143793507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patterns of Penetrance and Expressivity of Long-Term Outcomes in Classic Galactosemia","authors":"Nicole H. Smith,&nbsp;Olivia S. Garrett,&nbsp;Emma Hendrickson,&nbsp;Jared J. Druss,&nbsp;Judith L. Fridovich-Keil","doi":"10.1002/jimd.70020","DOIUrl":"https://doi.org/10.1002/jimd.70020","url":null,"abstract":"<div>\u0000 \u0000 <p>Long-term complications are common among patients with classic galactosemia (CG) and show both reduced penetrance and variable expressivity. Overall prevalence rates for complications in cognitive, motor, and speech/voice/language outcomes among US and European cohorts are known. However, age at presentation, whether these complications cluster, and what factors might associate with penetrance remain unknown. These gaps in knowledge limit prognostic accuracy for young patients and leave open the question of whether complications in different outcome domains may have shared modifiers. Here we addressed these questions using data from medical records and family survey responses from 164 patients and 77 controls. We found that for cases who experienced long-term complications, the median age at presentation of challenges in cognitive outcome was about 5 years, in motor outcome was about 3 years, and in speech/voice/language outcome was about 2 years. We also found highly significant clustering of complications in these three domains. Finally, we tested six factors for possible association with penetrance: history of severe neonatal symptoms, <i>GALT</i> genotype and predicted residual GALT activity, days of neonatal milk exposure, rigor of non-dairy galactose restriction in early childhood, peak red blood cell (RBC) galactose-1P level in infancy, and baseline RBC galactose-1P level in early childhood. Of these, only history of severe neonatal brain-related symptoms consistently associated with higher penetrance, and only detectable predicted residual GALT activity consistently associated with lower penetrance. Combined, these results substantially extend what is known about the natural history of long-term complications in CG.</p>\u0000 </div>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 3","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}