Journal of Inherited Metabolic Disease最新文献

{"title":"Beyond neuropsychological tests: AI speech analysis in PKU","authors":"Susan E. Waisbren,&nbsp;Raquel Norel,&nbsp;Carla Agurto,&nbsp;Shifali Singh,&nbsp;Zoe A. Connor,&nbsp;Marina G. Ebrahim,&nbsp;Guillermo A. Cecchi","doi":"10.1002/jimd.12831","DOIUrl":"10.1002/jimd.12831","url":null,"abstract":"<p>Phenylketonuria (PKU) is a rare inherited metabolic disorder characterized by toxic phenylalanine (Phe) concentrations in blood and brain. State-of-the-art analyses of speech detected a dimension of verbal discourse providing insights that extend beyond those captured by existing paradigms to measure performance associated with biochemical markers in PKU. The Cookie Theft Picture Task provided a standardized stimulus for eliciting spontaneous speech from 42 adults with PKU and 41 adults without PKU. Subtests measuring language and memory from the Wechsler Adult Intelligence Scale-Fourth Edition showed no differences between the groups and no correlations with biomarkers in PKU. In contrast, AI analyses of responses to the Cookie Theft Task revealed significant differences between the PKU and non-PKU groups on 23 linguistic features. Using multidimensional scaling (MDS), these features were aggregated into a single quantifiable Dimension 1 that significantly correlated with biomarkers. When extreme examples of Dimension 1 were presented to chatGPT, the differences noted reflected attention to detail, clarity in word choice, expression cohesion, contextual awareness and emotion recognition. We subsequently defined Dimension 1 as Proficiency in Verbal Discourse. This novel measure elucidated discourse styles possibly associated with suboptimal achievement and learning disabilities, often reported in PKU. In summary, AI captured a characteristic associated with metabolic status undetectable through traditional neuropsychological measures. Future studies will expand upon this novel paradigm, leveraging speech AI to quantify meaningful aspects of everyday functioning and possibly provide information for management decisions. Once validated, this measure holds promise for extension to other rare diseases and incorporation into clinical trials.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846772","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}

{"title":"Diagnosis, treatment, management and monitoring of patients with tyrosinaemia type 1: Consensus group recommendations from the German-speaking countries","authors":"Anibh M. Das,&nbsp;Diana Ballhausen,&nbsp;Dorothea Haas,&nbsp;Johannes Häberle,&nbsp;Tobias Hagedorn,&nbsp;Cecilia Janson-Mutsaerts,&nbsp;Nils Janzen,&nbsp;Johannes Sander,&nbsp;Peter Freisinger,&nbsp;Daniela Karall,&nbsp;Uta Meyer,&nbsp;Eberhard Mönch,&nbsp;Susanne Morlot,&nbsp;Stefanie Rosenbaum-Fabian,&nbsp;Sabine Scholl-Bürgi,&nbsp;Stephan vom Dahl,&nbsp;Natalie Weinhold,&nbsp;Jiri Zeman,&nbsp;Karin Lange","doi":"10.1002/jimd.12824","DOIUrl":"10.1002/jimd.12824","url":null,"abstract":"<p>Hepatorenal tyrosinaemia (HT1) is an autosomal recessive disorder of tyrosine degradation resulting in hepatic and renal dysfunction, neurological sequelae may occur in some patients. The use of nitisinone (NTBC) has revolutionised treatment and outcome of this disorder. NTBC has to be combined with a low protein diet. While NTBC modulates the disease course in HT1 patients, several issues are open. Optimal dosage, doses per day, therapeutic range of NTBC concentration, mode of protein restriction and biomarkers are not well defined. HCC and neurocognitive deficits are long-term sequelae. Early diagnosis and treatment are essential to minimise the risk for these complications. Clinical guidance for management of HT1-patients is required. Randomised clinical studies are difficult in the presence of therapeutic options. We discussed these issues in a consensus group of 10 paediatricians, 1 adult hepatologist, 1 geneticist, 2 dieticians, 2 newborn screening specialists with experience in HT1, 1 psychologist and 2 representatives of a patient group from the German-speaking countries (DACH). Recommendations were based on scientific literature and expert opinion, also taking into account recent experience with newborn screening. There was strong consensus that newborn screening using succinylacetone (SA) and early treatment are essential for a good outcome. The dose of NTBC should be as low as possible without losing metabolic control. This has to be accompanied by a low protein diet, in some patients a simplified diet without calculation of protein intake. Specific education and psychosocial support are recommended. Indications for liver transplantation were defined. Monitoring shall include clinical findings, levels of SA, tyrosine, phenylalanine and NTBC in (dried) blood.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828943","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":"Executive and adaptive function impacts long-term outcomes for adults with maple syrup urine disease","authors":"Jessica I. Gold,&nbsp;Alanna Strong,&nbsp;Nina B. Gold,&nbsp;Marc Yudkoff,&nbsp;Dava Szalda,&nbsp;Sophia Jan,&nbsp;Lisa A. Schwartz,&nbsp;Rebecca Ganetzky","doi":"10.1002/jimd.12827","DOIUrl":"10.1002/jimd.12827","url":null,"abstract":"<p>Successful transition to independent adulthood requires intact executive and adaptive function. These neurocognitive domains are frequently impaired in inherited metabolic disorders (IMD), despite optimal management. For many IMDs, the impact of executive and adaptive dysfunction on long-term outcomes remains undefined. Standardized assessments linking neurocognitive status with functional outcomes are needed to improve prognostication and tailor support for affected emerging adults. Maple syrup urine disease (MSUD), a relatively prevalent IMD, is primarily diagnosed in the first week of life through newborn screening. Despite early intervention, executive and adaptive dysfunction persist. We designed a remote, interactive battery of neurocognitive and functional assessments for adults (≥21 years) with MSUD to correlate neurocognition and long-term outcomes. Participants were selectively recruited for racial, ethnic, socio-economic, and geographic diversity. Assessments completed by 28 adults with MSUD (82% diagnosed after symptom onset, 25% from minority communities) show a wide range in educational attainment, employment, and residence. Executive and adaptive function were significantly impaired in adults with MSUD compared to controls. Executive and adaptive deficits correlated negatively with educational attainment, employment, and obtaining skills needed for adult-oriented healthcare or independent living. Clinical history did not predict functional outcomes, but neurocognitive assessments suggest the benefits of pre-symptomatic diagnosis. Independent adulthood is attainable for individuals with MSUD. Routine assessment of neurocognition and interventions targeting executive and adaptive function may improve long-term functional outcomes in IMD.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142801136","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}

{"title":"Integration of multi-omics layers empowers precision diagnosis through unveiling pathogenic mechanisms on maple syrup urine disease","authors":"Juan Ramón Tejedor,&nbsp;Alejandro Soriano-Sexto,&nbsp;Leonardo Beccari,&nbsp;Natalia Castejón-Fernández,&nbsp;Patricia Correcher,&nbsp;Lidia Sainz-Ledo,&nbsp;Juan José Alba-Linares,&nbsp;Rocío G. Urdinguio,&nbsp;Magdalena Ugarte,&nbsp;Agustín F. Fernández,&nbsp;Pilar Rodríguez-Pombo,&nbsp;Mario F. Fraga,&nbsp;Belén Pérez","doi":"10.1002/jimd.12829","DOIUrl":"10.1002/jimd.12829","url":null,"abstract":"<p>Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder characterized by deficient activity of the branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, required to metabolize the amino acids leucine, isoleucine, and valine. Despite its profound metabolic implications, the molecular alterations underlying this metabolic impairment had not yet been completely elucidated. We performed a comprehensive multi-omics integration analysis, including genomic, epigenomic, and transcriptomic data from fibroblasts derived from a cohort of MSUD patients and unaffected controls to genetically characterize an MSUD case and to unravel the MSUD pathophysiology. MSUD patients exhibit a defined episignature that reshapes the global DNA methylation landscape, resulting in the stimulation of HOX cluster genes and the restriction of cell cycle gene-related signatures. Subsequent data integration revealed the impact of AP1-related and CEBPB transcription factors on the observed molecular reorganization, with MEIS1 emerging as a potential downstream candidate affected by robust epigenetic repression in MSUD patients. Furthermore, the integration of multi-omics layers facilitated the identification of a strong epigenetic repression in the <i>DBT</i> promoter in a patient wherein no BCKDH pathogenic variants had been detected. A Circular Chromatin Conformation Capture assay indicated a disturbance of the interactions of <i>DBT</i> promoter, thereby unveiling alternative modes of disease inheritance. Integration of multi-omics data unveiled underlying molecular networks rewired in MSUD patients and represents a powerful approach with diagnostic potential for rare genetic disorders with unknown genetic bases.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807158","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":"Circulatory response to exercise relative to oxygen uptake assessed in the follow-up of patients with fatty acid beta-oxidation disorders","authors":"Apolline Imbard,&nbsp;Hortense de Calbiac,&nbsp;Edouard Le Guillou,&nbsp;Pascal Laforêt,&nbsp;Manuel Schiff,&nbsp;Anaïs Brassier,&nbsp;Elise Thevenet,&nbsp;Clément Pontoizeau,&nbsp;Bertrand Lefrère,&nbsp;Chris Ottolenghi,&nbsp;Elise Lebigot,&nbsp;Pauline Gaignard,&nbsp;Stéphanie Gobin,&nbsp;Cécile Acquaviva-Bourdain,&nbsp;Jean-François Benoist,&nbsp;Caroline Tuchmann-Durand,&nbsp;Antoine Legendre,&nbsp;Pascale de Lonlay","doi":"10.1002/jimd.12819","DOIUrl":"10.1002/jimd.12819","url":null,"abstract":"<p>Patients with fatty acid oxidation disorders (FAODs) experience muscle symptoms due to impaired ATP metabolism and the toxicity of accumulated mitochondrial FAO substrates or intermediates, especially during catabolic states. A major issue is the absence of specific and sensible biomarkers to evaluate metabolic equilibrium. The relationship between cardiac output (Q) and oxygen consumption (VO₂) during incremental exercise (dQ/dVO₂) provides an indirect surrogate of mitochondrial function. A high dQ/dVO₂ slope indicates impaired oxidative phosphorylation in skeletal muscle during exercise. Our study aimed to evaluate dQ/dVO₂ as a potential marker of the severity of FAODs. We retrospectively collected clinical, laboratory parameters and treatment data for FAOD patients over 6 years old, including a disease severity score, plasma acylcarnitines and cardiopulmonary exercise tests with Q measurement via thoracic bioelectrical impedance. FAO flux was measured in whole blood and in myoblasts when available. We included 27 FAOD patients followed from 2015 to 2022, with deficiencies in LCHAD (<i>n</i> = 10), CPT2 (<i>n</i> = 6), VLCAD (<i>n</i> = 7), or MADD (<i>n</i> = 4). CPT2 deficient patients with severe scores had the highest C18:1-, C16-, C18-acylcarnitines, and dQ/dVO₂. In these patients, dQ/dVO₂ was positively correlated with C18:1, C16, and C18 acylcarnitines. In a linear multivariate regression model, dQ/dVO₂ was significantly associated with the severity score (B = 0.831, <i>p =</i> 0.008) and triheptanoin treatment (B = −0.547, <i>p =</i> 0.025). dQ/dVO₂ and plasma long-chain acylcarnitines might be useful to monitor CPT2D, as these parameters associate with our clinical severity score and could reflect altered mitochondrial functions.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794916","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":"Imaging readiness in the gene therapy era-exploring standardized protocols for response assessment","authors":"Asthik Biswas,&nbsp;Audrey K. S. Soo,&nbsp;Manju A. Kurian,&nbsp;Ulrike Löbel,&nbsp;Felice D'Arco,&nbsp;Spyros Batzios,&nbsp;Sniya Sudhakar,&nbsp;Kshitij Mankad,&nbsp;the IMaging Assessment in Gene and Enzyme Replacement therapies (IMAGER) study group","doi":"10.1002/jimd.12828","DOIUrl":"10.1002/jimd.12828","url":null,"abstract":"","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794921","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}

{"title":"Clinical severity and cardiac phenotype in phosphomannomutase 2-congenital disorders of glycosylation : Insights into genetics and management recommendations","authors":"Veronika Holubova,&nbsp;Rita Barone,&nbsp;Stephanie Grunewald,&nbsp;Markéta Tesařová,&nbsp;Hana Hansíková,&nbsp;Jana Augustínová,&nbsp;Jolanta Sykut-Cegielska,&nbsp;Francesca De Nictolis,&nbsp;Unai Diaz-Moreno,&nbsp;Ramyia Elangovan,&nbsp;Florencia Epifani,&nbsp;Serena Gasperini,&nbsp;Mirian Jansen,&nbsp;Dirk Lefeber,&nbsp;Dorota Maksym-Gasiorek,&nbsp;Martinelli Diego,&nbsp;Katrin Ounap,&nbsp;Fabio Pettinato,&nbsp;Haide Põder,&nbsp;Daisy Rymen,&nbsp;Mari-Anne Vals,&nbsp;Mercedes Serrano,&nbsp;Peter Witters,&nbsp;Tomáš Honzík","doi":"10.1002/jimd.12826","DOIUrl":"10.1002/jimd.12826","url":null,"abstract":"<p>Cardiac involvement (CI) in phosphomannomutase 2-congenital disorders of glycosylation (PMM2-CDG) is part of the multisystemic presentation contributing to high mortality rates. The most common cardiac manifestations are pericardial effusion, cardiomyopathy, and structural heart defects. A genotype–phenotype correlation with organ involvement has not yet been described. We analyzed clinical, biochemical, and molecular genetic data of 222 patients from eight European centers and characterized the natural course of patients with CI. Fifty-seven patients (45 children) presented with CI, of whom 24 died (median age 21 months, standard deviation 49.8). Pericardial effusion was the most frequent manifestation (55.4%), occurring mostly within the first 6 months of life. The most common pathogenic variants in patients with CI were p.(Arg141His) in 74%, followed by p.(Val231Met) in 36%, which is 3.5 times higher than in PMM2-CDG patients without CI (<i>p</i> &lt; 0.0001). Twenty-one out of 36 patients with p.(Val231Met) had CI; among them, 15 died, compared to 33 out of 166 patients without p.(Val231Met) who had CI (<i>p</i> &lt; 0.0001). Nine out of 33 patients died (<i>p</i> = 0.0015), indicating greater clinical severity. Furthermore, the p.(Val231Met) variant is predominant in Eastern Europe, suggesting a founder effect. Cardiac complications in PMM2-CDG patients are common and serious. The variant p.(Val231Met) profoundly influences the extent of CI and mortality rates. Therefore, we recommend cardiac surveillance be included in the follow-up protocols for PMM2-CDG.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142780355","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}

{"title":"Mapping challenges in the accessibility of treatment products for urea cycle disorders: A survey of European healthcare professionals","authors":"Nina N. Stolwijk,&nbsp;Johannes Häberle,&nbsp;Hidde H. Huidekoper,&nbsp;Margreet A. E. M. Wagenmakers,&nbsp;Carla E. M. Hollak,&nbsp;Annet M. Bosch,&nbsp;the E-IMD and MetabERN Working Group on the Real-World Use of products for UCD Management","doi":"10.1002/jimd.12815","DOIUrl":"10.1002/jimd.12815","url":null,"abstract":"<p>Current management guidelines for urea cycle disorders (UCDs) offer clear strategies, incorporating both authorized and non-authorized medicinal products (including intravenous formulations and products regulated as food). These varying product categories are subject to specific accessibility challenges related to availability, reimbursement, and pricing. The aim of this study is to identify potential obstacles to optimal UCD treatment implementation in European clinical practice. A survey aimed at metabolic healthcare professionals (HCPs) managing patients with UCDs in Europe was disseminated through the European Reference Network for Hereditary Metabolic Disorders and the European registry and network for intoxication type metabolic diseases. Forty-eight survey responses were collected from 21 European countries. In 16 of these countries, at least one metabolic HCP reported challenges in accessing UCD products. Reimbursement issues were reported for most products (8/10), including both authorized and non-authorized products. Availability-related challenges were also reported for 8/10 products, although unavailability was limited to non-authorized products. Prices impacted accessibility for all authorized products (3/3) and one non-authorized IV product. The accessibility of UCD treatment products varied across Europe, although no clear regional variations could be discerned. Survey data revealed that metabolic HCPs experience challenges in accessing both authorized and non-authorized products for UCD management in the majority of European countries. This indicates that registering unauthorized products may not resolve all issues. Improved reimbursement policies and fair pricing models, as well as (adjusted) authorization procedures may help address these concerns, thereby optimizing treatment access for UCD patients.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769703","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":"Reversible white matter changes following a 4-week high phenylalanine exposure in adults with phenylketonuria","authors":"Raphaela Muri,&nbsp;Murray Bruce Reed,&nbsp;Stephanie Maissen-Abgottspon,&nbsp;Roland Kreis,&nbsp;Michel Hochuli,&nbsp;Rupert Lanzenberger,&nbsp;Roman Trepp,&nbsp;Regula Everts","doi":"10.1002/jimd.12823","DOIUrl":"10.1002/jimd.12823","url":null,"abstract":"<p>Alterations in brain structure are frequently observed in adults with early-treated phenylketonuria (PKU) compared to healthy controls, with cerebral white matter (WM) being particularly affected. The extent to which temporary elevation of phenylalanine (Phe) levels impacts WM remains unclear. We conducted a double-blind, randomised, placebo-controlled crossover trial to investigate the effects of a 4-week high Phe exposure on cerebral WM and its relationship to cognitive performance and metabolic parameters in adults with PKU. In this study, 27 adults with early-treated classical PKU (aged 19–48 years) underwent diffusion tensor imaging (DTI) before and after the 4-week Phe and placebo interventions. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were analysed using tract-based spatial statistics. Neuropsychological examinations at each timepoint evaluated executive functions and attention. Additionally, brain Phe levels were measured using MR spectroscopy, and blood levels of Phe, tyrosine, and tryptophan were assessed after an overnight fast. Following the Phe period, significant decreases in AD, MD, and RD were observed compared to the placebo period, particularly in the posterior corona radiata and optic radiation. Notably, these WM changes were reversible in patients who first received Phe (<i>n</i> = 13). Cognitive performance and metabolic parameters were not significantly related to DTI scalars after the Phe period. In conlcusion, a 4-week Phe elevation induced reversible microstructural alterations in cerebral WM. Further investigation is necessary to determine the clinical implication of these changes.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739748","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":"Uncommon case of mitochondrial disease: Mild amyotrophy of the legs and symmetrical lipomatosis of the arms","authors":"Leslie Bercu,&nbsp;Patrizia Amati-Bonneau,&nbsp;Valérie Desquiret-Dumas,&nbsp;Vincent Procaccio,&nbsp;François Maillot","doi":"10.1002/jimd.12820","DOIUrl":"10.1002/jimd.12820","url":null,"abstract":"&lt;p&gt;A 42-year-old woman was investigated for exercise intolerance. She already had a medical follow-up because of a hypokinetic dilated cardiomyopathy identified at the age of 28 years and a chronic kidney disease, both secondary to a malignant hypertension episode. She complained about muscle pain and dyspnea on exertion, and was limited to a walking range of 200 m. She also experienced postexercise muscle pain. On clinical examination, no strength deficit was noted. She had mild amyotrophy of lower limbs and a symmetrical lipomatosis of her proximal upper limbs (Figure 1). No other localizations of lipomatosis were noted. Blood tests showed CK 1165 UI/L (26–192) and troponin 58.5 ng/L (3–14). The plasma redox cycle showed fasting lactate of 3 mmol/L, postprandial lactate up to 5.9 mmol/L along with a lactate/pyruvate ratio &gt;20. Genetic tests revealed the presence of the pathogenic mitochondrial DNA (mtDNA) mutation m.8363A&gt;G (MT-TK)&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; with a 45% mutant load in blood.&lt;/p&gt;&lt;p&gt;This case illustrates that lipomatosis can be a feature of mitochondrial disease, as shown by Musumeci et al., who reviewed 1300 patients reported in the database of the nationwide Italian Collaborative Network of Mitochondrial Disease.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; In this study, lipomatosis has been identified in 22 (1.7%) patients with primary mitochondrial disease. Interestingly, lipomatosis could be the sole manifestation of pathogenic mtDNA mutations. Among them, two patients carried the same mtDNAcm.8363 A&gt;G variant as our patient, 18 harbored the m.A8344G&gt;A variant and 2 patients had multiple deletions. Moreover, in a family study and a literature review, Virgilio et al. showed that mitochondrial DNA m.8363A&gt;G mutation in the tRNALys gene was associated with a heterogeneous disease phenotype, including some rare cases of lipomas.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; As described in our clinical case, lipomatosis associated with mtDNA mutations is usually distributed in the upper body, affecting arms, shoulders, neck, and thoracic region.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; As multiple symmetric lipomatosis has a low prevalence of 1:25 000 in the general population and is a rare feature of mitochondrial disease, the case described here illustrates a very rare situation. Thus, it seems advisable to recommend mtDNA sequencing from blood and urine samples, mostly when the clinical picture is evocative of a mitochondrial disease, as in our observation. Regarding pathophysiology, Guallar et al. have shown that lipomatosis due to tRNA(Lys) mutations was associated with a pattern of altered expression of master regulators of adipogenesis consistent with enhanced proliferation of adipocytes, and with a distorted pattern of brown versus white adipocyte differentiation.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; In our case, such pattern could not be demonstrated because we did not perform any biopsy of the lipomas (considered as being nonrelevant for diagnosis).&lt;/p&gt;&lt;p&gt;To date, there is ","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":"48 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142729657","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}