Molecular Genetics and Metabolism Reports最新文献

{"title":"A novel mitochondrial DNA variant in MT-ND6: m.14430A>C p.(Trp82Gly) identified in a patient with Leigh syndrome and complex I deficiency","authors":"Surita Meldau ,&nbsp;Sally Ackermann ,&nbsp;Gillian Riordan ,&nbsp;George F. van der Watt ,&nbsp;Careni Spencer ,&nbsp;Sharika Raga ,&nbsp;Kashief Khan ,&nbsp;Dee M. Blackhurst ,&nbsp;Francois H. van der Westhuizen","doi":"10.1016/j.ymgmr.2024.101078","DOIUrl":"https://doi.org/10.1016/j.ymgmr.2024.101078","url":null,"abstract":"<div><p>Leigh syndrome is a severe progressive mitochondrial disorder mainly affecting children under the age of 5 years. It is caused by pathogenic variants in any one of more than 75 known genes in the nuclear or mitochondrial genomes.</p><p>A 19-week-old male infant presented with lactic acidosis and encephalopathy following a 2-week history of irritability, neuroregression and poor weight gain. He was hypotonic with pathological reflexes, impaired vision, and nystagmus. Brain MRI showed extensive bilateral symmetrical T2 hyperintense lesions in basal ganglia, thalami, and brainstem. Metabolic workup showed elevated serum alanine, and heavy lactic aciduria with increased ketones, fumarate, malate, and alpha-ketoglutarate as well as reduced succinate on urine organic acid analysis. Lactic acidemia persisted, with only a marginally elevated lactate:pyruvate ratio (16.46, ref. 0–10). He demised at age 7 months due to respiratory failure.</p><p>Exome sequencing followed by virtual gene panel analysis for pyruvate metabolism and mitochondrial defects could not identify any nuclear cause for Leigh syndrome. Mitochondrial DNA (mtDNA) genome sequencing revealed 88% heteroplasmy for a novel variant, NC_012920.1(MT-ND6):m.14430A&gt;C p.(Trp82Gly), in blood DNA. This variant was absent from the unaffected mother's blood, fibroblast, and urine DNA, and detected at a level of 5% in her muscle DNA.</p><p>Mitochondrial respiratory chain analysis revealed markedly reduced mitochondrial complex I activity in patient fibroblasts (34% of parent and control cells), and reduced NADH-linked respirometry (less than half of parental and control cells), while complex II driven respirometry remained intact. The combined clinical, genetic, and biochemical findings suggest that the novel MT-ND6 variant is the likely cause of Leigh syndrome in this patient. The mitochondrial ND6 protein is a subunit of complex I.</p><p>An interesting finding was the absence of a significantly elevated lactate:pyruvate ratio in the presence of severe lactatemia, which directed initial diagnostic efforts towards excluding a pyruvate metabolism defect. This case highlights the value of a multidisciplinary approach and complete genetic workup to diagnosing mitochondrial disorders in South African patients.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"39 ","pages":"Article 101078"},"PeriodicalIF":1.9,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000314/pdfft?md5=3fac8c12079ef6688a2119e5aef48845&pid=1-s2.0-S2214426924000314-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140328631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A case of gaucher disease with a rare complication of gaucheroma and protein-losing enteropathy","authors":"Tianbo Zhang ,&nbsp;Xialin Zhang ,&nbsp;Ningning Zhang ,&nbsp;Junrong Yan ,&nbsp;Lina Wang ,&nbsp;Weihong Yan ,&nbsp;Zhuanzhuan Yu ,&nbsp;Yonghong Zhang ,&nbsp;Yanlong Duan ,&nbsp;Ruijuan Zhang","doi":"10.1016/j.ymgmr.2024.101075","DOIUrl":"https://doi.org/10.1016/j.ymgmr.2024.101075","url":null,"abstract":"<div><p>This case report describes a patient initially diagnosed with Gaucher disease (GD) with type I with homozygous mutation c.1448T &gt; C p. (Leu483Pro) at age of 2, presenting with hepatosplenomegaly and cytopenia. Imiglucerase replacement therapy was initiated. At age 17, bilateral hearing loss developed, with subsequent Cranial MRI revealing thalamic damage, leading to a reclassification as type 3 GD. By age of 20, the patient presented with a range of symptoms, including abdominal pain, diarrhea, hypoproteinemia, multiple lymphadenopathy, edema, and Gaucher cell infiltration in the lymph nodes. Comprehensive diagnosis identifies Gaucher tumor and protein-losing enteropathy. Imiglucerase therapy at 90‐120 U/kg every 2 weeks significantly improved clinical symptoms, emphasizing the importance of tailored interventions for managing GD manifestations.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"39 ","pages":"Article 101075"},"PeriodicalIF":1.9,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000284/pdfft?md5=6a9ca47733793eff8dcf71168e66ba93&pid=1-s2.0-S2214426924000284-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140290590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel mutation of COG5 in a Taiwanese girl with congenital disorders of glycosylation manifesting as developmental delay","authors":"Yu-Chi Wang ,&nbsp;Dau-Ming Niu ,&nbsp;Li-Zhen Chen ,&nbsp;Yun-Ru Chen ,&nbsp;Chia-Feng Yang","doi":"10.1016/j.ymgmr.2024.101072","DOIUrl":"https://doi.org/10.1016/j.ymgmr.2024.101072","url":null,"abstract":"<div><p>We are documenting the case of An 11-year-old girl who has been followed up at our out-patient clinic since birth with clinical presentations including intrauterine growth restriction, recurrent periodic fever in infancy, hypotonia, global developmental delay, liver function impairment with cirrhotic changes, and clinodactyly. Congenital abnormalities were suspected but a series of examinations including brain MRI, liver biopsy and muscle biopsy yielded insignificant findings. Whole genome sequencing (WGS) was conducted and revealed three novel mutations (c2T &gt; G, c1826T &gt; C, c.556–560delAGTAAinsCT) of the <em>COG5</em> gene. A diagnosis of COG5-congenital disorders of glycosylation (COG5-CDG, or CDG IIi), with neurologic presentation was established. Sanger sequencing in the patient and her parents confirmed the compound heterozygous mutation. Upon literature review, we identified the patient as the first case of COG5-CDG in Taiwan. Our study enhances the clarity of the correlation between the mutative genes and the presentation of COG5-CDG.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"39 ","pages":"Article 101072"},"PeriodicalIF":1.9,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000259/pdfft?md5=48a14994b462dec4b7f6e0f67bb39b90&pid=1-s2.0-S2214426924000259-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140191836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin therapy in acute decompensation of holocarboxylase synthetase deficiency with hyperglycemia and ketoacidosis","authors":"Tanguy Demaret ,&nbsp;Jean-Sébastien Joyal ,&nbsp;Aspasia Karalis ,&nbsp;Fabienne Parente ,&nbsp;Marie-Ange Delrue ,&nbsp;Grant A. Mitchell","doi":"10.1016/j.ymgmr.2024.101073","DOIUrl":"https://doi.org/10.1016/j.ymgmr.2024.101073","url":null,"abstract":"<div><p>An 11-month-old girl with severe acidosis, lethargy and vomiting, was diagnosed with holocarboxylase synthetase deficiency. She received biotin and was stable until age 8 years when vomiting, severe acidosis, hypoglycemia, and hyperammonemia developed. Management with intravenous glucose aiming to stimulate anabolism led to hyperglycemic ketoacidosis. Insulin therapy rapidly corrected biochemical parameters, and clinical status improved. We propose that secondary Krebs cycle disturbances affecting pancreatic beta cells impaired glucose-stimulated insulin secretion, resulting in insulinopenia.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"39 ","pages":"Article 101073"},"PeriodicalIF":1.9,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000260/pdfft?md5=09ad3ca0ac9a7e5b27ab222de4644a77&pid=1-s2.0-S2214426924000260-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140181161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards genomic-Newborn Screening: Technical feasibility of Exome Sequencing starting from dried blood spots","authors":"Alessia Mauri ,&nbsp;Clarissa Berardo ,&nbsp;Davide Biganzoli ,&nbsp;Andrea Meta ,&nbsp;Sara Benedetti ,&nbsp;Federica Rey ,&nbsp;Letizia Messa ,&nbsp;Gian Vincenzo Zuccotti ,&nbsp;Stephana Carelli ,&nbsp;Luisella Alberti ,&nbsp;Cristina Cereda","doi":"10.1016/j.ymgmr.2024.101074","DOIUrl":"https://doi.org/10.1016/j.ymgmr.2024.101074","url":null,"abstract":"<div><p>Each year thousands of babies are born with rare genetic disorders not identified by current NBS panels, due to programs which are not yet optimal. Next-generation sequencing technologies have the potential to overcome many NBS drawbacks and provide large amounts of molecular data, broadening the number of diseases investigated. Here, we design and set up an NGS-based approach to evaluate the feasibility of NGS from dried blood spot starting from 34 DBSs.</p><p>After assessing gDNA yield and integrity, libraries were performed using three target enrichment approaches, sequenced on NS500 platform, and analyzed on commercial platform. Specifically, we focus on virtual gene panels related to highly actionable neonatal/pediatric disorders.</p><p>WES show that amount and quality of DBS-extracted gDNA are suitable for high-throughput sequencing. We obtain 500–1500 ng for each specimen, 1.7–1.8 260/280 wavelength, and DIN of 7 resulting DNA integrity, on par with traditional venous blood collection. A high read depth with 94.3% coverage uniformity is achieved for all samples.</p><p>Data results on mean coverage are comparable among the different workflows tested and demonstrate that DBS from newborn collected at birth is a suitable material for the developing of gNBS programs.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"39 ","pages":"Article 101074"},"PeriodicalIF":1.9,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000272/pdfft?md5=3b8dbb2ef919290400ae7ae5c142e095&pid=1-s2.0-S2214426924000272-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140162994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An attenuated, adult case of AADC deficiency demonstrated by protein characterization","authors":"Giovanni Bisello ,&nbsp;Christiaan G.J. Saris ,&nbsp;Rossella Franchini ,&nbsp;Marcel M. Verbeek ,&nbsp;Michel A.A.P. Willemsen ,&nbsp;Massimiliano Perduca ,&nbsp;Mariarita Bertoldi","doi":"10.1016/j.ymgmr.2024.101071","DOIUrl":"https://doi.org/10.1016/j.ymgmr.2024.101071","url":null,"abstract":"<div><p>A case of an adult with borderline AADC deficiency symptoms is presented here. Genetic analysis revealed that the patient carries two AADC variants (NM_000790.3: c.1040G &gt; A and c.679G &gt; C) in compound heterozygosis, resulting in p.Arg347Gln and p.Glu227Gln amino acid alterations. While p.Arg347Gln is a known pathogenic variant, p.Glu227Gln is unknown. Combining clinical features to bioinformatic and molecular characterization of the AADC protein population of the patient (p.Arg347Gln/p.Arg347Gln homodimer, p.Glu227Gln/p.Glu227Gln homodimer, and p.Glu227Gln/p.Arg347Gln heterodimer), we determined that: i) the p.Arg347Gln/p.Arg347Gln homodimer is inactive since the alteration affects a catalytically essential structural element at the active site, ii) the p.Glu227Gln/p.Glu227Gln homodimer is as active as the wild-type AADC since the alteration occurs at the surface and does not change the chemical nature of the amino acid, and iii) the p.Glu227Gln/p.Arg347Gln heterodimer has a catalytic efficiency 75% that of the wild-type since only one of the two active sites is compromised, thus demonstrating a positive complementation. By this approach, the molecular basis for the mild presentation of the disease is provided, and the experience made can also be useful for personalized therapeutic decisions in other mild AADC deficiency patients. Interestingly, in the last few years, many previously undiagnosed or misdiagnosed patients have been identified as mild cases of AADC deficiency, expanding the phenotype of this neurotransmitter disease.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"39 ","pages":"Article 101071"},"PeriodicalIF":1.9,"publicationDate":"2024-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000247/pdfft?md5=6067ef66fcfdc3c055473993ab47e545&pid=1-s2.0-S2214426924000247-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140138883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The evaluation of inherited metabolic diseases presenting with rhabdomyolysis from Turkey: Single center experience","authors":"Huseyin Bilgin ,&nbsp;Ayse Ergul Bozaci","doi":"10.1016/j.ymgmr.2024.101070","DOIUrl":"https://doi.org/10.1016/j.ymgmr.2024.101070","url":null,"abstract":"<div><h3>Aim</h3><p>It was aimed to identify markers that would indicate which cases presenting with rhabdomyolysis are more likely to be associated with inherited metabolic diseases.</p></div><div><h3>Methods</h3><p>We analyzed 327 children who applied to our Hospital Pediatric Nutrition and Metabolic Diseases Clinic with rhabdomyolysis. The diagnosis of rhabdomyolysis was made by measuring the serum creatinine kinase level in cases presenting with muscle pain, weakness and dark urine.</p></div><div><h3>Results</h3><p>Metabolic disease was detected in 29 (16/13, M/F) patients from 26 different families. 298 patients (165/133, M/F) had normal metabolic work-up. We detected glutaric aciduria type 2 in 13 patients (44,6%), glycogen storage disease type 5 in three patients (10,3%), MCAD deficiency in three patients(10,3%), mitochondrial disease in three patients (10,3%), glycogen storage disease type 9 in one patient (3,5%), VLCAD deficiency in one patient (3,5%), LCHAD deficiency in one patient (3,5%), CPT2 deficiency in one patient(3,5%), Tango2 deficiency in one patient (3,5%), lipin-1 deficiency in one patient (3,5%) and primary carnitine deficiency in one patient (3,5%).</p></div><div><h3>Conclusion</h3><p>In our study, consanguineous marriage, developmental delay, and intellectual disability were found more frequently in patients with metabolic disease. In addition, CK levels above 2610 U/L was found to be significantly correlated with metabolic disease.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"39 ","pages":"Article 101070"},"PeriodicalIF":1.9,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000235/pdfft?md5=8a8d9de1a289c05648435bb0d7bb6324&pid=1-s2.0-S2214426924000235-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140134796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Induced pluripotent stem cell (iPSC) modeling validates reduced GBE1 enzyme activity due to a novel variant, p.Ile694Asn, found in a patient with suspected glycogen storage disease IV","authors":"Chie Naito ,&nbsp;Karis Kosar ,&nbsp;Eriko Kishimoto ,&nbsp;Loren Pena ,&nbsp;Yilun Huang ,&nbsp;Kaili Hao ,&nbsp;Anas Bernieh ,&nbsp;Jennifer Kasten ,&nbsp;Chet Villa ,&nbsp;Priya Kishnani ,&nbsp;Bali Deeksha ,&nbsp;Mingxia Gu ,&nbsp;Akihiro Asai","doi":"10.1016/j.ymgmr.2024.101069","DOIUrl":"https://doi.org/10.1016/j.ymgmr.2024.101069","url":null,"abstract":"<div><h3>Background</h3><p>Glycogen Storage disease type 4 (GSD4), a rare disease caused by glycogen branching enzyme 1 (GBE1) deficiency, affects multiple organ systems including the muscles, liver, heart, and central nervous system. Here we report a GSD4 patient, who presented with severe hepatosplenomegaly and cardiac ventricular hypertrophy. <em>GBE1</em> sequencing identified two variants: a known pathogenic missense variant, c.1544G&gt;A (p.Arg515His), and a missense variant of unknown significance (VUS), c.2081T&gt;A (p. Ile694Asn). As a liver transplant alone can exacerbate heart dysfunction in GSD4 patients, a precise diagnosis is essential for liver transplant indication. To characterize the disease-causing variant, we modeled patient-specific GBE1 deficiency using CRISPR/Cas9 genome-edited induced pluripotent stem cells (iPSCs).</p></div><div><h3>Methods</h3><p>iPSCs from a healthy donor (iPSC-WT) were genome-edited by CRISPR/Cas9 to induce homozygous p.Ile694Asn in <em>GBE1</em> (iPSC-GBE1-I694N) and differentiated into hepatocytes (iHep) or cardiomyocytes (iCM). GBE1 enzyme activity was measured, and PAS-D staining was performed to analyze polyglucosan deposition in these cells.</p></div><div><h3>Results</h3><p>iPSC^GBE1-I694N differentiated into iHep and iCM exhibited reduced GBE1 protein level and enzyme activity in both cell types compared to iPSC^wt. Both iHep^GBE1-I694N and iCM^GBE1-I694N showed polyglucosan deposits correlating to the histologic patterns of the patient's biopsies.</p></div><div><h3>Conclusions</h3><p>iPSC-based disease modeling supported a loss of function effect of p.Ile694Asn in <em>GBE1</em>. The modeling of GBE1 enzyme deficiency in iHep and iCM cell lines had multi-organ findings, demonstrating iPSC-based modeling usefulness in elucidating the effects of novel VUS in ultra-rare diseases.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"39 ","pages":"Article 101069"},"PeriodicalIF":1.9,"publicationDate":"2024-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000223/pdfft?md5=b3ff0c2ce4739601665c06e0786a8802&pid=1-s2.0-S2214426924000223-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140134795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Congenital disorder of glycosylation type Ia in a Chinese family: Function analysis of a novel PMM2 complex heterozygosis mutation","authors":"Dan Zhong ,&nbsp;Xiujuan Huang ,&nbsp;Taoshan Feng ,&nbsp;Jieqing Zeng ,&nbsp;Shanshan Gu ,&nbsp;Fan Ning ,&nbsp;Yue Yang ,&nbsp;Jinyuan Zhu ,&nbsp;Yajun Wang ,&nbsp;Riling Chen ,&nbsp;Guoda Ma","doi":"10.1016/j.ymgmr.2024.101067","DOIUrl":"https://doi.org/10.1016/j.ymgmr.2024.101067","url":null,"abstract":"<div><p>Congenital disorder of glycosylation type Ia (CDG-Ia) is an autosomal recessive genetic disease caused by a mutation in the phosphomannomutase 2 (PMM2) gene. We have identified a 13-month-old boy who has been diagnosed with CDG-Ia. He displays several characteristic symptoms, including cerebellar hypoplasia, severe developmental retardation, hypothyroidism, impaired liver function, and abnormal serum ferritin levels. Through whole-exome sequencing, we discovered novel complex heterozygous mutations in the PMM2 gene, specifically the c.663C &gt; G (p.F221L) mutation and loss of exon 2. Further analysis revealed that the enzymatic activity of the mutant PMM2 protein was significantly reduced by 44.97% (<em>p</em> &lt; 0.05) compared to the wild-type protein.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"39 ","pages":"Article 101067"},"PeriodicalIF":1.9,"publicationDate":"2024-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221442692400020X/pdfft?md5=49db97c26ee35c922e479be07117bc20&pid=1-s2.0-S221442692400020X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139945100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Induced pluripotent stem cell-derived hepatocytes reveal TCA cycle disruption and the potential basis for triheptanoin treatment for malate dehydrogenase 2 deficiency","authors":"Déborah Mathis ,&nbsp;Jasmine Koch ,&nbsp;Sophie Koller ,&nbsp;Kay Sauter ,&nbsp;Christa Flück ,&nbsp;Anne-Christine Uldry ,&nbsp;Patrick Forny ,&nbsp;D. Sean Froese ,&nbsp;Alexander Laemmle","doi":"10.1016/j.ymgmr.2024.101066","DOIUrl":"https://doi.org/10.1016/j.ymgmr.2024.101066","url":null,"abstract":"<div><p>Mitochondrial malate dehydrogenase 2 (MDH2) is crucial to cellular energy generation through direct participation in the tricarboxylic acid (TCA) cycle and the malate aspartate shuttle (MAS). Inherited MDH2 deficiency is an ultra-rare metabolic disease caused by bi-allelic pathogenic variants in the <em>MDH2</em> gene, resulting in early-onset encephalopathy, psychomotor delay, muscular hypotonia and frequent seizures. Currently, there is no cure for this devastating disease. We recently reported symptomatic improvement of a three-year-old girl with MDH2 deficiency following treatment with the triglyceride triheptanoin. Here, we aimed to better characterize this disease and improve our understanding of the potential utility of triheptanoin treatment. Using fibroblasts derived from this patient, we generated induced pluripotent stem cells (hiPSCs) and differentiated them into hepatocytes (hiPSC-Heps). Characterization of patient-derived hiPSCs and hiPSC-Heps revealed significantly reduced MDH2 protein expression. Untargeted proteotyping of hiPSC-Heps revealed global dysregulation of mitochondrial proteins, including upregulation of TCA cycle and fatty acid oxidation enzymes. Metabolomic profiling confirmed TCA cycle and MAS dysregulation, and demonstrated normalization of malate, fumarate and aspartate following treatment with the triheptanoin components glycerol and heptanoate. Taken together, our results provide the first patient-derived hiPSC-Hep-based model of MDH2 deficiency, confirm altered TCA cycle function, and provide further evidence for the implementation of triheptanoin therapy for this ultra-rare disease.</p></div><div><h3>Synopsis</h3><p>This study reveals altered expression of mitochondrial pathways including the tricarboxylic acid cycle and changes in metabolite profiles in malate dehydrogenase 2 deficiency and provides the molecular basis for triheptanoin treatment in this ultra-rare disease.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"39 ","pages":"Article 101066"},"PeriodicalIF":1.9,"publicationDate":"2024-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000193/pdfft?md5=fcc6bf1689c2b25a5d5e9b5c15b2baa3&pid=1-s2.0-S2214426924000193-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139935493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}