Molecular Genetics and Metabolism Reports最新文献

{"title":"Genetic analyses of very long-chain acyl-coenzyme A dehydrogenase deficiency: A case report with a novel ACADVL variant","authors":"Wei Zhou,&nbsp;Huizhong Li,&nbsp;Li Yang","doi":"10.1016/j.ymgmr.2024.101184","DOIUrl":"10.1016/j.ymgmr.2024.101184","url":null,"abstract":"<div><h3>Background</h3><div>Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD) is a rare autosomal recessive disease associated with variants in the <em>ACADVL</em> gene.</div></div><div><h3>Methods</h3><div>In December 2021, a neonate with VLCADD was identified via newborn screening in Xuzhou, China. Genetic testing and genetic family verification were performed via high-throughput sequencing combined with Sanger sequencing. The pathogenicity and functional impacts of novel variants were predicted using bioinformatics methods.</div></div><div><h3>Results</h3><div>Initial results obtained from tandem mass spectrometry blood screening were suggestive of VLCADD. Two compound heterozygous variants, c.753 T &gt; G (p.S251R) and c.1276G &gt; A (p.A426T), inherited from the father and mother, respectively, were detected in the <em>ACADVL</em> gene of this individual. The c.753 T &gt; G variant is novel and unreported.</div></div><div><h3>Conclusion</h3><div>These findings broaden the known mutational spectrum of the <em>ACADVL</em> gene in a Chinese population.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101184"},"PeriodicalIF":1.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008439","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":"Efficacy and safety of avalglucosidase alfa in Japanese patients with late-onset and infantile-onset Pompe diseases: A case series from clinical trials","authors":"Madoka Mori-Yoshimura ,&nbsp;Hirotaka Ohki ,&nbsp;Hideaki Mashimo ,&nbsp;Kenji Inoue ,&nbsp;Satoko Kumada ,&nbsp;Takashi Kiyono ,&nbsp;Akihiro Arimori ,&nbsp;Mitsunobu Ikeda ,&nbsp;Hirofumi Komaki","doi":"10.1016/j.ymgmr.2024.101163","DOIUrl":"10.1016/j.ymgmr.2024.101163","url":null,"abstract":"<div><h3>Background</h3><div>The efficacy and safety of avalglucosidase alfa for Pompe disease (PD) have been demonstrated in a global Phase 3 trial (COMET) in patients with late-onset PD (LOPD) and a global Phase 2 trial (Mini-COMET) in patients with infantile-onset PD (IOPD). This case series examines the individual results of three Japanese patients enrolled in these trials.</div></div><div><h3>Methods</h3><div>Case reports were assembled from data collected in the COMET and Mini-COMET trials. Detailed methods have been reported previously. The primary endpoint of COMET was change from baseline to week 49 in upright forced vital capacity percent (FVC %) predicted. The primary endpoint of Mini-COMET was safety and tolerability of avalglucosidase alfa. In both trials, key secondary endpoints included motor function tests and other qualitative measures of improvement. Changes in biomarkers and anti-drug antibodies were also assessed in both trials.</div></div><div><h3>Results</h3><div>Results for Japanese patients were representative of those from the overall populations in the COMET and Mini-COMET trials. We detail results for one Japanese patient with LOPD enrolled in the COMET trial and two Japanese patients with IOPD enrolled in the Mini-COMET trial. Importantly, avalglucosidase alfa was well tolerated at doses of both 20 mg/kg and 40 mg/kg in Japanese patients with LOPD and IOPD, respectively.</div></div><div><h3>Conclusions</h3><div>Although the number of patients was small, avalglucosidase alfa provides an efficacy and safety profile in Japanese patients representative of the overall populations from key global clinical trials.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101163"},"PeriodicalIF":1.8,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008091","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":"Lessons learned from 5 years of pegvaliase in US clinics: A case series","authors":"Erin Cooney ,&nbsp;Zineb Ammous ,&nbsp;Tricia Bender ,&nbsp;Gillian E. Clague ,&nbsp;Marilyn Clifford ,&nbsp;Angela Crutcher ,&nbsp;Laura Davis-Keppen ,&nbsp;Kirsten Havens ,&nbsp;Melissa Lah ,&nbsp;Stephanie Sacharow ,&nbsp;Amarilis Sanchez-Valle ,&nbsp;Erika Vucko ,&nbsp;Bridget Wardley ,&nbsp;Leah Wessenberg ,&nbsp;Hans C. Andersson","doi":"10.1016/j.ymgmr.2024.101181","DOIUrl":"10.1016/j.ymgmr.2024.101181","url":null,"abstract":"<div><h3>Objective</h3><div>To provide insights and strategies for pegvaliase management in challenging cases with phenylketonuria (PKU) based on the first 5 years of experience with pegvaliase in real-world clinical practice.</div></div><div><h3>Methods</h3><div>Twelve PKU experts gathered during a one-day, in-person meeting to discuss clinical cases illustrating important lessons from their experiences treating patients with pegvaliase in real-world clinical practice. Challenges with pegvaliase experienced prior to and during treatment and corresponding strategies to overcome them were discussed.</div></div><div><h3>Results</h3><div>Twelve cases of adults with PKU (eight females and four males, aged 18 to 68 years) receiving pegvaliase were reviewed and discussed. Challenges of the cases included medical or mental health comorbidities, executive function deficits, challenging social or socioeconomic situations, logistical or geographic barriers, or a combination of these; one was considering pregnancy. Despite challenges, pegvaliase was initiated successfully in most cases. Strategies to overcome barriers included individualized education, including side effect action plans, help from support organizations, collaboration with local providers, and use of telemedicine. Recommendations from the clinicians included that comorbid conditions should be monitored closely after treatment initiation and may require collaboration with other healthcare providers. A collaborative relationship with the clinic, ongoing education, and supportive relatives or friends can help individuals to remain adherent to pegvaliase. Suboptimal adherence may be addressed by a daily reminder system, telemedicine, in-home support, or a modified titration plan. Treated individuals with eating disorders require additional follow-up and support to achieve a healthy relationship with food. In most cases, including late-diagnosed individuals, reduced blood Phe levels resulted in improved PKU-related symptoms, including neurological issues.</div></div><div><h3>Conclusion</h3><div>Experience from the presented cases and 5 years of expert experience with pegvaliase in the real-world setting provide insight and guidance for healthcare professionals initiating and managing pegvaliase treatment in complex PKU cases. These cases demonstrate that, through comprehensive assessment and addressing barriers, pegvaliase treatment can be successful in adults with PKU, regardless of prior treatment success, age, socioeconomic, cognitive, or executive function challenges, as well as in those with comorbidities or considering pregnancy. Ongoing documentation of clinical experience is crucial for advancing the management of individuals receiving this treatment.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101181"},"PeriodicalIF":1.8,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008444","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":"Unbalanced long-chain fatty acid beta-oxidation in newborns with cystic fibrosis and congenital hypothyroidism","authors":"Catherina T. Pinnaro ,&nbsp;Kelli K. Ryckman ,&nbsp;Aliye Uc ,&nbsp;Andrew W. Norris","doi":"10.1016/j.ymgmr.2024.101182","DOIUrl":"10.1016/j.ymgmr.2024.101182","url":null,"abstract":"<div><h3>Background</h3><div>Immediately after birth, adaptation to the extrauterine environment includes an upregulation of fatty acid catabolism. Cystic fibrosis and untreated hypothyroidism exert a life-long impact on fatty acid metabolism, but their influence during this transitional period is unknown. Children and adults with cystic fibrosis exhibit unbalanced fatty acid composition, most prominently a relative deficit of linoleic acid. Lipid catabolism is downregulated in hypothyroidism.</div></div><div><h3>Methods</h3><div>We analyzed acylcarnitine data in newborn screening blood spot samples from infants with cystic fibrosis, with congenital hypothyroidism, or without congenital disorders. Eight long-chain acylcarnitine species were quantified. Of primary interest was the relative composition of linoleoylcarnitine (C18:2), the acylcarnitine of linoleic acid. Mixed effects modeling was used to determine the impact of disease status on acylcarnitine levels, accounting for possible covariates including birth weight, gestational age, sex and race.</div></div><div><h3>Results</h3><div>Total long-chain acylcarnitine levels were diminished in newborns with cystic fibrosis and with congenital hypothyroidism. Contrary to expectations, C18:2 composition was elevated in newborns with cystic fibrosis and with congenital hypothyroidism, as compared to those without congenital disorders. Furthermore, higher thyroid-stimulating hormone levels, indicative of more severe hypothyroidism, predicted higher C18:2 composition.</div></div><div><h3>Conclusions</h3><div>Decreased total long-chain acylcarnitine concentrations in newborns with cystic fibrosis and congenital hypothyroidism suggest diminished beta-oxidation. However, the unexpected relative increase in C18:2 indicates selective preservation of linoleic acid beta-oxidation in both conditions. This is especially surprising in cystic fibrosis where linoleic acid levels become diminished and suggests that linoleic acid beta-oxidation contributes to the deficiency of linoleic acid in cystic fibrosis.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101182"},"PeriodicalIF":1.8,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11732690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143008394","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":"Clinical characterization and genetic analysis of transient abnormal myelopoiesis without the down syndrome phenotype","authors":"Junpeng Cai ,&nbsp;Xiaomin Zhou ,&nbsp;Yu Zhou ,&nbsp;Guanghuan Pi","doi":"10.1016/j.ymgmr.2024.101177","DOIUrl":"10.1016/j.ymgmr.2024.101177","url":null,"abstract":"<div><h3>Background</h3><div>Transient abnormal myelopoiesis (TAM) is a congenital leukemia specific to neonates with Down syndrome (DS) or trisomy 21. However, rare cases of TAM can also occur with acquired trisomy 21 mutations or mosaic trisomy 21, leading to potential misdiagnosis due to the absence of the DS phenotypes.</div></div><div><h3>Method</h3><div>We present a case of TAM in a neonate without typical DS phenotypic features. We documented medical records from hospitalizations and a one-year follow-up period. Additionally, through a literature review, we summarized the clinical phenotype and genotypic characteristics observed in similar neonates.</div></div><div><h3>Results</h3><div>Despite the lack of typical DS phenotype the neonate was diagnosed with TAM upon detection of trisomy 21 and the GATA1 gene mutation, the condition resolved spontaneously without requiring chemotherapy. We monitored the neonate for a full year, during which no hematologic or developmental abnormalities were observed. Thirteen previous cases of neonates with TAM but without the DS phenotype have been reported. During the onset of TAM, the presence of trisomy 21 can be detected in peripheral blood cells or bone marrow cells, but some patients may not show evidence of trisomy 21 in fibroblasts. In these patients, trisomy 21 in peripheral blood cells or bone marrow cells may gradually decrease and even disappear as TAM improves. All patients experienced self-limiting remission with a favorable prognosis, although one case progressed to myeloid leukemia associated with DS by age two.</div></div><div><h3>Conclusions</h3><div>A negative obstetrical diagnosis and the absence of clinical DS phenotype should not preclude the consideration of TAM in neonates, especially when trisomy 21 mutations are detected.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101177"},"PeriodicalIF":1.8,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143131491","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":"Patient experience with acute hepatic porphyria before and after long-term givosiran treatment in a qualitative interview study","authors":"Hetanshi Naik ,&nbsp;Michelle Brown ,&nbsp;Stephen Meninger ,&nbsp;Stephen Lombardelli","doi":"10.1016/j.ymgmr.2024.101174","DOIUrl":"10.1016/j.ymgmr.2024.101174","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Acute hepatic porphyria (AHP) is characterized by debilitating and potentially life-threatening neurovisceral attacks, possible chronic symptoms, and long-term complications. In a phase 1/2 open-label extension (OLE) study and the phase 3 ENVISION study, givosiran led to sustained improvement in annualized attack rate and quality of life (QOL) measures. To capture the patient experience of symptoms and impacts of AHP, and any changes experienced during treatment with givosiran, qualitative interviews were conducted with study participants.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Participants who continued givosiran treatment after completing the phase 1/2 OLE study and the phase 3 ENVISION study participated in semi-structured interviews (i.e., loosely structured interviews on a predetermined topic without strict adherence to wording or order of questions) in 2022 that were developed and executed by RTI Health Solutions. Transcripts were assessed using thematic analysis methods. Authors/investigators categorized symptoms as likely acute attack-related or chronic based on the participants' descriptions. Select clinical trial results (baseline characteristics and QOL scores from the phase 1/2 and ENVISION studies) from interview participants were compiled.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Duration of givosiran treatment in the 21 participants at the time of interview was approximately 4–5 years (mean [SD], 51.8 [7.9] months; median [range], 49.7 [41.4, 69.1] months). Participants reported experiencing AHP symptoms prior to the phase 1/2 OLE or phase 3 studies, including abdominal pain (&lt;em&gt;n&lt;/em&gt; = 20/21 [95 %]) and fatigue (&lt;em&gt;n&lt;/em&gt; = 20/21 [95 %]), with impacts including work/school (&lt;em&gt;n&lt;/em&gt; = 21/21 [100 %]) and family and intimate relationships (&lt;em&gt;n&lt;/em&gt; = 20/21 [95 %]). Post-treatment, participants reported improvements in symptoms including abdominal pain (&lt;em&gt;n&lt;/em&gt; = 20/20 [100 %] participants), fatigue (&lt;em&gt;n&lt;/em&gt; = 20/20 [100 %]), and nausea (&lt;em&gt;n&lt;/em&gt; = 19/19 [100 %]), and in impacts, including family and intimate relationships (&lt;em&gt;n&lt;/em&gt; = 20/20 [100 %]) and work/school (&lt;em&gt;n&lt;/em&gt; = 19/21 [90 %]). Most participants (&lt;em&gt;n&lt;/em&gt; = 19/21 [90 %]) used opioids prior to the trials, and many reported stopping opioids (&lt;em&gt;n&lt;/em&gt; = 10/17 [59 %]) or using a lower dose (&lt;em&gt;n&lt;/em&gt; = 4/17 [24 %]). Participants reported complete relief of certain symptoms, including vomiting (&lt;em&gt;n&lt;/em&gt; = 8/11 [73 %]), nausea (&lt;em&gt;n&lt;/em&gt; = 10/15 [67 %]), and abdominal pain (&lt;em&gt;n&lt;/em&gt; = 8/19 [42 %]). Participants with complete relief of pain or cessation of opioid use tended to be younger and more recently diagnosed, with higher baseline EuroQOL visual analog scale scores during the clinical trials. Participants with prior hemin prophylaxis at entry into the clinical trials were more likely to have experienced abdominal pain, neuropathic pain/paresthesia, and gastrointestinal symptoms before the study, and were generally more ","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101174"},"PeriodicalIF":1.8,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142984217","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":"Cytosolic PEPCK deficiency caused by a novel homozygous frame-shift variant presenting as resolved hypoglycemia and acute liver failure at birth","authors":"Daniel Burg ,&nbsp;Gheona Altarescu ,&nbsp;Stanley Korman ,&nbsp;Eyal Shteyer ,&nbsp;Dalit May","doi":"10.1016/j.ymgmr.2024.101175","DOIUrl":"10.1016/j.ymgmr.2024.101175","url":null,"abstract":"<div><div>Cytosolic phosphoenolpyruvate carboxykinase (PEPCK) is an enzyme encoded by the PCK1 gene and plays a rate limiting step in gluconeogenesis occurring mainly in the liver during prolonged fasting. Biallelic deficiency of this enzyme results in a rare inborn error of metabolism disorder (OMIM # <span><span>261680</span><svg><path></path></svg></span>). The main clinical and laboratory manifestations include fasting hypoglycemia and lactic acidosis with urinary excretion of Tricarboxylic Acid (TCA) cycles metabolites, particularly fumarate. The initial presentation varies between individuals in terms of age at initial presentation and clinical manifestations, however clinical information is lacking as it was diagnosed so far in less than 30 patients with a total of 6 different mutations which are all either missense or splice variants. We describe the first homozygous frame-shift mutation in the PCK1 gene, leading to cytosolic PEPCK deficiency. This resulted in transient hypoglycemia and acute liver failure with extreme hyperferritinemia (&gt;40,000 ng/ml) during the first days of life. This severe very early-onset presentation that was not described earlier expands our clinical and genetic spectrum of this rare metabolic disorder.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101175"},"PeriodicalIF":1.8,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143131403","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":"Dose-intensive therapy (DIT) for infantile Pompe disease: A pilot study","authors":"Jeanine R. Jarnes ,&nbsp;Nishitha R. Pillai ,&nbsp;Alia Ahmed ,&nbsp;Sofia Shrestha ,&nbsp;Molly Stark ,&nbsp;Chester B. Whitley","doi":"10.1016/j.ymgmr.2024.101179","DOIUrl":"10.1016/j.ymgmr.2024.101179","url":null,"abstract":"<div><h3>Background</h3><div>The current standard of care for infantile-onset Pompe disease (IOPD), a severe form of acid α-glucosidase enzyme activity deficiency is: (1) detection by newborn screening, (2) early initiation of intravenous enzyme replacement therapy (ERT) using recombinant human acid alpha-glucosidase (rhGAA), with higher doses of rhGAA increasingly used to improve clinical outcomes, and (3) immune tolerization induction (ITI) using to prevent anti-rhGAA antibody formation, with methotrexate (MTX), rituximab, and IVIG used for patients who are cross-reactive immunologic material negative (CRIM-) and monotherapy with MTX used in patients who are cross-reactive immunologic material positive (CRIM+).</div></div><div><h3>Objectives/methods</h3><div>A pilot study evaluates a dose-intensive therapy (DIT) using high-dose ERT (40 mg/kg/week) and more frequent exposure to ERT (i.e., 3 times weekly administration) to mitigate anti-rhGAA antibody formation, as an alternative to the standard therapeutic approach for IOPD.</div></div><div><h3>Results</h3><div>In the first patient, DIT resulted in rapid normalization of the following: (1) bi-ventricular hypertrophy, (2) urine HEX-4, (3) CK, (4) liver transaminases. At 7 years of age, the patient continues the DIT regimen. To date, all pediatric developmental milestones have been met on time, anti-rhGAA antibodies have been negative and the patient is able to attend school and maintain normal activities of daily living.</div></div><div><h3>Conclusions</h3><div>Over a 7-year period, DIT for CRIM-positive IOPD was well tolerated in the first patient treated. Excellent clinical outcomes were achieved, and anti-rhGAA antibodies levels were consistently undetectable. Assessments of more patients, that includes patients with CRIM-, as well as CRIM+ IOPD, will determine if this approach consistently achieves improved clinical outcomes and immune tolerization.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101179"},"PeriodicalIF":1.8,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11720876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971656","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":"Reassessing very long chain fatty acids elevations: Sitosterolemia as a non-peroxisomal cause","authors":"Merve Yoldaş Çelik ,&nbsp;Burcu Köşeci ,&nbsp;Ezgi Burgaç ,&nbsp;Kanay Yararbaş","doi":"10.1016/j.ymgmr.2024.101178","DOIUrl":"10.1016/j.ymgmr.2024.101178","url":null,"abstract":"<div><div>Very-long-chain fatty acids (VLCFAs) are commonly used to diagnose peroxisomal disorders, but elevated levels may also result from other non-peroxisomal causes, leading to diagnostic challenges. We report the case of a 2-year-old girl presenting with growth retardation and diarrhea, with laboratory investigations revealing elevated VLCFA levels suggestive of a peroxisomal disorder. Despite initial suspicion, genetic panels for peroxisomal and dyslipidemia-associated genes were negative. Whole exome sequencing (WES) ultimately revealed a pathogenic variant in the ABCG8 gene, consistent with a diagnosis of sitosterolemia, a rare autosomal recessive condition characterized by elevated plant sterols. Elevated plant sterols in sitosterolemia may interfere with VLCFA analysis, potentially leading to falsely elevated results and incorrect suspicion of peroxisomal dysfunction. This case underscores the importance of including sitosterolemia in the differential diagnosis for elevated VLCFA levels, particularly in patients with atypical presentations for peroxisomal disorders. It also highlights the role of WES in establishing an accurate diagnosis when biochemical findings are ambiguous. More studies are needed to evaluate the effects of plant sterols on VLCFA measurements. This report contributes to the literature by demonstrating the utility of genetic testing in clarifying challenging diagnostic scenarios involving elevated VLCFAs.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101178"},"PeriodicalIF":1.8,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11719374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971658","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":"In depth profiling of dihydrolipoamide dehydrogenase deficiency in primary patients fibroblasts reveals metabolic reprogramming secondary to mitochondrial dysfunction","authors":"Uri Sprecher ,&nbsp;Jeevitha Dsouza ,&nbsp;Monzer Marisat ,&nbsp;Dinorah Barasch ,&nbsp;Kumudesh Mishra ,&nbsp;Or Kakhlon Ph.D. ,&nbsp;Joshua Manor MD.Ph.D. ,&nbsp;Yair Anikster MD. Ph.D. ,&nbsp;Miguel Weil Ph.D.","doi":"10.1016/j.ymgmr.2024.101172","DOIUrl":"10.1016/j.ymgmr.2024.101172","url":null,"abstract":"<div><div>Dihydrolipoamide dehydrogenase (DLD) deficiency is an autosomal recessive disorder characterized by a functional disruption in several critical mitochondrial enzyme complexes, including pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. Despite DLD's pivotal role in cellular energy metabolism, detailed molecular and metabolic consequences of DLD deficiency (DLDD) remain poorly understood. This study represents the first in-depth multi-omics analysis, specifically metabolomic and transcriptomic, of fibroblasts derived from a DLD-deficient patient compound heterozygous for a common Ashkenazi Jewish variant (c.685G &gt; T) and a novel North African variant (c.158G &gt; A). The investigation reveals significant metabolic disruptions that distinguish the cellular phenotype of DLDD from other metabolic disorders and healthy controls. Employing a range of cellular and molecular techniques, including live-cell imaging, mitochondrial activity assays, immunofluorescence, transcriptomics and metabolomic analysis, we compared DLDD fibroblasts with fibroblasts from glycogen storage disease type 1 A (GSD1a) patients and healthy controls (HC) subjects. Our metabolomics analysis identified significant alterations in mitochondrial metabolism, particularly reduced glycine cleavage, altered one carbon metabolism and serine catabolism. Transcriptome profiling highlighted dysregulation in genes associated with metabolic stress and mitochondrial dysfunction. Our findings highlight reduced mitochondrial activity and respiratory capacity in DLDD fibroblasts, similar to observations in GSD1a fibroblasts. This multi-omics approach not only advances our understanding of the pathophysiology of DLDD, but also illustrates the potential for developing targeted diagnostics and therapeutic strategies.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101172"},"PeriodicalIF":1.8,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11719413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971657","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}