Molecular Genetics and Metabolism Reports最新文献

{"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}

{"title":"Identification of a new COQ4 spliceogenic variant causing severe primary coenzyme Q deficiency","authors":"María Alcázar-Fabra ,&nbsp;Elsebet Østergaard ,&nbsp;Daniel J.M. Fernández-Ayala ,&nbsp;María Andrea Desbats ,&nbsp;Valeria Morbidoni ,&nbsp;Laura Tomás-Gallado ,&nbsp;Laura García-Corzo ,&nbsp;María del Mar Blanquer-Roselló ,&nbsp;Abigail K. Bartlett ,&nbsp;Ana Sánchez-Cuesta ,&nbsp;Lucía Sena ,&nbsp;Ana Cortés-Rodríguez ,&nbsp;María Victoria Cascajo-Almenara ,&nbsp;David J. Pagliarini ,&nbsp;Eva Trevisson ,&nbsp;Sabine W. Gronborg ,&nbsp;Gloria Brea-Calvo","doi":"10.1016/j.ymgmr.2024.101176","DOIUrl":"10.1016/j.ymgmr.2024.101176","url":null,"abstract":"<div><h3>Background and aims</h3><div>Primary Coenzyme Q (CoQ) deficiency caused by <em>COQ4</em> defects is a clinically heterogeneous mitochondrial condition characterized by reduced levels of CoQ₁₀ in tissues. Next-generation sequencing has lately boosted the genetic diagnosis of an increasing number of patients. Still, functional validation of new variants of uncertain significance is essential for an adequate diagnosis, proper clinical management, treatment, and genetic counseling.</div></div><div><h3>Materials and methods</h3><div>Both fibroblasts from a proband with <em>COQ4</em> deficiency and a <em>COQ4</em> knockout cell model have been characterized by a combination of biochemical and genetic analysis (HPLC lipid analysis, Oxygen consumption, minigene analysis, RNAseq, among others).</div></div><div><h3>Results</h3><div>Here, we report the case of a subject harboring a new variant of the <em>COQ4</em> gene in compound heterozygosis, which shows severe clinical manifestations. We present the molecular characterization of this new pathogenic variant affecting the splicing of <em>COQ4</em>.</div></div><div><h3>Conclusion</h3><div>Our results highlight the importance of expanding the genetic analysis beyond the coding sequence to reduce the misdiagnosis of primary CoQ deficiency patients.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101176"},"PeriodicalIF":1.8,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142932361","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":"Corrigendum to “Classic and atypical late infantile neuronal ceroid lipofuscinosis in Latin America: Clinical and genetic aspects, and treatment outcome with cerliponase alfa.” [Molecular Genetics and Metabolism ReportsVolume 38 (2024) 101060]","authors":"Norberto Guelbert ,&nbsp;Oscar Mauricio Espitia Segura ,&nbsp;Carolina Amoretti ,&nbsp;Angélica Arteaga Arteaga ,&nbsp;Nora Graciela Atanacio ,&nbsp;Natacha Sabrina Bazan ,&nbsp;Ellaine Doris Fernandes Carvalho ,&nbsp;Maria Denise Fernandes Carvalho de Andrade ,&nbsp;Inés María Denzler ,&nbsp;Consuelo Durand ,&nbsp;Erlane Ribeiro ,&nbsp;Juan Carlos Giugni ,&nbsp;Gabriel González ,&nbsp;Dolores González Moron ,&nbsp;Guillermo Guelbert ,&nbsp;Zulma Janneth Hernández Rodriguez ,&nbsp;Katiane Embiruçu Emilia ,&nbsp;Marcelo Andrés Kauffman ,&nbsp;Nury Isabel Mancilla ,&nbsp;Laureano Marcon ,&nbsp;María Mercedes Villanueva","doi":"10.1016/j.ymgmr.2024.101081","DOIUrl":"10.1016/j.ymgmr.2024.101081","url":null,"abstract":"","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101081"},"PeriodicalIF":1.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140786908","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":"Biallelic variants in the NDUFAF6 cause mitochondrial respiratory complex assembly defects associated with Leigh syndrome in probands","authors":"Yuwei Zhou ,&nbsp;Xiaofei Zeng ,&nbsp;Luyi Zhang ,&nbsp;Xiaojie Yin ,&nbsp;Xue Ma ,&nbsp;Keyi Li ,&nbsp;Peijing Qiu ,&nbsp;Xiaoting Lou ,&nbsp;Liqin Jin ,&nbsp;Ya Wang ,&nbsp;Yanling Yang ,&nbsp;Ting Shen","doi":"10.1016/j.ymgmr.2024.101168","DOIUrl":"10.1016/j.ymgmr.2024.101168","url":null,"abstract":"<div><h3>Background</h3><div>Variants in <em>NDUFAF6</em> have been reported to be associated with Leigh syndrome. However, further expansion of the <em>NDUFAF6</em>-phenotype and variants spectrum of <em>NDUFAF6</em>-related Leigh syndrome are still required.</div></div><div><h3>Methods</h3><div>Two patients diagnosed with Leigh syndrome were recruited, and whole-exome sequencing was performed to identify the genetic variants responsible for the abnormal gait, dystonia, and bilateral basal ganglia lesions, followed by validation using Sanger sequencing. Detailed medical records of the patients were collected and reviewed. Patient-derived immortalized B lymphocytes were generalized for functional assays. The clinical manifestations of the patients in this study and previously reported studies are summarized.</div></div><div><h3>Results</h3><div>Two patients developed gait dystonia followed by rapid progression to generalized dystonia and psychomotor regression. Brain magnetic resonance images showed lesions in bilateral symmetric basal ganglia. We identified that patient 1 and patient 2 had two missense changes (NM_152416 c.371 T &gt; C, c.923 T &gt; C and c.371 T &gt; C, c.920 A &gt; T) in <em>NDUFAF6</em>, respectively. The deficiency of mature super complex of complex I was confirmed in patient-derived immortalized B lymphocytes. Meanwhile, cellular ATP production was decreased, and mitochondrial ROS was increased. A literature review of 18 patients carrying variants in <em>NDUFAF6</em> was conducted, focusing on neurological presentation.</div></div><div><h3>Conclusions</h3><div><em>NDUFAF6</em>-related Leigh syndrome is a relevant cause of initial symptoms with abnormal gait, dystonia, and bilateral basal ganglia lesions. Two novel genetic variants, c.923 T &gt; C and c.920 A &gt; T were reported, which expands <em>NDUFAF6</em>-related Leigh syndrome and is advantageous for genetic counseling.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101168"},"PeriodicalIF":1.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884844","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 study of lethal neonatal CPT II deficiency: Novel insights from genetic analysis","authors":"Thi Chi Mai Tran ,&nbsp;Van-Thao Ta ,&nbsp;Thi Bao Bui ,&nbsp;Chi Dung Vu ,&nbsp;Thuy Ngoc Pham","doi":"10.1016/j.ymgmr.2024.101170","DOIUrl":"10.1016/j.ymgmr.2024.101170","url":null,"abstract":"<div><h3>Introduction</h3><div>Carnitine Palmitoyltransferase II (CPT II) deficiency encompasses a spectrum of disorders, with the lethal neonatal form (LNF) representing the rarest and most severe. While there are numerous <em>CPT2</em> gene variants that can cause CPT II deficiency, only 16 variants of these are known to be associated with LNF. This report presents the case of a neonatal male diagnosed with lethal CPT II deficiency, characterized by the presence of two heterogeneous variants. Additionally, we provide a comprehensive review of all clinical symptoms, biochemistry, and reported pathogenic variants associated with LNF CPT II deficiency.</div></div><div><h3>Case presentation</h3><div>A neonatal male exhibited typical symptoms and biochemical features of CPT II deficiency, along with abnormal long-chain fatty acid profiles, notably an exceptionally high level of C18OH. Genetic analysis of the dried blood spot (DBS) sample revealed two heterozygous variants: <em>CPT2</em> p.E174K and p.R554X. Both the healthy father and mother carried heterozygous variants, p.R554X and p.E174K, respectively.</div></div><div><h3>Discussion</h3><div>The symptoms of the LNF CPT II deficiency are characterized by the unavailability of fatty acids for energy production and the accumulation of lipids in tissues, primarily due to the extremely low activity of CPT II. The genetic variants associated with these cases are notably limited, and all of them are classified as ‘severe’ variants. In the presented case, the co-occurrence of p.R554X with another severe variant, p.E174K, manifests as LNF, this compelling evidence strongly supports the assertion that p.R554X is a potentially severe pathogenic variant contributing to CPT II deficiency.</div></div><div><h3>Conclusion</h3><div>This report represents the initial documentation of a LNF CPT II deficiency case characterized by the presence of two heterozyous <em>CPT2</em> variants: p.E174K and p.R554X. As a result, the p.R554X variant is potentially classified as a severe pathogenic variant. It further emphasizes the significance of early detection and precise mutation classification for effective disease.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101170"},"PeriodicalIF":1.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11667183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886137","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}