Molecular Genetics and Metabolism Reports最新文献

{"title":"Newborn screening and genetic diagnosis of 3-methylcrotonyl-CoA carboxylase deficiency in Quanzhou,China","authors":"Weihua Lin ,&nbsp;Kunyi Wang ,&nbsp;Yanru Chen ,&nbsp;Zhenzhu Zheng ,&nbsp;Yiming Lin","doi":"10.1016/j.ymgmr.2024.101127","DOIUrl":"10.1016/j.ymgmr.2024.101127","url":null,"abstract":"<div><h3>Background and aims</h3><p>3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCD) is an autosomal recessive leucine catabolism condition caused by 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency due to <em>MCCC1</em>/<em>MCCC2</em> variants. We investigated its incidence and features in Quanzhou, China.</p></div><div><h3>Materials and methods</h3><p>We screened 643,606 newborns (January 2014 to December 2022) for elevated 3-hydroxyisovalerylcarnitine (C5OH) levels using tandem mass spectrometry (MS/MS). Molecular analyses identified <em>MCCC1</em>/<em>MCCC2</em> variants in suspected 3-MCCD cases.</p></div><div><h3>Results</h3><p>Seventeen neonates, two maternal patients, and one paternal patient had 3-MCCD. Its incidence in the Quanzhou study population was 1/37,859 newborns. All patients and neonates with 3-MCCD exhibited increased C5OH concentrations. Most patients [76.5%(13/17)] had increased urinary 3-methylcrotonylglycine (3-MCG) and 3-hydroxyisovaleric acid (3-HIVA) levels. Eight neonates and all adults with 3-MCCD had secondary carnitine deficiency. We identified seventeen variants, including 6 novel ones.<em>MCCC1</em>and <em>MCCC2</em> variants were found in 47.1% and 52.9% of patients,with c.1331G &gt; A (31.3%) and c.351_353delTGG (50.0%) being the most prevalent, respectively. Clinical symptoms were observed in 11.8% of patients.</p></div><div><h3>Conclusion</h3><p>We identified six new <em>MCCC1</em>/<em>MCCC2</em> variants, enhancing our understanding of the 3-MCCD molecular profile. Secondary carnitine deficiency occurred in eight neonates and all adult patients. Although clinical symptoms were observed in 11.8% of patients, whether they were related to 3-MCCD remain unclear. Therefore, further studies are required to decide whether 3-MCCD and C5OH indicators should continue to be used.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"40 ","pages":"Article 101127"},"PeriodicalIF":1.8,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000806/pdfft?md5=e3970176d6cb4d7b8b66d6fcd0a8a509&pid=1-s2.0-S2214426924000806-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933874","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":"Navigating social determinants of health barriers in the management of phenylketonuria","authors":"","doi":"10.1016/j.ymgmr.2024.101080","DOIUrl":"10.1016/j.ymgmr.2024.101080","url":null,"abstract":"<div><p>Phenylketonuria (PKU) is an inborn error of amino acid metabolism that is typically identified by newborn screening. With lifelong treatment consisting of dietary management, frequent laboratory monitoring, and regular metabolic clinic visits, patients with PKU can maintain good health and metabolic control. Here, we describe the case of an 8-year-old patient with PKU who has been followed by a metabolic clinic since birth. Despite responsiveness to sapropterin, this patient has had periods of poor metabolic control throughout her life due to her family's economic hardships, including limited access to transportation, housing, food, and health insurance. This case illustrates how social determinants of health may negatively affect rare disease management and potential strategies for addressing barriers to care.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"39 ","pages":"Article 101080"},"PeriodicalIF":1.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000338/pdfft?md5=b1acd3c4849ed32c782aecfa45727869&pid=1-s2.0-S2214426924000338-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141041199","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":"Title Page","authors":"","doi":"10.1016/S2214-4269(24)00082-X","DOIUrl":"10.1016/S2214-4269(24)00082-X","url":null,"abstract":"","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"39 ","pages":"Article 101129"},"PeriodicalIF":1.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221442692400082X/pdfft?md5=e922a060f652a7d8563dd9ebdd269f0c&pid=1-s2.0-S221442692400082X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142149047","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":"Treating the whole patient: Facilitating health care for patients facing health inequity","authors":"","doi":"10.1016/j.ymgmr.2024.101082","DOIUrl":"10.1016/j.ymgmr.2024.101082","url":null,"abstract":"<div><p>Social determinants of health (SDOH) are conditions in which people are born, grow, live, work, and age. Variations in these conditions are largely responsible for health inequities, the differences in health status or distribution of health resources within a population. Despite recent increases in attention to SDOH in research and clinical practice, few, if any, resources exist to describe how these complex dynamics impact patients with inborn errors of metabolism. Recognizing the role real-life narratives have as a powerful educational tool, we compiled a series of 3 original cases, published as part of this special supplement, to illustrate challenges and learnings related to SDOH within the context of urea cycle disorders and phenylketonuria.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"39 ","pages":"Article 101082"},"PeriodicalIF":1.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000351/pdfft?md5=54c5e045100205fa5336d6906dce7d54&pid=1-s2.0-S2214426924000351-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140757855","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":"Fatal consequences of limited health literacy in a patient with a rare metabolic disease","authors":"Markey C. McNutt","doi":"10.1016/j.ymgmr.2024.101121","DOIUrl":"10.1016/j.ymgmr.2024.101121","url":null,"abstract":"<div><p>A Black young adult female diagnosed with argininosuccinate lyase deficiency at 6 months of age encountered significant barriers to care for the first 16 years of her life due to socioeconomic factors and parental neglect. Once in the care of her paternal grandmother, she received appropriate treatment with a nitrogen scavenger, amino acid supplementation, and a low-protein diet. However, due to repeated hyperammonemic crises early in her life, she was minimally communicative and unable to perform activities of daily living. During her final hyperammonemic crisis, she presented to a hospital unfamiliar with urea cycle disorders and without a metabolic service. As a result, she did not receive optimal care and died.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"39 ","pages":"Article 101121"},"PeriodicalIF":1.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000740/pdfft?md5=0f72a44cf784400fcb54d6647c86943c&pid=1-s2.0-S2214426924000740-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141706644","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":"Management of a urea cycle disorder in the setting of socioeconomic and language barriers","authors":"Erika Vucko ,&nbsp;Joshua Baker ,&nbsp;Karen Becker ,&nbsp;Kirsten Havens ,&nbsp;Katherine Arduini ,&nbsp;Soo Shim","doi":"10.1016/j.ymgmr.2024.101108","DOIUrl":"10.1016/j.ymgmr.2024.101108","url":null,"abstract":"<div><p>Argininosuccinic aciduria (ASA) is a disorder that results from a deficiency in the urea cycle enzyme argininosuccinate lyase. Variable manifestations of this hereditary disorder are associated with hyperammonemia and can include lethargy, somnolence, and respiratory alkalosis in neonates, and vomiting, headaches, and neurocognitive deficiencies later in life. Management of ASA includes rapid measures to address hyperammonemia and long-term steps to maintain metabolic stability. Management paradigms should also consider social determinants of health, which are non-medical factors that influence health outcomes. Here, we describe the case of a male pediatric patient with ASA whose treatment has included considerations for his family's refugee status, language barriers, cultural adjustments, limited income, and transportation challenges.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"39 ","pages":"Article 101108"},"PeriodicalIF":1.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000612/pdfft?md5=9e4b03c24f392e7f05c1bb3933e325c5&pid=1-s2.0-S2214426924000612-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142149049","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 GALNT3 mutation causing Hyperphosphatemic familial Tumoral calcinosis","authors":"Aijia Wu ,&nbsp;Bangxiang Yang ,&nbsp;Xijie Yu","doi":"10.1016/j.ymgmr.2024.101128","DOIUrl":"10.1016/j.ymgmr.2024.101128","url":null,"abstract":"<div><p><strong><em>Aim</em></strong>Hyperphosphatemic Familial Tumoral Calcinosis (HFTC) is an autosomal recessive disorder. This study investigates the etiology of HFTC in offspring from consanguineous parents.</p></div><div><h3>Methods</h3><p>Clinical assessment, imaging, and direct sequencing were utilized to elucidate the condition. Previously reported cases were also reviewed.</p></div><div><h3>Result</h3><p>We identified a consanguineous Chinese family with HFTC caused by an interesting homozygous G to A substitution in GALNT3 (c.1626 + 1G &gt; A). The parents were carriers.</p></div><div><h3>Conclusion</h3><p>This study represents the first report of HFTC in a consanguineous Chinese family due to an interesting GALNT3 mutation. We reviewed known GALNT3 variants and associated clinical features of calcification disorders. The phenotypic difference between homozygous and complex heterozygous mutations is not clinically significant. Gene mutations affect the function of proteins mainly by affecting their binding to polyvalent ligands.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"40 ","pages":"Article 101128"},"PeriodicalIF":1.8,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000818/pdfft?md5=4392db20c521b201ccb09db1efb083e5&pid=1-s2.0-S2214426924000818-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141872252","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 presentation and molecular genetics of Iranian patients with Niemann-pick type C disease and report of 6 NPC1 gene novel variants: A case series","authors":"Hedyeh Saneifard ,&nbsp;Marjan Shakiba ,&nbsp;Mohammadreza Alaei ,&nbsp;Asieh Mosallanejad ,&nbsp;Shirin Ghanefard ,&nbsp;Mehrdad Yasaei ,&nbsp;Kimia Karimi Toudeshki","doi":"10.1016/j.ymgmr.2024.101124","DOIUrl":"10.1016/j.ymgmr.2024.101124","url":null,"abstract":"<div><p>Niemann Pick Type C disease is a rare and progressive neurodegenerative lysosomal storage disorder caused by autosomal recessive mutations in the NPC1 and NPC2 genes. It is characterized by the accumulation of multiple lipid species in the endolysosomal compartment, leading to neurodegeneration and involvement of the liver, spleen, and lungs. Niemann Pick Type C has a wide range of presentations and severities at different ages with different progression rates. According to the Human Gene Mutation Database, to date, 486 disease-causing mutations in the highly polymorphic NPC1 gene and &gt;20 mutations in the NPC2 have been reported. In the present study, we described the clinical, biochemical, and molecular profiles of 18 Iranian patients with Niemann-Pick Type C disease. Also, we describe six novel variants of the NPC1 gene, to our knowledge, not reported to date<strong>.</strong></p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"40 ","pages":"Article 101124"},"PeriodicalIF":1.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000776/pdfft?md5=9c238334068df416a7f398e9f895688e&pid=1-s2.0-S2214426924000776-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141872253","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 features and GCDH gene variants in three Chinese families with glutaric aciduria type 1: A case series and literature review","authors":"Yunxi Chen ,&nbsp;Qinghua Zhang ,&nbsp;Lei Cao ,&nbsp;Xuan Feng ,&nbsp;Pengwu Lin ,&nbsp;Shaohua Zhu ,&nbsp;Furong Liu ,&nbsp;Xing Wang ,&nbsp;Shengju Hao ,&nbsp;Yafei Cao ,&nbsp;Hongyan Wang ,&nbsp;Yali Ni","doi":"10.1016/j.ymgmr.2024.101123","DOIUrl":"10.1016/j.ymgmr.2024.101123","url":null,"abstract":"<div><h3>Aim</h3><p>To analyze the clinical phenotype and genetic etiology of three cases of glutaric aciduria type 1 (GA1) in Chinese children.</p></div><div><h3>Methods</h3><p>We performed genetic and metabolic testing using tandem mass spectrometry (MS/MS) and gas chromatography–mass spectrometry (GC/MS), followed by trio whole-exome sequencing (trio-WES) and Sanger sequencing. A literature review on glutaric aciduria type 1 (GA1) in Chinese patients was also conducted.</p></div><div><h3>Results</h3><p>Sequencing results showed each case had compound heterozygous variants in <em>GCDH</em>(NM_000159.4): c.214C &gt; G (p.Arg72Gly) and c.411C &gt; G (p.Tyr137Term) (Case 1), c.214C &gt; G (p.Arg72Gly) and c.1204C &gt; T (p.Arg402Trp) (Case 2), and c.1228G &gt; T (p.Val410Leu) and c.395G &gt; A (p.Arg132Gln) (Case 3). These variants were inherited from their respective parents. Notably, the c.214C &gt; G variant found in two children was a novel variant not previously reported. A review of the literature revealed that, clinically, the majority of patients experienced onset in infancy and early childhood (82%). Additionally, 38.36% were diagnosed through newborn screening, with the primary reasons for the initial visit being delayed development (32.43%) and infections (21.61%). The most common clinical manifestations included increased head circumference (77.19%) and motor developmental delay (65.15%). Biochemically, patients exhibited significant elevations in C5DC (98.51%) and C5DC/C8 (94.87%) in blood, as well as GA (94.37%) and 3OHGA (69.39%) in urine. Radiographically, patients showed a high prevalence of abnormalities in cranial MRI (86.15%) and EEG (73.33%). Genetically, 67 distinct <em>GCDH</em> gene variants were identified among 73 patients, with missense variants being the most prevalent type (73.97%). The most frequent variant was c.1244-2 A &gt; C, observed in 17.12% of cases. Additionally, the majority of variant sites were located in exons 11 (25.37%) and 6 (22.39%).</p></div><div><h3>Conclusion</h3><p><em>GCDH</em> variants were identified as the causative factors in the three children. The discovery of the novel variant (c.214C &gt; G) expands the spectrum of pathogenic <em>GCDH</em> variants. These findings facilitate the diagnosis and treatment of affected children and provide a basis for genetic counseling and prenatal diagnosis for their families.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"40 ","pages":"Article 101123"},"PeriodicalIF":1.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2214426924000764/pdfft?md5=06a5dceb24df8be6f0d4d4a4be63f7c2&pid=1-s2.0-S2214426924000764-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141872254","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":"Avalglucosidase alfa in infantile-onset Pompe disease: A snapshot of real-world experience in Italy","authors":"Agata Fiumara ,&nbsp;Annamaria Sapuppo ,&nbsp;Serena Gasperini ,&nbsp;Viola Crescitelli ,&nbsp;Michele Sacchini ,&nbsp;Elena Procopio ,&nbsp;Vincenza Gragnaniello ,&nbsp;Alberto Burlina","doi":"10.1016/j.ymgmr.2024.101126","DOIUrl":"10.1016/j.ymgmr.2024.101126","url":null,"abstract":"<div><h3>Introduction</h3><p>Infantile-onset Pompe disease (IOPD) is due to mutations in the <em>GAA</em> gene leading to profound deficiency of the lysosomal enzyme α-1,4-glucosidase. The disease is characterized by severe hypotonia, hypertrophic cardiomyopathy, macroglossia, and liver enlargement with onset in the first months of life. In the late-onset form (LOPD), muscle signs predominate with a clinical picture resembling muscle dystrophies. Enzyme replacement therapy with alglucosidase alfa (rhGAA) has been available since 2006 and patients treated with the enzyme show improved outcomes. Nevertheless, there is evidence that some patients have a suboptimal response or, after an initial improvement, reach a plateau with stabilization of the clinical picture. Thus, a new enzyme formulation, avalglucosidase alfa (neoGAA), with a higher degree of mannosylation, was developed.</p></div><div><h3>Methods</h3><p>We conducted a multicenter survey that collected data on four patients with IOPD, aged 6 to 16 years, who were switched to neoGAA thanks to a compassionate use program, after being treated for an average of 11.5 years with rhGAA. Follow-up data, including biochemical parameters and clinical features, were analyzed to determine clinical outcomes and the safety profile after a mean of 9 months.</p></div><div><h3>Results</h3><p>Patients with IOPD who were treated with neoGAA showed a positive change in biomarker levels. Moreover, the clinical picture revealed improved motor performance and cardiac parameters in patients who previously responded poorly.</p></div><div><h3>Conclusion</h3><p>This study highlights the improved efficacy of neoGAA, as a next generation enzyme replacement therapy, in 4 Italian patients with IOPD. Several clinical parameters showed a positive response to the new formulation suggesting that, if used at diagnosis, neoGAA may result in better outcomes for patients with IOPD.</p></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"40 ","pages":"Article 101126"},"PeriodicalIF":1.8,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S221442692400079X/pdfft?md5=a4b241ce8693ff7d5b4f6c6c636e3b13&pid=1-s2.0-S221442692400079X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141872282","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}