Molecular genetics and metabolism最新文献

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Developing a scoring system for gene curation prioritization in lysosomal diseases 开发溶酶体疾病基因整理优先级评分系统
IF 3.7 2区 生物学
Molecular genetics and metabolism Pub Date : 2024-09-01 DOI: 10.1016/j.ymgme.2024.108572
{"title":"Developing a scoring system for gene curation prioritization in lysosomal diseases","authors":"","doi":"10.1016/j.ymgme.2024.108572","DOIUrl":"10.1016/j.ymgme.2024.108572","url":null,"abstract":"<div><h3>Introduction</h3><p>Diseases caused by lysosomal dysfunction often exhibit multisystemic involvement, resulting in substantial morbidity and mortality. Ensuring accurate diagnoses for individuals with lysosomal diseases (LD) is of great importance, especially with the increasing prominence of genetic testing as a primary diagnostic method. As the list of genes associated with LD continues to expand due to the use of more comprehensive tests such as exome and genome sequencing, it is imperative to understand the clinical validity of the genes, as well as identify appropriate genes for inclusion in multi-gene testing and sequencing panels. The Clinical Genome Resource (ClinGen) works to determine the clinical importance of genes and variants to support precision medicine. As part of this work, ClinGen has developed a semi-quantitative framework to assess the strength of evidence for the role of a gene in a disease. Given the diversity in gene composition across LD panels offered by various laboratories and the evolving comprehension of genetic variants affecting secondary lysosomal functions, we developed a scoring system to define LD (Lysosomal Disease Scoring System - LDSS). This system sought to aid in the prioritization of genes for clinical validity curation and assess their suitability for LD-targeted sequencing panels.</p></div><div><h3>Methods</h3><p>Through literature review encompassing terms associated with both classically designated LD and LFRD, we identified 14 criteria grouped into “Overall Definition,” “Phenotype,” and “Pathophysiology.” These criteria included concepts such as the “accumulation of undigested or partially digested macromolecules within the lysosome” and being “associated with a wide spectrum of clinical manifestations impacting multiple organs and systems.” The criteria, along with their respective weighted values, underwent refinement through expert panel evaluation differentiating them between “major” and “minor” criteria. Subsequently, the LDSS underwent validation on 12 widely acknowledged LD and was later tested by applying these criteria to the Lysosomal Disease Network's (LDN) official Gene List.</p></div><div><h3>Results</h3><p>The final LDSS comprised 4 major criteria and 10 minor criteria, with a cutoff of 2 major or 1 major and 3 minor criteria established to define LD. Interestingly, when applied to both the LDN list and a comprehensive gene list encompassing genes included in clinical panels and published as LFRD genes, we identified four genes (<em>GRN, SLC29A3, CLN7</em> and <em>VPS33A</em>) absent from the LDN list, that were deemed associated with LD. Conversely, a subset of non-classic genes included in the LDN list, such as <em>MTOR</em>, <em>OCRL</em>, and <em>SLC9A6</em>, received lower LDSS scores for their associated disease entities. While these genes may not be suitable for inclusion in clinical LD multi-gene panels, they could be considered for inclusion on other, non-LD gene panel","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142168557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Treatment of congenital disorders of glycosylation: An overview 先天性糖基化紊乱的治疗:概述
IF 3.7 2区 生物学
Molecular genetics and metabolism Pub Date : 2024-09-01 DOI: 10.1016/j.ymgme.2024.108567
{"title":"Treatment of congenital disorders of glycosylation: An overview","authors":"","doi":"10.1016/j.ymgme.2024.108567","DOIUrl":"10.1016/j.ymgme.2024.108567","url":null,"abstract":"<div><p>While the identification and diagnosis of congenital disorders of glycosylation (CDG) have rapidly progressed, the available treatment options are still quite limited. Mostly, we are only able to manage the disease symptoms rather than to address the underlying cause. However, recent years have brought about remarkable advances in treatment approaches for some CDG. Innovative therapies, targeting both the root cause and resulting manifestations, have transitioned from the research stage to practical application. The present paper aims to provide a detailed overview of these exciting developments and the rising concepts that are used to treat these ultra-rare diseases.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004517/pdfft?md5=11fe9626a95e4fd00999824a20760034&pid=1-s2.0-S1096719224004517-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142137123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Assessing carnosinase 1 activity for diagnosing congenital disorders of glycosylation 评估肌肽酶 1 的活性以诊断先天性糖基化紊乱。
IF 3.7 2区 生物学
Molecular genetics and metabolism Pub Date : 2024-09-01 DOI: 10.1016/j.ymgme.2024.108571
{"title":"Assessing carnosinase 1 activity for diagnosing congenital disorders of glycosylation","authors":"","doi":"10.1016/j.ymgme.2024.108571","DOIUrl":"10.1016/j.ymgme.2024.108571","url":null,"abstract":"<div><p>Diagnosing Congenital Disorders of Glycosylation (CDG) is challenging due to clinical heterogeneity and the limited sensitivity of the classic serum transferrin isoelectric focusing (IEF) or capillary zone electrophoresis test. This study investigates the potential of using the glycoprotein carnosinase 1 (CN1) activity as a diagnostic marker for CDG patients. CN1 activity was measured photometrically in serum from 81 genetically confirmed CDG patients and healthy individuals. While the IEF transferrin method detected 77 patients, four remained undetected.</p><p>In healthy individuals, serum CN1 activity ranged from 0.1 to 6.4 μmol/ml/h depending on age, with mean CN1 activities up to four-fold higher than in CDG patients. CDG patients´ CN1 activities never exceeded 2,04 μmol/ml/h. Using the 25th percentile to differentiate between groups, the test performance varied by age. For children over 10 years old, the sensitivity and specificity were 96 % and 83 %, respectively. For those under 10, sensitivity and specificity dropped to 71 % and to 64 %. However, CN1 activity successfully identified three of four patients with normal IEF patterns.</p><p>Although mean CN1 activity in CDG patients is significantly lower than in healthy controls, the test's reliability for classic CDG diagnosis is limited, as the diagnosis is usually made at a young age. Nevertheless, it is a simple, cost-effective assay that can complement classic tests, especially in settings with limited access to complex methods or for patients with normal transferrin patterns but suspicious for CDG.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004554/pdfft?md5=7d0d0abfac617b127769b9b702d30650&pid=1-s2.0-S1096719224004554-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Continuous glucose monitoring metrics in people with liver glycogen storage disease and idiopathic ketotic hypoglycemia: A single-center, retrospective, observational study 肝糖原贮积症和特发性酮症性低血糖患者的连续血糖监测指标:一项单中心、回顾性、观察性研究。
IF 3.7 2区 生物学
Molecular genetics and metabolism Pub Date : 2024-09-01 DOI: 10.1016/j.ymgme.2024.108573
{"title":"Continuous glucose monitoring metrics in people with liver glycogen storage disease and idiopathic ketotic hypoglycemia: A single-center, retrospective, observational study","authors":"","doi":"10.1016/j.ymgme.2024.108573","DOIUrl":"10.1016/j.ymgme.2024.108573","url":null,"abstract":"<div><h3>Background</h3><p>Cohort data on continuous glucose monitoring (CGM) metrics are scarce for liver glycogen storage diseases (GSDs) and idiopathic ketotic hypoglycemia (IKH). The aim of this study was to retrospectively describe CGM metrics for people with liver GSDs and IKH.</p></div><div><h3>Patients and methods</h3><p>CGM metrics (descriptive, glycemic variation and glycemic control parameters) were calculated for 47 liver GSD and 14 IKH patients, categorized in cohorts by disease subtype, age and treatment status, and compared to published age-matched CGM metrics from healthy individuals. Glycemic control was assessed as time-in-range (TIR; ≥3.9 - ≤7.8 and ≥3.9 - ≤10.0 mmol/L), time-below-range (TBR; &lt;3.0 mmol/L and ≥3.0 - ≤3.9 mmol/L), and time-above-range (TAR; &gt;7.8 and &gt;10.0 mmol/L).</p></div><div><h3>Results</h3><p>Despite all patients receiving dietary treatment, GSD cohorts displayed significantly different CGM metrics compared to healthy individuals. Decreased TIR together with increased TAR were noted in GSD I, GSD III, and GSD XI (Fanconi-Bickel syndrome) cohorts (all <em>p</em> &lt; 0.05). In addition, all GSD I cohorts showed increased TBR (all <em>p</em> &lt; 0.05). In GSD IV an increased TBR (p &lt; 0.05) and decreased TAR were noted (p &lt; 0.05). In GSD IX only increased TAR was observed (p &lt; 0.05). IKH patient cohorts, both with and without treatment, presented CGM metrics similar to healthy individuals.</p></div><div><h3>Conclusion</h3><p>Despite dietary treatment, most liver GSD cohorts do not achieve CGM metrics comparable to healthy individuals. International recommendations on the use of CGM and clinical targets for CGM metrics in liver GSD patients are warranted, both for patient care and clinical trials.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004578/pdfft?md5=4652934eedba1477b5d1d0c1f830c15e&pid=1-s2.0-S1096719224004578-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Severity-adjusted evaluation of initial dialysis on short-term health outcomes in urea cycle disorders 尿素循环障碍患者初始透析对短期健康结果的严重程度调整评估
IF 3.7 2区 生物学
Molecular genetics and metabolism Pub Date : 2024-09-01 DOI: 10.1016/j.ymgme.2024.108566
{"title":"Severity-adjusted evaluation of initial dialysis on short-term health outcomes in urea cycle disorders","authors":"","doi":"10.1016/j.ymgme.2024.108566","DOIUrl":"10.1016/j.ymgme.2024.108566","url":null,"abstract":"<div><h3>Objective</h3><p>In individuals with urea cycle disorders (UCDs) and neonatal disease onset, extracorporeal detoxification by continuous kidney replacement therapy is considered the therapeutic method of choice in addition to metabolic emergency treatment to resolve hyperammonemic decompensation. However, the indications for the initiation of dialysis are heterogeneously implemented transnationally, thereby hampering our understanding of (optimal) short-term health outcomes.</p></div><div><h3>Methods</h3><p>We performed a retrospective comparative analysis evaluating the therapeutic effects of initial dialysis on survival as well as neurocognitive outcome parameters in individuals with UCDs in comparison to a severity-adjusted non-dialyzed control cohort. Overall, 108 individuals with a severe phenotype of male ornithine transcarbamylase deficiency (mOTC-D), citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) were investigated by stratification based on a recently established and validated genotype-specific disease prediction model.</p></div><div><h3>Results</h3><p>Mortality is associated with the height of initial peak plasma ammonium concentration, but appears to be independent from treatment with initial dialysis in mOTC-D. However, improved survival after initial dialysis was observed in CTLN1, while there was a trend towards improved survival in ASA. In survivors, annual frequency of (subsequent) metabolic decompensations did not differ between the dialyzed and non-dialyzed cohorts. Moreover, treatment with initial dialysis was not associated with improved neurocognitive outcomes.</p></div><div><h3>Interpretation</h3><p>The present severity-adjusted comparative analysis reveals that general practice of initial dialysis is neither associated with improved survival in individuals with mOTC-D nor does it differ with regard to the neurocognitive outcome for the investigated UCD subtypes. However, initial dialysis might potentially prove beneficial for survival in CTLN1 and ASA.</p><p><strong>Clinical trial registration</strong>: The UCDC database is recorded at the US National Library of Medicine (<span><span>https://clinicaltrials.gov</span><svg><path></path></svg></span>).</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004505/pdfft?md5=95d6eb8d68af172011e052eabd55c6b2&pid=1-s2.0-S1096719224004505-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142240409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Base editing of the GLB1 gene is therapeutic in GM1 gangliosidosis patient-derived cells 碱基编辑 GLB1 基因对 GM1 神经节苷脂病患者衍生细胞有治疗作用
IF 3.7 2区 生物学
Molecular genetics and metabolism Pub Date : 2024-09-01 DOI: 10.1016/j.ymgme.2024.108568
{"title":"Base editing of the GLB1 gene is therapeutic in GM1 gangliosidosis patient-derived cells","authors":"","doi":"10.1016/j.ymgme.2024.108568","DOIUrl":"10.1016/j.ymgme.2024.108568","url":null,"abstract":"<div><p>GM1 gangliosidosis is an autosomal recessive neurodegenerative lysosomal storage disease caused by pathogenic variants in the <em>GLB1</em> gene, limiting the production of active lysosomal β-galactosidase. Phenotypic heterogeneity is due in part to variant type, location within <em>GLB1</em>, and the amount of residual enzyme activity; in the most severe form, death occurs in infancy. With no FDA approved therapeutics, development of efficacious strategies for the disease is pivotal. CRISPR/Cas based approaches have revolutionized precision medicine and have been indispensable to the development of treatments for several monogenic disorders with bespoke strategies central to current research pipelines. We used CRISPR/Cas-adenine base editing to correct the <em>GLB1</em> c.380G&gt;A (p.Cys127Tyr) variant in patient-derived dermal fibroblasts compound heterozygous with the <em>GLB1</em> c.481T&gt;G (p.Trp161Gly) pathogenic variant. Nucleofection of plasmids encoding the target sgRNA and ABEmax restored the canonical guanine (32.2 ± 2.2 % of the target allele) and synthesis of active β-galactosidase. Analysis of cellular markers of pathology revealed normalization of both primary glycoconjugate storage and lysosomal pathology. Furthermore, analysis of off-target sites nominated by the <em>in silico</em> tools Cas-OFFinder and/or CRISTA revealed no significant editing or indels. This study supports the use of CRISPR/Cas-based approaches for the treatment of GM1 gangliosidosis, and provides foundational data for future translational studies.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004529/pdfft?md5=caf784a9b2901b28fddc7475115c9100&pid=1-s2.0-S1096719224004529-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142274475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Systemic complications of Aicardi Goutières syndrome using real-world data 利用真实世界的数据研究艾卡迪-古蒂耶尔综合征的全身并发症
IF 3.7 2区 生物学
Molecular genetics and metabolism Pub Date : 2024-09-01 DOI: 10.1016/j.ymgme.2024.108578
{"title":"Systemic complications of Aicardi Goutières syndrome using real-world data","authors":"","doi":"10.1016/j.ymgme.2024.108578","DOIUrl":"10.1016/j.ymgme.2024.108578","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;div&gt;Aicardi Goutières Syndrome (AGS) is a rare genetic interferonopathy associated with diverse multisystemic complications. A critical gap exists in our understanding of its longitudinal, systemic disease burden, complicated by delayed diagnosis. To address this need, real-world data extracted from existing medical records were used to characterize the longitudinal disease burden.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;All subjects (&lt;em&gt;n&lt;/em&gt; = 167) with genetically confirmed AGS enrolled in the Myelin Disorders Biorepository Project (MDBP) were included. As available in medical records, information was collected on subject demographics, age of onset, and disease complications. Information from published cases of AGS (2007–2022; &lt;em&gt;n&lt;/em&gt; = 129) with individual-level data was also collected. Neurologic severity at the last available encounter was determined by retrospectively assigning the AGS Severity Scale [severe (0–3), moderate (4–8), and mild (9–11)].&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;The genotype frequency in the natural history cohort was &lt;em&gt;TREX1&lt;/em&gt; (&lt;em&gt;n&lt;/em&gt; = 26, 15.6 %), &lt;em&gt;RNASEH2B&lt;/em&gt; (&lt;em&gt;n&lt;/em&gt; = 50, 29.9 %), &lt;em&gt;RNASEH2C&lt;/em&gt; (&lt;em&gt;n&lt;/em&gt; = 3, 1.8 %), &lt;em&gt;RNASEH2A&lt;/em&gt; (&lt;em&gt;n&lt;/em&gt; = 7, 4.2 %), &lt;em&gt;SAMHD1&lt;/em&gt; (&lt;em&gt;n&lt;/em&gt; = 25, 15.0 %), &lt;em&gt;ADAR&lt;/em&gt; (&lt;em&gt;n&lt;/em&gt; = 34, 20.4 %), &lt;em&gt;IFIH1&lt;/em&gt; (&lt;em&gt;n&lt;/em&gt; = 19, 11.4 %), and &lt;em&gt;RNU7–1&lt;/em&gt; (n = 3, 1.8 %). The median age of systemic onset was 0.15 years [IQR = 0.67 years; median range by genotype: 0 (&lt;em&gt;TREX1&lt;/em&gt;) - 0.62 (&lt;em&gt;ADAR)&lt;/em&gt; years], while the median neurological onset was 0.33 years [IQR = 0.82 years; median range by genotype: 0.08 (&lt;em&gt;TREX1&lt;/em&gt;) - 0.90 (&lt;em&gt;ADAR)&lt;/em&gt; year].&lt;/div&gt;&lt;div&gt;The most common early systemic complications were gastrointestinal, including dysphagia or feeding intolerance (&lt;em&gt;n&lt;/em&gt; = 124) and liver abnormalities (&lt;em&gt;n&lt;/em&gt; = 67). Among postnatal complications, thrombocytopenia appeared earliest (&lt;em&gt;n&lt;/em&gt; = 29, median 0.06 years). Tone abnormalities (axial hypotonia: &lt;em&gt;n&lt;/em&gt; = 145, 86.8 %; dystonia: &lt;em&gt;n&lt;/em&gt; = 123, 73.7 %), irritability (&lt;em&gt;n&lt;/em&gt; = 115, 68.9 %), and gross motor delay (&lt;em&gt;n&lt;/em&gt; = 112, 7.1 %) emerged as the most prevalent neurological symptoms. Previously published case reports demonstrated similar patterns.&lt;/div&gt;&lt;div&gt;The median AGS score for the entire cohort was 4 (IQR = 7). The most severe neurologic phenotype occurred in &lt;em&gt;TREX1-&lt;/em&gt;related AGS (&lt;em&gt;n&lt;/em&gt; = 19, median AGS severity score 2, IQR = 2). Time to feeding tube placement, chilblains, early gross motor delay, early cognitive delay, and motor regression were significantly associated with genotype (Fleming-Harrington log-rank: &lt;em&gt;p&lt;/em&gt; = 0.0002, &lt;em&gt;p&lt;/em&gt; &lt; 0.0001, &lt;em&gt;p&lt;/em&gt; = 0.0038, p &lt; 0.0001, &lt;em&gt;p&lt;/em&gt; = 0.0001, respectively). Microcephaly, feeding tube placement, and seizures were associated with lower AGS scores (All: Wilcoxon rank sum test, p &lt; 0.0001).&lt;/div&gt;&lt;div&gt;Among the qualifying case reports (&lt;em","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Maple syrup urine disease diagnosis in Brazilian patients by massive parallel sequencing 通过大规模平行测序诊断巴西患者的枫糖尿病
IF 3.7 2区 生物学
Molecular genetics and metabolism Pub Date : 2024-09-01 DOI: 10.1016/j.ymgme.2024.108569
{"title":"Maple syrup urine disease diagnosis in Brazilian patients by massive parallel sequencing","authors":"","doi":"10.1016/j.ymgme.2024.108569","DOIUrl":"10.1016/j.ymgme.2024.108569","url":null,"abstract":"<div><p>Biallelic pathogenic variants cause maple syrup urine disease (MSUD) in one of the branched-chain α-keto acid dehydrogenase (BCKDH) complex genes (<em>BCKDHA</em>, <em>BCKDHB</em>, <em>DBT</em>, <em>DLD</em>, and <em>PPM1K</em>) leading to the accumulation of leucine, isoleucine, and valine. This study aimed to perform a molecular diagnosis of Brazilian patients with MSUD using gene panels and massive parallel sequencing. Eighteen Brazilian patients with a biochemical diagnosis of MSUD were analyzed by massive parallel sequencing in the Ion PGM Torrent Server using a gene panel with the <em>BCKDHA</em>, <em>BCKDHB</em>, and <em>DBT</em> genes. The American College of Medical Genetics and Genomics guidelines were used to determine variant pathogenicity. Thirteen patients had both variants found by massive parallel sequencing, whereas 3 patients had only one variant found. In 2 patients, the variants were not found by this analysis. These 5 patients required additional Sanger sequencing to confirm their genotype. Twenty-five pathogenic variants were identified in the 3 MSUD-related genes (<em>BCKDHA</em>, <em>BCKDHB</em>, and <em>DBT</em>). Most variants were present in the <em>BCKDHB</em> gene, and no common variants were found. Nine novel variants were observed: c.922 A &gt; G, c.964C &gt; A, and c.1237 T &gt; C in the <em>BCKDHA</em> gene; and c.80_90dup, c.384delA, c.478 A &gt; T, c.528C &gt; G, c.977 T &gt; C, and c.1039-2 A &gt; G in the <em>BCKDHB</em> gene. All novel variants were classified as pathogenic. Molecular modeling of the novel variants indicated that the binding of monomers was affected in the BCKDH complex tetramer, which could lead to a change in the stability and activity of the enzyme. Massive parallel sequencing with targeted gene panels seems to be a cost-effective method that can provide a molecular diagnosis of MSUD.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142168556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Standardized emergency protocols to improve the management of patients with suspected or confirmed inherited metabolic disorders (IMDs): An initiative of the French IMDs Healthcare Network for Rare Diseases 标准化急救协议,改善对疑似或确诊遗传性代谢紊乱(IMDs)患者的管理:法国IMDs罕见病医疗网络的一项倡议
IF 3.7 2区 生物学
Molecular genetics and metabolism Pub Date : 2024-09-01 DOI: 10.1016/j.ymgme.2024.108579
{"title":"Standardized emergency protocols to improve the management of patients with suspected or confirmed inherited metabolic disorders (IMDs): An initiative of the French IMDs Healthcare Network for Rare Diseases","authors":"","doi":"10.1016/j.ymgme.2024.108579","DOIUrl":"10.1016/j.ymgme.2024.108579","url":null,"abstract":"<div><h3>Objectives</h3><p>Patients with inherited metabolic disorders (IMDs) may require emergency hospital care to prevent life-threatening situations such as metabolic decompensation. To date, over one thousand different rare IMDs have been identified, which means that healthcare professionals (HCPs) initiating emergency treatment may not be familiar with these conditions. The objective of this initiative was to provide HCPs with practical guidance for the acute management of children and adults with IMDs who need emergency care, regardless of the underlying reason.</p></div><div><h3>Methods</h3><p>We outline how a multidisciplinary working group from the French IMDs Healthcare Network for Rare Diseases, known as G2M, has created concise and standardized protocols _each consisting of a single double-sided A4 sheet _ focused on a specific disease, a group of diseases, or a particular symptom. Prior to validation, these protocols were reviewed by all French reference and competence centres for IMDs, as well as by medical experts from other specialities when necessary, physicians from emergency and intensive care units, and representatives from patient associations.</p></div><div><h3>Results and conclusion</h3><p>In total, 51 emergency protocols containing essential information have been developed and provided to affected patients. All the emergency protocols are freely available in both French and English at <span><span>https://www.filiere-g2m.fr/urgences</span><svg><path></path></svg></span>. These standardized protocols aim to enhance the emergency care of patients without delay, while also assisting HCPs by increasing their confidence and efficiency, minimizing the risk of dosage errors when administering specialized treatments, saving time, and reducing the number of phone calls to metabolic medicine specialists on night duty. The protocols are scheduled for annual review to facilitate further improvements based on feedback from HCPs and patients, as well as to accommodate any changes in management practices as they evolve.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142274476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genotype–phenotype findings in patients with mucopolysaccharidosis II from the Hunter Outcome Survey 亨特结果调查得出的黏多醣症II患者基因型-表型结果
IF 3.7 2区 生物学
Molecular genetics and metabolism Pub Date : 2024-09-01 DOI: 10.1016/j.ymgme.2024.108576
{"title":"Genotype–phenotype findings in patients with mucopolysaccharidosis II from the Hunter Outcome Survey","authors":"","doi":"10.1016/j.ymgme.2024.108576","DOIUrl":"10.1016/j.ymgme.2024.108576","url":null,"abstract":"<div><h3>Purpose</h3><p>This study investigated the relationship between mucopolysaccharidosis II (MPS II) iduronate-2-sulfatase gene (<em>IDS</em>) variants and phenotypic characteristics, particularly cognitive impairment, using data from the Hunter Outcome Survey (HOS) registry.</p></div><div><h3>Methods</h3><p>HOS data for male patients (<em>n</em> = 650) aged ≥5 years at latest cognitive assessment with available genetic data were analyzed. Predefined genotype categories were used to classify <em>IDS</em> variants and report phenotypic characteristics by genotype.</p></div><div><h3>Results</h3><p>At their latest cognitive assessment, 411 (63.2%) of 650 patients had cognitive impairment. Missense variants were the most common MPS II genotype, with about equal frequency for patients with and patients without cognitive impairment. Complete deletions/large rearrangements were associated with cognitive impairment. Cognitive impairment and behavioral issues were most common, and height and weight abnormalities most apparent, in patients with large <em>IDS</em> structural changes. Broadly, missense variants NM-000202.8:c.998C&gt;T p.(Ser333Leu), NM-000202.8:c.1402C&gt;T p.(Arg468Trp), NM-000202.8:c.1403G&gt;A p.(Arg468Gln) and NM-000202.8:c.262C&gt;T p.(Arg88Cys), and splice site variant NM-000202.8:c.257C&gt;T p.(Pro86Leu), were associated with cognitive impairment, and variants NM-000202.8:c.253G&gt;A p.(Ala85Thr), NM-000202.8:c.187 A&gt;G p.(Asn63Asp), NM-000202.8:c.1037C&gt;T p.(Ala346Val), NM-000202.8:c.182C&gt;T p.(Ser61Phe) and NM-000202.8:c.1122C&gt;T were not.</p></div><div><h3>Conclusion</h3><p>This analysis contributes toward the understanding of MPS II genotype–phenotype relationships, confirming and expanding on existing findings in a large, geographically diverse population.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142254960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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