Molecular genetics and metabolism最新文献

{"title":"Severity-adjusted evaluation of initial dialysis on short-term health outcomes in urea cycle disorders","authors":"Matthias Zielonka ,&nbsp;Stefan Kölker ,&nbsp;Sven F. Garbade ,&nbsp;Florian Gleich ,&nbsp;Sandesh C.S. Nagamani ,&nbsp;Andrea L. Gropman ,&nbsp;Ann-Catrin Druck ,&nbsp;Nesrine Ramdhouni ,&nbsp;Laura Göde ,&nbsp;Georg F. Hoffmann ,&nbsp;Roland Posset","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":"143 1","pages":"Article 108566"},"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}

{"title":"Systemic complications of Aicardi Goutières syndrome using real-world data","authors":"Isabella Peixoto de Barcelos ,&nbsp;Amanda K. Jan ,&nbsp;Nicholson Modesti ,&nbsp;Sarah Woidill ,&nbsp;Francesco Gavazzi ,&nbsp;David Isaacs ,&nbsp;Russell D'Aiello ,&nbsp;Anjana Sevagamoorthy ,&nbsp;Lauren Charlton ,&nbsp;Amy Pizzino ,&nbsp;Johanna Schmidt ,&nbsp;Keith van Haren ,&nbsp;Stephanie Keller ,&nbsp;Florian Eichler ,&nbsp;Lisa T. Emrick ,&nbsp;Jamie L. Fraser ,&nbsp;Justine Shults ,&nbsp;Adeline Vanderver ,&nbsp;Laura A. Adang","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":"143 1","pages":"Article 108578"},"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}

{"title":"Base editing of the GLB1 gene is therapeutic in GM1 gangliosidosis patient-derived cells","authors":"Allisandra K. Rha ,&nbsp;Shih-Hsin Kan ,&nbsp;Perla Andrade-Heckman ,&nbsp;Chloe L. Christensen ,&nbsp;Jerry F. Harb ,&nbsp;Raymond Y. Wang","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":"143 1","pages":"Article 108568"},"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}

{"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":"Juliette Bouchereau ,&nbsp;Camille Wicker ,&nbsp;Karine Mention ,&nbsp;Clothilde Marbach ,&nbsp;Jeremy Do Cao ,&nbsp;Claire-Marine Berat ,&nbsp;Marianne Jaroussie ,&nbsp;Aline Cano ,&nbsp;Magali Gorce ,&nbsp;Alexa Garros ,&nbsp;Alice Kuster ,&nbsp;Célia Hoebeke ,&nbsp;Claire Mayer ,&nbsp;Anaïs Brassier ,&nbsp;Laurent Gouya ,&nbsp;Cécile Schrimpf ,&nbsp;Jean-Baptiste Arnoux ,&nbsp;Manuel Schiff ,&nbsp;Cécile Acquaviva-Bourdain ,&nbsp;Jean-François Benoist ,&nbsp;Pascale de Lonlay","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":"143 1","pages":"Article 108579"},"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}

{"title":"Maple syrup urine disease diagnosis in Brazilian patients by massive parallel sequencing","authors":"Rafael Hencke Tresbach ,&nbsp;Fernanda Sperb-Ludwig ,&nbsp;Rodrigo Ligabue-Braun ,&nbsp;Fernanda Hendges de Bitencourt ,&nbsp;Tássia Tonon ,&nbsp;Carolina Fischinger Moura de Souza ,&nbsp;Fabiano de Oliveira Poswar ,&nbsp;Maria Efigênia de Queiroz Leite ,&nbsp;Tatiana Amorim ,&nbsp;Gilda Porta ,&nbsp;João Seda Neto ,&nbsp;Irene Kazumi Miura ,&nbsp;Carlos Eduardo Steiner ,&nbsp;Ana Maria Martins ,&nbsp;André Luiz Santos Pessoa ,&nbsp;Erlane Marques Ribeiro ,&nbsp;Ida Vanessa Doederlein Schwartz","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":"143 1","pages":"Article 108569"},"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}

{"title":"Genotype–phenotype findings in patients with mucopolysaccharidosis II from the Hunter Outcome Survey","authors":"Joseph Muenzer ,&nbsp;Hernan Amartino ,&nbsp;Barbara K. Burton ,&nbsp;Maurizio Scarpa ,&nbsp;Anna Tylki-Szymańska ,&nbsp;Jennifer Audi ,&nbsp;Jaco Botha ,&nbsp;Daniel Fertek ,&nbsp;David Merberg ,&nbsp;Madhusudan Natarajan ,&nbsp;David A.H. Whiteman ,&nbsp;Roberto Giugliani","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":"143 1","pages":"Article 108576"},"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}

{"title":"CIC variants and folinic acid-responsive seizures","authors":"Meshal Almutair ,&nbsp;Farah Thabet ,&nbsp;Khalid Hundallah ,&nbsp;Brahim Tabarki","doi":"10.1016/j.ymgme.2024.108574","DOIUrl":"10.1016/j.ymgme.2024.108574","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108574"},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142137124","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}

{"title":"Sensitivity of transferrin isoform analysis for PMM2-CDG","authors":"Patrica L. Hall,&nbsp;Kris Liedke,&nbsp;Coleman Turgeon,&nbsp;Amy White,&nbsp;Gesele Bentz Pino,&nbsp;Dawn Peck,&nbsp;April Studinski,&nbsp;Dimitar Gavrilov,&nbsp;Silvia Tortorelli,&nbsp;Devin Oglesbee,&nbsp;Dietrich Matern,&nbsp;Kimiyo Raymond,&nbsp;Matthew J. Schultz","doi":"10.1016/j.ymgme.2024.108564","DOIUrl":"10.1016/j.ymgme.2024.108564","url":null,"abstract":"<div><p>Transferrin isoform analysis is an established laboratory test for congenital disorders of glycosylation (CDG). Despite its long history of clinical use, little has been published about its empirical sensitivity for specific conditions. We conducted a retrospective analysis of ten years of testing data and report our experience with transferrin testing for type I profiles and its sensitivity for the most common congenital disorder of glycosylation, PMM2-CDG. The data demonstrate 94% overall test sensitivity for PMM2-CDG and importantly demonstrate two known, recurrent variants enriched in false positive cases highlighting an important limitation of the test. The data confirm the clinical validity of transferrin isotype analysis as a screening test for disorders of protein N-linked glycosylation and as functional test for <em>PMM2</em> genotypes of uncertain significance.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108564"},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004487/pdfft?md5=488429242a92f1e3b46725149e4da88c&pid=1-s2.0-S1096719224004487-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142098970","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}

{"title":"Development of a signs and symptoms outcome measure for caregivers of patients with methylmalonic acidemia and propionic acidemia (MMAPAQ)","authors":"Vanja Sikirica ,&nbsp;Ethan J. Schwartz ,&nbsp;Jerry Vockley ,&nbsp;Kathy Stagni ,&nbsp;M. Alex Bellenger ,&nbsp;Geetanjoli Banerjee ,&nbsp;Neha Durgam ,&nbsp;Olga Moshkovich","doi":"10.1016/j.ymgme.2024.108577","DOIUrl":"10.1016/j.ymgme.2024.108577","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background and objective&lt;/h3&gt;&lt;p&gt;Methylmalonic acidemia (MMA) and propionic acidemia (PA) are rare inborn errors of metabolism with shared signs and symptoms that are associated with significant morbidity and mortality. No disease-specific clinical outcomes assessment instruments for MMA and/or PA currently exist to capture the patient perspective in clinical trials. Because patients with these conditions are generally young and have cognitive impairments, an observer-reported outcome (ObsRO) instrument is crucial. We report results from qualitative research supporting development of the Methylmalonic Acidemia and Propionic Acidemia Questionnaire (MMAPAQ), a signs and symptoms ObsRO measure for caregivers of patients with MMA and/or PA.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;Concept elicitation (CE) interviews were conducted with 35 participants across 2 studies who were aged ≥18 years and caregivers of patients with a confirmed diagnosis of MMA or PA, and an additional 5 patients aged ≥6 years with MMA or PA in Study 1, to identify core signs/symptoms for inclusion in the MMAPAQ. All interviews were conducted in English. Study 2 included cognitive interviews (CI) with caregivers and clinical experts to further assess content validity. CE and a conceptual framework review were also conducted with clinical experts to further support findings.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;A consistent set of signs/symptoms of MMA and PA were reported by eligible caregivers interviewed in study 1 (&lt;em&gt;n&lt;/em&gt; = 21) and study 2 (&lt;em&gt;n&lt;/em&gt; = 14), representing 11 patients with MMA and 20 with PA. Based on concepts reported in study 1, a draft instrument was constructed and compared with the Pediatric Quality of Life Inventory™ (PedsQL™) and Family Impact module, demonstrating face validity for measuring key signs/symptoms important to patients and caregivers. The PedsQL™ and Family Impact modules were preferred to assess patient and caregiver impacts. Two waves of CE and CIs were conducted in study 2, with wave 1 resulting in removal of 7 items and other revisions to improve clarity, and wave 2 resulting in modification of examples used for 2 items. The final instrument consisted of the following 7 items assessed over the past 7 days using a Likert-type response scale ranging from “never” to “very often”: uncontrollable or involuntary movements, dehydration, rapid breathing at rest, appearing lethargic, appearing disinterested in eating, refusing to eat, and vomiting.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;p&gt;This study establishes the content validity of the MMAPAQ as the first ObsRO questionnaire for measuring core signs and symptoms of MMA and PA in clinical trials and community research. Scoring and psychometric measurement properties of the MMAPAQ will be established in future studies. The PedsQL™ was found to have face validity in measuring concepts that affect the MMA and PA patient populations and should also be considered for use in clinical trials in MMA and","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108577"},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S109671922400461X/pdfft?md5=2f6d364f0bed4c7573b3801b3060eed7&pid=1-s2.0-S109671922400461X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142240410","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}

{"title":"Cover 2 / Ed. Board","authors":"","doi":"10.1016/S1096-7192(24)00467-0","DOIUrl":"10.1016/S1096-7192(24)00467-0","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 1","pages":"Article 108583"},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142419634","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}