Molecular genetics and metabolism最新文献

{"title":"Response to therapy of creatine transporter deficiency caused by a hypomorphic variant in SLC6A8","authors":"Nicola Longo ,&nbsp;Laura Alane Voss ,&nbsp;Marta Frigeni ,&nbsp;Bijina Balakrishnan ,&nbsp;Marzia Pasquali","doi":"10.1016/j.ymgme.2024.108595","DOIUrl":"10.1016/j.ymgme.2024.108595","url":null,"abstract":"<div><div>Cerebral creatine deficiency syndromes (CCDS) are rare inherited metabolic disorders caused by defective biosynthesis or transport of creatine. These conditions are characterized by reduced accumulation of creatine in the brain, mild to severe intellectual disability, global developmental delay, and speech-language disorders. The amount of brain creatine reduction needed to cause symptoms is not known. Here we report a new patient with creatine transporter deficiency (CTD) who presented at 15 months of age with seizures and global delays with no speech at 3 years of age. Brain MRI was normal, but brain MRS indicated creatine levels reduced to about 20 % of normal. He had normal levels of creatine and guanidinoacetate in plasma, but increased creatine/creatinine ratio in urine. DNA sequencing identified a hemizygous c.832C &gt; T (p.Arg278Cys) variant in the creatine transporter gene <em>SLC6A8.</em> Fibroblasts from this patient had about 25 % of normal creatine transport activity, a value much higher than that measured in patients whose variants introduced premature stop codons in <em>SLC6A8</em>. The child was started on supplements of creatine, glycine, and arginine. His speech improved dramatically, and he had no more seizures, even during episodes of fever. Despite the clinical improvement, a repeat MRS demonstrated similar levels of brain creatine. This study suggests that a reduction in creatine transporter activity to 25 % or less is sufficient to cause symptoms of brain creatine deficiency and that functionally milder forms of CTD might respond to supplements aimed at replenishing brain creatine.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 3","pages":"Article 108595"},"PeriodicalIF":3.7,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142446871","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":"Assessment of genes involved in lysosomal diseases using the ClinGen clinical validity framework","authors":"Emily Groopman ,&nbsp;Shruthi Mohan ,&nbsp;Amber Waddell ,&nbsp;Matheus Wilke ,&nbsp;Raquel Fernandez ,&nbsp;Meredith Weaver ,&nbsp;Hongjie Chen ,&nbsp;Hongbin Liu ,&nbsp;Deeksha Bali ,&nbsp;Heather Baudet ,&nbsp;Lorne Clarke ,&nbsp;Christina Hung ,&nbsp;Rong Mao ,&nbsp;Filippo Pinto e Vairo ,&nbsp;Lemuel Racacho ,&nbsp;Tatiana Yuzyuk ,&nbsp;William J. Craigen ,&nbsp;Jennifer Goldstein","doi":"10.1016/j.ymgme.2024.108593","DOIUrl":"10.1016/j.ymgme.2024.108593","url":null,"abstract":"<div><div>Lysosomal diseases (LDs) are a heterogeneous group of rare genetic disorders that result in impaired lysosomal function, leading to progressive multiorgan system dysfunction. Accurate diagnosis is paramount to initiating targeted therapies early in the disease process in addition to providing prognostic information and appropriate support for families. In recent years, genomic sequencing technologies have become the first-line approach in the diagnosis of LDs. Understanding the clinical validity of the role of a gene in a disease is critical for the development of genomic technologies, such as which genes to include on next generation sequencing panels, and the interpretation of results from exome and genome sequencing. To this aim, the ClinGen Lysosomal Diseases Gene Curation Expert Panel utilized a semi-quantitative framework incorporating genetic and experimental evidence to assess the clinical validity of the 56 LD-associated genes on the Lysosomal Disease Network's list. Here, we describe the results, and the key themes and challenges encountered.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 3","pages":"Article 108593"},"PeriodicalIF":3.7,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470358","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":"Pompe disease: Unmet needs and emerging therapies","authors":"Kelly A. George,&nbsp;Allyson L. Anding,&nbsp;Arjan van der Flier,&nbsp;Giulio S. Tomassy,&nbsp;Kenneth I. Berger,&nbsp;Tracy Y. Zhang,&nbsp;S. Pablo Sardi","doi":"10.1016/j.ymgme.2024.108590","DOIUrl":"10.1016/j.ymgme.2024.108590","url":null,"abstract":"<div><div>Pompe disease is a debilitating and life-threatening disease caused by aberrant accumulation of glycogen resulting from reduced acid alpha-glucosidase activity. The first treatment for Pompe disease, the enzyme replacement therapy, Myozyme® (recombinant human acid alpha-glucosidase, alglucosidase alfa), is a lifesaving treatment for the most severe form of the disease and provided clinically meaningful benefits to patients with milder phenotypes. Nonetheless, many patients display suboptimal responses or clinical decline following years of alglucosidase alfa treatment. The approval of avalglucosidase alfa (Nexviazyme®) and cipaglucosidase alfa (Pombiliti®) with miglustat (Opfolda®) represents a new generation of enzyme replacement therapies seeking to further improve patient outcomes beyond alglucosidase alfa. However, the emergence of a complicated new phenotype with central nervous system involvement following long-term treatment, coupled with known and anticipated unmet needs of patients receiving enzyme replacement therapy, has prompted development of innovative new treatments.</div><div>This review provides an overview of the challenges of existing treatments and a summary of emerging therapies currently in preclinical or clinical development for Pompe disease and related lysosomal storage disorders. Key treatments include tissue-targeted enzyme replacement therapy, which seeks to enhance enzyme concentration in target tissues such as the central nervous system; substrate reduction therapy, which reduces intracellular glycogen concentrations via novel mechanisms; and gene therapy, which may restore endogenous production of deficient acid alpha-glucosidase. Each of these proposed treatments shows promise as a future therapeutic option to improve quality of life in Pompe disease by more efficiently treating the underlying cause of disease progression: glycogen accumulation.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 3","pages":"Article 108590"},"PeriodicalIF":3.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142446818","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":"Findings from the individualized management of a patient with Acyl-CoA Oxidase-1 (ACOX1) deficiency: A bedside-to-bench-to-bedside strategy","authors":"Camille Moreau ,&nbsp;Adrien Paquot ,&nbsp;Gustavo Soto Ares ,&nbsp;Anne-Frédérique Dessein ,&nbsp;Benoit Deprez ,&nbsp;Terence Beghyn ,&nbsp;Dries Dobbelaere","doi":"10.1016/j.ymgme.2024.108581","DOIUrl":"10.1016/j.ymgme.2024.108581","url":null,"abstract":"<div><div>Acyl-CoA Oxidase-1 (ACOX1) deficiency (MIM <span><span>264470</span><svg><path></path></svg></span>) is an autosomal recessive disease characterized by impairments in the desaturation of acyl-CoAs to 2-<em>trans</em>-enoyl-CoAs, which is the first step in the catalysis of the β-oxidative breakdown of very long chain fatty acids (VLCFA) occuring in peroxisomes. The deleterious accumulation of VLCFA in several organs, including the brain, is a key biochemical feature of this disease which has devastating neurological consequences. ACOX1 deficiency is ultra-rare; as such, few studies have been conducted to determine the leading causes of symptoms or uncover new therapeutics. When confronted with one such case, we decided to bring drug discovery tools to the patient's bedside in an attempt to identify a cure. A skin biopsy was performed on a young patient with ACOX1 deficiency, following which screening technologies and mass spectrometry analysis techniques were applied to design a cellular assay that enabled the direct measurement of the effect of small molecules on the patient's primary fibroblasts. This approach is particularly well adapted to inherited metabolic disorders such as ACOX1 deficiency. Through the evaluation of a proprietary library of repurposable drugs, we found that the anthelmintic drug niclosamide led to a significant reduction in VLCFA <em>in vitro</em>. This drug was subsequently administered to the patient for more than six years. This study outlines the screening and drug selection processes. Additionally, we present our comprehensive clinical and biochemical findings that aided in understanding the patient's natural history and analysis of the progression of the patient's symptoms throughout the treatment period. Although the patient's overall lifespan was extended compared to the average age at death in severe early onset cases of ACOX1 deficiency, we did not observe any definitive evidence of clinical or biochemical improvement during niclosamide treatment. Nonetheless, our study shows a good safety profile of long-term niclosamide administration in a child with a rare neurodegenerative disease, and illustrates the potential of individualized therapeutic strategies in the management of inherited metabolic disorders, which could benefit both patients and the broader scientific and medical communities.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 3","pages":"Article 108581"},"PeriodicalIF":3.7,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365858","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":"Pegvaliase treatment normalizes blood neurotransmitter metabolites in adults with phenylketonuria","authors":"Monika A. Sigg ,&nbsp;Christopher Wilson ,&nbsp;Gillian E. Clague ,&nbsp;Huiyu Zhou ,&nbsp;Cheng Su ,&nbsp;Geoffrey Y. Berguig","doi":"10.1016/j.ymgme.2024.108580","DOIUrl":"10.1016/j.ymgme.2024.108580","url":null,"abstract":"<div><div>Phenylketonuria (PKU) is caused by deficient activity of phenylalanine hydroxylase (PAH), the enzyme that converts phenylalanine (Phe) to tyrosine (Tyr), leading to a toxic accumulation of Phe and reduced Tyr in the blood and brain. Abnormal Phe and Tyr levels in the brain disrupt normal neurotransmitter biosynthesis and may contribute to the cognitive and psychiatric deficits observed in individuals with PKU. Blood neurotransmitter metabolites (NTMs) may serve as biomarkers that reflect neurotransmitter levels in the brain. In this study, blood NTMs correlated with brain NTMs and neurotransmitters in wild-type and <em>PAH</em>-deficient mice treated with <em>PAH</em> gene therapy. Pegvaliase is an enzyme substitution therapy that lowers blood Phe levels and is approved for individuals with PKU and uncontrolled blood Phe concentrations (&gt;600 μmol/L) despite prior management. The current work evaluated the relationship between blood NTMs and blood Phe in pegvaliase-treated, Phase 3, PRISM-1 (<span><span>NCT01819727</span><svg><path></path></svg></span>) and PRISM-2 (<span><span>NCT01889862</span><svg><path></path></svg></span>) study participants (Pegvaliase Group; <em>N =</em> 109). At baseline, individuals in the Pegvaliase Group had lower levels of the NTMs homovanillic acid (HVA), 3-methoxy-4-hydroxyphenyl glycol (MOPEG), and 5-hydroxyindoleacetic acid (5HIAA), and higher levels of the NTM phenylacetylglutamine (PAG) than age- and sex-matched healthy controls. PAG levels correlated positively with Phe levels (<em>r</em> = 0.833; <em>p</em> &lt; 0.001), while HVA, MOPEG, and 5HIAA levels correlated negatively with Phe levels (<em>r</em> = −0.588, −0.561, and −0.857, respectively; all <em>p</em> &lt; 0.001) across all timepoints. In participants with longitudinal NTM measurements available at baseline, 12 months, and 24 months (Pegvaliase Subgroup; <em>n =</em> 91), blood NTM levels improved from baseline with pegvaliase treatment at 12 months and 24 months, and median levels were normalized with blood Phe level reductions below 360 μmol/L after 24 months of treatment with pegvaliase, including in participants with blood Phe &lt;30 μmol/L. In conclusion, blood NTM levels correlated with blood Phe levels, and pegvaliase improved blood NTM levels in a large cohort of individuals with PKU.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 3","pages":"Article 108580"},"PeriodicalIF":3.7,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400790","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":"Treatment of congenital disorders of glycosylation: An overview","authors":"Dulce Quelhas ,&nbsp;Jaak Jaeken","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":"143 1","pages":"Article 108567"},"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}

{"title":"Developing a scoring system for gene curation prioritization in lysosomal diseases","authors":"Matheus Vernet Machado Bressan Wilke ,&nbsp;Jennifer Goldstein ,&nbsp;Emily Groopman ,&nbsp;Shruthi Mohan ,&nbsp;Amber Waddell ,&nbsp;Raquel Fernandez ,&nbsp;Hongjie Chen ,&nbsp;Deeksha Bali ,&nbsp;Heather Baudet ,&nbsp;Lorne Clarke ,&nbsp;Christina Hung ,&nbsp;Rong Mao ,&nbsp;Tatiana Yuzyuk ,&nbsp;William J. Craigen ,&nbsp;Filippo Pinto e Vairo","doi":"10.1016/j.ymgme.2024.108572","DOIUrl":"10.1016/j.ymgme.2024.108572","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;p&gt;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.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;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.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;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 (&lt;em&gt;GRN, SLC29A3, CLN7&lt;/em&gt; and &lt;em&gt;VPS33A&lt;/em&gt;) 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 &lt;em&gt;MTOR&lt;/em&gt;, &lt;em&gt;OCRL&lt;/em&gt;, and &lt;em&gt;SLC9A6&lt;/em&gt;, 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":"143 1","pages":"Article 108572"},"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}

{"title":"Assessing carnosinase 1 activity for diagnosing congenital disorders of glycosylation","authors":"Livia Interdonato ,&nbsp;Nastassja Himmelreich ,&nbsp;Sven F. Garbade ,&nbsp;Dan Wen ,&nbsp;Marina Morath ,&nbsp;Rosanna Di Paola ,&nbsp;Vittorio Calabrese ,&nbsp;Christian Thiel ,&nbsp;Verena Peters","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":"143 1","pages":"Article 108571"},"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}

{"title":"Continuous glucose monitoring metrics in people with liver glycogen storage disease and idiopathic ketotic hypoglycemia: A single-center, retrospective, observational study","authors":"Ruben J. Overduin ,&nbsp;Annieke Venema ,&nbsp;Charlotte M.A. Lubout ,&nbsp;Marieke J. Fokkert-Wilts ,&nbsp;Foekje De Boer ,&nbsp;Andrea B. Schreuder ,&nbsp;Alessandro Rossi ,&nbsp;Terry G.J. Derks","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":"143 1","pages":"Article 108573"},"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}

{"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}