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Corrigendum to "The effects of casein glycomacropeptide on general health status in children with PKU: A randomized crossover trial" [Molecular Genetics and Metabolism Volume 143, Issue 4, December 2024, 108607].
IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-03-17 DOI: 10.1016/j.ymgme.2025.109077
Alex Pinto, Anne Daly, Camille Newby, Abigail Robotham, Simon Heales, Simon Eaton, Helen Aitkenhead, Kimberly Gilmour, Richard Jackson, Catherine Ashmore, Sharon Evans, Júlio Cesar Rocha, Fatma Ilgaz, Mary Hickson, Anita MacDonald
{"title":"Corrigendum to \"The effects of casein glycomacropeptide on general health status in children with PKU: A randomized crossover trial\" [Molecular Genetics and Metabolism Volume 143, Issue 4, December 2024, 108607].","authors":"Alex Pinto, Anne Daly, Camille Newby, Abigail Robotham, Simon Heales, Simon Eaton, Helen Aitkenhead, Kimberly Gilmour, Richard Jackson, Catherine Ashmore, Sharon Evans, Júlio Cesar Rocha, Fatma Ilgaz, Mary Hickson, Anita MacDonald","doi":"10.1016/j.ymgme.2025.109077","DOIUrl":"https://doi.org/10.1016/j.ymgme.2025.109077","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":" ","pages":"109077"},"PeriodicalIF":3.7,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657811","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
Extracellular chaperones in lysosomal storage diseases
IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-03-15 DOI: 10.1016/j.ymgme.2025.109086
Aslı İnci , Serap Dökmeci
Lysosomal storage disorders (LSDs) are a diverse group of inherited metabolic disorders characterized by the accumulation of undegraded substrates within lysosomes due to defective lysosomal function. Recent research has highlighted the pivotal role of extracellular chaperones in the pathophysiology of LSDs, revealing their crucial involvement in modulating disease progression. These chaperones aid in stabilizing and refolding misfolded lysosomal enzymes, enhancing their proper trafficking and function, which in turn reduces substrate accumulation. Furthermore, extracellular chaperones have emerged as promising biomarkers, with their levels in bodily fluids offering potential for disease diagnosis and monitoring. This review explores the current understanding of extracellular chaperones in the context of LSDs, examining their mechanisms of action, biomarker and therapeutic potential, and future directions in clinical application of LSDs.
{"title":"Extracellular chaperones in lysosomal storage diseases","authors":"Aslı İnci ,&nbsp;Serap Dökmeci","doi":"10.1016/j.ymgme.2025.109086","DOIUrl":"10.1016/j.ymgme.2025.109086","url":null,"abstract":"<div><div>Lysosomal storage disorders (LSDs) are a diverse group of inherited metabolic disorders characterized by the accumulation of undegraded substrates within lysosomes due to defective lysosomal function. Recent research has highlighted the pivotal role of extracellular chaperones in the pathophysiology of LSDs, revealing their crucial involvement in modulating disease progression. These chaperones aid in stabilizing and refolding misfolded lysosomal enzymes, enhancing their proper trafficking and function, which in turn reduces substrate accumulation. Furthermore, extracellular chaperones have emerged as promising biomarkers, with their levels in bodily fluids offering potential for disease diagnosis and monitoring. This review explores the current understanding of extracellular chaperones in the context of LSDs, examining their mechanisms of action, biomarker and therapeutic potential, and future directions in clinical application of LSDs.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109086"},"PeriodicalIF":3.7,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143643537","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
Acid sphingomyelinase deficiency: Laboratory diagnosis, genetic and epidemiologic aspects of a 50-year French cohort
IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-03-11 DOI: 10.1016/j.ymgme.2025.109081
Roseline Froissart , Magali Pettazzoni , Cécile Pagan , Thierry Levade , Marie T. Vanier
<div><h3>Objectives</h3><div>Laboratory diagnosis of acid sphingomyelinase (ASM) deficiency (ASMD) was implemented in France in the early 1970s. The aims of this study were (i) to review the combined use of successively developed strategies - enzyme measurement, genetic testing, and biomarkers analysis – and (ii) to describe the mutational spectrum and epidemiological characteristics of a large patient cohort followed in French hospitals.</div></div><div><h3>Results</h3><div>During the 1974–2023 period, 271 patients with ASMD (238 families) were diagnosed. The chronic visceral form (historical Niemann-Pick type B) constituted 68 % of the cases, the infantile neurovisceral (type A) form 23 %, and the chronic neurovisceral (type AB) form 9 %. Profoundly deficient ASM activities were constantly observed in the neuronopathic forms. Elevated plasma concentrations of LysoSM and LysoSM-509/PPCS proved useful to comfort interpretation of ASM activities near cut-off found in leukocytes or dried blood spots of some patients with ASMD type B. Although not specific, LysoSM-509/PPCS appeared as the most sensitive biomarker. The spectrum of <em>SMPD1</em> variants was investigated in 183 families. A total of 93 different <em>SMPD1</em> variants (26 novel ones) was identified (58 % missense, 19 % frameshift, and 12 % nonsense ones). The proportion of null variants was much larger in ASMD type A (63 %) than in type B (24 %). In type AB, c.1177 T > G (p.Trp393Gly) contributed 32 % of the mutant alleles, most patients having Romani or Northwestern-Balkanic roots, while c.880C > A (p.Gln294Lys) only accounted for 9 %. Homoallelic variants in neuronopathic patients allowed genotype/phenotype correlations. In type B, c.1829_1831delGCC (p.Arg610del) represented 57 % of alleles, with a wide diversity of other variants. Among type B families, approximately one-third had a North African origin, and this variant accounted for 91 % alleles in this subgroup, compared to 40 % in non-North-African families. In patients homozygous for p.Arg610del (<em>n</em> = 69), the age at biological diagnosis was significantly higher (34.0 years; IQR 7.4–45.3) than in patients with either one (<em>n</em> = 41) [4.3 years; IQR 2.77–18.30] or no such allele (<em>n</em> = 43) [6.3 years; IQR 2.2–31.7]. A further observation was the proportional increase in the number of type B patients diagnosed after the age of 30 years since 2015. This nearly complete national cohort allowed a tentative evaluation of (minimal) incidences at birth as follows: ASMD (all clinical forms): 0.70/100,000; type B: 0.48/100,000; neuronopathic types (A and AB): 0.22/100,000.</div></div><div><h3>Conclusions</h3><div>This comprehensive cohort (i) summarizes the real-life experience of laboratory diagnosis of ASMD in two expert centres, (ii) confirms the high frequency of the p.Arg610del allele in France and discloses some characteristics of patients homozygous for this variant; (iii) provides for the first time d
{"title":"Acid sphingomyelinase deficiency: Laboratory diagnosis, genetic and epidemiologic aspects of a 50-year French cohort","authors":"Roseline Froissart ,&nbsp;Magali Pettazzoni ,&nbsp;Cécile Pagan ,&nbsp;Thierry Levade ,&nbsp;Marie T. Vanier","doi":"10.1016/j.ymgme.2025.109081","DOIUrl":"10.1016/j.ymgme.2025.109081","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Objectives&lt;/h3&gt;&lt;div&gt;Laboratory diagnosis of acid sphingomyelinase (ASM) deficiency (ASMD) was implemented in France in the early 1970s. The aims of this study were (i) to review the combined use of successively developed strategies - enzyme measurement, genetic testing, and biomarkers analysis – and (ii) to describe the mutational spectrum and epidemiological characteristics of a large patient cohort followed in French hospitals.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;During the 1974–2023 period, 271 patients with ASMD (238 families) were diagnosed. The chronic visceral form (historical Niemann-Pick type B) constituted 68 % of the cases, the infantile neurovisceral (type A) form 23 %, and the chronic neurovisceral (type AB) form 9 %. Profoundly deficient ASM activities were constantly observed in the neuronopathic forms. Elevated plasma concentrations of LysoSM and LysoSM-509/PPCS proved useful to comfort interpretation of ASM activities near cut-off found in leukocytes or dried blood spots of some patients with ASMD type B. Although not specific, LysoSM-509/PPCS appeared as the most sensitive biomarker. The spectrum of &lt;em&gt;SMPD1&lt;/em&gt; variants was investigated in 183 families. A total of 93 different &lt;em&gt;SMPD1&lt;/em&gt; variants (26 novel ones) was identified (58 % missense, 19 % frameshift, and 12 % nonsense ones). The proportion of null variants was much larger in ASMD type A (63 %) than in type B (24 %). In type AB, c.1177 T &gt; G (p.Trp393Gly) contributed 32 % of the mutant alleles, most patients having Romani or Northwestern-Balkanic roots, while c.880C &gt; A (p.Gln294Lys) only accounted for 9 %. Homoallelic variants in neuronopathic patients allowed genotype/phenotype correlations. In type B, c.1829_1831delGCC (p.Arg610del) represented 57 % of alleles, with a wide diversity of other variants. Among type B families, approximately one-third had a North African origin, and this variant accounted for 91 % alleles in this subgroup, compared to 40 % in non-North-African families. In patients homozygous for p.Arg610del (&lt;em&gt;n&lt;/em&gt; = 69), the age at biological diagnosis was significantly higher (34.0 years; IQR 7.4–45.3) than in patients with either one (&lt;em&gt;n&lt;/em&gt; = 41) [4.3 years; IQR 2.77–18.30] or no such allele (&lt;em&gt;n&lt;/em&gt; = 43) [6.3 years; IQR 2.2–31.7]. A further observation was the proportional increase in the number of type B patients diagnosed after the age of 30 years since 2015. This nearly complete national cohort allowed a tentative evaluation of (minimal) incidences at birth as follows: ASMD (all clinical forms): 0.70/100,000; type B: 0.48/100,000; neuronopathic types (A and AB): 0.22/100,000.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;This comprehensive cohort (i) summarizes the real-life experience of laboratory diagnosis of ASMD in two expert centres, (ii) confirms the high frequency of the p.Arg610del allele in France and discloses some characteristics of patients homozygous for this variant; (iii) provides for the first time d","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109081"},"PeriodicalIF":3.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143643539","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
Using multiple modalities to confirm diagnosis in patients with suspected peroxisome biogenesis disorders
IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-03-11 DOI: 10.1016/j.ymgme.2025.109080
Anthony C.T. Cheung , Erminia Di Pietro , Catherine Argyriou , Eric Bareke , Yasmin D'Souza , Ratna Dua Puri , P. Muhammed Shabeer , Rebecca Ganetzky , Amy Goldstein , Adeline Vanderver , Shruthi Mohan , Jacek Majewski , Christine Yergeau , Nancy Braverman
Zellweger spectrum disorder (ZSD) results from biallelic variants in any one of 13 PEX genes involved in peroxisome biogenesis and function. The majority of ZSD cases result from pathogenic variants in PEX1. Here, we present 3 patients with suspected PEX1-related ZSD and non-diagnostic whole exome sequencing and describe the use of multiple modalities to ascertain their diagnosis. We confirmed peroxisomal dysfunction in the patients by demonstrating abnormal peroxisome metabolite levels in blood and peroxisome import dysfunction in patient fibroblasts. RNA studies including RNA-seq and RT-PCR, followed by Sanger sequencing showed leaky splice variants including an intron 13 variant causing exon 14 skipping (Patient 1), an intron 22 variant causing intron 22 retention (Patient 2), and a synonymous splice-site variant causing exon 16 skipping (Patient 3). All three patients had very low amounts of canonical PEX1 transcripts on RNA-seq, as well as residual but reduced PEX1 protein levels on immunoblotting, which likely explains their non-severe ZSD phenotype. This study suggests that a multi-modality approach combining biochemical testing, functional assays in fibroblasts and molecular investigations including sequencing of non-coding regions and RNA analysis may aid in diagnosis of patients with suspected PBD-ZSD and inconclusive WES.
{"title":"Using multiple modalities to confirm diagnosis in patients with suspected peroxisome biogenesis disorders","authors":"Anthony C.T. Cheung ,&nbsp;Erminia Di Pietro ,&nbsp;Catherine Argyriou ,&nbsp;Eric Bareke ,&nbsp;Yasmin D'Souza ,&nbsp;Ratna Dua Puri ,&nbsp;P. Muhammed Shabeer ,&nbsp;Rebecca Ganetzky ,&nbsp;Amy Goldstein ,&nbsp;Adeline Vanderver ,&nbsp;Shruthi Mohan ,&nbsp;Jacek Majewski ,&nbsp;Christine Yergeau ,&nbsp;Nancy Braverman","doi":"10.1016/j.ymgme.2025.109080","DOIUrl":"10.1016/j.ymgme.2025.109080","url":null,"abstract":"<div><div>Zellweger spectrum disorder (ZSD) results from biallelic variants in any one of 13 <em>PEX</em> genes involved in peroxisome biogenesis and function. The majority of ZSD cases result from pathogenic variants in <em>PEX1</em>. Here, we present 3 patients with suspected <em>PEX1</em>-related ZSD and non-diagnostic whole exome sequencing and describe the use of multiple modalities to ascertain their diagnosis. We confirmed peroxisomal dysfunction in the patients by demonstrating abnormal peroxisome metabolite levels in blood and peroxisome import dysfunction in patient fibroblasts. RNA studies including RNA-seq and RT-PCR, followed by Sanger sequencing showed leaky splice variants including an intron 13 variant causing exon 14 skipping (Patient 1), an intron 22 variant causing intron 22 retention (Patient 2), and a synonymous splice-site variant causing exon 16 skipping (Patient 3). All three patients had very low amounts of canonical PEX1 transcripts on RNA-seq, as well as residual but reduced PEX1 protein levels on immunoblotting, which likely explains their non-severe ZSD phenotype. This study suggests that a multi-modality approach combining biochemical testing, functional assays in fibroblasts and molecular investigations including sequencing of non-coding regions and RNA analysis may aid in diagnosis of patients with suspected PBD-ZSD and inconclusive WES.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109080"},"PeriodicalIF":3.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143643540","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
Argentine program of home infusions with enzyme replacement therapy for lysosomal diseases: Results in safety, quality of life and adherence
IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-03-11 DOI: 10.1016/j.ymgme.2025.109076
Guillermo Drelichman , Juan M. Politei , Nicolás Fernandez Escobar , Barbara Soberón , Nora Basack , Norberto Guelbert , Nora Watman , Norberto Antongiovanni , Fernanda Cuello , Gerardo Mogni , María Larroude , Gabriel Aguilar , Paola Reichel , Alberto Dubrovsky , Gustavo Cabrera , Adriana Arizo , Marcela Corrales , Adriana Degano , Alejandro Faimboin , Analía Carvani , Fernando Perretta
With over 25 years of experience, enzyme replacement therapies have proven to be safe and effective for patients with Fabry, Gaucher, Pompe, Mucopolysaccharidosis I (MPS I) diseases. As with many chronic conditions, one of the keys to achieving therapeutic goals is to avoid interruptions in infusions to ensure proper adherence (AD). Treatment interruptions are associated with the recurrence of previously resolved clinical manifestations depending on the length of the interruption, and the reaccumulation of substrate at the cellular level. The Argentine home infusion program (HI) was established in 2012 in response to recognizing low treatment adherence. This is a retrospective review of the program's safety, quality of life, and treatment adherence after 11 years. A total of 147 treating physicians enrolled 378 patients from 22 Argentine provinces into the program. A total of 85,060 home infusions were performed during the study period. No patients experienced serious adverse events requiring hospitalization. Throughout the follow-up period, 21,600 infusions were suspended, with the most frequent cause being lack of supply from the payer. Adherence to enzyme replacement therapy showed an annual adherence rate of over 80 % across all pathologies. All patients (100 %) reported that the program had improved their quality of life. The Argentine home infusion program has demonstrated an improvement in adherence and quality of life, which is considered significant for enhancing long-term therapeutic outcomes.
{"title":"Argentine program of home infusions with enzyme replacement therapy for lysosomal diseases: Results in safety, quality of life and adherence","authors":"Guillermo Drelichman ,&nbsp;Juan M. Politei ,&nbsp;Nicolás Fernandez Escobar ,&nbsp;Barbara Soberón ,&nbsp;Nora Basack ,&nbsp;Norberto Guelbert ,&nbsp;Nora Watman ,&nbsp;Norberto Antongiovanni ,&nbsp;Fernanda Cuello ,&nbsp;Gerardo Mogni ,&nbsp;María Larroude ,&nbsp;Gabriel Aguilar ,&nbsp;Paola Reichel ,&nbsp;Alberto Dubrovsky ,&nbsp;Gustavo Cabrera ,&nbsp;Adriana Arizo ,&nbsp;Marcela Corrales ,&nbsp;Adriana Degano ,&nbsp;Alejandro Faimboin ,&nbsp;Analía Carvani ,&nbsp;Fernando Perretta","doi":"10.1016/j.ymgme.2025.109076","DOIUrl":"10.1016/j.ymgme.2025.109076","url":null,"abstract":"<div><div>With over 25 years of experience, enzyme replacement therapies have proven to be safe and effective for patients with Fabry, Gaucher, Pompe, Mucopolysaccharidosis I (MPS I) diseases. As with many chronic conditions, one of the keys to achieving therapeutic goals is to avoid interruptions in infusions to ensure proper adherence (AD). Treatment interruptions are associated with the recurrence of previously resolved clinical manifestations depending on the length of the interruption, and the reaccumulation of substrate at the cellular level. The Argentine home infusion program (HI) was established in 2012 in response to recognizing low treatment adherence. This is a retrospective review of the program's safety, quality of life, and treatment adherence after 11 years. A total of 147 treating physicians enrolled 378 patients from 22 Argentine provinces into the program. A total of 85,060 home infusions were performed during the study period. No patients experienced serious adverse events requiring hospitalization. Throughout the follow-up period, 21,600 infusions were suspended, with the most frequent cause being lack of supply from the payer. Adherence to enzyme replacement therapy showed an annual adherence rate of over 80 % across all pathologies. All patients (100 %) reported that the program had improved their quality of life. The Argentine home infusion program has demonstrated an improvement in adherence and quality of life, which is considered significant for enhancing long-term therapeutic outcomes.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109076"},"PeriodicalIF":3.7,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619598","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
Maternal health outcomes in ornithine transcarbamylase deficiency: A comparative analysis of pregnancies in symptomatic and asymptomatic heterozygotes
IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-03-10 DOI: 10.1016/j.ymgme.2025.109083
Margo Sheck Breilyn , Kara Simpson , Sara A. Elsbecker , John R. Barber , Members of the Urea Cycle Disorders Consortium (UCDC), Kia Bryan , Susan A. Berry

Introduction

Ornithine transcarbamylase deficiency (OTCD, MIM: 311250) is an X-linked disorder of ureagenesis caused by pathogenic variants in OTC (MIM: 300461). Due to varying X-inactivation patterns, female heterozygotes can range from asymptomatic to severe disease with recurrent hyperammonemia.
There is a paucity of data regarding the safety of pregnancy in symptomatic versus asymptomatic OTC heterozygotes. Existing case reports suggest a high risk of morbidity and mortality associated with pregnancy.

Materials and methods

This study investigated the maternal health outcomes from a large cohort of OTC heterozygote participants who were enrolled in a multicenter, observational, natural history study conducted by the Urea Cycle Disorders Consortium.

Results

We evaluated maternal morbidity and mortality from 109 pregnancies in 49 OTC heterozygotes and found that pregnancy was well-tolerated without metabolic decompensations in individuals with asymptomatic OTCD. Thirty-one participants (63.3 %) had a second pregnancy. Among individuals with symptomatic disease, hyperammonemia was observed in 5 of the 21 pregnancies. Three of these episodes were in a single individual across three different pregnancies. One individual required ICU admission. There was no maternal mortality in either group.

Conclusions

Our results indicate that pregnancy is well-tolerated in asymptomatic OTC heterozygotes, with no metabolic decompensations observed. Close monitoring with a metabolic center is strongly recommended for OTC heterozygotes in pregnancy, in particular for symptomatic individuals to mitigate the risk of metabolic decompensation.
{"title":"Maternal health outcomes in ornithine transcarbamylase deficiency: A comparative analysis of pregnancies in symptomatic and asymptomatic heterozygotes","authors":"Margo Sheck Breilyn ,&nbsp;Kara Simpson ,&nbsp;Sara A. Elsbecker ,&nbsp;John R. Barber ,&nbsp;Members of the Urea Cycle Disorders Consortium (UCDC),&nbsp;Kia Bryan ,&nbsp;Susan A. Berry","doi":"10.1016/j.ymgme.2025.109083","DOIUrl":"10.1016/j.ymgme.2025.109083","url":null,"abstract":"<div><h3>Introduction</h3><div>Ornithine transcarbamylase deficiency (OTCD, MIM: <span><span>311250</span><svg><path></path></svg></span>) is an X-linked disorder of ureagenesis caused by pathogenic variants in <em>OTC</em> (MIM: <span><span>300461</span><svg><path></path></svg></span>). Due to varying X-inactivation patterns, female heterozygotes can range from asymptomatic to severe disease with recurrent hyperammonemia.</div><div>There is a paucity of data regarding the safety of pregnancy in symptomatic versus asymptomatic OTC heterozygotes. Existing case reports suggest a high risk of morbidity and mortality associated with pregnancy.</div></div><div><h3>Materials and methods</h3><div>This study investigated the maternal health outcomes from a large cohort of OTC heterozygote participants who were enrolled in a multicenter, observational, natural history study conducted by the Urea Cycle Disorders Consortium.</div></div><div><h3>Results</h3><div>We evaluated maternal morbidity and mortality from 109 pregnancies in 49 OTC heterozygotes and found that pregnancy was well-tolerated without metabolic decompensations in individuals with asymptomatic OTCD. Thirty-one participants (63.3 %) had a second pregnancy. Among individuals with symptomatic disease, hyperammonemia was observed in 5 of the 21 pregnancies. Three of these episodes were in a single individual across three different pregnancies. One individual required ICU admission. There was no maternal mortality in either group.</div></div><div><h3>Conclusions</h3><div>Our results indicate that pregnancy is well-tolerated in asymptomatic OTC heterozygotes, with no metabolic decompensations observed. Close monitoring with a metabolic center is strongly recommended for OTC heterozygotes in pregnancy, in particular for symptomatic individuals to mitigate the risk of metabolic decompensation.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 4","pages":"Article 109083"},"PeriodicalIF":3.7,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143609884","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
Corrigendum to "Pompe disease: Unmet needs and emerging therapies" [Mol Genet Metab. 2024 Nov;143(3):108590].
IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-03-10 DOI: 10.1016/j.ymgme.2025.109078
Kelly A George, Allyson L Anding, Arjan van der Flier, Giulio S Tomassy, Kenneth I Berger, Tracy Y Zhang, S Pablo Sardi
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引用次数: 0
Challenges in Gaucher disease: Perspectives from an expert panel
IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-03-10 DOI: 10.1016/j.ymgme.2025.109074
Gregory A. Grabowski , Priya S. Kishnani , Roy N. Alcalay , S. Grace Prakalapakorn , Barry E. Rosenbloom , Dominick A. Tuason , Neal J. Weinreb
<div><div>This focused review concentrates on eight topics of high importance for Gaucher disease (GD) clinicians and researchers: 1) The consideration of GD as distinct types rather than a spectrum. A review of the literature clearly supports the view that there are distinct types of GD. Type 1 is characterized by the absence of primary neuronopathic involvement, while types 2 and 3 are characterized by progressive primary neuronopathic disease. 2) Neurologic and neuronopathic manifestations. A growing body of evidence indicates that the peripheral nervous system may be involved in GD type 1 and that there may also be signs and symptoms of central nervous system (CNS) disease in this group. However, GD type 1 is characterized by the absence of primary neuronopathic disease, whereas GD types 2 and 3 are characterized by progressive, albeit variable, primary neuronopathic disease. Abnormalities in saccadic eye movements have been suggested as being diagnostic for neuronopathic GD, but they may also occur in GD type 1 and in other inflammatory diseases. 3) The importance of whole <em>GBA1</em> sequencing. This approach is superior to exome sequencing because of potential effects of deep intronic variants on gene expression. It also has the capacity to detect variant alleles that might be missed with gene panels. 4) Monoclonal gammopathy of undetermined significance (MGUS). The risks of MGUS, multiple myeloma, and non-Hodgkin's lymphoma are elevated in patients with GD compared to the general population and strong evidence indicates that lyso-Gb1 stimulates the formation of monoclonal immunoglobulins (M-protein) in patients with GD and MGUS. 5) Pulmonary involvement in GD. Pulmonary complications can be identified through spirometry in up to 45 % of patients with GD type 1 and 55 % of those with GD type 3. Limited evidence exists that enzyme replacement therapy (ERT) reduces the severity of these complications in patients with GD type 1. 6) Gaucheromas. These may occur in patients with GD types 1 or 3, but there is little detailed information about their inception, mechanisms underlying growth, cellular organization, and biochemical activities, and no definitive guidance for their management. Gaucheromas behave like benign (i.e. non-metastasizing) neoplasms, and it may be reasonable to classify them as such. 7) Bone and joint involvement. Dual-energy X-ray absorptiometry scans alone are insufficient for monitoring all changes in bone that may occur in patients with GD. Quantitative magnetic resonance imaging (MRI) techniques using Dixon quantitative chemical shift imaging have provided results that correlate with GD severity scores, bone complications, and biomarkers for GD bone involvement. Thoracic kyphosis is a common complication of GD types 1 and 3, and there is very limited information regarding the effects of ERT or substrate synthesis inhibition therapy (SSIT) on this condition. 8) Treatment initiation, selection, combination, and switching.
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引用次数: 0
Beyond sialylation: Exploring the multifaceted role of GNE in GNE myopathy
IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-03-03 DOI: 10.1016/j.ymgme.2025.109075
Beatriz L. Pereira , Mariana Barbosa , Pedro Granjo , Hanns Lochmüller , Paula A. Videira
Defects in sialic acid metabolism disrupt the sialylation of glycoproteins and glycolipids, contributing to a spectrum of diseases, including GNE myopathy (GNEM). This rare disorder is caused by mutations in the GNE gene that encodes for a bifunctional enzyme required for sialic acid biosynthesis, resulting in progressive muscle atrophy and weakness. There is no approved treatment for GNEM, and the number of affected individuals is underestimated. Although hyposialylation is considered the hallmark of GNEM, evidence showed lack of consistent correlation with GNEM severity and unveiled additional roles of GNE that contribute to the onset and/or progression of GNEM. Recent findings indicate that these mechanisms extend beyond glycosylation, encompassing cytoskeletal dynamics, oxidative stress, and muscle regeneration pathways. Understanding how GNE mutations result in a cascade of cellular and molecular dysregulations is crucial for developing targeted therapies aimed at improving the quality of life of patients.
This review comprehensively examines GNEM's pathophysiology, clinical presentation, and therapeutic strategies, highlighting key findings on non-canonical GNE functions that account to GNEM clinical outcomes and emerging therapeutic targets. We propose future research directions to explore alternative target pathways that can ultimately support clinical development.
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引用次数: 0
Cover 2 / Ed. Board
IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2025-03-01 DOI: 10.1016/S1096-7192(25)00052-6
{"title":"Cover 2 / Ed. Board","authors":"","doi":"10.1016/S1096-7192(25)00052-6","DOIUrl":"10.1016/S1096-7192(25)00052-6","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 3","pages":"Article 109061"},"PeriodicalIF":3.7,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511147","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
期刊
Molecular genetics and metabolism
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