Pub Date : 2025-11-03DOI: 10.1016/j.ymgme.2025.109280
David Watkins , Caitlin Zacharias , Kyana Arbabian-Urquilla , Krithika Ragupathi , Brian M. Gilfix , Daniel Jimenez , Natascia Anastasio , Jean-Baptiste Rivière , David S. Rosenblatt
Purpose
The cblG inborn error of vitamin B12 metabolism is associated with pathogenic variants in the MTR gene, which encodes methionine synthase. Approximately 50 patients with the disorder have been reported, and 54 potentially causal MTR variants published.
Methods
We performed next generation sequencing and copy number variant analysis of MTR on genomic DNA from 29 cblG patients, including 7 patients that had been previously sequenced with incomplete results. All patients had been diagnosed using somatic cell complementation analysis.
Results
We identified two potential causal variants in each of the patients analyzed, although parental phasing was not done. 39 different variants were identified, including 24 not previously described in the published literature. The most common identified causal variant was c.3518C > T, p.P1173L (8 alleles). The previously identified deep intronic variants c.340-166 A > T and c.609 + 1088G > A were also seen frequently (6 alleles each). Among the newly identified variants, the most common were c.2020C > T p.Arg674Cys (3 alleles) and c.1325C > A, p.Ala442Glu (2 alleles).
Conclusion
Identification of pathogenic or likely pathogenic variants was enhanced by knowledge of complementation status which has become less frequent as somatic cell testing becomes less readily available.
目的cblG先天性维生素B12代谢错误与编码蛋氨酸合成酶的MTR基因致病性变异有关。大约有50例患者报道了这种疾病，并发表了54例潜在的因果MTR变异。方法对29例cblG患者的基因组DNA进行下一代测序和MTR拷贝数变异分析，其中7例患者先前测序结果不完整。所有患者均采用体细胞互补分析进行诊断。结果我们在分析的每个患者中确定了两个潜在的因果变异，尽管没有进行亲代分期。发现了39种不同的变异，包括24种以前未在发表文献中描述的变异。最常见的致病变异为c.3518C >； T, p.P1173L（8个等位基因）。先前发现的深层内含子变异c.340-166 A >； T和c.609 + 1088G >； A也经常出现（每个等位基因6个）。在新发现的变异中，最常见的是c.2020C > T . p.a arg674cys（3个等位基因）和c.1325C >； A, p.a ala442glu（2个等位基因）。结论随着体细胞检测技术的发展，对互补状态的了解减少了对致病性或可能致病性变异的识别。
{"title":"Identification of variants of the MTR gene in patients with the cblG inborn error of cobalamin metabolism diagnosed by somatic cell complementation analysis","authors":"David Watkins , Caitlin Zacharias , Kyana Arbabian-Urquilla , Krithika Ragupathi , Brian M. Gilfix , Daniel Jimenez , Natascia Anastasio , Jean-Baptiste Rivière , David S. Rosenblatt","doi":"10.1016/j.ymgme.2025.109280","DOIUrl":"10.1016/j.ymgme.2025.109280","url":null,"abstract":"<div><h3>Purpose</h3><div>The <em>cblG</em> inborn error of vitamin B<sub>12</sub> metabolism is associated with pathogenic variants in the <em>MTR</em> gene, which encodes methionine synthase. Approximately 50 patients with the disorder have been reported, and 54 potentially causal <em>MTR</em> variants published.</div></div><div><h3>Methods</h3><div>We performed next generation sequencing and copy number variant analysis of <em>MTR</em> on genomic DNA from 29 <em>cblG</em> patients, including 7 patients that had been previously sequenced with incomplete results. All patients had been diagnosed using somatic cell complementation analysis.</div></div><div><h3>Results</h3><div>We identified two potential causal variants in each of the patients analyzed, although parental phasing was not done. 39 different variants were identified, including 24 not previously described in the published literature. The most common identified causal variant was c.3518C > T, p.P1173L (8 alleles). The previously identified deep intronic variants c.340-166 A > T and c.609 + 1088G > A were also seen frequently (6 alleles each). Among the newly identified variants, the most common were c.2020C > T p.Arg674Cys (3 alleles) and c.1325C > A, p.Ala442Glu (2 alleles).</div></div><div><h3>Conclusion</h3><div>Identification of pathogenic or likely pathogenic variants was enhanced by knowledge of complementation status which has become less frequent as somatic cell testing becomes less readily available.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 4","pages":"Article 109280"},"PeriodicalIF":3.5,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145468216","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}
Pub Date : 2025-11-03DOI: 10.1016/j.ymgme.2025.109283
Michelle M. Nguyen , Sevil Mahfoozi , Devon Bonner , Daphne O. Martschenko , Alisha Giri , Charis Tang , Undiagnosed Diseases Network, Jonathan A. Bernstein , Matthew T. Wheeler , Meghan C. Halley
Background
Well-recognized challenges in rare disease diagnosis include limited awareness of rare diseases among healthcare providers and barriers to accessing genetic testing. Less well understood are the ways in which communication between parents of undiagnosed children and providers may impact access to diagnosis, as well as quality of care broadly. We sought to characterize key dynamics of communication between parents of undiagnosed children and healthcare providers during the diagnostic odyssey.
Methods
Parents of undiagnosed children undergoing genomic sequencing were recruited from clinical and research settings and Facebook groups. Participants completed up to three sequential, in-depth interviews. Data were analyzed inductively to identify key themes.
Results
Parents (n = 36) identified three key dimensions of their experiences communicating with providers during the diagnostic odyssey, including examples of both effective and challenging communication related to: 1) providers' availability and responsiveness; 2) trust and validation of their concerns by providers; and 3) communication across multiple providers. Parents also described employing divergent strategies, such as increased persistence and advocacy, or minimized communication and resignation, in response to challenges.
Conclusions
Our study identified ways in which parent-provider communication can facilitate or hinder access to diagnosis and care for children with undiagnosed diseases. However, communication challenges were not universal, suggesting opportunities for intervention. Additional research is needed to identify interventions to improve parent-provider interactions during the diagnostic odyssey and to systematically evaluate the impact on time to diagnosis, access to care and patient health outcomes.
{"title":"“Nobody listened to us for years”: Parents' experiences of provider communication in the diagnostic odyssey","authors":"Michelle M. Nguyen , Sevil Mahfoozi , Devon Bonner , Daphne O. Martschenko , Alisha Giri , Charis Tang , Undiagnosed Diseases Network, Jonathan A. Bernstein , Matthew T. Wheeler , Meghan C. Halley","doi":"10.1016/j.ymgme.2025.109283","DOIUrl":"10.1016/j.ymgme.2025.109283","url":null,"abstract":"<div><h3>Background</h3><div>Well-recognized challenges in rare disease diagnosis include limited awareness of rare diseases among healthcare providers and barriers to accessing genetic testing. Less well understood are the ways in which communication between parents of undiagnosed children and providers may impact access to diagnosis, as well as quality of care broadly. We sought to characterize key dynamics of communication between parents of undiagnosed children and healthcare providers during the diagnostic odyssey.</div></div><div><h3>Methods</h3><div>Parents of undiagnosed children undergoing genomic sequencing were recruited from clinical and research settings and Facebook groups. Participants completed up to three sequential, in-depth interviews. Data were analyzed inductively to identify key themes.</div></div><div><h3>Results</h3><div>Parents (<em>n</em> = 36) identified three key dimensions of their experiences communicating with providers during the diagnostic odyssey, including examples of both effective and challenging communication related to: 1) providers' availability and responsiveness; 2) trust and validation of their concerns by providers; and 3) communication across multiple providers. Parents also described employing divergent strategies, such as increased persistence and advocacy, or minimized communication and resignation, in response to challenges.</div></div><div><h3>Conclusions</h3><div>Our study identified ways in which parent-provider communication can facilitate or hinder access to diagnosis and care for children with undiagnosed diseases. However, communication challenges were not universal, suggesting opportunities for intervention. Additional research is needed to identify interventions to improve parent-provider interactions during the diagnostic odyssey and to systematically evaluate the impact on time to diagnosis, access to care and patient health outcomes.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 4","pages":"Article 109283"},"PeriodicalIF":3.5,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513527","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}
Carriers of the mitochondrial variant m.3243A>G have a high risk of diabetes mellitus and frequently report gastrointestinal symptoms, suggesting a dual endocrine and exocrine pancreas dysfunction. Whether changes in pancreatic morphology, abdominal or ectopic fat distribution contribute to these conditions, remains unknown.
Methods
Twelve m.3243A>G carriers with diabetes, 11 carriers without diabetes, and 23 healthy controls underwent abdominal magnetic resonance imaging (MRI). T1 relaxation time and magnetic resonance elastography (MRE) stiffness estimated pancreatic fibrosis. Pancreas volume was assessed by MRI and combined with faecal elastase measurements to evaluate exocrine pancreatic function. The ectopic fat content of muscle and the pancreas was estimated using proton density fat fraction, alongside abdominal fat measurements of cross-sectional areas (CSA) of visceral and subcutaneous adipose tissue. The homeostasis model assessment 2 (HOMA2) was used to estimate insulin resistance (HOMA2-IR).
Results
Compared to healthy controls, carriers with diabetes had an increased median [IQR] T1 relaxation time (909 ms [868–1085] vs. 823 ms [785–852], p < 0.001) and MRE stiffness (1.32 kPa [1.24–1.43] vs. 1.23 kPa [1.12–1.28], p = 0.03). There was no difference in pancreas volume or evidence of exocrine pancreatic dysfunction evaluated by faecal elastase. Visceral adipose tissue CSA median [IQR] was increased in m.3243A>G carriers compared to controls (61.0 cm2 [26.4–100.9] vs. 27.9 cm2 [17.2–65.0], p = 0.03) and correlated positively with HOMA2-IR (rs = 0.7, p < 0.001).
Conclusion
Increased T1 relaxation time and MRE stiffness indicate mild pancreatic fibrosis in m.3243A>G carriers with diabetes, without further evidence of exocrine insufficiency. Visceral fat was increased in m.3243A>G carriers and associated with insulin resistance, implying metabolic dysregulation.
线粒体变异m.3243A>；G的携带者患糖尿病的风险高，且经常报告胃肠道症状，提示胰腺内分泌和外分泌双重功能障碍。胰腺形态、腹部或异位脂肪分布的改变是否会导致这些疾病，目前尚不清楚。方法对12例糖尿病m.3243A>；G携带者、11例非糖尿病携带者和23例健康对照者进行腹部磁共振成像（MRI）检查。T1松弛时间和磁共振弹性成像（MRE）刚度估计胰腺纤维化。通过MRI评估胰腺体积，并结合粪便弹性酶测量来评估外分泌胰腺功能。肌肉和胰腺的异位脂肪含量是用质子密度脂肪分数来估计的，同时腹部脂肪测量内脏和皮下脂肪组织的横截面积（CSA）。使用稳态模型评估2 （HOMA2）来评估胰岛素抵抗（HOMA2- ir）。结果与健康对照组相比，糖尿病患者T1舒张时间中位数（909 ms[868-1085]比823 ms [785-852]， p < 0.001）和MRE僵硬度（1.32 kPa[1.24-1.43]比1.23 kPa [1.12-1.28], p = 0.03）增加。通过粪便弹性蛋白酶评估胰腺体积或外分泌胰腺功能障碍的证据没有差异。与对照组相比，m.3243A>；G携带者的内脏脂肪组织CSA中位数[IQR]升高（61.0 cm2[26.4-100.9]对27.9 cm2 [17.2-65.0], p = 0.03），并与HOMA2-IR呈正相关（rs = 0.7, p < 0.001）。结论T1松弛时间和MRE僵硬度增加提示m.3243A>；G型糖尿病患者有轻度胰腺纤维化，无外分泌功能不全的进一步证据。m.3243A>；G携带者内脏脂肪增加，并与胰岛素抵抗相关，暗示代谢失调。
{"title":"Mild pancreatic fibrosis with preserved exocrine function and increased visceral adipose tissue in m.3243A>G carriers: A magnetic resonance imaging study","authors":"Simone Rask Nielsen , Mimoza Gjela , Malene Pontoppidan Stoico , Asbjørn Mohr Drewes , Søren Schou Olesen , Kurt Højlund , Inge Søkilde Pedersen , Christina Brock , Jens Brøndum Frøkjær , Anja Lisbeth Frederiksen","doi":"10.1016/j.ymgme.2025.109282","DOIUrl":"10.1016/j.ymgme.2025.109282","url":null,"abstract":"<div><h3>Background</h3><div>Carriers of the mitochondrial variant m.3243A>G have a high risk of diabetes mellitus and frequently report gastrointestinal symptoms, suggesting a dual endocrine and exocrine pancreas dysfunction. Whether changes in pancreatic morphology, abdominal or ectopic fat distribution contribute to these conditions, remains unknown.</div></div><div><h3>Methods</h3><div>Twelve m.3243A>G carriers with diabetes, 11 carriers without diabetes, and 23 healthy controls underwent abdominal magnetic resonance imaging (MRI). T1 relaxation time and magnetic resonance elastography (MRE) stiffness estimated pancreatic fibrosis. Pancreas volume was assessed by MRI and combined with faecal elastase measurements to evaluate exocrine pancreatic function. The ectopic fat content of muscle and the pancreas was estimated using proton density fat fraction, alongside abdominal fat measurements of cross-sectional areas (CSA) of visceral and subcutaneous adipose tissue. The homeostasis model assessment 2 (HOMA2) was used to estimate insulin resistance (HOMA2-IR).</div></div><div><h3>Results</h3><div>Compared to healthy controls, carriers with diabetes had an increased median [IQR] T1 relaxation time (909 ms [868–1085] vs. 823 ms [785–852], <em>p</em> < 0.001) and MRE stiffness (1.32 kPa [1.24–1.43] vs. 1.23 kPa [1.12–1.28], <em>p</em> = 0.03). There was no difference in pancreas volume or evidence of exocrine pancreatic dysfunction evaluated by faecal elastase. Visceral adipose tissue CSA median [IQR] was increased in m.3243A>G carriers compared to controls (61.0 cm<sup>2</sup> [26.4–100.9] vs. 27.9 cm<sup>2</sup> [17.2–65.0], <em>p</em> = 0.03) and correlated positively with HOMA2-IR (r<sub>s</sub> = 0.7, <em>p</em> < 0.001).</div></div><div><h3>Conclusion</h3><div>Increased T1 relaxation time and MRE stiffness indicate mild pancreatic fibrosis in m.3243A>G carriers with diabetes, without further evidence of exocrine insufficiency. Visceral fat was increased in m.3243A>G carriers and associated with insulin resistance, implying metabolic dysregulation.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 4","pages":"Article 109282"},"PeriodicalIF":3.5,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145468316","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}
Pub Date : 2025-11-02DOI: 10.1016/j.ymgme.2025.109284
Joseph Muenzer , Jaco Botha , Hernan Amartino , Roberto Giugliani , Paul Harmatz , Christoph Kampmann , Bianca Link , Shuan-Pei Lin , David Molter , Julian Raiman , Maurizio Scarpa , Anna Tylki-Szymańska , Siddharth Jain , David A.H. Whiteman , Barbara K. Burton
Background
Mucopolysaccharidosis II (MPS II) is a rare, progressive, X-linked lysosomal storage disease. Enzyme replacement therapy (ERT) with intravenous (IV) idursulfase has been approved for the treatment of patients with MPS II since 2005. The Hunter Outcome Survey (HOS; NCT03292887) was established as a condition of approval to monitor the long-term safety and effectiveness of idursulfase. Here, we report the final results from HOS.
Methods
HOS was a multicenter, long-term, observational registry that enrolled patients with a biochemically and/or genetically confirmed diagnosis of MPS II who were untreated or treated with idursulfase and/or bone marrow transplant. Patients were enrolled prospectively (alive at enrollment) and retrospectively (deceased at enrollment). For prospectively enrolled patients, it was requested that data from routine examinations were recorded after each follow-up visit and/or a minimum of every 6 months. The safety population (SP) included patients who received at least one dose of idursulfase and were alive at HOS entry. The treatment outcomes population (TOP) included patients who received at least one dose of idursulfase and were alive at HOS entry, excluding patients who received a bone marrow transplant, patients for whom an informed consent form could not be generated by the center, and patients with a missing date of birth. Safety and effectiveness endpoints were analyzed with descriptive statistics.
Results
In total, 1332 patients were enrolled in HOS. For patients in the SP (N = 1014), the median (10th percentile, 90th percentile) age at initiation of ERT with idursulfase was 5.7 (1.6, 18.1) years, ranging from 0.0 to 65.5 years. In the TOP (N = 989), a consistent and sustained decline in urinary glycosaminoglycan levels, trends of sustained improvements in walking capacity and left ventricular mass index, and reductions in liver and spleen size were observed. Treated patients also demonstrated a median increase in survival time of approximately 10 years and a 57.9 % lower risk of death compared with an unmatched cohort of untreated patients. In the SP, 691 patients (68.1 %) experienced at least one adverse event and 269 (26.5 %) experienced at least one infusion-related reaction (IRR); most were mild or moderate in severity. There was no relationship observed between anti-drug antibody status and IRR rates.
Conclusion
Data from HOS, collected for over 18 years, represent the largest dataset of patients with MPS II to date. The effectiveness and safety profile of idursulfase support its use for the long-term treatment of patients with MPS II.
{"title":"Clinical characteristics and real-world outcomes in patients with mucopolysaccharidosis II over 18 years: final report of the Hunter Outcome Survey","authors":"Joseph Muenzer , Jaco Botha , Hernan Amartino , Roberto Giugliani , Paul Harmatz , Christoph Kampmann , Bianca Link , Shuan-Pei Lin , David Molter , Julian Raiman , Maurizio Scarpa , Anna Tylki-Szymańska , Siddharth Jain , David A.H. Whiteman , Barbara K. Burton","doi":"10.1016/j.ymgme.2025.109284","DOIUrl":"10.1016/j.ymgme.2025.109284","url":null,"abstract":"<div><h3>Background</h3><div>Mucopolysaccharidosis II (MPS II) is a rare, progressive, X-linked lysosomal storage disease. Enzyme replacement therapy (ERT) with intravenous (IV) idursulfase has been approved for the treatment of patients with MPS II since 2005. The Hunter Outcome Survey (HOS; <span><span>NCT03292887</span><svg><path></path></svg></span>) was established as a condition of approval to monitor the long-term safety and effectiveness of idursulfase. Here, we report the final results from HOS.</div></div><div><h3>Methods</h3><div>HOS was a multicenter, long-term, observational registry that enrolled patients with a biochemically and/or genetically confirmed diagnosis of MPS II who were untreated or treated with idursulfase and/or bone marrow transplant. Patients were enrolled prospectively (alive at enrollment) and retrospectively (deceased at enrollment). For prospectively enrolled patients, it was requested that data from routine examinations were recorded after each follow-up visit and/or a minimum of every 6 months. The safety population (SP) included patients who received at least one dose of idursulfase and were alive at HOS entry. The treatment outcomes population (TOP) included patients who received at least one dose of idursulfase and were alive at HOS entry, excluding patients who received a bone marrow transplant, patients for whom an informed consent form could not be generated by the center, and patients with a missing date of birth. Safety and effectiveness endpoints were analyzed with descriptive statistics.</div></div><div><h3>Results</h3><div>In total, 1332 patients were enrolled in HOS. For patients in the SP (<em>N</em> = 1014), the median (10th percentile, 90th percentile) age at initiation of ERT with idursulfase was 5.7 (1.6, 18.1) years, ranging from 0.0 to 65.5 years. In the TOP (<em>N</em> = 989), a consistent and sustained decline in urinary glycosaminoglycan levels, trends of sustained improvements in walking capacity and left ventricular mass index, and reductions in liver and spleen size were observed. Treated patients also demonstrated a median increase in survival time of approximately 10 years and a 57.9 % lower risk of death compared with an unmatched cohort of untreated patients. In the SP, 691 patients (68.1 %) experienced at least one adverse event and 269 (26.5 %) experienced at least one infusion-related reaction (IRR); most were mild or moderate in severity. There was no relationship observed between anti-drug antibody status and IRR rates.</div></div><div><h3>Conclusion</h3><div>Data from HOS, collected for over 18 years, represent the largest dataset of patients with MPS II to date. The effectiveness and safety profile of idursulfase support its use for the long-term treatment of patients with MPS II.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 4","pages":"Article 109284"},"PeriodicalIF":3.5,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145513552","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}
In Gaucher disease (GD), clinical management is complicated by heterogeneity and the lack of standardized guidelines for treatment initiation. As patients are being identified pre-symptomatically or as mildly affected through carrier and newborn screening programs, timing of treatment is an increasingly important issue. This study evaluated the utility of plasma lyso-GL1 as an objective biomarker to inform treatment decisions. Retrospective data were analyzed from 240 GD patients with lyso-GL1 levels measured primarily at a single laboratory between June 2018 and September 2023. The study population included both adult (n = 194, 80.8 %) and pediatric (n = 46, 19.2 %) patients predominantly diagnosed with type 1 GD (n = 234, 97.5 %) and self-identified as Jewish (82.1 %). Among 25 patients who initiated GD-specific treatment during the study period with available pre-treatment lyso-GL1 data, the median age at treatment initiation was 33 years. In this group, the median baseline lyso-GL1 was 91.6 ng/mL, which declined to 19.5 ng/mL following treatment with a median follow-up of 2.9 years. In contrast, untreated patients had a median baseline lyso-GL1 of 14.2 ng/mL, which increased to 17.0 ng/mL over a similar follow-up period. Logistic regression and receiver operating characteristic analysis identified a lyso-GL1 threshold of 78.9 ng/mL that effectively discriminated treatment status in GD1 patients, with an area under the curve of 0.865, sensitivity of 73 %, and specificity of 96 %. The predictive performance of this identified threshold was comparable to that reported in a previous study, underscoring the reproducibility and potential utility of lyso-GL1 as a reliable and objective biomarker to guide treatment initiation in Gaucher disease.
{"title":"Correlation of Plasma Lyso-GL1 Levels with Clinical Phenotype and Treatment Decisions in Patients with Gaucher Disease","authors":"Chloe Cheung , Luca Fierro , Catherine McDonough , Chanan Stauffer , Rachel Kaplan , Louise Bier , Chunli Yu , Rachel Evard , Jaya Ganesh , Manisha Balwani","doi":"10.1016/j.ymgme.2025.109286","DOIUrl":"10.1016/j.ymgme.2025.109286","url":null,"abstract":"<div><div>In Gaucher disease (GD), clinical management is complicated by heterogeneity and the lack of standardized guidelines for treatment initiation. As patients are being identified pre-symptomatically or as mildly affected through carrier and newborn screening programs, timing of treatment is an increasingly important issue. This study evaluated the utility of plasma lyso-GL1 as an objective biomarker to inform treatment decisions. Retrospective data were analyzed from 240 GD patients with lyso-GL1 levels measured primarily at a single laboratory between June 2018 and September 2023. The study population included both adult (<em>n</em> = 194, 80.8 %) and pediatric (<em>n</em> = 46, 19.2 %) patients predominantly diagnosed with type 1 GD (<em>n</em> = 234, 97.5 %) and self-identified as Jewish (82.1 %). Among 25 patients who initiated GD-specific treatment during the study period with available pre-treatment lyso-GL1 data, the median age at treatment initiation was 33 years. In this group, the median baseline lyso-GL1 was 91.6 ng/mL, which declined to 19.5 ng/mL following treatment with a median follow-up of 2.9 years. In contrast, untreated patients had a median baseline lyso-GL1 of 14.2 ng/mL, which increased to 17.0 ng/mL over a similar follow-up period. Logistic regression and receiver operating characteristic analysis identified a lyso-GL1 threshold of 78.9 ng/mL that effectively discriminated treatment status in GD1 patients, with an area under the curve of 0.865, sensitivity of 73 %, and specificity of 96 %. The predictive performance of this identified threshold was comparable to that reported in a previous study, underscoring the reproducibility and potential utility of lyso-GL1 as a reliable and objective biomarker to guide treatment initiation in Gaucher disease.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 4","pages":"Article 109286"},"PeriodicalIF":3.5,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145468267","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}
Pub Date : 2025-11-01DOI: 10.1016/j.ymgme.2025.109281
Yuxuan Gao, Weili Wang, Jiapeng Leng
{"title":"Commentary on the article “Progressive activation of the astrocyte A1 phenotype underlies microglia-astroglia crosstalk and contributes to neuroinflammation in neuronopathic MPS”","authors":"Yuxuan Gao, Weili Wang, Jiapeng Leng","doi":"10.1016/j.ymgme.2025.109281","DOIUrl":"10.1016/j.ymgme.2025.109281","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 4","pages":"Article 109281"},"PeriodicalIF":3.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145459235","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}
Pub Date : 2025-11-01DOI: 10.1016/j.ymgme.2025.109266
Liene Thys , Diane Beysen , Katrien Janssens , Anna C. Jansen , Naig Gueguen , Morgane LeMao , Fanny Fontaine , Stéphane Allouche , Guy Lenaers , Marije Meuwissen
Background
Biallelic variants in RTN4IP1 (OPA10) are associated with a wide phenotypic spectrum including optic atrophy with or without ataxia, impaired intellectual development and seizures (OMIM 616732). Brain imaging ranges from normal to white matter changes and cerebral atrophy. Earlier literature has reported a combined complex I and IV deficiency in RTN4IP1 cases.
Results
We report on three siblings, compound heterozygous for novel RTN4IP1 variants who presented with a movement disorder with pronounced dyskinesia along with developmental delay, optic atrophy and ataxia. Furthermore, atypical brain MRI findings with symmetrical bilateral substantia nigra abnormalities were observed in two of them. Blue native polyacrylamide gel electrophoresis performed on fibroblasts of two patients revealed a defect in the complex I assembly process.
Conclusion
Thus, we expand the clinical spectrum of RTN4IP1-associated disease with movement disorder, substantia nigra abnormalities and complex I assembly defects.
{"title":"Accumulation of complex I assembly intermediates in a novel presentation of RTN4IP1-related disorder with developmental delay, ataxia and dyskinesia","authors":"Liene Thys , Diane Beysen , Katrien Janssens , Anna C. Jansen , Naig Gueguen , Morgane LeMao , Fanny Fontaine , Stéphane Allouche , Guy Lenaers , Marije Meuwissen","doi":"10.1016/j.ymgme.2025.109266","DOIUrl":"10.1016/j.ymgme.2025.109266","url":null,"abstract":"<div><h3>Background</h3><div>Biallelic variants in <em>RTN4IP1</em> (<em>OPA10</em>) are associated with a wide phenotypic spectrum including optic atrophy with or without ataxia, impaired intellectual development and seizures (OMIM <span><span>616732</span><svg><path></path></svg></span>). Brain imaging ranges from normal to white matter changes and cerebral atrophy. Earlier literature has reported a combined complex I and IV deficiency in <em>RTN4IP1</em> cases.</div></div><div><h3>Results</h3><div>We report on three siblings, compound heterozygous for novel <em>RTN4IP1</em> variants who presented with a movement disorder with pronounced dyskinesia along with developmental delay, optic atrophy and ataxia. Furthermore, atypical brain MRI findings with symmetrical bilateral substantia nigra abnormalities were observed in two of them. Blue native polyacrylamide gel electrophoresis performed on fibroblasts of two patients revealed a defect in the complex I assembly process.</div></div><div><h3>Conclusion</h3><div>Thus, we expand the clinical spectrum of <em>RTN4IP1</em>-associated disease with movement disorder, <em>substantia nigra</em> abnormalities and complex I assembly defects.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109266"},"PeriodicalIF":3.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145401333","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}
Pub Date : 2025-11-01DOI: 10.1016/j.ymgme.2025.109252
Andrew C. Edmondson , Tomas Honzik , Christina Lam , Katrin Ounap , Peter McWilliams , Eva Morava
{"title":"Corrigendum to “Incidence and prevalence of phosphomannomutase 2-congenital disorder of glycosylation: Past, present, and future [Molecular Genetics and Metabolism 146 (2025) 109188]”","authors":"Andrew C. Edmondson , Tomas Honzik , Christina Lam , Katrin Ounap , Peter McWilliams , Eva Morava","doi":"10.1016/j.ymgme.2025.109252","DOIUrl":"10.1016/j.ymgme.2025.109252","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 3","pages":"Article 109252"},"PeriodicalIF":3.5,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145302068","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}
Pub Date : 2025-10-30DOI: 10.1016/j.ymgme.2025.109268
Bibiche den Hollander , Marieke Rothuizen-Lindenschot , Hoang Lan Le , Jennifer R. Ramautar , Annelieke R. Müller , Lisa Geertjens , Frédéric M. Vaz , Agnies M. van Eeghen , Martina C. Cornel , Bart A.W. Jacobs , Hilgo Bruining , Peter M. van de Ven , Marion M. Brands , Clara D. van Karnebeek
Background
GRIN2B-neurodevelopmental disorder (GRIN2B-NDD) is a rare genetic disorder caused by pathogenic variants in GRIN2B, leading to impaired N-methyl d-aspartate receptor (NMDAR) function. l-serine, a precursor to d-serine that modulates NMDAR activity, has shown therapeutic potential for GRIN2B loss-of-function (LoF) variants.
Methods
The efficacy of oral l-serine supplementation in 4 children with GRIN2B LoF variants were evaluated in the first double-blind, randomized, placebo-controlled, one-year n-of-1 trials. The trial consisted of 2 cycles of 6 months.
Results
The Perceive, Recall, Plan, and Perform Assessment (PRPP-A) showed a significant improvement in Performance Mastery at 1.5 months (p = 0.0373), while 11 of 14 other PRPP-A measures showed mean differences that were numerically in the same direction toward a positive l-serine effect (not significant). Secondary outcomes varied across patients, for those with statistical group analysis, no significant difference were observed. Individual improvements were noted in information processing/adaptive function (n = 3/4), quality of life (n = 3/4), sleep (n = 1/2), irritability (n = 2/4), and language (n = 1/3), based on objective assessments and anecdotal parent reports.
Conclusion
These pioneering n-of-1 trials provide insights into l-serine's potential for GRIN2B-NDD, with improvements in two of four patients, though no clear distinguishing responder-characteristics were identified. Future trials should focus on refining patient selection, the use of multiple baseline designs, establishing a core outcome set and pooling treatment data to better understand patient-specific responses.
{"title":"Potential benefits of l-serine in children with GRIN2B loss-of-function variants: Randomized n-of-1 trials","authors":"Bibiche den Hollander , Marieke Rothuizen-Lindenschot , Hoang Lan Le , Jennifer R. Ramautar , Annelieke R. Müller , Lisa Geertjens , Frédéric M. Vaz , Agnies M. van Eeghen , Martina C. Cornel , Bart A.W. Jacobs , Hilgo Bruining , Peter M. van de Ven , Marion M. Brands , Clara D. van Karnebeek","doi":"10.1016/j.ymgme.2025.109268","DOIUrl":"10.1016/j.ymgme.2025.109268","url":null,"abstract":"<div><h3>Background</h3><div>GRIN2B-neurodevelopmental disorder (GRIN2B-NDD) is a rare genetic disorder caused by pathogenic variants in <em>GRIN2B</em>, leading to impaired <em>N</em>-methyl <span>d</span>-aspartate receptor (NMDAR) function. <span>l</span>-serine, a precursor to <span>d</span>-serine that modulates NMDAR activity, has shown therapeutic potential for <em>GRIN2B</em> loss-of-function (LoF) variants.</div></div><div><h3>Methods</h3><div>The efficacy of oral <span>l</span>-serine supplementation in 4 children with <em>GRIN2B</em> LoF variants were evaluated in the first double-blind, randomized, placebo-controlled, one-year n-of-1 trials. The trial consisted of 2 cycles of 6 months.</div></div><div><h3>Results</h3><div>The Perceive, Recall, Plan, and Perform Assessment (PRPP-A) showed a significant improvement in Performance Mastery at 1.5 months (<em>p</em> = 0.0373), while 11 of 14 other PRPP-A measures showed mean differences that were numerically in the same direction toward a positive <span>l</span>-serine effect (not significant). Secondary outcomes varied across patients, for those with statistical group analysis, no significant difference were observed. Individual improvements were noted in information processing/adaptive function (<em>n</em> = 3/4), quality of life (<em>n</em> = 3/4), sleep (<em>n</em> = 1/2), irritability (<em>n</em> = 2/4), and language (<em>n</em> = 1/3), based on objective assessments and anecdotal parent reports.</div></div><div><h3>Conclusion</h3><div>These pioneering n-of-1 trials provide insights into <span>l</span>-serine's potential for GRIN2B-NDD, with improvements in two of four patients, though no clear distinguishing responder-characteristics were identified. Future trials should focus on refining patient selection, the use of multiple baseline designs, establishing a core outcome set and pooling treatment data to better understand patient-specific responses.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"146 4","pages":"Article 109268"},"PeriodicalIF":3.5,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564724","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}
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