Pub Date : 2025-06-27DOI: 10.1016/j.ymgmr.2025.101238
M. Vela-Amieva , C. Fernández-Lainez , S. Guillén-López , L. López-Mejía , M.A. Alcántara-Ortigoza , A. González del Angel , L. Fernández-Hernández , M.E. Reyna-Fabián , B. Estandía-Ortega , I. Ibarra-González , S.W. Ryu , H. Lee , on behalf of Rare Diseases Mexican Effort Group (RaDiMEG)
Arginase deficiency (ARG1d) is an inborn error of metabolism caused by pathogenic variants in ARG1 gene, which causes a defective hydrolysis of arginine (Arg) to urea and ornithine. The molecular landscape of ARG1d in Mexico is poorly known. In this study, we present for the first time the clinical and genotypic overview of the largest cohort of ARG1d in Mexico. A retrospective analysis of the medical records of 24 ARG1d patients from a historical cohort of individuals with inborn errors of intermediary metabolism (1994–2024) from the National Institute of Pediatrics in Mexico City, was performed. Clinical, demographical, biochemical, anthropometric and molecular data were investigated in two moments, at diagnosis and at the last follow-up evaluation. It was found that only 7/24 patients were diagnosed by newborn screening (NBS). Additionally, we highlight the presence of the Portuguese NM_000045.4(ARG1):c.61C>T or p.(Arg21*) variant as the most frequent cause of ARG1d in Mexico, carried by 27.7 % of the patients. Our findings emphasize the debilitating and progressive nature of ARG1d, the prolonged diagnostic odyssey experienced by the patients (6.7 years), and the importance of training healthcare professionals to recognize the clinical features suggestive of the disease. We also underscore the critical need to advance early detection through expanded NBS in our country, as the early-diagnosed patients exhibited less severe outcomes and improved nutritional status compared to late-diagnosed ones. It was also noted that Mexican ARG1d patients have significant difficulties adhering to current nutritional treatment, and access to ammonium scavengers, thus other therapeutic options could be desirable.
{"title":"Arginase deficiency in Mexico: Insights from the experience of a metabolic reference center","authors":"M. Vela-Amieva , C. Fernández-Lainez , S. Guillén-López , L. López-Mejía , M.A. Alcántara-Ortigoza , A. González del Angel , L. Fernández-Hernández , M.E. Reyna-Fabián , B. Estandía-Ortega , I. Ibarra-González , S.W. Ryu , H. Lee , on behalf of Rare Diseases Mexican Effort Group (RaDiMEG)","doi":"10.1016/j.ymgmr.2025.101238","DOIUrl":"10.1016/j.ymgmr.2025.101238","url":null,"abstract":"<div><div>Arginase deficiency (ARG1d) is an inborn error of metabolism caused by pathogenic variants in <em>ARG1</em> gene, which causes a defective hydrolysis of arginine (Arg) to urea and ornithine. The molecular landscape of ARG1d in Mexico is poorly known. In this study, we present for the first time the clinical and genotypic overview of the largest cohort of ARG1d in Mexico. A retrospective analysis of the medical records of 24 ARG1d patients from a historical cohort of individuals with inborn errors of intermediary metabolism (1994–2024) from the National Institute of Pediatrics in Mexico City, was performed. Clinical, demographical, biochemical, anthropometric and molecular data were investigated in two moments, at diagnosis and at the last follow-up evaluation. It was found that only 7/24 patients were diagnosed by newborn screening (NBS). Additionally, we highlight the presence of the Portuguese NM_000045.4(ARG1):c.61C>T or p.(Arg21*) variant as the most frequent cause of ARG1d in Mexico, carried by 27.7 % of the patients. Our findings emphasize the debilitating and progressive nature of ARG1d, the prolonged diagnostic odyssey experienced by the patients (6.7 years), and the importance of training healthcare professionals to recognize the clinical features suggestive of the disease. We also underscore the critical need to advance early detection through expanded NBS in our country, as the early-diagnosed patients exhibited less severe outcomes and improved nutritional status compared to late-diagnosed ones. It was also noted that Mexican ARG1d patients have significant difficulties adhering to current nutritional treatment, and access to ammonium scavengers, thus other therapeutic options could be desirable.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"Article 101238"},"PeriodicalIF":1.8,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144492151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder resulted from mutations in the ABCD1 gene located at the Xq28 locus. This gene encodes a transporter protein responsible for importing very-long-chain fatty acids into peroxisomes. This research seeks to elucidate the clinical manifestations linked to various mutations in the ABCD gene among Iranian patients with X-ALD, considering the diverse severity of symptoms observed in this disease. Totally, six variants, including a novel variant (c.1781-47G > A) were identified in the ABCD1 gene in the patients. All but one variant were classified as pathogenic or likely pathogenic; the remaining variant, c.1781-47G > A, was identified as a variant of uncertain significance. This study broadens the spectrum of ABCD1 mutations among Iranian patients, providing applicable information for appropriate genetic counseling in the affected families.
x -连锁肾上腺脑白质营养不良（X-ALD）是一种由位于Xq28位点的ABCD1基因突变引起的遗传性疾病。该基因编码一种转运蛋白，负责将长链脂肪酸输入过氧化物酶体。考虑到在这种疾病中观察到的不同严重程度的症状，本研究旨在阐明伊朗X-ALD患者中与ABCD基因各种突变相关的临床表现。总共有六个变种，包括一个新的变种(c.1781-47G >；A)在患者的ABCD1基因中被鉴定。除了一种变异外，所有变异都被归类为致病性或可能致病性；剩下的型号c.1781-47G >；A，被认定为意义不确定的变体。这项研究拓宽了伊朗患者ABCD1突变的范围，为受影响家庭提供适当的遗传咨询提供了适用的信息。
{"title":"Overview of genetic mutations causing adrenoleukodystrophy: A case-series study","authors":"Mohadeseh Fathi , Sheyda Khalilian , Arezou Sayad , Parvaneh Karimzadeh , Farzad Ahmadabadi , Soudeh Ghafouri-Fard , Mohammad Miryounesi","doi":"10.1016/j.ymgmr.2025.101237","DOIUrl":"10.1016/j.ymgmr.2025.101237","url":null,"abstract":"<div><div>X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder resulted from mutations in the <em>ABCD1</em> gene located at the Xq28 locus. This gene encodes a transporter protein responsible for importing very-long-chain fatty acids into peroxisomes. This research seeks to elucidate the clinical manifestations linked to various mutations in the <em>ABCD</em> gene among Iranian patients with X-ALD, considering the diverse severity of symptoms observed in this disease. Totally, six variants, including a novel variant (c.1781-47G > A) were identified in the <em>ABCD1</em> gene in the patients. All but one variant were classified as pathogenic or likely pathogenic; the remaining variant, c.1781-47G > A, was identified as a variant of uncertain significance. This study broadens the spectrum of <em>ABCD1</em> mutations among Iranian patients, providing applicable information for appropriate genetic counseling in the affected families.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"Article 101237"},"PeriodicalIF":1.8,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144470215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01DOI: 10.1016/j.ymgmr.2025.101236
Jess G. Thoene
Untreated nephropathic cystinosis is a lethal autosomal recessive disease. The current specific therapy, cysteamine, ameliorates the renal function loss, but does not alter the renal Fanconi syndrome, short stature, muscle weakness, male infertility, and other concerns. The primary biochemical/physiological defect in cystinosis is failure to supply cysteine to mTOR via cystinosin. This leads mTOR to react in starvation mode, which stops cell differentiation, leading to proximal tubule loss, and ultimately renal failure. It also increases apoptosis and autophagocytosis rates, which may contribute to impaired growth. Many of the defects which occur in cystinosis are corrected by taurine in other conditions as described. Cystinosis patients have been shown to be severely deficient in plasma taurine. Although use of taurine is not yet reported in cystinosis in vitro or in vivo, given the safety of taurine, its deficiency in cystinosis, and its potency in correcting similar defects in other conditions, it appears reasonable to engage in a clinical trial of taurine in nephropathic cystinosis.
{"title":"Hypothesis: Taurine therapy of nephropathic cystinosis may correct the deficiencies of cysteamine therapy","authors":"Jess G. Thoene","doi":"10.1016/j.ymgmr.2025.101236","DOIUrl":"10.1016/j.ymgmr.2025.101236","url":null,"abstract":"<div><div>Untreated nephropathic cystinosis is a lethal autosomal recessive disease. The current specific therapy, cysteamine, ameliorates the renal function loss, but does not alter the renal Fanconi syndrome, short stature, muscle weakness, male infertility, and other concerns. The primary biochemical/physiological defect in cystinosis is failure to supply cysteine to mTOR via cystinosin. This leads mTOR to react in starvation mode, which stops cell differentiation, leading to proximal tubule loss, and ultimately renal failure. It also increases apoptosis and autophagocytosis rates, which may contribute to impaired growth. Many of the defects which occur in cystinosis are corrected by taurine in other conditions as described. Cystinosis patients have been shown to be severely deficient in plasma taurine. Although use of taurine is not yet reported in cystinosis <em>in vitro</em> or <em>in vivo</em>, given the safety of taurine, its deficiency in cystinosis, and its potency in correcting similar defects in other conditions, it appears reasonable to engage in a clinical trial of taurine in nephropathic cystinosis.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101236"},"PeriodicalIF":1.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144253361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The challenges encountered by women living with Fabry disease in Japan are not well understood. This study aimed to elucidate the experiences of women with Fabry disease and their support networks from both female and male perspectives. A 22-question survey was conducted among patients with Fabry disease and their caregivers (≥18 years) in Japan between August and October 2023. Sixty-two recipients completed the questionnaire (11.5 % response rate); 47 (75.8 %) were female and the mean age was 52.4 years. Overall, 51 respondents (82.3 %) identified as patients, 2 (3.2 %) as caregivers, 6 (9.7 %) as both a patient and caregiver, and 3 (4.8 %) as “other”. In total, 43 respondents (69.4 %) were women with Fabry disease. Among life events surveyed, Fabry disease had the greatest impact for women during family planning. The most commonly reported concerns for women were inheritance of Fabry disease and impact on children, the main reasons for which were prejudice, stigma, and sense of guilt associated with inheritance. In all, 28.1 % of respondents felt family and colleagues understood women's challenges with Fabry disease, while 37.9 % believed their primary care physicians and 48.3 % felt their specialist physicians understood these challenges; 26.3 % thought women received tailored care, and 75.9 % felt the condition affects mental health. Women with Fabry disease in Japan face substantial emotional burdens and lack support from their community and physicians. Healthcare professionals can play a pivotal role by offering genetic counseling and developing support programs to alleviate mental burdens and provide education about the disease and family planning implications.
{"title":"Exploring the burdens of women living with Fabry disease in Japan: A patient survey of 62 respondents","authors":"Masahisa Kobayashi , Ikuko Kaku , Nanae Goto , Mio Tsuchiya , Norio Sakai","doi":"10.1016/j.ymgmr.2025.101231","DOIUrl":"10.1016/j.ymgmr.2025.101231","url":null,"abstract":"<div><div>The challenges encountered by women living with Fabry disease in Japan are not well understood. This study aimed to elucidate the experiences of women with Fabry disease and their support networks from both female and male perspectives. A 22-question survey was conducted among patients with Fabry disease and their caregivers (≥18 years) in Japan between August and October 2023. Sixty-two recipients completed the questionnaire (11.5 % response rate); 47 (75.8 %) were female and the mean age was 52.4 years. Overall, 51 respondents (82.3 %) identified as patients, 2 (3.2 %) as caregivers, 6 (9.7 %) as both a patient and caregiver, and 3 (4.8 %) as “other”. In total, 43 respondents (69.4 %) were women with Fabry disease. Among life events surveyed, Fabry disease had the greatest impact for women during family planning. The most commonly reported concerns for women were inheritance of Fabry disease and impact on children, the main reasons for which were prejudice, stigma, and sense of guilt associated with inheritance. In all, 28.1 % of respondents felt family and colleagues understood women's challenges with Fabry disease, while 37.9 % believed their primary care physicians and 48.3 % felt their specialist physicians understood these challenges; 26.3 % thought women received tailored care, and 75.9 % felt the condition affects mental health. Women with Fabry disease in Japan face substantial emotional burdens and lack support from their community and physicians. Healthcare professionals can play a pivotal role by offering genetic counseling and developing support programs to alleviate mental burdens and provide education about the disease and family planning implications.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101231"},"PeriodicalIF":1.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144178013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-06-01DOI: 10.1016/j.ymgmr.2025.101235
Mai Thi Thanh Do , Dung Chi Vu , Mai Thi Chi Tran , Thao Phuong Bui , Ngoc Thi Bich Can , Khanh Ngoc Nguyen
Background
Familial hypercholesterolemia (FH) results in elevated LDL cholesterol, contributing to atherosclerosis and early-onset cardiovascular disease. Mutations in the low-density lipoprotein receptor gene are the most common cause of familial hypercholesterolemia. Information regarding hypercholesterolemia in low- and middle-income nations is inadequate. This research aimed to characterise the phenotype and genotype of Vietnamese children diagnosed with familial hypercholesterolemia.
Methods
This study included twenty-one children diagnosed with familial hypercholesterolemia from 15 unrelated families. Data regarding physical characteristics, biochemical testing, cardiac ultrasound, coronary angiography, and dual-source computed tomography were gathered at diagnosis and follow-up. Next-generation and Sanger sequencing were performed to identify disease-causing variants in twenty-one index cases.
Results
We found eighteen heterozygous and two homozygous/one compound heterozygous FH cases. Fourteen distinct variants were identified, with the most prevalent being c.664 T > C and c.681C>G, and exon 15 deletion. Furthermore, we identified the c.161A>C variant, which remains unreported in the literature. The median age at diagnosis was 6.7 years (0.5–17.5) and 8.3 years (6.3–13.3) in heterozygous and homozygous/compound heterozygous groups, respectively. 100 % homozygous/compound heterozygous cases and 16.7 % heterozygous cases presented xanthomas. The median plasma levels of LDL in heterozygous and homozygous/compound heterozygous groups were 6.6 mmol/l (3.8–12) and 10.8 mmol/l (10.7–11.7), respectively.
Conclusions
FH can appear early in childhood, and xanthomas primarily manifest in homozygous FH patients. LDLR gene variants in Vietnamese FH children were diverse, with 14 variants in 21 cases.
{"title":"Family hypercholesterolemia due to LDLR gene in Vietnamese children: characteristics of phenotype and genotype","authors":"Mai Thi Thanh Do , Dung Chi Vu , Mai Thi Chi Tran , Thao Phuong Bui , Ngoc Thi Bich Can , Khanh Ngoc Nguyen","doi":"10.1016/j.ymgmr.2025.101235","DOIUrl":"10.1016/j.ymgmr.2025.101235","url":null,"abstract":"<div><h3>Background</h3><div>Familial hypercholesterolemia (FH) results in elevated LDL cholesterol, contributing to atherosclerosis and early-onset cardiovascular disease. Mutations in the low-density lipoprotein receptor gene are the most common cause of familial hypercholesterolemia. Information regarding hypercholesterolemia in low- and middle-income nations is inadequate. This research aimed to characterise the phenotype and genotype of Vietnamese children diagnosed with familial hypercholesterolemia.</div></div><div><h3>Methods</h3><div>This study included twenty-one children diagnosed with familial hypercholesterolemia from 15 unrelated families. Data regarding physical characteristics, biochemical testing, cardiac ultrasound, coronary angiography, and dual-source computed tomography were gathered at diagnosis and follow-up. Next-generation and Sanger sequencing were performed to identify disease-causing variants in twenty-one index cases.</div></div><div><h3>Results</h3><div>We found eighteen heterozygous and two homozygous/one compound heterozygous FH cases. Fourteen distinct variants were identified, with the most prevalent being c.664 T > C and c.681C>G, and exon 15 deletion. Furthermore, we identified the c.161A>C variant, which remains unreported in the literature. The median age at diagnosis was 6.7 years (0.5–17.5) and 8.3 years (6.3–13.3) in heterozygous and homozygous/compound heterozygous groups, respectively. 100 % homozygous/compound heterozygous cases and 16.7 % heterozygous cases presented xanthomas. The median plasma levels of LDL in heterozygous and homozygous/compound heterozygous groups were 6.6 mmol/l (3.8–12) and 10.8 mmol/l (10.7–11.7), respectively.</div></div><div><h3>Conclusions</h3><div>FH can appear early in childhood, and xanthomas primarily manifest in homozygous FH patients. <em>LDLR</em> gene variants in Vietnamese FH children were diverse, with 14 variants in 21 cases.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101235"},"PeriodicalIF":1.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144196303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-28DOI: 10.1016/j.ymgmr.2025.101233
Eugen Mengel , Marc C. Patterson , Rosalia M. Da Riol , Mireia Del Toro , Federica Deodato , Matthias Gautschi , Stephanie Grunewald , Sabine Weller Grønborg , Paul Harmatz , Julia B. Hennermann , Bénédicte Héron , Esther M. Maier , Agathe Roubertie , Saikat Santra , Anna Tylki-Szymanska , Lisa LaGorio , Elizabeth Berry-Kravis , Forbes D. Porter , Beth Solomon , Louise Himmelstrup , Christine í Dali
Background
In the 12-month, randomized, double-blind, placebo-controlled Phase 2/3 NPC-002 study (NCT02612129), arimoclomol significantly reduced annual disease progression versus placebo, measured by the 5-domain NPC Clinical Severity Scale (5DNPCCSS). Arimoclomol has been approved in the US for treatment of Niemann-Pick disease type C (NPC) in combination with miglustat. This paper introduces the rescored 4-domain NPCCSS (R4DNPCCSS) as a post-hoc primary endpoint in NPC-002, discusses its validation, and presents the results of the post-hoc primary analysis.
Methods
To more accurately assess changes in disease course over a 12-month time period in a heterogeneous group of patients, the Cognition domain was removed from the 5DNPCCSS and the Swallow domain was rescored to reflect linearity in disease progression. Rescoring of the Swallow domain was based on input from clinical NPC and swallow experts from a qualitative interview-based study (N = 12), resulting in the R4DNPCCSS. To supplement prior validation analyses, data supporting the overall validity and reliability of the R4DNPCCSS was gathered through additional analyses of construct and convergent validity. The NPC-002 prespecified primary efficacy endpoint analysis based on the 5DNPCCSS score change from baseline to 12 months was repeated with R4DNPCCSS.
Results
Construct validity analysis demonstrated high agreement between the R4DNPCCSS domain scores and the Clinical Global Impression Scale of Severity (CGI-S) and NPC Clinical Database (NPC-cdb) scores. Convergent validity was confirmed by strong correlations between the R4DNPCCSS domains and corresponding items on the Scale for Assessment and Rating of Ataxia (SARA), 9-hole peg test (9-HPT), and Video Fluoroscopic Swallowing Study (VFSS) performance tests. The NPC-002 post-hoc primary analysis showed a mean standard error (SE) change in R4DNPCCSS score of 0.35 (0.40) with arimoclomol (N = 34) versus 2.05 (0.54) with placebo (N = 16), and a treatment effect in favor of arimoclomol over placebo of −1.70 (p = 0.0155). In the miglustat subgroup analysis, mean (SE) change in R4DNPCCSS score was −0.23 (1.02) with arimoclomol (N = 22) versus 1.92 (3.37) with placebo (N = 12), representing a treatment effect of −2.21 (p = 0.0077).
Conclusion
The R4DNPCCSS is a valid and reliable measure of disease progression demonstrating consistent outcomes with the prespecified 5DNPCCSS endpoint. Arimoclomol significantly slowed disease progression through 12 months as measured by the R4DNPCCSS versus placebo.
{"title":"Efficacy results from a 12-month double-blind randomized trial of arimoclomol for treatment of Niemann-Pick disease type C (NPC): Presenting a rescored 4-domain NPC Clinical Severity Scale","authors":"Eugen Mengel , Marc C. Patterson , Rosalia M. Da Riol , Mireia Del Toro , Federica Deodato , Matthias Gautschi , Stephanie Grunewald , Sabine Weller Grønborg , Paul Harmatz , Julia B. Hennermann , Bénédicte Héron , Esther M. Maier , Agathe Roubertie , Saikat Santra , Anna Tylki-Szymanska , Lisa LaGorio , Elizabeth Berry-Kravis , Forbes D. Porter , Beth Solomon , Louise Himmelstrup , Christine í Dali","doi":"10.1016/j.ymgmr.2025.101233","DOIUrl":"10.1016/j.ymgmr.2025.101233","url":null,"abstract":"<div><h3>Background</h3><div>In the 12-month, randomized, double-blind, placebo-controlled Phase 2/3 NPC-002 study (<span><span>NCT02612129</span><svg><path></path></svg></span>), arimoclomol significantly reduced annual disease progression versus placebo, measured by the 5-domain NPC Clinical Severity Scale (5DNPCCSS). Arimoclomol has been approved in the US for treatment of Niemann-Pick disease type C (NPC) in combination with miglustat. This paper introduces the rescored 4-domain NPCCSS (R4DNPCCSS) as a <em>post-hoc</em> primary endpoint in NPC-002, discusses its validation, and presents the results of the <em>post-hoc</em> primary analysis.</div></div><div><h3>Methods</h3><div>To more accurately assess changes in disease course over a 12-month time period in a heterogeneous group of patients, the Cognition domain was removed from the 5DNPCCSS and the Swallow domain was rescored to reflect linearity in disease progression. Rescoring of the Swallow domain was based on input from clinical NPC and swallow experts from a qualitative interview-based study (<em>N</em> = 12), resulting in the R4DNPCCSS. To supplement prior validation analyses, data supporting the overall validity and reliability of the R4DNPCCSS was gathered through additional analyses of construct and convergent validity. The NPC-002 prespecified primary efficacy endpoint analysis based on the 5DNPCCSS score change from baseline to 12 months was repeated with R4DNPCCSS.</div></div><div><h3>Results</h3><div>Construct validity analysis demonstrated high agreement between the R4DNPCCSS domain scores and the Clinical Global Impression Scale of Severity (CGI-S) and NPC Clinical Database (NPC-cdb) scores. Convergent validity was confirmed by strong correlations between the R4DNPCCSS domains and corresponding items on the Scale for Assessment and Rating of Ataxia (SARA), 9-hole peg test (9-HPT), and Video Fluoroscopic Swallowing Study (VFSS) performance tests. The NPC-002 <em>post-hoc</em> primary analysis showed a mean standard error (SE) change in R4DNPCCSS score of 0.35 (0.40) with arimoclomol (<em>N</em> = 34) versus 2.05 (0.54) with placebo (<em>N</em> = 16), and a treatment effect in favor of arimoclomol over placebo of −1.70 (<em>p</em> = 0.0155). In the miglustat subgroup analysis, mean (SE) change in R4DNPCCSS score was −0.23 (1.02) with arimoclomol (<em>N</em> = 22) versus 1.92 (3.37) with placebo (N = 12), representing a treatment effect of −2.21 (<em>p</em> = 0.0077).</div></div><div><h3>Conclusion</h3><div>The R4DNPCCSS is a valid and reliable measure of disease progression demonstrating consistent outcomes with the prespecified 5DNPCCSS endpoint. Arimoclomol significantly slowed disease progression through 12 months as measured by the R4DNPCCSS versus placebo.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101233"},"PeriodicalIF":1.8,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144154850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mitochondrial myopathies are progressive muscle disorders caused by impaired mitochondrial oxidative phosphorylation, leading to reduced adenosine triphosphate production. Skeletal muscles have a high energy demand and are often the first to be affected. In addition to muscular symptoms (muscle weakness, effort intolerance, fatigue), the disease can affect the central and peripheral nervous systems, as well as the heart, liver, kidneys and endocrine system (diabetes). Molecular genetic diagnostic is currently based on leukocyte DNA obtained from blood samples, considered less invasive than muscle biopsy. We report four patients from three families with mitochondrial myopathy associated with ptosis, sensorineural hearing loss, epilepsy, tubulointerstitial nephropathy and cardiomyopathy. Genetic studies identified MT-TF variants (m.586G > A, m.601G > A, m.616 T > C) with highly variable heteroplasmy levels in the same patient from one tissue to another (5 % to 70 % mutant load in circulating blood leukocytes and in muscle respectively).
We emphasize the importance of performing mtDNA analysis on muscle DNA, even in patients with negative blood leukocytes mtDNA sequencing, if there is strong clinical suspicion of mitochondrial myopathy.
{"title":"Tissue-specific mitochondrial DNA, MT-TF, pathogenic variants in mitochondrial myopathies","authors":"Sylvia Rose , Aurélien Trimouille , Didier Lacombe , Edoardo Malfatti , Zahra Assouline , Julie Steffann , Isabelle Desguerre , Arnold Munnich , Agnès Rötig , Giulia Barcia","doi":"10.1016/j.ymgmr.2025.101230","DOIUrl":"10.1016/j.ymgmr.2025.101230","url":null,"abstract":"<div><div>Mitochondrial myopathies are progressive muscle disorders caused by impaired mitochondrial oxidative phosphorylation, leading to reduced adenosine triphosphate production. Skeletal muscles have a high energy demand and are often the first to be affected. In addition to muscular symptoms (muscle weakness, effort intolerance, fatigue), the disease can affect the central and peripheral nervous systems, as well as the heart, liver, kidneys and endocrine system (diabetes). Molecular genetic diagnostic is currently based on leukocyte DNA obtained from blood samples, considered less invasive than muscle biopsy. We report four patients from three families with mitochondrial myopathy associated with ptosis, sensorineural hearing loss, epilepsy, tubulointerstitial nephropathy and cardiomyopathy. Genetic studies identified <em>MT-TF</em> variants (m.586G > A, m.601G > A, m.616 T > C) with highly variable heteroplasmy levels in the same patient from one tissue to another (5 % to 70 % mutant load in circulating blood leukocytes and in muscle respectively).</div><div>We emphasize the importance of performing mtDNA analysis on muscle DNA, even in patients with negative blood leukocytes mtDNA sequencing, if there is strong clinical suspicion of mitochondrial myopathy.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101230"},"PeriodicalIF":1.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144137879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-26DOI: 10.1016/j.ymgmr.2025.101232
Ariane De Preter , Anne Rochtus , Peter Witters , Daisy Rymen
Primary adrenal insufficiency (PAI) in children is rare. It is mainly due to monogenetic disorders, with congenital adrenal hyperplasia being the most common cause in the first year of life. Although several inborn errors of metabolism (IEM) have been associated with PAI, increased awareness of PAI in IEM among both metabolic specialists and endocrinologists may improve patient outcomes. Here, we present a case series of patients with PAI and an IEM. Through a literature review, we discuss the various IEM that have been associated with adrenal insufficiency and explore the pathophysiological mechanisms linking these IEM to PAI. Based on the available data, pitfalls in the diagnosis of PAI in IEM are discussed and recommendations for early diagnosis are suggested. In addition, a non-exhaustive list of susceptible IEM was elaborated to encourage screening for PAI in IEM and vice versa.
{"title":"Adrenal insufficiency in inborn errors of metabolism and vice versa: Case reports and review of the literature","authors":"Ariane De Preter , Anne Rochtus , Peter Witters , Daisy Rymen","doi":"10.1016/j.ymgmr.2025.101232","DOIUrl":"10.1016/j.ymgmr.2025.101232","url":null,"abstract":"<div><div>Primary adrenal insufficiency (PAI) in children is rare. It is mainly due to monogenetic disorders, with congenital adrenal hyperplasia being the most common cause in the first year of life. Although several inborn errors of metabolism (IEM) have been associated with PAI, increased awareness of PAI in IEM among both metabolic specialists and endocrinologists may improve patient outcomes. Here, we present a case series of patients with PAI and an IEM. Through a literature review, we discuss the various IEM that have been associated with adrenal insufficiency and explore the pathophysiological mechanisms linking these IEM to PAI. Based on the available data, pitfalls in the diagnosis of PAI in IEM are discussed and recommendations for early diagnosis are suggested. In addition, a non-exhaustive list of susceptible IEM was elaborated to encourage screening for PAI in IEM and vice versa.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101232"},"PeriodicalIF":1.8,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-05-23DOI: 10.1016/j.ymgmr.2025.101234
Dolat Singh Shekhawat , Amit Mittal , Kuldeep Singh
{"title":"Cost analysis of newborn screening for spinal muscular atrophy using digital PCR vs. MLPA","authors":"Dolat Singh Shekhawat , Amit Mittal , Kuldeep Singh","doi":"10.1016/j.ymgmr.2025.101234","DOIUrl":"10.1016/j.ymgmr.2025.101234","url":null,"abstract":"","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101234"},"PeriodicalIF":1.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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