Pub Date : 2025-08-07eCollection Date: 2025-09-01DOI: 10.1016/j.ymgmr.2025.101244
Jariya Upadia, Grace Noh, Kea Crivelly, Jennifer Smith, Hans C Andersson
Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder caused by a deficiency of the branched-chain α-ketoacid dehydrogenase (BCKAD) complex. It is classified into four subtypes: classic, intermediate, intermittent, and thiamine-responsive. We report a case of a female infant who presented with global developmental delay at 8 months of age. Plasma amino acid analysis revealed markedly elevated levels of leucine (1863 μmol/L), isoleucine (790 μmol/L), valine (1011 μmol/L), and alloisoleucine (427 μmol/L). The patient demonstrated marked improvement in biochemical markers, increased tolerance of dietary leucine intake, and developmental progress following thiamine supplementation. This case highlights a novel thiamine-responsive MSUD genotype and emphasizes the importance of recognizing this treatable subtype, the therapeutic potential of high-dose thiamine, and the possibility of false-negative results in newborn screening.
{"title":"Thiamine-responsive maple syrup urine disease missed by newborn screen: A case report.","authors":"Jariya Upadia, Grace Noh, Kea Crivelly, Jennifer Smith, Hans C Andersson","doi":"10.1016/j.ymgmr.2025.101244","DOIUrl":"10.1016/j.ymgmr.2025.101244","url":null,"abstract":"<p><p>Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder caused by a deficiency of the branched-chain α-ketoacid dehydrogenase (BCKAD) complex. It is classified into four subtypes: classic, intermediate, intermittent, and thiamine-responsive. We report a case of a female infant who presented with global developmental delay at 8 months of age. Plasma amino acid analysis revealed markedly elevated levels of leucine (1863 μmol/L), isoleucine (790 μmol/L), valine (1011 μmol/L), and alloisoleucine (427 μmol/L). The patient demonstrated marked improvement in biochemical markers, increased tolerance of dietary leucine intake, and developmental progress following thiamine supplementation. This case highlights a novel thiamine-responsive MSUD genotype and emphasizes the importance of recognizing this treatable subtype, the therapeutic potential of high-dose thiamine, and the possibility of false-negative results in newborn screening.</p>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"101244"},"PeriodicalIF":1.9,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12351175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, resulting in deficient or dysfunctional α-galactosidase A (AGAL) activity. Newborn screening (NBS) enables early detection and management; however, ascertaining the pathogenicity of unknown GLA variants remains a diagnostic challenge. This study aimed to evaluate the clinical significance of GLA gene variants detected through NBS in Japan, utilizing biochemical, genetic, and structural analyses. A total of 22 individuals, including newborns and their relatives carrying GLA gene variants, were analyzed. Plasma AGAL activity, plasma globotriaosylsphingosine (Lyso-Gb3), and urinary globotriaosylceramide levels were measured. In silico predictions, structural modeling, and variant classification databases were employed to assess pathogenicity. Significant reductions in AGAL activity and elevated Lyso-Gb3 levels were observed in variants, such as p.R112H and p.K391E, suggesting a high likelihood of being pathogenic variants. Variants like p.W209R, p.I242T, p.M267T, and p.R356Q demonstrated mild biochemical abnormalities, indicating limited pathogenic potential or non-pathogenicity. Variants, such as p.E66Q and c.-10C > T, showed no significant biochemical effects, indicating that they are benign. This study underscores the diverse pathogenicity of GLA gene variants identified through NBS, emphasizing the need for integrated diagnostic strategies, including biomarker analysis, structural assessments, and long-term clinical follow-up. These findings contribute to improving genotype-phenotype correlations and optimizing diagnostic precision for FD.
{"title":"Evaluation of <i>GLA</i> variants detected in newborn screening for Fabry disease using biomarker analysis.","authors":"Takaaki Sawada, Jun Kido, Takahiro Tsukimura, Keishin Sugawara, Tomoko Shiga, Seiji Saito, Tadayasu Togawa, Takahito Inoue, Yoriko Watanabe, Junpei Hamada, Hitoshi Sakuraba, Kimitoshi Nakamura","doi":"10.1016/j.ymgmr.2025.101245","DOIUrl":"10.1016/j.ymgmr.2025.101245","url":null,"abstract":"<p><p>Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the <i>GLA</i> gene, resulting in deficient or dysfunctional α-galactosidase A (AGAL) activity. Newborn screening (NBS) enables early detection and management; however, ascertaining the pathogenicity of unknown <i>GLA</i> variants remains a diagnostic challenge. This study aimed to evaluate the clinical significance of <i>GLA</i> gene variants detected through NBS in Japan, utilizing biochemical, genetic, and structural analyses. A total of 22 individuals, including newborns and their relatives carrying <i>GLA</i> gene variants, were analyzed. Plasma AGAL activity, plasma globotriaosylsphingosine (Lyso-Gb3), and urinary globotriaosylceramide levels were measured. <i>In silico</i> predictions, structural modeling, and variant classification databases were employed to assess pathogenicity. Significant reductions in AGAL activity and elevated Lyso-Gb3 levels were observed in variants, such as p.R112H and p.K391E, suggesting a high likelihood of being pathogenic variants. Variants like p.W209R, p.I242T, p.M267T, and p.R356Q demonstrated mild biochemical abnormalities, indicating limited pathogenic potential or non-pathogenicity. Variants, such as p.E66Q and c.-10C > T, showed no significant biochemical effects, indicating that they are benign. This study underscores the diverse pathogenicity of <i>GLA</i> gene variants identified through NBS, emphasizing the need for integrated diagnostic strategies, including biomarker analysis, structural assessments, and long-term clinical follow-up. These findings contribute to improving genotype-phenotype correlations and optimizing diagnostic precision for FD.</p>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"101245"},"PeriodicalIF":1.9,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12351176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-18DOI: 10.1016/j.ymgmr.2025.101242
Montaha Almudhry , Chitra Prasad , Keng Yow Tay , C. Anthony Rupar , Harold Atkins , Asuri N. Prasad
Objectives
To compare delayed-onset Krabbe disease (KD) and outcomes between two siblings in relation to allogeneic hematopoietic stem cell transplantation (HSCT).
Methods
We provide a descriptive report on two siblings with late-onset KD and their clinical course before and after HSCT.
Results
The index case presented with neurological symptoms that were presumptively diagnosed with multiple sclerosis (MS). Despite treatment with immunotherapy, the patient continued to decline progressively, prompting reassessment in the neurometabolic clinic 17 years after symptom onset. Symmetrical white matter changes in the pyramidal tract and optic radiation on MRI, absence of GALC enzyme activity in the blood, and identification of a pathogenic and likely pathogenic GALC variants confirmed the diagnosis of late-onset KD. After the proband's diagnosis, late-onset KD was also confirmed in his two siblings. In contrast to the index case, the younger sibling underwent HSCT with milder symptoms, stabilizing neurocognitive status, and imaging findings. Despite advanced disease, the proband's condition has stabilized following HSCT.
Discussion
Late-onset KD is clinically heterogeneous in presentation. Recognizing its progressive course, variable clinical features, positive family history (if present), and characteristic imaging can enable timely recognition. Earlier intervention with HSCT may modify the outcome.
{"title":"Outcome of two siblings with late-onset Krabbe disease following allogeneic hematopoietic stem cell transplantation: And review of literature","authors":"Montaha Almudhry , Chitra Prasad , Keng Yow Tay , C. Anthony Rupar , Harold Atkins , Asuri N. Prasad","doi":"10.1016/j.ymgmr.2025.101242","DOIUrl":"10.1016/j.ymgmr.2025.101242","url":null,"abstract":"<div><h3>Objectives</h3><div>To compare delayed-onset Krabbe disease (KD) and outcomes between two siblings in relation to allogeneic hematopoietic stem cell transplantation (HSCT).</div></div><div><h3>Methods</h3><div>We provide a descriptive report on two siblings with late-onset KD and their clinical course before and after HSCT.</div></div><div><h3>Results</h3><div>The index case presented with neurological symptoms that were presumptively diagnosed with multiple sclerosis (MS). Despite treatment with immunotherapy, the patient continued to decline progressively, prompting reassessment in the neurometabolic clinic 17 years after symptom onset. Symmetrical white matter changes in the pyramidal tract and optic radiation on MRI, absence of GALC enzyme activity in the blood, and identification of a pathogenic and likely pathogenic <em>GALC</em> variants confirmed the diagnosis of late-onset KD. After the proband's diagnosis, late-onset KD was also confirmed in his two siblings. In contrast to the index case, the younger sibling underwent HSCT with milder symptoms, stabilizing neurocognitive status, and imaging findings. Despite advanced disease, the proband's condition has stabilized following HSCT.</div></div><div><h3>Discussion</h3><div>Late-onset KD is clinically heterogeneous in presentation. Recognizing its progressive course, variable clinical features, positive family history (if present), and characteristic imaging can enable timely recognition. Earlier intervention with HSCT may modify the outcome.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"Article 101242"},"PeriodicalIF":1.8,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657236","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 : 2025-07-16DOI: 10.1016/j.ymgmr.2025.101243
Gabija Kaciulyte , Goknur Yorulmaz , Reena Sharma , Simon A. Jones , Robert Wynn , Heather Church , Karen Tylee , Muzaffer Bilgin , Ana Jovanovic , Peter Woolfson , Karolina M. Stepien
Mucopolysaccharidoses are a heterogeneous group of rare lysosomal storage disorders (LSDs) caused by genetic mutations resulting in the deficiency of lysosomal enzymes responsible for the degradation of glycosaminoglycans (GAGs). The potential association of hematological abnormalities and clinical manifestations in MPS disorder highlights the importance of exploring the role of regular iron studies and hematological tests in at risk MPS patients as undiagnosed anemia has been shown to worsen clinical outcomes. In this study, therefore, we aimed to describe the hematological abnormalities and iron studies in adult patients with MPS disorders in the context of their therapies. Ninety-seven patients with MPS types I, II, III, IV and VI were included in the study (46 % females). The overall prevalence of iron deficiency anemia is 38 % in adult MPS cohort and affects 63 % of MPS III and 50 % of MPS I patients. It is more common in females with MPS I and IVA than males, post cardiac valve surgery and in patients with gastrointestinal dysfunction. There was high variability in Hb, mean corpuscular volume, serum iron and transferrin saturation among all the MPS subgroups, with results being higher in the HSCT and ERT group as compared to treatment naïve patients. The urine GAGs/creatine ratio negatively correlated with several critical parameters, including iron saturation (−0.07), serum iron (−0.06), Hb (−0.16), and hematocrit (−0.08). It was more pronounced among MPS III patients. Pancytopenia in treatment naive MPS III is associated with 7 to 20 fold increase of urine GAGs excretion. It is important to take into consideration hematological and iron study abnormalities in the management of MPS patients, as special approaches may be required for both intestinal health and anemia treatment.
{"title":"Iron metabolism and hematological abnormalities in adult patients affected with mucopolysaccharidoses","authors":"Gabija Kaciulyte , Goknur Yorulmaz , Reena Sharma , Simon A. Jones , Robert Wynn , Heather Church , Karen Tylee , Muzaffer Bilgin , Ana Jovanovic , Peter Woolfson , Karolina M. Stepien","doi":"10.1016/j.ymgmr.2025.101243","DOIUrl":"10.1016/j.ymgmr.2025.101243","url":null,"abstract":"<div><div>Mucopolysaccharidoses are a heterogeneous group of rare lysosomal storage disorders (LSDs) caused by genetic mutations resulting in the deficiency of lysosomal enzymes responsible for the degradation of glycosaminoglycans (GAGs). The potential association of hematological abnormalities and clinical manifestations in MPS disorder highlights the importance of exploring the role of regular iron studies and hematological tests in at risk MPS patients as undiagnosed anemia has been shown to worsen clinical outcomes. In this study, therefore, we aimed to describe the hematological abnormalities and iron studies in adult patients with MPS disorders in the context of their therapies. Ninety-seven patients with MPS types I, II, III, IV and VI were included in the study (46 % females). The overall prevalence of iron deficiency anemia is 38 % in adult MPS cohort and affects 63 % of MPS III and 50 % of MPS I patients. It is more common in females with MPS I and IVA than males, post cardiac valve surgery and in patients with gastrointestinal dysfunction. There was high variability in Hb, mean corpuscular volume, serum iron and transferrin saturation among all the MPS subgroups, with results being higher in the HSCT and ERT group as compared to treatment naïve patients. The urine GAGs/creatine ratio negatively correlated with several critical parameters, including iron saturation (−0.07), serum iron (−0.06), Hb (−0.16), and hematocrit (−0.08). It was more pronounced among MPS III patients. Pancytopenia in treatment naive MPS III is associated with 7 to 20 fold increase of urine GAGs excretion. It is important to take into consideration hematological and iron study abnormalities in the management of MPS patients, as special approaches may be required for both intestinal health and anemia treatment.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"Article 101243"},"PeriodicalIF":1.8,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144633977","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 : 2025-07-04DOI: 10.1016/j.ymgmr.2025.101241
Henry Skocy , Amber McFerren , Daniel Cairns , H. Mark Kenney , Eran Tallis , Amit S. Dhamoon , Ellie Garbade , Samuel J. Mackenzie
TANGO2 Deficiency Disorder (TDD) is an autosomal recessive condition, most commonly diagnosed in childhood. Clinical features may include episodic movement disorders, seizures, cognitive impairment, hypothyroidism, and metabolic crises marked by rhabdomyolysis and life-threatening cardiac symptoms. A small number of adults, thought to largely represent the milder end of the phenotypic spectrum, have received a diagnosis of TDD in their 30's or 40's, though no genotype-phenotype correlations have been established to date. In this case report, we present a 61-year-old man with mild intellectual disability and recurrent muscle weakness who was diagnosed with TDD during an inpatient hospitalization for diverticulitis, prostatitis, and muscle weakness, ultimately attributed to rhabdomyolysis. Genetic testing revealed a deletion of exons 3–9 in TANGO2 along with a novel missense variant (c.187G > T; p.Gly63Cys) on the other allele. The patient was started on vitamin B-complex with additional pantothenic acid (500 mg daily) and subsequently noted improvement in his speech and energy levels. To our knowledge, this case describes the oldest known individual living with TDD by two decades. Additionally, the patient's relatively mild symptom profile and previously unreported missense variant in TANGO2 may represent the first known example of genotype-phenotype correlation in TDD.
{"title":"TANGO2 deficiency disorder in a 61-year-old male with episodic weakness, rhabdomyolysis, myotonia, and a novel missense variant","authors":"Henry Skocy , Amber McFerren , Daniel Cairns , H. Mark Kenney , Eran Tallis , Amit S. Dhamoon , Ellie Garbade , Samuel J. Mackenzie","doi":"10.1016/j.ymgmr.2025.101241","DOIUrl":"10.1016/j.ymgmr.2025.101241","url":null,"abstract":"<div><div>TANGO2 Deficiency Disorder (TDD) is an autosomal recessive condition, most commonly diagnosed in childhood. Clinical features may include episodic movement disorders, seizures, cognitive impairment, hypothyroidism, and metabolic crises marked by rhabdomyolysis and life-threatening cardiac symptoms. A small number of adults, thought to largely represent the milder end of the phenotypic spectrum, have received a diagnosis of TDD in their 30's or 40's, though no genotype-phenotype correlations have been established to date. In this case report, we present a 61-year-old man with mild intellectual disability and recurrent muscle weakness who was diagnosed with TDD during an inpatient hospitalization for diverticulitis, prostatitis, and muscle weakness, ultimately attributed to rhabdomyolysis. Genetic testing revealed a deletion of exons 3–9 in <em>TANGO2</em> along with a novel missense variant (c.187G > T; p.Gly63Cys) on the other allele. The patient was started on vitamin B-complex with additional pantothenic acid (500 mg daily) and subsequently noted improvement in his speech and energy levels. To our knowledge, this case describes the oldest known individual living with TDD by two decades. Additionally, the patient's relatively mild symptom profile and previously unreported missense variant in <em>TANGO2</em> may represent the first known example of genotype-phenotype correlation in TDD.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"Article 101241"},"PeriodicalIF":1.8,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144550056","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 : 2025-07-01DOI: 10.1016/j.ymgmr.2025.101240
Shangyi Yang, Jine Yang
GNE myopathy (GNE-M) is an ultra-rare disease characterized by muscle weakness in the extremities. The main etiology is that a pathogenic variation in the GNE gene leads to a reduction in sialic acid synthesis. However, whether it is associated with premature ovarian failure (POF) isunknown. Here we report a case of GNE-M with premature ovarian failure (GNE-M-POF). The clinical data of a case of GNE-M-POF in our hospital were collected. The historical trajectory, molecular features, diagnosis and treatment were analyzed retrospectively, and the literature was reviewed. Over the course of 12 years, the patient presents with a slow and progressively worsening clinical manifestation. She was amenorrheic at the age of 35 and never conceived. Her calf muscles, and some of her thigh muscles were severely atrophied, leaving her unable to walk on her own. POF may be an extra-muscular manifestation of GNE-M, and further research is needed to verify the association.
{"title":"GNE myopathy with premature ovarian failure: Case report and review of the literature","authors":"Shangyi Yang, Jine Yang","doi":"10.1016/j.ymgmr.2025.101240","DOIUrl":"10.1016/j.ymgmr.2025.101240","url":null,"abstract":"<div><div>GNE myopathy (GNE-M) is an ultra-rare disease characterized by muscle weakness in the extremities. The main etiology is that a pathogenic variation in the <em>GNE</em> gene leads to a reduction in sialic acid synthesis. However, whether it is associated with premature ovarian failure (POF) isunknown. Here we report a case of GNE-M with premature ovarian failure (GNE-M-POF). The clinical data of a case of GNE-M-POF in our hospital were collected. The historical trajectory, molecular features, diagnosis and treatment were analyzed retrospectively, and the literature was reviewed. Over the course of 12 years, the patient presents with a slow and progressively worsening clinical manifestation. She was amenorrheic at the age of 35 and never conceived. Her calf muscles, and some of her thigh muscles were severely atrophied, leaving her unable to walk on her own. POF may be an extra-muscular manifestation of GNE-M, and further research is needed to verify the association.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"Article 101240"},"PeriodicalIF":1.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144518672","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 : 2025-06-27DOI: 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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号