Carbamoyl phosphate synthetase 1 (CPS1) deficiency (OMIM#237300) is a rare inherited disorder due to complete or partial lack of the CPS1 enzyme. Polymyositis is a relatively rare systemic inflammatory autoimmune disease. Here, we report a 59-year-old Japanese woman diagnosed with late-onset CPS1 deficiency during polymyositis treatment. The polymyositis appeared two years before the diagnosis of CPS1 deficiency. Prednisolone (PSL) at 35 mg/day initial dosage, promptly alleviated the symptoms. However, the patient, without apparent cause, suddenly developed confusion progressing to unconsciousness and coma. Upon admission, the patient’s plasma ammonia levels were 458 μg/dL (269 μM). Plasma amino acid analysis revealed decreased citrulline levels and elevated glutamine levels. Genetic analysis of CPS1 (OMIM *608307) showed homozygosity for the likely pathogenic variant c.2397G > A (p.Met799Ile), leading to the diagnosis of CPS1 deficiency. The patient responded to pharmacotherapy and continuous hemodialysis. However, the patient experienced hyperammonemia decompensation events while on pharmacotherapy at home, which were successfully managed with emergency treatment and/or hemodialysis. Subsequently, after liver transplantation, the patient's plasma ammonia levels consistently remained at normal. This case illustrates late-onset CPS1 deficiency manifested in an adult treated with PSL for polymyositis, and the cure of its enzyme deficiency by live-donor liver transplantation.
{"title":"Carbamoyl phosphate synthetase 1 deficiency manifested in an adult treated with prednisone for polymyositis, and cured by live-donor liver transplantation","authors":"Kazuhiro Yokota , Akira Ohtake , Taro Yamazaki , Takuma Tsuzuki-Wada , Megumi Saito-Tsuruoka , Takuya Fushimi , Kei Murayama , Yuji Akiyama , Toshihide Mimura","doi":"10.1016/j.ymgmr.2025.101200","DOIUrl":"10.1016/j.ymgmr.2025.101200","url":null,"abstract":"<div><div>Carbamoyl phosphate synthetase 1 (CPS1) deficiency (OMIM#<span><span>237300</span><svg><path></path></svg></span>) is a rare inherited disorder due to complete or partial lack of the CPS1 enzyme. Polymyositis is a relatively rare systemic inflammatory autoimmune disease. Here, we report a 59-year-old Japanese woman diagnosed with late-onset CPS1 deficiency during polymyositis treatment. The polymyositis appeared two years before the diagnosis of CPS1 deficiency. Prednisolone (PSL) at 35 mg/day initial dosage, promptly alleviated the symptoms. However, the patient, without apparent cause, suddenly developed confusion progressing to unconsciousness and coma. Upon admission, the patient’s plasma ammonia levels were 458 μg/dL (269 μM). Plasma amino acid analysis revealed decreased citrulline levels and elevated glutamine levels. Genetic analysis of <em>CPS1</em> (OMIM *608307) showed homozygosity for the likely pathogenic variant c.2397G > A (p.Met799Ile), leading to the diagnosis of CPS1 deficiency. The patient responded to pharmacotherapy and continuous hemodialysis. However, the patient experienced hyperammonemia decompensation events while on pharmacotherapy at home, which were successfully managed with emergency treatment and/or hemodialysis. Subsequently, after liver transplantation, the patient's plasma ammonia levels consistently remained at normal. This case illustrates late-onset CPS1 deficiency manifested in an adult treated with PSL for polymyositis, and the cure of its enzyme deficiency by live-donor liver transplantation.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101200"},"PeriodicalIF":1.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143549698","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 : 2025-03-04DOI: 10.1016/j.ymgmr.2025.101201
Karin Lange , Jens Böhmer , Yvonne Deich , Daniel Dickneite , Pascale Fuchs , Verena Naunheim , Angelika Scholz , Christian Heimbold
Objectives
Many publications describe experiences of healthcare professionals (HCPs) on managing phenylketonuria (PKU), but literature on the perspectives of individuals with PKU is limited. Nevertheless, patient insights and strategies to address challenges of living with PKU can provide guidance to HCPs and the PKU community to further optimise PKU care.
Methods
A virtual meeting was held to elucidate the lived experience of patients with PKU and brainstorm best practice recommendations from the patient perspective. The meeting was moderated by a psychologist and attended by seven adults with PKU and one caregiver. Based on the outcomes of this meeting and subsequent online rating rounds, consensus statements (≥75 % agreement) reflecting patient focused considerations were developed using a modified Delphi approach.
Results
Consensus was reached for 18 statements on five topics: the PKU diet, experience with HCPs throughout life, impact of PKU on everyday life, connecting with the PKU community, and future aspirations to facilitate life with PKU.
To minimise the burden of diet, avoidance of hunger and offering new treatment options were identified, together with adequate education and support. Maintaining metabolic control throughout adulthood could be facilitated by easier access to clinics beyond in-person visits and by availability of treatment teams specifically equipped to provide PKU-adult care. To further support adults in reaching target blood Phe concentrations and personal goals, pegvaliase can be offered to those eligible. Finally, exchanging experiences with others from the PKU community through social media and live/virtual meetings may help individuals with PKU and caregivers to improve their knowledge and skills to manage PKU.
Conclusion
These consensus statements provide unique insights on how challenges faced by individuals with PKU may be addressed and may provide guidance to HCPs as well as the PKU community and caregivers on ways to improve patient care and support.
{"title":"Our lives with PKU: German patient voices - “Nothing about us without us”","authors":"Karin Lange , Jens Böhmer , Yvonne Deich , Daniel Dickneite , Pascale Fuchs , Verena Naunheim , Angelika Scholz , Christian Heimbold","doi":"10.1016/j.ymgmr.2025.101201","DOIUrl":"10.1016/j.ymgmr.2025.101201","url":null,"abstract":"<div><h3>Objectives</h3><div>Many publications describe experiences of healthcare professionals (HCPs) on managing phenylketonuria (PKU), but literature on the perspectives of individuals with PKU is limited. Nevertheless, patient insights and strategies to address challenges of living with PKU can provide guidance to HCPs and the PKU community to further optimise PKU care.</div></div><div><h3>Methods</h3><div>A virtual meeting was held to elucidate the lived experience of patients with PKU and brainstorm best practice recommendations from the patient perspective. The meeting was moderated by a psychologist and attended by seven adults with PKU and one caregiver. Based on the outcomes of this meeting and subsequent online rating rounds, consensus statements (≥75 % agreement) reflecting patient focused considerations were developed using a modified Delphi approach.</div></div><div><h3>Results</h3><div>Consensus was reached for 18 statements on five topics: the PKU diet, experience with HCPs throughout life, impact of PKU on everyday life, connecting with the PKU community, and future aspirations to facilitate life with PKU.</div><div>To minimise the burden of diet, avoidance of hunger and offering new treatment options were identified, together with adequate education and support. Maintaining metabolic control throughout adulthood could be facilitated by easier access to clinics beyond in-person visits and by availability of treatment teams specifically equipped to provide PKU-adult care. To further support adults in reaching target blood Phe concentrations and personal goals, pegvaliase can be offered to those eligible. Finally, exchanging experiences with others from the PKU community through social media and live/virtual meetings may help individuals with PKU and caregivers to improve their knowledge and skills to manage PKU.</div></div><div><h3>Conclusion</h3><div>These consensus statements provide unique insights on how challenges faced by individuals with PKU may be addressed and may provide guidance to HCPs as well as the PKU community and caregivers on ways to improve patient care and support.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101201"},"PeriodicalIF":1.8,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143534192","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 : 2025-03-03DOI: 10.1016/j.ymgmr.2025.101203
Shanshan Fan , Guangpu Su , Mingfeng Li , Yunmiao Guo , Lei Wang , Jinliang Li
Tropomyosin 3 (TPM3) encodes the slow α-tropomyosin isoform (Tpm3.12), an actin-binding protein that plays a critical role in the regulation of muscle contraction. Mutations in TPM3 are associated with the characteristic features of congenital myopathy (CM).
A 15-year-old boy had a history of developmental delay, he had long narrow face with a myopathic facial appearance, mild scoliosis of the spine, grade IV muscle strength in the extremities, low muscle tone, absent bilateral knee tendon reflexes, and negative pathological findings. MRI revealed fat infiltration in the leg muscles and the surrounding muscle spaces. Muscle biopsy indicated muscle fiber type disproportion. A novel heterozygous mutation of unknown significance, c.44A > G(p.Asp15Gly), in TPM3 gene was identified. This mutation was confirmed to be de novo and was not present in the proband's parents or sister. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), this variant was classified as pathogenic. PyMOL software analysis indicated that the variant affects the intermolecular interactions within the Tpm3.12. Interestingly, we also found that the patient has been mouth-breathing since infancy, along with a skeletal open bite. This phenotype that has not been previously described.
Our study expands the mutation spectrum of TPM3 and offers valuable insights for the clinical diagnosis and genetic counseling of children with CMYP4A.
{"title":"A novel pathogenic variant c.44A > G (p. Asp15Gly) in TPM3 causing the phenotype of CMYP4A: A case report","authors":"Shanshan Fan , Guangpu Su , Mingfeng Li , Yunmiao Guo , Lei Wang , Jinliang Li","doi":"10.1016/j.ymgmr.2025.101203","DOIUrl":"10.1016/j.ymgmr.2025.101203","url":null,"abstract":"<div><div>Tropomyosin 3 (<em>TPM3</em>) encodes the slow α-tropomyosin isoform (Tpm3.12), an actin-binding protein that plays a critical role in the regulation of muscle contraction. Mutations in <em>TPM3</em> are associated with the characteristic features of congenital myopathy (CM).</div><div>A 15-year-old boy had a history of developmental delay, he had long narrow face with a myopathic facial appearance, mild scoliosis of the spine, grade IV muscle strength in the extremities, low muscle tone, absent bilateral knee tendon reflexes, and negative pathological findings. MRI revealed fat infiltration in the leg muscles and the surrounding muscle spaces. Muscle biopsy indicated muscle fiber type disproportion. A novel heterozygous mutation of unknown significance, c.44A > G(p.Asp15Gly), in <em>TPM3</em> gene was identified. This mutation was confirmed to be de novo and was not present in the proband's parents or sister. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), this variant was classified as pathogenic. PyMOL software analysis indicated that the variant affects the intermolecular interactions within the Tpm3.12. Interestingly, we also found that the patient has been mouth-breathing since infancy, along with a skeletal open bite. This phenotype that has not been previously described.</div><div>Our study expands the mutation spectrum of <em>TPM3</em> and offers valuable insights for the clinical diagnosis and genetic counseling of children with CMYP4A.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101203"},"PeriodicalIF":1.8,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143529746","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 : 2025-02-28DOI: 10.1016/j.ymgmr.2025.101202
Kirkland A. Wilson , Yun Zhou , Gary Cunningham , Kimberly Chapman , Marshall Summar , Debra Regier
Objectives
An assessment of amino acid and amine concentrations is important for the diagnosis and management of inherited metabolic disorders (IMDs). Methods exist that measure these biologically important metabolites but are cost-prohibitive and/or time consuming. We therefore sought to develop a novel methodology, applicable to IMDs, that is both high-throughput and low cost.
Methods
Previously, we developed a methodology for rapid, repeatable, and cost-efficient separation of approximately 20 amines as a proof of concept and now expand it to amines relevant to IMDs. We describe our separation methodology using reverse phase high performance liquid chromatography with ultraviolet-visible spectrum absorbance paired with pre-column derivatization with o-pthalaldehyde.
Results
We show reproducibility via concentration assessments, in triplicate, for each amine. We assess amines in prepared standard solutions and in biologic samples from patients with IMDs. We also detected and assessed the amino group containing compounds glutathione (oxidized and reduced forms) and ammonia. Validation was established using absolute area under the curve (AUC) and via comparison using a single internal standard.
Conclusions
We report good separation of 40 primary amino group containing metabolites, in a single, 53 min run. This rapid, low cost, and accurate methodology only requires a small volume of sample and can greatly increase availability and access. Finally, the numerous amines and unique compounds detected in our single run has large utility and can potentially increase clinical efficiency and broaden access to research, both important as the need for analysis of amines grows globally.
{"title":"A novel, high throughput, and low-cost method for the detection of 40 amines relevant to inborn errors of metabolism, in under 60 min, using reverse phase high performance liquid chromatography","authors":"Kirkland A. Wilson , Yun Zhou , Gary Cunningham , Kimberly Chapman , Marshall Summar , Debra Regier","doi":"10.1016/j.ymgmr.2025.101202","DOIUrl":"10.1016/j.ymgmr.2025.101202","url":null,"abstract":"<div><h3>Objectives</h3><div>An assessment of amino acid and amine concentrations is important for the diagnosis and management of inherited metabolic disorders (IMDs). Methods exist that measure these biologically important metabolites but are cost-prohibitive and/or time consuming. We therefore sought to develop a novel methodology, applicable to IMDs, that is both high-throughput and low cost.</div></div><div><h3>Methods</h3><div>Previously, we developed a methodology for rapid, repeatable, and cost-efficient separation of approximately 20 amines as a proof of concept and now expand it to amines relevant to IMDs. We describe our separation methodology using reverse phase high performance liquid chromatography with ultraviolet-visible spectrum absorbance paired with pre-column derivatization with <em>o</em>-pthalaldehyde.</div></div><div><h3>Results</h3><div>We show reproducibility via concentration assessments, in triplicate, for each amine. We assess amines in prepared standard solutions and in biologic samples from patients with IMDs. We also detected and assessed the amino group containing compounds glutathione (oxidized and reduced forms) and ammonia. Validation was established using absolute area under the curve (AUC) and via comparison using a single internal standard.</div></div><div><h3>Conclusions</h3><div>We report good separation of 40 primary amino group containing metabolites, in a single, 53 min run. This rapid, low cost, and accurate methodology only requires a small volume of sample and can greatly increase availability and access. Finally, the numerous amines and unique compounds detected in our single run has large utility and can potentially increase clinical efficiency and broaden access to research, both important as the need for analysis of amines grows globally.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"43 ","pages":"Article 101202"},"PeriodicalIF":1.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511048","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 disease caused by mutations in GLA, which encodes α-galactosidase A (GLA). The loss or reduced activity of GLA leads to damage to multiple organs, resulting in the intracellular accumulation of globotriaosylceramide in various organs, including the heart, kidneys, and nervous system. Pathological changes in the heart typically result in concentric left ventricular hypertrophy. Hypertrophic cardiomyopathy (HCM) is an intractable disease characterized by unexplained left ventricular hypertrophy and diastolic dysfunction and is typically characterized by asymmetric left ventricular hypertrophy. We performed a causative gene analysis in patients with a rare subtype of HCM, HCM with mid-ventricular obstruction (HCM-MVO), and identified four patients with different pathogenic variants of GLA, which were clinically confirmed as FD. All four patients with FD and rare HCM-MVO morphology were female, and all cases involved the classical form of the disease. Three cases in whom lymphocyte Lyso-Gb3 was measured showed a marked decrease in Lyso-Gb3 after initiating enzyme replacement therapy (ERT). However, even after ERT, myocardial involvement worsened in the long term, and two patients experienced fatal arrhythmias. Therefore, it is difficult to determine the efficacy of myocardial involvement in FD using a lymphocyte-based Lyso-Gb3 assay system. In addition, none of these female patients had renal dysfunction, indicating a different pattern of organ damage compared with that previously reported in male patients.
{"title":"Clinical characteristics of female Fabry disease patients with hypertrophic cardiomyopathy with mid-ventricular obstruction","authors":"Natsuko Inagaki , Yasuyoshi Takei , Tsuguhisa Hatano , Yasuyuki Takada , Yoshinao Yazaki , Hisanori Kosuge , Masatake Kobayashi , Shinji Suzuki , Tomohiro Umezu , Masahiko Kuroda , Kazuhiro Satomi , Takeharu Hayashi","doi":"10.1016/j.ymgmr.2025.101196","DOIUrl":"10.1016/j.ymgmr.2025.101196","url":null,"abstract":"<div><div>Fabry disease (FD) is an X-linked lysosomal storage disease caused by mutations in <em>GLA</em>, which encodes α-galactosidase A (GLA). The loss or reduced activity of GLA leads to damage to multiple organs, resulting in the intracellular accumulation of globotriaosylceramide in various organs, including the heart, kidneys, and nervous system. Pathological changes in the heart typically result in concentric left ventricular hypertrophy. Hypertrophic cardiomyopathy (HCM) is an intractable disease characterized by unexplained left ventricular hypertrophy and diastolic dysfunction and is typically characterized by asymmetric left ventricular hypertrophy. We performed a causative gene analysis in patients with a rare subtype of HCM, HCM with mid-ventricular obstruction (HCM-MVO), and identified four patients with different pathogenic variants of <em>GLA</em>, which were clinically confirmed as FD. All four patients with FD and rare HCM-MVO morphology were female, and all cases involved the classical form of the disease. Three cases in whom lymphocyte Lyso-Gb3 was measured showed a marked decrease in Lyso-Gb3 after initiating enzyme replacement therapy (ERT). However, even after ERT, myocardial involvement worsened in the long term, and two patients experienced fatal arrhythmias. Therefore, it is difficult to determine the efficacy of myocardial involvement in FD using a lymphocyte-based Lyso-Gb3 assay system. In addition, none of these female patients had renal dysfunction, indicating a different pattern of organ damage compared with that previously reported in male patients.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101196"},"PeriodicalIF":1.8,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143372440","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}
Carnitine-acylcarnitine translocase deficiency (CACTD) is a rare autosomal recessive fatty acid oxidation disorder resulting in energy deficiency due to impaired mitochondrial long-chain fatty acid transport. Hyperammonemia is a critical complication, often resistant to conventional treatment. Here, we report the case of a 7-month-old patient with CACTD, initially diagnosed at 10 days old, who presented with persistent hyperammonemia despite optimized medical nutrition therapy and conventional nitrogen scavenging with sodium benzoate. When hyperammonemia persisted, carglumic acid was introduced, leading to a sustained decrease in ammonia levels and effective long-term control. Carglumic acid, typically indicated for organic acidemias, proved beneficial in this CACTD case. The administration of carglumic acid not only provided acute resolution but also stabilized ammonia levels over prolonged follow-up. This case highlights carglumic acid as a potential therapeutic option for managing hyperammonemia in CACTD, underscoring the need for further studies to confirm its efficacy in long-term management of hyperammonemia in fatty acid oxidation disorders.
{"title":"Carglumic acid as a treatment for persistent hyperammonemia in carnitine-acylcarnitine translocase deficiency: A case study","authors":"Hanım Babazade , Tanyel Zubarioglu , Esma Uygur , Mehmet Şerif Cansever , Ertuğrul Kiykim , Çiğdem Aktuğlu Zeybek","doi":"10.1016/j.ymgmr.2025.101199","DOIUrl":"10.1016/j.ymgmr.2025.101199","url":null,"abstract":"<div><div>Carnitine-acylcarnitine translocase deficiency (CACTD) is a rare autosomal recessive fatty acid oxidation disorder resulting in energy deficiency due to impaired mitochondrial long-chain fatty acid transport. Hyperammonemia is a critical complication, often resistant to conventional treatment. Here, we report the case of a 7-month-old patient with CACTD, initially diagnosed at 10 days old, who presented with persistent hyperammonemia despite optimized medical nutrition therapy and conventional nitrogen scavenging with sodium benzoate. When hyperammonemia persisted, carglumic acid was introduced, leading to a sustained decrease in ammonia levels and effective long-term control. Carglumic acid, typically indicated for organic acidemias, proved beneficial in this CACTD case. The administration of carglumic acid not only provided acute resolution but also stabilized ammonia levels over prolonged follow-up. This case highlights carglumic acid as a potential therapeutic option for managing hyperammonemia in CACTD, underscoring the need for further studies to confirm its efficacy in long-term management of hyperammonemia in fatty acid oxidation disorders.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101199"},"PeriodicalIF":1.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143349376","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}
The human mitochondrial methionyl-tRNA is crucial for mitochondrial translation, serving as both initiator and elongator in polypeptide chains. The MARS2 gene is responsible for binding methionine to mitochondrial tRNA. The clinical characteristics of MARS2 intragenic variants are still largely unknown, since only a pair of siblings has been reported. The present patient presented with psychomotor developmental delay, growth failure, and spondylar dysplasia, which attracted attention in infancy and deteriorated with age.
Case presentation
A 7-month-old Japanese girl presented with failure to thrive, feeding difficulties, and psychomotor developmental delay. Radiological examination showed generalized skeletal alterations including mild spondylar dysplasia and abnormal ilia, which resembled mucopolysaccharidosis; however, the urinary glycosaminoglycan levels and alpha-L-iduronidase activity in the filter paper blood were normal. At age 33 months, she showed hyperlactatemia, and genetic analysis showed compound heterozygous novel variants (NM_138395.4: c.[277G > A]; [409C > T]: p.([Asp93Asn]; [Arg137Cys])) in the MARS2 gene. After starting vitamin supplementation, her growth and development improved. Radiological examination at ages 2 and 4 years demonstrated a skeletal phenotype: platyspondyly with anterior beaking of the vertebral bodies; large proximal femoral epiphyses; and mild brachymesophalangy. The results of the mitochondrial respiratory chain activity examination using skin fibroblasts were within the normal range.
Conclusion
The skeletal phenotype may be a syndromic component of this disorder associated with MARS2 intragenic variants.
{"title":"A girl with intragenic variants in MARS2 and a chondrodysplasia phenotype","authors":"Hiroyuki Iijima , Yuko Tsujioka , Yoshiyuki Tsutsumi , Gen Nishimura , Yasushi Okazaki , Kei Murayama , Mitsuru Kubota , Akira Ohtake","doi":"10.1016/j.ymgmr.2025.101198","DOIUrl":"10.1016/j.ymgmr.2025.101198","url":null,"abstract":"<div><h3>Background</h3><div>The human mitochondrial methionyl-tRNA is crucial for mitochondrial translation, serving as both initiator and elongator in polypeptide chains. The <em>MARS2</em> gene is responsible for binding methionine to mitochondrial tRNA. The clinical characteristics of <em>MARS2</em> intragenic variants are still largely unknown, since only a pair of siblings has been reported. The present patient presented with psychomotor developmental delay, growth failure, and spondylar dysplasia, which attracted attention in infancy and deteriorated with age.</div></div><div><h3>Case presentation</h3><div>A 7-month-old Japanese girl presented with failure to thrive, feeding difficulties, and psychomotor developmental delay. Radiological examination showed generalized skeletal alterations including mild spondylar dysplasia and abnormal ilia, which resembled mucopolysaccharidosis; however, the urinary glycosaminoglycan levels and alpha-L-iduronidase activity in the filter paper blood were normal. At age 33 months, she showed hyperlactatemia, and genetic analysis showed compound heterozygous novel variants (NM_138395.4: c.[277G > A]; [409C > T]: p.([Asp93Asn]; [Arg137Cys])) in the <em>MARS2</em> gene. After starting vitamin supplementation, her growth and development improved. Radiological examination at ages 2 and 4 years demonstrated a skeletal phenotype: platyspondyly with anterior beaking of the vertebral bodies; large proximal femoral epiphyses; and mild brachymesophalangy. The results of the mitochondrial respiratory chain activity examination using skin fibroblasts were within the normal range.</div></div><div><h3>Conclusion</h3><div>The skeletal phenotype may be a syndromic component of this disorder associated with <em>MARS2</em> intragenic variants.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101198"},"PeriodicalIF":1.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143354773","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}
Glycogen storage disease type 5 (GSD) is an autosomal recessive metabolic myopathy caused by pathogenic variants in the PYGM gene. We report the case of a patient with typical exercise intolerance with a “second wind” phenomenon, associated with camptocormia which is not commonly recognized as a feature of the disease. Molecular analysis of the PYGM gene the common c.148C > T [p.(Arg50*)] variant and a missense variant in exon 12, c.1471C > T [p.(Arg491Cys)]. GSD 5 and Pompe disease are both glycogen storage diseases in which axial involvement has been described. Although probably underestimated, severe axial myopathy has been rarely reported in GSD 5. We suggest that the long-lasting symptoms associated with camptocormia should be considered as possible initial features of GSD 5.
{"title":"Camptocormia as a feature of Mc Ardle's disease: A case report","authors":"Mathilde Nicolas , Chloé Giret , Sybille Pellieux , Annick Toutain , Anne-Marie Bergemer-Fouquet , Pascal Laforêt , Loic Bouilleau , François Maillot","doi":"10.1016/j.ymgmr.2025.101197","DOIUrl":"10.1016/j.ymgmr.2025.101197","url":null,"abstract":"<div><div>Glycogen storage disease type 5 (GSD) is an autosomal recessive metabolic myopathy caused by pathogenic variants in the <em>PYGM</em> gene. We report the case of a patient with typical exercise intolerance with a “second wind” phenomenon, associated with camptocormia which is not commonly recognized as a feature of the disease. Molecular analysis of the <em>PYGM</em> gene the common c.148C > T [p.(Arg50*)] variant and a missense variant in exon 12, c.1471C > T [p.(Arg491Cys)]. GSD 5 and Pompe disease are both glycogen storage diseases in which axial involvement has been described. Although probably underestimated, severe axial myopathy has been rarely reported in GSD 5. We suggest that the long-lasting symptoms associated with camptocormia should be considered as possible initial features of GSD 5.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101197"},"PeriodicalIF":1.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143131346","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 : 2025-01-25DOI: 10.1016/j.ymgmr.2025.101192
Mahim Jain , Mehul Shah , Kamlesh M. Thakker , Andrew Rava , Agness Pelts Block , Colette Ndiba-Markey , Lionel Pinto
Background and objectives
Classical homocystinuria (HCU) is a rare autosomal recessive disease that can affect multiple organ systems leading to increased health care resource utilization (HCRU) and costs. In this study, we aimed to utilize United States claims data to describe the all-cause HCRU and costs of HCU and to compare these when stratified by total homocysteine (tHcy) level.
Methods
This was a retrospective cohort study using Optum's de-identified Market Clarity Data from January 01, 2016, through September 30, 2021. Patients were initially selected if they had at least 1 International Classification of Diseases, Tenth Revision diagnosis code for homocystinuria (E72.11) or homocystinuria signs, disease, and symptoms term in the Market Clarity Dataset. Patients were subsequently selected by using a multi-parameter algorithm encompassing clinical and phenotypic characteristics and tHcy levels. Patients were excluded if they had cancer, a COVID-19 hospitalization, or pregnancy. Unadjusted all-cause HCRU and costs (adjusted to 2021 United States dollars) per patient per month (PPPM) over the follow-up period were reported by health care setting using descriptive statistics. Unadjusted linear regression was used for comparisons across tHcy levels.
Results
The overall study cohort included 143 eligible patients, 61 (42.7 %) had a tHcy level < 50 μM and 82 (57.3 %) had a tHcy level ≥ 50 μM. Within the subgroup with tHcy level ≥ 50 μM, 54 (65.9 %) had a tHcy level 50 to < 100 μM, and 28 (34.1 %) had a tHcy level ≥ 100 μM. In the overall cohort, 44.1 % of patients were female, mean age was 47.8 years, and most patients were White (76.9 %). Patients with higher tHcy levels had more unadjusted all-cause outpatient visits and pharmacy claims PPPM compared with those with lower tHcy levels. Mean total health care costs PPPM were $5139, $2722, and $925 in patients with tHcy ≥ 100 μM, 50 to < 100 μM, and < 50 μM, respectively (p < 0.001). Among patients with tHcy ≥ 100 μM, mean costs of pharmacy claims ($1886), inpatient admissions ($1611), and outpatient visits ($1523) contributed the most to the total health care costs and total, inpatient, outpatient, and pharmacy costs were all significantly higher in patients with higher tHcy levels (all p ≤ 0.01).
Conclusions
All-cause HCRU and costs in patients with HCU were higher in patients with higher tHcy levels. A major portion of the costs were related to inpatient admissions, outpatient visits, and pharmacy claims. These results provide support for lowering tHcy levels through appropriate diet and treatment combination to reduce HCRU and the associated economic burden of HCU.
{"title":"Impact of classical homocystinuria on health care resource utilization and costs in the United States: A retrospective cohort study","authors":"Mahim Jain , Mehul Shah , Kamlesh M. Thakker , Andrew Rava , Agness Pelts Block , Colette Ndiba-Markey , Lionel Pinto","doi":"10.1016/j.ymgmr.2025.101192","DOIUrl":"10.1016/j.ymgmr.2025.101192","url":null,"abstract":"<div><h3>Background and objectives</h3><div>Classical homocystinuria (HCU) is a rare autosomal recessive disease that can affect multiple organ systems leading to increased health care resource utilization (HCRU) and costs. In this study, we aimed to utilize United States claims data to describe the all-cause HCRU and costs of HCU and to compare these when stratified by total homocysteine (tHcy) level.</div></div><div><h3>Methods</h3><div>This was a retrospective cohort study using Optum's de-identified Market Clarity Data from January 01, 2016, through September 30, 2021. Patients were initially selected if they had at least 1 International Classification of Diseases, Tenth Revision diagnosis code for homocystinuria (E72.11) or <em>homocystinuria</em> signs, disease, and symptoms term in the Market Clarity Dataset. Patients were subsequently selected by using a multi-parameter algorithm encompassing clinical and phenotypic characteristics and tHcy levels. Patients were excluded if they had cancer, a COVID-19 hospitalization, or pregnancy. Unadjusted all-cause HCRU and costs (adjusted to 2021 United States dollars) per patient per month (PPPM) over the follow-up period were reported by health care setting using descriptive statistics. Unadjusted linear regression was used for comparisons across tHcy levels.</div></div><div><h3>Results</h3><div>The overall study cohort included 143 eligible patients, 61 (42.7 %) had a tHcy level < 50 μM and 82 (57.3 %) had a tHcy level ≥ 50 μM. Within the subgroup with tHcy level ≥ 50 μM, 54 (65.9 %) had a tHcy level 50 to < 100 μM, and 28 (34.1 %) had a tHcy level ≥ 100 μM. In the overall cohort, 44.1 % of patients were female, mean age was 47.8 years, and most patients were White (76.9 %). Patients with higher tHcy levels had more unadjusted all-cause outpatient visits and pharmacy claims PPPM compared with those with lower tHcy levels. Mean total health care costs PPPM were $5139, $2722, and $925 in patients with tHcy ≥ 100 μM, 50 to < 100 μM, and < 50 μM, respectively (<em>p</em> < 0.001). Among patients with tHcy ≥ 100 μM, mean costs of pharmacy claims ($1886), inpatient admissions ($1611), and outpatient visits ($1523) contributed the most to the total health care costs and total, inpatient, outpatient, and pharmacy costs were all significantly higher in patients with higher tHcy levels (all <em>p</em> ≤ 0.01).</div></div><div><h3>Conclusions</h3><div>All-cause HCRU and costs in patients with HCU were higher in patients with higher tHcy levels. A major portion of the costs were related to inpatient admissions, outpatient visits, and pharmacy claims. These results provide support for lowering tHcy levels through appropriate diet and treatment combination to reduce HCRU and the associated economic burden of HCU.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101192"},"PeriodicalIF":1.8,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143131402","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 : 2025-01-25DOI: 10.1016/j.ymgmr.2025.101195
Katelyn Sawyer , William Miller , Courtney Popp , Chloe Strege , Cindy Eide , Jakub Tolar
Background
Disorders of fatty acid oxidation (FAOD) are estimated to account for around 1 in 10,000 live births, and with modern newborn screens, these conditions are often identified in childhood. However, not all parents will receive regular medical follow-up, and varying levels of parental health literacy can influence their reliance on online resources for information. Therefore, assessing the readability of online materials is critical to ensuring accessible and comprehensible patient education. Understanding the readability landscape informs our efforts to improve the quality of online resources and to support parents and patients in navigating the diagnosis of an FAOD.
Objective
Our goal was to evaluate the readability of public facing online materials concerning the 10 most common disorders of fatty acid oxidation, with consideration given to the recommended reading levels by the National Institutes of Health (NIH) and the American Medical Association (AMA).
Methods
Using Flesch-Kincaid, Coleman-Liau, and SMOG readability indices, we analyzed the top 25 internet search results for each disorder. Excluding empty or paywalled content, 232 publicly accessible materials were assessed.
Results
Mean readability ranged from 11.64 to 12.85, indicating generally higher complexity than recommended. Only 15.5 % of materials met NIH's 8th grade reading level guideline, and 3.9 % met AMA's 6th grade level. Variability existed between disorders, with percentages meeting guidelines ranging from 0 % to 25 % for NIH and 0 % to 8.3 % for AMA.
Conclusion
Ensuring readability of online resources for rare disorders of fatty acid oxidation is crucial, particularly given the prevalence of childhood diagnosis and varying levels of parental health literacy. Parents may rely on easily accessible but potentially complex materials found through online searches, highlighting the importance of aligning online content with recommended reading levels. Improving readability can enhance accessibility and understanding and facilitate informed decision-making and optimal care for patients.
{"title":"Analysis of readability of the top web searches for pediatric inborn errors of fatty acid metabolism","authors":"Katelyn Sawyer , William Miller , Courtney Popp , Chloe Strege , Cindy Eide , Jakub Tolar","doi":"10.1016/j.ymgmr.2025.101195","DOIUrl":"10.1016/j.ymgmr.2025.101195","url":null,"abstract":"<div><h3>Background</h3><div>Disorders of fatty acid oxidation (FAOD) are estimated to account for around 1 in 10,000 live births, and with modern newborn screens, these conditions are often identified in childhood. However, not all parents will receive regular medical follow-up, and varying levels of parental health literacy can influence their reliance on online resources for information. Therefore, assessing the readability of online materials is critical to ensuring accessible and comprehensible patient education. Understanding the readability landscape informs our efforts to improve the quality of online resources and to support parents and patients in navigating the diagnosis of an FAOD.</div></div><div><h3>Objective</h3><div>Our goal was to evaluate the readability of public facing online materials concerning the 10 most common disorders of fatty acid oxidation, with consideration given to the recommended reading levels by the National Institutes of Health (NIH) and the American Medical Association (AMA).</div></div><div><h3>Methods</h3><div>Using Flesch-Kincaid, Coleman-Liau, and SMOG readability indices, we analyzed the top 25 internet search results for each disorder. Excluding empty or paywalled content, 232 publicly accessible materials were assessed.</div></div><div><h3>Results</h3><div>Mean readability ranged from 11.64 to 12.85, indicating generally higher complexity than recommended. Only 15.5 % of materials met NIH's 8th grade reading level guideline, and 3.9 % met AMA's 6th grade level. Variability existed between disorders, with percentages meeting guidelines ranging from 0 % to 25 % for NIH and 0 % to 8.3 % for AMA.</div></div><div><h3>Conclusion</h3><div>Ensuring readability of online resources for rare disorders of fatty acid oxidation is crucial, particularly given the prevalence of childhood diagnosis and varying levels of parental health literacy. Parents may rely on easily accessible but potentially complex materials found through online searches, highlighting the importance of aligning online content with recommended reading levels. Improving readability can enhance accessibility and understanding and facilitate informed decision-making and optimal care for patients.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"42 ","pages":"Article 101195"},"PeriodicalIF":1.8,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143131401","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}
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