D-glyceric aciduria (DGA) is caused by D-glycerate-2-kinase deficiency due to biallelic pathogenic variants in GLYCTK. It is associated with variable neurological symptoms. DGA is extremely rare, and genetic variants are only known in 7 previously described patients. We report a new patient with DGA and a novel homozygous GLYCTK variant.
D 型甘油酸尿症（DGA）是由于 GLYCTK 双重致病变体导致 D 型甘油酸-2-激酶缺乏引起的。它与不同的神经症状有关。DGA 极其罕见，目前仅发现 7 例先前描述过的患者存在基因变异。我们报告了一名新的 DGA 患者和一个新的同基因 GLYCTK 变异体。
{"title":"D-glyceric aciduria due to GLYCTK mutation: Disease or non-disease?","authors":"Sandra D.K. Kingma , Laura K.M. Steinbusch , Sietse M. Aukema , Margje Sinnema , Bianca Panis , Joost Nicolai , Estela Rubio-Gozalbo","doi":"10.1016/j.ymgmr.2024.101159","DOIUrl":"10.1016/j.ymgmr.2024.101159","url":null,"abstract":"<div><div>D-glyceric aciduria (DGA) is caused by D-glycerate-2-kinase deficiency due to biallelic pathogenic variants in <em>GLYCTK.</em> It is associated with variable neurological symptoms. DGA is extremely rare, and genetic variants are only known in 7 previously described patients. We report a new patient with DGA and a novel homozygous <em>GLYCTK</em> variant.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101159"},"PeriodicalIF":1.8,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142650670","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 : 2024-11-09DOI: 10.1016/j.ymgmr.2024.101158
Theodoros Georgiou , Olga Grafakou , Anna Malekkou , Emilia Athanasiou , Ioannis Ioannou , Vivi Choleva , Maria Dionysiou , Gabriella Mavrikiou , Anthi Demetriadou , Violetta Anastasiadou , Anthi Drousiotou , Petros P. Petrou
Methylmalonic aciduria and homocystinuria, CblC type, is an inborn error of intracellular vitamin B12 (cobalamin) metabolism caused, in the majority of cases, by mutations in the MMACHC gene. Five Cypriot patients (four males and one female) were diagnosed with a CblC defect. Age at diagnosis ranged from 10 days to 9 months. We present here the clinical, biochemical and molecular findings of these patients. Our retrospective study indicates that all patients were carriers of the known p.Arg91LysfsTer14 variant in either a homozygous or compound heterozygous state with other known MMACHC pathogenic variants. Out of three patients sharing the same genotype the one diagnosed and initiated treatment in the neonatal period displayed an improved clinical outcome.
{"title":"A case series of Cypriot patients with CblC defect: Clinical, biochemical and molecular characteristics","authors":"Theodoros Georgiou , Olga Grafakou , Anna Malekkou , Emilia Athanasiou , Ioannis Ioannou , Vivi Choleva , Maria Dionysiou , Gabriella Mavrikiou , Anthi Demetriadou , Violetta Anastasiadou , Anthi Drousiotou , Petros P. Petrou","doi":"10.1016/j.ymgmr.2024.101158","DOIUrl":"10.1016/j.ymgmr.2024.101158","url":null,"abstract":"<div><div>Methylmalonic aciduria and homocystinuria, CblC type, is an inborn error of intracellular vitamin B12 (cobalamin) metabolism caused, in the majority of cases, by mutations in the <em>MMACHC</em> gene. Five Cypriot patients (four males and one female) were diagnosed with a CblC defect. Age at diagnosis ranged from 10 days to 9 months. We present here the clinical, biochemical and molecular findings of these patients. Our retrospective study indicates that all patients were carriers of the known p.Arg91LysfsTer14 variant in either a homozygous or compound heterozygous state with other known <em>MMACHC</em> pathogenic variants. Out of three patients sharing the same genotype the one diagnosed and initiated treatment in the neonatal period displayed an improved clinical outcome.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101158"},"PeriodicalIF":1.8,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142650669","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 : 2024-10-30DOI: 10.1016/j.ymgmr.2024.101157
Joana Fernandes , João Moura , João Tarrio , Jorge Oliveira , Ana Lopes , João Parente Freixo , Gonçalo Videira
Background and objectives
Adult-onset leukodystrophies are a rare group of neurological disorders characterized by progressive degeneration of the cerebral white matter. One of these diseases is caused by biallelic pathogenic variants in the AARS2 gene. We describe a patient with late-onset AARS2-related leukoencephalopathy, a milder phenotype and a novel disease-causing variant.
Methods
The patient was characterized during routine clinical practice.
Results
A 40-year-old male was evaluated for chronic headaches. Six years before, he was hospitalized for a major depression with psychotic features. The first neurological examination was normal, except for a slow downbeat nystagmus. Brain MRI revealed significant hyperintensities in T2 and T2-FLAIR bilaterally in the frontal lobes, with periventricular and corpus callosum involvement, and without restricted diffusion. A multigene panel for leukodystrophies based on whole-exome sequencing identified two heterozygous variants in the AARS2 gene: one previously reported in the literature, already classified as pathogenic, NM_020745.4:c.595C > T (p.(Arg199Cys)), and one novel variant c.730G > A (p.(Val244Ile)), later reclassified as likely pathogenic. Nine years have passed since the first symptoms without clear clinical progression.
Discussion
This case underlines that adult-onset leukodystrophy caused by variants in AARS2 may have a wide range of phenotypes and patterns of progression. The new variant c.730G > A (p.(Val244Ile)) herein described may induce a milder clinical picture and a less severe radiological pattern.
Practical implications
Adult-onset leukoencephalopathies may present with milder clinical signs than what is generally perceived, and novel disease-causing variants are being identified.
{"title":"A novel disease-causing variant associated with a milder phenotype of AARS2-related leukodystrophy — A case report","authors":"Joana Fernandes , João Moura , João Tarrio , Jorge Oliveira , Ana Lopes , João Parente Freixo , Gonçalo Videira","doi":"10.1016/j.ymgmr.2024.101157","DOIUrl":"10.1016/j.ymgmr.2024.101157","url":null,"abstract":"<div><h3>Background and objectives</h3><div>Adult-onset leukodystrophies are a rare group of neurological disorders characterized by progressive degeneration of the cerebral white matter. One of these diseases is caused by biallelic pathogenic variants in the <em>AARS2</em> gene. We describe a patient with late-onset <em>AARS2</em>-related leukoencephalopathy, a milder phenotype and a novel disease-causing variant.</div></div><div><h3>Methods</h3><div>The patient was characterized during routine clinical practice.</div></div><div><h3>Results</h3><div>A 40-year-old male was evaluated for chronic headaches. Six years before, he was hospitalized for a major depression with psychotic features. The first neurological examination was normal, except for a slow downbeat nystagmus. Brain MRI revealed significant hyperintensities in T2 and T2-FLAIR bilaterally in the frontal lobes, with periventricular and corpus callosum involvement, and without restricted diffusion. A multigene panel for leukodystrophies based on whole-exome sequencing identified two heterozygous variants in the <em>AARS2</em> gene: one previously reported in the literature, already classified as pathogenic, NM_020745.4:c.595C > T (p.(Arg199Cys)), and one novel variant c.730G > A (p.(Val244Ile)), later reclassified as likely pathogenic. Nine years have passed since the first symptoms without clear clinical progression.</div></div><div><h3>Discussion</h3><div>This case underlines that adult-onset leukodystrophy caused by variants in <em>AARS2</em> may have a wide range of phenotypes and patterns of progression. The new variant c.730G > A (p.(Val244Ile)) herein described may induce a milder clinical picture and a less severe radiological pattern.</div></div><div><h3>Practical implications</h3><div>Adult-onset leukoencephalopathies may present with milder clinical signs than what is generally perceived, and novel disease-causing variants are being identified.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101157"},"PeriodicalIF":1.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142553122","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 : 2024-10-18DOI: 10.1016/j.ymgmr.2024.101156
Mahmood Noori , Omar Jarrah , Aisha Al Shamsi
Background
Protein metabolism and urea production maintain protein and amino acid homeostasis in normal status. Ammonia results from amino acid turnover and is produced by intestinal urease-positive bacteria. Ammonia must be detoxified, and the urea cycle converts ammonia into urea. CPS1 is an enzyme in the urea cycle that catalyzes ammonia and bicarbonate condensation. CPS1 deficiency presents in the neonatal period with hyperammonemia, resulting in death or neurological sequelae if patients survive.
Objectives/aims
To share the experience of patients with CPS1 deficiency from Tawam Hospital and to shed light on the spectrum of variants found in those patients.
Methods
A retrospective chart review was done. All patients with CPS1 deficiency admitted to Tawam Hospital from 2010 to 2023 were included. Collected data included age and ammonia level at presentation, the time needed to drop ammonia level below 100 μmol/L, acute management modality provided, long-term neurological sequelae, sequence variants, severity, and duration of hyperammonemia encephalopathy, age at last follow-up, and, if applicable, survival for at least six months.
Results
Only five patients with CPS1 deficiency over 13 years were found; two males and three females. Three patients are doing relatively well at 18 months, 7, and 9 years of age. The presented age was in the neonatal period except in one patient. One patient was found to have frameshift, resulting in a premature stop codon in the CPS1 gene, had a devastating course that ended with death. One patient had recurrent hyperammonemia episodes in her first year of life, which led to microcephaly and global developmental delay. One patient underwent hemodialysis, and one patient underwent peritoneal dialysis. All patients except one were on Carglumic acid which could contribute to their survival and disease control. All variants reported here are novel except one.
Conclusion
Although the presentation was different in severity, three patients are doing relatively well and approaching their developmental milestones. Thus, early recognition, prompt actions to drop high ammonia level, and good follow-up plans are emphasized. Further studies are needed to correlate the genotype-phenotype of reported variants here, which can help predict the severity of CPS1 deficiency.
{"title":"Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review","authors":"Mahmood Noori , Omar Jarrah , Aisha Al Shamsi","doi":"10.1016/j.ymgmr.2024.101156","DOIUrl":"10.1016/j.ymgmr.2024.101156","url":null,"abstract":"<div><h3>Background</h3><div>Protein metabolism and urea production maintain protein and amino acid homeostasis in normal status. Ammonia results from amino acid turnover and is produced by intestinal urease-positive bacteria. Ammonia must be detoxified, and the urea cycle converts ammonia into urea. CPS1 is an enzyme in the urea cycle that catalyzes ammonia and bicarbonate condensation. CPS1 deficiency presents in the neonatal period with hyperammonemia, resulting in death or neurological sequelae if patients survive.</div></div><div><h3>Objectives/aims</h3><div>To share the experience of patients with CPS1 deficiency from Tawam Hospital and to shed light on the spectrum of variants found in those patients.</div></div><div><h3>Methods</h3><div>A retrospective chart review was done. All patients with CPS1 deficiency admitted to Tawam Hospital from 2010 to 2023 were included. Collected data included age and ammonia level at presentation, the time needed to drop ammonia level below 100 μmol/L, acute management modality provided, long-term neurological sequelae, sequence variants, severity, and duration of hyperammonemia encephalopathy, age at last follow-up, and, if applicable, survival for at least six months.</div></div><div><h3>Results</h3><div>Only five patients with CPS1 deficiency over 13 years were found; two males and three females. Three patients are doing relatively well at 18 months, 7, and 9 years of age. The presented age was in the neonatal period except in one patient. One patient was found to have frameshift, resulting in a premature stop codon in the <em>CPS1</em> gene, had a devastating course that ended with death. One patient had recurrent hyperammonemia episodes in her first year of life, which led to microcephaly and global developmental delay. One patient underwent hemodialysis, and one patient underwent peritoneal dialysis. All patients except one were on Carglumic acid which could contribute to their survival and disease control. All variants reported here are novel except one.</div></div><div><h3>Conclusion</h3><div>Although the presentation was different in severity, three patients are doing relatively well and approaching their developmental milestones. Thus, early recognition, prompt actions to drop high ammonia level, and good follow-up plans are emphasized. Further studies are needed to correlate the genotype-phenotype of reported variants here, which can help predict the severity of CPS1 deficiency.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101156"},"PeriodicalIF":1.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142522471","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}
Isolated methylmalonic acidemia (iMMA) is a group of monogenic metabolic disorders affecting methylmalonate and cobalamin metabolism. Five iMMA-responsible genes have been described to date: MMUT (MIM *609058), MMAA (MIM *607481, MMAB (MIM *607568), MMADHC (MIM *611935), and MCEE (MIM *608419). Although iMMA is the most common form of organic acidemia reported in Mexico, its genotypic spectrum is still largely unknown. We performed a clinical exome analysis on 42 unrelated Mexican patients with iMMA. MMUT deficiency accounted for 73.8 % of all cases, followed by MMAA (14.2 %), MMAB (7.2 %), and MMADHC (2.4 %) deficiencies. One patient presented MMUT and MMAA double heterozygosity, which should be further experimentally confirmed to prove that synergistic heterozygosity could be another inheritance mechanism in iMMA. The most frequent MMUT genotype involved the Hispanic variant NM_000255.4:c. [322C > T];[322C > T] or p.[Arg108Cys];[Arg108Cys] (14.3 %). Two novel MMUT variants, NM_000255.4:c.589G > A or p.(Ala197Thr) and c.1476C > A or p.(Tyr492*), were identified in a deceased newborn presenting the neonatal-onset severe form of the disease. In silico protein modeling of the p.(Arg108Cys) and novel p.(Ala197Thr) MMUT variants suggested disruption of the substrate-binding and catalytic domains of the protein, respectively. This study expands the current knowledge on the molecular spectrum of iMMA in the Mexican population and reinforces the importance of genetic analysis in guiding clinical management.
孤立性甲基丙二酸血症（iMMA）是一组影响甲基丙二酸和钴胺素代谢的单基因代谢性疾病。迄今已描述了五种 iMMA 基因：MMUT（MIM *609058）、MMAA（MIM *607481）、MMAB（MIM *607568）、MMADHC（MIM *611935）和 MCEE（MIM *608419）。尽管 iMMA 是墨西哥报道的最常见的有机酸血症，但其基因型谱在很大程度上仍不为人所知。我们对 42 名无关的墨西哥 iMMA 患者进行了临床外显子组分析。MMUT 缺乏症占所有病例的 73.8%，其次是 MMAA（14.2%）、MMAB（7.2%）和 MMADHC（2.4%）缺乏症。有一名患者出现 MMUT 和 MMAA 双杂合子，应进一步通过实验证实协同杂合子可能是 iMMA 的另一种遗传机制。最常见的 MMUT 基因型涉及西班牙变体 NM_000255.4:c。[322C > T];[322C > T] or p.[Arg108Cys];[Arg108Cys] (14.3 %)。在一名患有新生儿重症的已故新生儿身上发现了两个新的 MMUT 变体，NM_000255.4:c.589G >A或p.(Ala197Thr)和c.1476C >A或p.(Tyr492*)。对p.(Arg108Cys)和新型p.(Ala197Thr)MMUT变体的硅学蛋白质建模表明，它们分别破坏了蛋白质的底物结合域和催化域。这项研究拓展了目前对墨西哥人群中 iMMA 分子谱的了解，并加强了基因分析在指导临床治疗方面的重要性。
{"title":"Isolated methylmalonic acidemia in Mexico: Genotypic spectrum, report of two novel MMUT variants and a possible synergistic heterozygosity effect","authors":"Cynthia Fernández-Lainez , Marcela Vela-Amieva , Miriam Reyna-Fabián , Liliana Fernández-Hernández , Sara Guillén-López , Lizbeth López-Mejía , Miguel Ángel Alcántara-Ortigoza , Ariadna González-del Angel , Rosa Itzel Carrillo-Nieto , Enrique Ortega-Valdez , Mauricio Rojas-Maruri , Cecilia Ridaura-Sanz","doi":"10.1016/j.ymgmr.2024.101155","DOIUrl":"10.1016/j.ymgmr.2024.101155","url":null,"abstract":"<div><div>Isolated methylmalonic acidemia (iMMA) is a group of monogenic metabolic disorders affecting methylmalonate and cobalamin metabolism. Five iMMA-responsible genes have been described to date: <em>MMUT</em> (MIM *609058), <em>MMAA</em> (MIM *607481, <em>MMAB</em> (MIM *607568), <em>MMADHC</em> (MIM *611935), and <em>MCEE</em> (MIM *608419). Although iMMA is the most common form of organic acidemia reported in Mexico, its genotypic spectrum is still largely unknown. We performed a clinical exome analysis on 42 unrelated Mexican patients with iMMA. <em>MMUT</em> deficiency accounted for 73.8 % of all cases, followed by <em>MMAA</em> (14.2 %), <em>MMAB</em> (7.2 %), and <em>MMADHC</em> (2.4 %) deficiencies. One patient presented <em>MMUT</em> and <em>MMAA</em> double heterozygosity, which should be further experimentally confirmed to prove that synergistic heterozygosity could be another inheritance mechanism in iMMA. The most frequent <em>MMUT</em> genotype involved the Hispanic variant NM_000255.4:c. [322C > T];[322C > T] or p.[Arg108Cys];[Arg108Cys] (14.3 %). Two novel <em>MMUT</em> variants, NM_000255.4:c.589G > A or p.(Ala197Thr) and c.1476C > A or p.(Tyr492*), were identified in a deceased newborn presenting the neonatal-onset severe form of the disease. <em>In silico</em> protein modeling of the p.(Arg108Cys) and novel p.(Ala197Thr) <em>MMUT</em> variants suggested disruption of the substrate-binding and catalytic domains of the protein, respectively. This study expands the current knowledge on the molecular spectrum of iMMA in the Mexican population and reinforces the importance of genetic analysis in guiding clinical management.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101155"},"PeriodicalIF":1.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441956","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 : 2024-10-16DOI: 10.1016/j.ymgmr.2024.101150
Victoria Sokalski , Kolja Lau , Tereza Cairns , Claudia Sommer , Nurcan Üçeyler , Peter Nordbeck
<div><h3>Background</h3><div>The worldwide Covid19 pandemic caused by the rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represented a unique challenge for patients and healthcare professionals. Patients with chronic rare diseases had to face novel burdens, like the inability to perform regular on-site visits or even difficulties in the supply of medication. Patients with Fabry disease (FD) are affected by a variety of organ manifestations leading to physical but also psychological burden and limitations, which are usually presented in low health-related quality of life (HR-QoL). We sought to examine the impact of the Covid19 pandemic on HR-QoL in patients with FD and their implications for the future care of patients with rare diseases.</div></div><div><h3>Methods</h3><div>This single-center study included patients seen shortly prior to and after the peak of the Covid19 pandemic in 2020 at our study site. All patients had a confirmed genetic diagnosis of FD. Subjects with presumed apathogenic to benigne genetic variants in the GLA gene were excluded. The Short Form (36) Health Survey (SF-36) was used to obtain patients‘self-reported outcome. Clinical data and SF-36 scores were collected and analysed for the time period prior to and after the peak of the pandemic.</div></div><div><h3>Results</h3><div>In total, 60 patients (mean age 47.9 ± 15 years, 53.3 % male) were included. The majority presented with a pathogenic gene variant (63.3 %) associated with classic phenotype. At baseline, 66.7 % were on enzyme replacement therapy (ERT), and 21.7 % on chaperone therapy. Predominant organ manifestations were cardiac (42/60, 70.0 %) and neurological (39/60, 65.0 %). After paired comparison prior and post peak of the pandemic in 2020, all eight items of the SF-36 score showed a numeric decline. Three items presented with a intergroup difference: social functioning (72.5 ± 29.3 vs. 64.8 ± 29.3, <em>p</em> = 0.012), energy/fatigue (56.8 ± 21.7 vs. 48.3 ± 23.9, <em>p</em> < 0.001), and role limitations due to physical health (64.2 ± 42.0 vs. 51.1 ± 45.5, <em>p</em> = 0.007).</div><div>Subgroup analysis (regarding gender, age, and treatment) revealed that especially male and older (≥50 years) patients with FD showed reductions in multiple categories of HR-QoL. The item “energy/fatigue“ presented significant declines among all subgroups.</div></div><div><h3>Conclusions</h3><div>The worldwide Covid19 pandemic had a persistent negative affect on self-reported HR-QoL in patients with FD, including both mental and physical aspects. It remains unclear to what extend the disease itself and accompanying circumstances including local and governmental actions and restrictions contributed to these deteriorations. Our findings stress the importance for meticulous and constant interdisciplinary care including psychosocial aspects in patients with chronic progressive diseases as well as the need for a change in mindset concerning futur
{"title":"Impact of the Covid19 pandemic on health-related quality of life in patients with Fabry disease - implications for future care of patients with rare diseases","authors":"Victoria Sokalski , Kolja Lau , Tereza Cairns , Claudia Sommer , Nurcan Üçeyler , Peter Nordbeck","doi":"10.1016/j.ymgmr.2024.101150","DOIUrl":"10.1016/j.ymgmr.2024.101150","url":null,"abstract":"<div><h3>Background</h3><div>The worldwide Covid19 pandemic caused by the rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represented a unique challenge for patients and healthcare professionals. Patients with chronic rare diseases had to face novel burdens, like the inability to perform regular on-site visits or even difficulties in the supply of medication. Patients with Fabry disease (FD) are affected by a variety of organ manifestations leading to physical but also psychological burden and limitations, which are usually presented in low health-related quality of life (HR-QoL). We sought to examine the impact of the Covid19 pandemic on HR-QoL in patients with FD and their implications for the future care of patients with rare diseases.</div></div><div><h3>Methods</h3><div>This single-center study included patients seen shortly prior to and after the peak of the Covid19 pandemic in 2020 at our study site. All patients had a confirmed genetic diagnosis of FD. Subjects with presumed apathogenic to benigne genetic variants in the GLA gene were excluded. The Short Form (36) Health Survey (SF-36) was used to obtain patients‘self-reported outcome. Clinical data and SF-36 scores were collected and analysed for the time period prior to and after the peak of the pandemic.</div></div><div><h3>Results</h3><div>In total, 60 patients (mean age 47.9 ± 15 years, 53.3 % male) were included. The majority presented with a pathogenic gene variant (63.3 %) associated with classic phenotype. At baseline, 66.7 % were on enzyme replacement therapy (ERT), and 21.7 % on chaperone therapy. Predominant organ manifestations were cardiac (42/60, 70.0 %) and neurological (39/60, 65.0 %). After paired comparison prior and post peak of the pandemic in 2020, all eight items of the SF-36 score showed a numeric decline. Three items presented with a intergroup difference: social functioning (72.5 ± 29.3 vs. 64.8 ± 29.3, <em>p</em> = 0.012), energy/fatigue (56.8 ± 21.7 vs. 48.3 ± 23.9, <em>p</em> < 0.001), and role limitations due to physical health (64.2 ± 42.0 vs. 51.1 ± 45.5, <em>p</em> = 0.007).</div><div>Subgroup analysis (regarding gender, age, and treatment) revealed that especially male and older (≥50 years) patients with FD showed reductions in multiple categories of HR-QoL. The item “energy/fatigue“ presented significant declines among all subgroups.</div></div><div><h3>Conclusions</h3><div>The worldwide Covid19 pandemic had a persistent negative affect on self-reported HR-QoL in patients with FD, including both mental and physical aspects. It remains unclear to what extend the disease itself and accompanying circumstances including local and governmental actions and restrictions contributed to these deteriorations. Our findings stress the importance for meticulous and constant interdisciplinary care including psychosocial aspects in patients with chronic progressive diseases as well as the need for a change in mindset concerning futur","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101150"},"PeriodicalIF":1.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441955","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}
Phenylketonuria (PKU) results from a deficiency in phenylalanine hydroxylase, catalyzing the conversion of phenylalanine (Phe) to tyrosine. Premenstrual syndrome (PMS) consists of physical, behavioral, and emotional symptoms occurring during the last week of luteal phase. The aim of the study was to determine the incidence of PMS, and document menstrual cycle characteristics of PKU patients to reveal the relationship with blood Phe levels. The study was conducted on 74 patients with a mean age of 21.7 ± 5.4 years. The mean age at menarche was 12.7 ± 1.3 years and 82.4 % had regular menstrual cycles. The periods of most patients (47.2 %) lasted 4–5 days. Menstrual cycles of 21–28 days were reported by 73 %, less than 21 days by 8 %, and more than 28 days by 19 % of women. Menorrhagia and dysmenorrhea was observed in 6.7 % and 71.6 % respectively. Adherence to diet was lost in 7 patients during the menstrual period. No significant relationship was found between Phe levels and PMS symptoms (p > 0.05). According to PMSS subscales, 52.7 % of patients with PKU had depressive feelings, 16.2 % anxiety, 55.4 % fatigue, 52.7 % irritability, 28.3 % depressive thoughts, 39.1 % pain, 59.4 % changes in appetite, 28.3 % changes in sleeping habits and 43.2 % had swelling. The findings of the study revealed that PMS prevalence was 39.1 % among PKU women. Awareness about this syndrome, will improve the quality of life in women with PKU by evaluating and taking measures for PMS.
Synopsis
Evaluating menstrual cycle characteristics and premenstrual syndrome in phenylketonuria patients provides valuable insights for enhancing their overall health profile and personalizing treatment and management plans.
{"title":"The relationship between menstrual cycle characteristics, premenstrual syndrome prevalence and blood phenylalanine level in women with PKU","authors":"Arzu Selamioğlu , Zelal Tandoğan , Mehmet Cihan Balcı , Meryem Karaca , Tuğba Kozanoğlu , Alihan Yesil , Gülden Gökçay","doi":"10.1016/j.ymgmr.2024.101154","DOIUrl":"10.1016/j.ymgmr.2024.101154","url":null,"abstract":"<div><div>Phenylketonuria (PKU) results from a deficiency in phenylalanine hydroxylase, catalyzing the conversion of phenylalanine (Phe) to tyrosine. Premenstrual syndrome (PMS) consists of physical, behavioral, and emotional symptoms occurring during the last week of luteal phase. The aim of the study was to determine the incidence of PMS, and document menstrual cycle characteristics of PKU patients to reveal the relationship with blood Phe levels. The study was conducted on 74 patients with a mean age of 21.7 ± 5.4 years. The mean age at menarche was 12.7 ± 1.3 years and 82.4 % had regular menstrual cycles. The periods of most patients (47.2 %) lasted 4–5 days. Menstrual cycles of 21–28 days were reported by 73 %, less than 21 days by 8 %, and more than 28 days by 19 % of women. Menorrhagia and dysmenorrhea was observed in 6.7 % and 71.6 % respectively. Adherence to diet was lost in 7 patients during the menstrual period. No significant relationship was found between Phe levels and PMS symptoms (<em>p</em> > 0.05). According to PMSS subscales, 52.7 % of patients with PKU had depressive feelings, 16.2 % anxiety, 55.4 % fatigue, 52.7 % irritability, 28.3 % depressive thoughts, 39.1 % pain, 59.4 % changes in appetite, 28.3 % changes in sleeping habits and 43.2 % had swelling. The findings of the study revealed that PMS prevalence was 39.1 % among PKU women. Awareness about this syndrome, will improve the quality of life in women with PKU by evaluating and taking measures for PMS.</div></div><div><h3>Synopsis</h3><div>Evaluating menstrual cycle characteristics and premenstrual syndrome in phenylketonuria patients provides valuable insights for enhancing their overall health profile and personalizing treatment and management plans.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101154"},"PeriodicalIF":1.8,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142433111","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 : 2024-10-13DOI: 10.1016/j.ymgmr.2024.101153
Fuad Al Mutairi , Randa Alkhalaf , Abdul Rafiq Khan , Ali Al Othaim , Majid Alfadhel
Background
Elevated plasma levels of 3-hydroxyisovaleryl-carnitine (C5OH) and impaired leucine catabolism are frequently observed in newborn screening reports, necessitating consideration of various diseases in the differential diagnosis. This study aimed to analyze different forms of C5OH and explore their potential predictive value for diagnosis and outcomes.
Methods
A retrospective review of newborn screening positive cases for C5OH-related diseases from May 2011 to December 2023 was conducted. Clinical, biochemical, and molecular phenotypes of all confirmed positive cases during this period were examined.
Results
A total of 15 true positive cases were diagnosed. No significant correlation was found between the C5OH levels in newborn screening and the diagnosis of specific C5OH-related disorders or the presence of metabolic, neonatal, or developmental abnormalities. Outcomes varied based on the spectrum of diseases.
Conclusion
These findings indicate that relying solely on C5OH levels from newborn screening is insufficient for making accurate diagnoses or predictions regarding C5OH-related disorders. Further comprehensive evaluation and consideration of additional factors are essential for accurate diagnosis, management and outcome.
{"title":"Outcomes of cases with elevated 3-hydroxyisovaleryl carnitine report from the newborn screening program","authors":"Fuad Al Mutairi , Randa Alkhalaf , Abdul Rafiq Khan , Ali Al Othaim , Majid Alfadhel","doi":"10.1016/j.ymgmr.2024.101153","DOIUrl":"10.1016/j.ymgmr.2024.101153","url":null,"abstract":"<div><h3>Background</h3><div>Elevated plasma levels of 3-hydroxyisovaleryl-carnitine (C5OH) and impaired leucine catabolism are frequently observed in newborn screening reports, necessitating consideration of various diseases in the differential diagnosis. This study aimed to analyze different forms of C5OH and explore their potential predictive value for diagnosis and outcomes.</div></div><div><h3>Methods</h3><div>A retrospective review of newborn screening positive cases for C5OH-related diseases from May 2011 to December 2023 was conducted. Clinical, biochemical, and molecular phenotypes of all confirmed positive cases during this period were examined.</div></div><div><h3>Results</h3><div>A total of 15 true positive cases were diagnosed. No significant correlation was found between the C5OH levels in newborn screening and the diagnosis of specific C5OH-related disorders or the presence of metabolic, neonatal, or developmental abnormalities. Outcomes varied based on the spectrum of diseases.</div></div><div><h3>Conclusion</h3><div>These findings indicate that relying solely on C5OH levels from newborn screening is insufficient for making accurate diagnoses or predictions regarding C5OH-related disorders. Further comprehensive evaluation and consideration of additional factors are essential for accurate diagnosis, management and outcome.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101153"},"PeriodicalIF":1.8,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142433109","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 is the most frequently occurring form of lysosomal disease in Japan, and is characterized by a wide variety of conditions. Primarily, the three major types of concerns associated with Fabry disease observed during adulthood that must be prevented are central nervous system, renal, and cardiac complications. Cardiac complications, such as cardiomyopathy, cardiac muscle fibrosis, and severe arrhythmia, are the most common mortality causes in patients with Fabry disease. To predict cardiac complications of Fabry disease, we extracted RNA from the venous blood of patients for cap analysis of gene expression (CAGE), performed likelihood ratio tests for each RNA expression dataset obtained from individuals with and without cardiac complications, and analyzed the correlation between cardiac functional factors observed using magnetic resonance imaging data extracted using artificial intelligence algorithms and RNA expression. Our findings showed that CHN1 expression was significantly higher in male Fabry disease patients with cardiac complications and that it could be associated with many cardiac functional factors. CHN1 encodes a GTPase-activating protein, chimerin 1, which is specific to the GTP-binding protein Rac (involved in oxidative stress generation and the promotion of myocardial fibrosis). Thus, CHN1 is a potential predictive biomarker of cardiac complications in Fabry disease; however, further studies are required to confirm this observation.
{"title":"Using artificial intelligence and promoter-level transcriptome analysis to identify a biomarker as a possible prognostic predictor of cardiac complications in male patients with Fabry disease","authors":"Hiroshi Kobayashi , Norio Nakata , Sayoko Izuka , Kenichi Hongo , Masako Nishikawa","doi":"10.1016/j.ymgmr.2024.101152","DOIUrl":"10.1016/j.ymgmr.2024.101152","url":null,"abstract":"<div><div>Fabry disease is the most frequently occurring form of lysosomal disease in Japan, and is characterized by a wide variety of conditions. Primarily, the three major types of concerns associated with Fabry disease observed during adulthood that must be prevented are central nervous system, renal, and cardiac complications. Cardiac complications, such as cardiomyopathy, cardiac muscle fibrosis, and severe arrhythmia, are the most common mortality causes in patients with Fabry disease. To predict cardiac complications of Fabry disease, we extracted RNA from the venous blood of patients for cap analysis of gene expression (CAGE), performed likelihood ratio tests for each RNA expression dataset obtained from individuals with and without cardiac complications, and analyzed the correlation between cardiac functional factors observed using magnetic resonance imaging data extracted using artificial intelligence algorithms and RNA expression. Our findings showed that CHN1 expression was significantly higher in male Fabry disease patients with cardiac complications and that it could be associated with many cardiac functional factors. <em>CHN1</em> encodes a GTPase-activating protein, chimerin 1, which is specific to the GTP-binding protein Rac (involved in oxidative stress generation and the promotion of myocardial fibrosis). Thus, CHN1 is a potential predictive biomarker of cardiac complications in Fabry disease; however, further studies are required to confirm this observation.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101152"},"PeriodicalIF":1.8,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142433110","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}
Many adults with phenylketonuria (PKU) were discharged from clinics before lifelong treatment guidelines and new therapies. As part of the PKU lost to clinical care study, moderated focus groups were conducted to understand why individuals become lost to care and how to maintain patient engagement. Focus groups involved active clinic patients and those lost to PKU care. Discussions revealed desire for enhanced communication, improved support and access, and community connections.
{"title":"Patient voices on PKU care: Insights from focus groups with current and former patients","authors":"Emily Zhu , Suzanne Hollander , Stephanie Sacharow","doi":"10.1016/j.ymgmr.2024.101148","DOIUrl":"10.1016/j.ymgmr.2024.101148","url":null,"abstract":"<div><div>Many adults with phenylketonuria (PKU) were discharged from clinics before lifelong treatment guidelines and new therapies. As part of the PKU lost to clinical care study, moderated focus groups were conducted to understand why individuals become lost to care and how to maintain patient engagement. Focus groups involved active clinic patients and those lost to PKU care. Discussions revealed desire for enhanced communication, improved support and access, and community connections.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101148"},"PeriodicalIF":1.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142421596","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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