Pub Date : 2024-08-22DOI: 10.1186/s13023-024-03292-w
Agata Suleja, Katarzyna Milska-Musa, Łukasz Przysło, Marzena Bednarczyk, Marcin Kostecki, Dominik Cysewski, Paweł Matryba, Anna Rozensztrauch, Michał Dwornik, Marcin Opacki, Robert Śmigiel, Kacper Łukasiewicz
Background: Angelman syndrome (AS) is a rare neurodevelopmental disease caused by imprinting disorders that impede the production of the ubiquitin E3A ligase protein (UBE3A). AS affects multiple systems, with the main symptoms including epilepsy, psychomotor disorders and speech development disorders. To date, no study has been conducted in the Polish population to verify the condition's diagnosis and treatment process.
Results: Seventy patients with the median age of 60 months were included into the analysis. 80% of patients were diagnosed with deletion, 19.9% with a mutation of UBE3A gene, 4.3% with paternal uniparental disomy (UPD) and 2.8% with an imprinting defect. The mean age of first symptoms was 5 months, while the mean age of diagnosis was 29 months (earliest in deletion group at 23 months), and the median duration of diagnosis process was 7 months. The average time to a clinical geneticist appointment was 3 months. 37.9% of the patients initially received a different diagnosis. Epileptic seizures were present in 88.6% of the individuals. 98.6% of the studied group were under care of a pediatric neurologist, 47.1% of a gastroenterologist. A ketogenic diet was used in 7.1% of patients. Caregivers identified finding a specialist suitable for AS patients and access to genetic testing as the biggest problems.
Conclusions: The care of patients with AS in Poland is carried out according to the European and world standards, however there is an impeded access to clinical geneticist, and the knowledge about rare diseases among primary healthcare physicians could be improved. Moreover, access to AS care specialists and coordination of care is limited. There is a need for creation a specialized centers and databases for AS patients.
{"title":"Angelman syndrome in Poland: current diagnosis and therapy status-the caregiver perspective: a questionnaire study.","authors":"Agata Suleja, Katarzyna Milska-Musa, Łukasz Przysło, Marzena Bednarczyk, Marcin Kostecki, Dominik Cysewski, Paweł Matryba, Anna Rozensztrauch, Michał Dwornik, Marcin Opacki, Robert Śmigiel, Kacper Łukasiewicz","doi":"10.1186/s13023-024-03292-w","DOIUrl":"10.1186/s13023-024-03292-w","url":null,"abstract":"<p><strong>Background: </strong>Angelman syndrome (AS) is a rare neurodevelopmental disease caused by imprinting disorders that impede the production of the ubiquitin E3A ligase protein (UBE3A). AS affects multiple systems, with the main symptoms including epilepsy, psychomotor disorders and speech development disorders. To date, no study has been conducted in the Polish population to verify the condition's diagnosis and treatment process.</p><p><strong>Results: </strong>Seventy patients with the median age of 60 months were included into the analysis. 80% of patients were diagnosed with deletion, 19.9% with a mutation of UBE3A gene, 4.3% with paternal uniparental disomy (UPD) and 2.8% with an imprinting defect. The mean age of first symptoms was 5 months, while the mean age of diagnosis was 29 months (earliest in deletion group at 23 months), and the median duration of diagnosis process was 7 months. The average time to a clinical geneticist appointment was 3 months. 37.9% of the patients initially received a different diagnosis. Epileptic seizures were present in 88.6% of the individuals. 98.6% of the studied group were under care of a pediatric neurologist, 47.1% of a gastroenterologist. A ketogenic diet was used in 7.1% of patients. Caregivers identified finding a specialist suitable for AS patients and access to genetic testing as the biggest problems.</p><p><strong>Conclusions: </strong>The care of patients with AS in Poland is carried out according to the European and world standards, however there is an impeded access to clinical geneticist, and the knowledge about rare diseases among primary healthcare physicians could be improved. Moreover, access to AS care specialists and coordination of care is limited. There is a need for creation a specialized centers and databases for AS patients.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background and objectives: Congenital heart defect (CHD) is one of the most common birth defects. The aim of this cohort study was to evaluate the prevalence of chromosomal abnormalities and the clinical utility of chromosomal microarray analysis (CMA) in fetuses with different types of CHD, aiming to assist genetic counseling and clinical decision-making.
Methods: In this study, 642 fetuses with CHD were enrolled from a single center over a six-year period (2017-2022). Both conventional karyotyping and CMA were performed simultaneously on these fetuses.
Results: The diagnostic yield of CMA in fetuses with CHD in our study was 15.3% (98/642). Our findings revealed a significant increase in the diagnostic yield of CMA compared to karyotyping in fetuses with CHD. Among CHD subgroups, the diagnostic yields were high in complex CHD (34.9%), conotruncal defects (28.6%), right ventricular outflow tract obstructive defects (RVOTO) (25.9%), atrioventricular septal defects (AVSD) (25.0%) and left ventricular outflow tract obstructive defects (LVOTO) (24.1%), while those in other CHD (10.6%) and septal defects (10.9%) were relatively low. The overall detection rate of clinically significant chromosomal abnormalities was significantly higher in the non-isolated CHD group compared to the isolated CHD group (33.1% vs. 9.9%, P < 0.0001). Interestingly, numerical chromosomal abnormalities were more likely to occur in the non-isolated CHD group than in the isolated CHD group (20.3% vs. 2.0%, P < 0.0001). The rate of termination of pregnancy (TOP)/Still birth in the non-isolated CHD group was significantly higher than that in the isolated CHD group (40.5% vs. 20.6%, P < 0.0001). Compared to the isolated CHD group, the detection rate of clinically significant chromosomal abnormalities was significantly higher in the group of CHD with soft markers (35.6% vs. 9.9%, P < 0.0001) and in the group of CHD with additional structural anomalies (36.1% vs. 9.9%, P < 0.0001).
Conclusions: CMA is a reliable and high-resolution technique that should be recommended as the front-line test for prenatal diagnosis of fetuses with CHD. The prevalence of chromosomal abnormalities varies greatly among different subgroups of CHD, and special attention should be given to prenatal non-isolated cases of CHD, especially those accompanied by additional structural anomalies or soft markers.
{"title":"Prenatal chromosomal microarray analysis in a large Chinese cohort of fetuses with congenital heart defects: a single center study.","authors":"Qing Lu, Laipeng Luo, Baitao Zeng, Haiyan Luo, Xianjin Wang, Lijuan Qiu, Yan Yang, Chuanxin Feng, Jihui Zhou, Yanling Hu, Tingting Huang, Pengpeng Ma, Ting Huang, Kang Xie, Huizhen Yuan, Shuhui Huang, Bicheng Yang, Yongyi Zou, Yanqiu Liu","doi":"10.1186/s13023-024-03317-4","DOIUrl":"10.1186/s13023-024-03317-4","url":null,"abstract":"<p><strong>Background and objectives: </strong>Congenital heart defect (CHD) is one of the most common birth defects. The aim of this cohort study was to evaluate the prevalence of chromosomal abnormalities and the clinical utility of chromosomal microarray analysis (CMA) in fetuses with different types of CHD, aiming to assist genetic counseling and clinical decision-making.</p><p><strong>Methods: </strong>In this study, 642 fetuses with CHD were enrolled from a single center over a six-year period (2017-2022). Both conventional karyotyping and CMA were performed simultaneously on these fetuses.</p><p><strong>Results: </strong>The diagnostic yield of CMA in fetuses with CHD in our study was 15.3% (98/642). Our findings revealed a significant increase in the diagnostic yield of CMA compared to karyotyping in fetuses with CHD. Among CHD subgroups, the diagnostic yields were high in complex CHD (34.9%), conotruncal defects (28.6%), right ventricular outflow tract obstructive defects (RVOTO) (25.9%), atrioventricular septal defects (AVSD) (25.0%) and left ventricular outflow tract obstructive defects (LVOTO) (24.1%), while those in other CHD (10.6%) and septal defects (10.9%) were relatively low. The overall detection rate of clinically significant chromosomal abnormalities was significantly higher in the non-isolated CHD group compared to the isolated CHD group (33.1% vs. 9.9%, P < 0.0001). Interestingly, numerical chromosomal abnormalities were more likely to occur in the non-isolated CHD group than in the isolated CHD group (20.3% vs. 2.0%, P < 0.0001). The rate of termination of pregnancy (TOP)/Still birth in the non-isolated CHD group was significantly higher than that in the isolated CHD group (40.5% vs. 20.6%, P < 0.0001). Compared to the isolated CHD group, the detection rate of clinically significant chromosomal abnormalities was significantly higher in the group of CHD with soft markers (35.6% vs. 9.9%, P < 0.0001) and in the group of CHD with additional structural anomalies (36.1% vs. 9.9%, P < 0.0001).</p><p><strong>Conclusions: </strong>CMA is a reliable and high-resolution technique that should be recommended as the front-line test for prenatal diagnosis of fetuses with CHD. The prevalence of chromosomal abnormalities varies greatly among different subgroups of CHD, and special attention should be given to prenatal non-isolated cases of CHD, especially those accompanied by additional structural anomalies or soft markers.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142036522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1186/s13023-024-03310-x
Qiyu Dong, Xiaojie Yin, Shuanglong Fan, Sheng Zhong, Wenxin Yang, Keer Chen, Qian Wang, Xue Ma, Refiloe Laurentinah Mahlatsi, Yanling Yang, Jianxin Lyu, Hezhi Fang, Ya Wang
Background: Leigh syndrome (LS) is a common mitochondrial disease caused by mutations in both mitochondrial and nuclear genes. Isoleucyl-tRNA synthetase 2 (IARS2) encodes mitochondrial isoleucine-tRNA synthetase, and variants in IARS2 have been reported to cause LS. However, the pathogenic mechanism of IARS2 variants is still unclear.
Methods: Two unrelated patients, a 4-year-old boy and a 5-year-old boy diagnosed with LS, were recruited, and detailed clinical data were collected. The DNA of the patients and their parents was isolated from the peripheral blood for the identification of pathogenic variants using next-generation sequencing and Sanger sequencing. The ClustalW program, allele frequency analysis databases (gnomAD and ExAc), and pathogenicity prediction databases (Clinvar, Mutation Taster and PolyPhen2) were used to predict the conservation and pathogenicity of the variants. The gene expression level, oxygen consumption rate (OCR), respiratory chain complex activity, cellular adenosine triphosphate (ATP) production, mitochondrial membrane potential (MMP) and mitochondrial reactive oxygen species (ROS) levels were measured in patient-derived lymphocytes and IARS2-knockdown HEK293T cells to evaluate the pathogenicity of the variants.
Results: We reported 2 unrelated Chinese patients manifested with LS who carried biallelic IARS2 variants (c.1_390del and c.2450G > A from a 4-year-old boy, and c.2090G > A and c.2122G > A from a 5-year-old boy), of which c.1_390del and c.2090G > A were novel. Functional studies revealed that the patient-derived lymphocytes carrying c.1_390del and c.2450G > A variants exhibited impaired mitochondrial function due to severe mitochondrial complexes I and III deficiencies, which was also found in IARS2-knockdown HEK293T cells. The compensatory experiments in vitro cell models confirmed the pathogenicity of IARS2 variants since re-expression of wild-type IARS2 rather than mutant IARS2 could rescue complexes I and III deficiency, oxygen consumption, and cellular ATP content in IARS2 knockdown cells.
Conclusion: Our results not only expand the gene mutation spectrum of LS, but also reveal for the first time the pathogenic mechanism of IARS2 variants due to a combined deficiency of mitochondrial complexes I and III, which is helpful for the clinical diagnosis of IARS2 mutation-related diseases.
背景:莱氏综合征(LS)是一种常见的线粒体疾病,由线粒体和核基因突变引起。异亮氨酰-tRNA合成酶2(IARS2)编码线粒体异亮氨酰-tRNA合成酶,有报道称IARS2变体可导致LS。然而,IARS2变体的致病机制仍不清楚:方法:招募了两名无血缘关系的患者(一名 4 岁男孩和一名 5 岁男孩,诊断为 LS),并收集了详细的临床数据。从患者及其父母的外周血中分离DNA,利用新一代测序和桑格测序鉴定致病变体。利用ClustalW程序、等位基因频率分析数据库(gnomAD和ExAc)和致病性预测数据库(Clinvar、Mutation Taster和PolyPhen2)预测变异体的保守性和致病性。为了评估变异体的致病性,我们测定了患者淋巴细胞和IARS2-敲除的HEK293T细胞的基因表达水平、耗氧量(OCR)、呼吸链复合物活性、细胞三磷酸腺苷(ATP)产生量、线粒体膜电位(MMP)和线粒体活性氧(ROS)水平:我们报告了两名无血缘关系的中国LS患者,他们携带双倍拷贝IARS2变异体(一名4岁男孩的c.1_390del和c.2450G > A,一名5岁男孩的c.2090G > A和c.2122G > A),其中c.1_390del和c.2090G > A是新变异体。功能研究显示,携带 c.1_390del 和 c.2450G > A 变体的患者淋巴细胞由于线粒体复合物 I 和 III 严重缺乏而导致线粒体功能受损,在 IARS2- 敲除的 HEK293T 细胞中也发现了这种情况。体外细胞模型的补偿实验证实了 IARS2 变体的致病性,因为重新表达野生型 IARS2 而不是突变型 IARS2 可以挽救 IARS2 敲除细胞中复合体 I 和 III 的缺乏、耗氧量和细胞 ATP 含量:结论:我们的研究结果不仅扩大了LS的基因突变谱,而且首次揭示了IARS2变体因线粒体复合物I和III联合缺乏而致病的机制,有助于IARS2突变相关疾病的临床诊断。
{"title":"IARS2 mutations lead to Leigh syndrome with a combined oxidative phosphorylation deficiency.","authors":"Qiyu Dong, Xiaojie Yin, Shuanglong Fan, Sheng Zhong, Wenxin Yang, Keer Chen, Qian Wang, Xue Ma, Refiloe Laurentinah Mahlatsi, Yanling Yang, Jianxin Lyu, Hezhi Fang, Ya Wang","doi":"10.1186/s13023-024-03310-x","DOIUrl":"10.1186/s13023-024-03310-x","url":null,"abstract":"<p><strong>Background: </strong>Leigh syndrome (LS) is a common mitochondrial disease caused by mutations in both mitochondrial and nuclear genes. Isoleucyl-tRNA synthetase 2 (IARS2) encodes mitochondrial isoleucine-tRNA synthetase, and variants in IARS2 have been reported to cause LS. However, the pathogenic mechanism of IARS2 variants is still unclear.</p><p><strong>Methods: </strong>Two unrelated patients, a 4-year-old boy and a 5-year-old boy diagnosed with LS, were recruited, and detailed clinical data were collected. The DNA of the patients and their parents was isolated from the peripheral blood for the identification of pathogenic variants using next-generation sequencing and Sanger sequencing. The ClustalW program, allele frequency analysis databases (gnomAD and ExAc), and pathogenicity prediction databases (Clinvar, Mutation Taster and PolyPhen2) were used to predict the conservation and pathogenicity of the variants. The gene expression level, oxygen consumption rate (OCR), respiratory chain complex activity, cellular adenosine triphosphate (ATP) production, mitochondrial membrane potential (MMP) and mitochondrial reactive oxygen species (ROS) levels were measured in patient-derived lymphocytes and IARS2-knockdown HEK293T cells to evaluate the pathogenicity of the variants.</p><p><strong>Results: </strong>We reported 2 unrelated Chinese patients manifested with LS who carried biallelic IARS2 variants (c.1_390del and c.2450G > A from a 4-year-old boy, and c.2090G > A and c.2122G > A from a 5-year-old boy), of which c.1_390del and c.2090G > A were novel. Functional studies revealed that the patient-derived lymphocytes carrying c.1_390del and c.2450G > A variants exhibited impaired mitochondrial function due to severe mitochondrial complexes I and III deficiencies, which was also found in IARS2-knockdown HEK293T cells. The compensatory experiments in vitro cell models confirmed the pathogenicity of IARS2 variants since re-expression of wild-type IARS2 rather than mutant IARS2 could rescue complexes I and III deficiency, oxygen consumption, and cellular ATP content in IARS2 knockdown cells.</p><p><strong>Conclusion: </strong>Our results not only expand the gene mutation spectrum of LS, but also reveal for the first time the pathogenic mechanism of IARS2 variants due to a combined deficiency of mitochondrial complexes I and III, which is helpful for the clinical diagnosis of IARS2 mutation-related diseases.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11340112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1186/s13023-024-03250-6
Frédéric Gottrand, Usha Krishnan, Anke Widenmann, Michaela Dellenmark Blom, Luigi Dall'Oglio, Rene Wijnen, Michiel van Wijk, JoAnne Fruithof, Daniel von Allmen, Tom Kovesi, Christophe Faure
The International Network on Esophageal Atresia (INoEA) stands as a beacon of collaboration in addressing the complexities of this congenital condition on a global scale. The eleven board members, from various countries (USA, Canada, France, Australia, Italy, Sweden, Germany, and The Netherlands) and backgrounds (pediatric gastroenterology, pediatric surgery, pediatric pulmonology, nursing, and parents) met in a face-to-face symposium in Lille in November 2023, to identify challenges and solutions for improving global collaboration of the network.
{"title":"Navigating global collaboration: challenges faced by the international network on esophageal atresia.","authors":"Frédéric Gottrand, Usha Krishnan, Anke Widenmann, Michaela Dellenmark Blom, Luigi Dall'Oglio, Rene Wijnen, Michiel van Wijk, JoAnne Fruithof, Daniel von Allmen, Tom Kovesi, Christophe Faure","doi":"10.1186/s13023-024-03250-6","DOIUrl":"10.1186/s13023-024-03250-6","url":null,"abstract":"<p><p>The International Network on Esophageal Atresia (INoEA) stands as a beacon of collaboration in addressing the complexities of this congenital condition on a global scale. The eleven board members, from various countries (USA, Canada, France, Australia, Italy, Sweden, Germany, and The Netherlands) and backgrounds (pediatric gastroenterology, pediatric surgery, pediatric pulmonology, nursing, and parents) met in a face-to-face symposium in Lille in November 2023, to identify challenges and solutions for improving global collaboration of the network.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11337619/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-20DOI: 10.1186/s13023-024-03295-7
Hannah McBride, Sharon Evans, Alex Pinto, Anne Daly, Catherine Ashmore, Fatma Ilgaz, Suzanne Ford, Sharon Buckley, Anita MacDonald
Background: In phenylketonuria (PKU), attending multidisciplinary clinic reviews is an important aspect of life-long care. Since the COVID-19 pandemic, video and telephone clinics are used as alternative methods for people with PKU to have contact with their care team. There is limited research concerning patient preference, experience and perceptions of alternative types of clinic review. Individuals from the UK with PKU and their caregivers were invited to complete an online questionnaire, hosted on the National Society for PKU (NSPKU) website and social media platform.
Results: Data was available from 203 respondents. Forty one per cent of respondents (n = 49/119) preferred in-person clinics; 41% (n = 49) a hybrid of in-person, video and telephone clinics; 9% (n = 11) video clinics only, 6% (n = 7) telephone only and 3% (n = 3) were unsure. The main respondent obstacles to in-person clinics were costs, travel and time, but this was balanced by the benefits of a physical examination and better patient engagement/motivation. Twenty one per cent (n = 36/169) of respondents were uncomfortable with the number of healthcare professionals (HCPs) in a clinic room. Patients were less likely to consult with a doctor on video (64%, n = 91/143) or phone (50%, n = 59/119) reviews compared to in-person (80%, n = 146/183). Issues with video and telephone reviews included the shorter time length of review, distractions, technical issues and poor patient engagement.
Conclusions: Online video and telephone clinic platforms were effective in overcoming the challenging circumstances in management, monitoring and treatment of patients with PKU during the COVID-19 pandemic. However, in-person clinics remain the preferred respondent option. It is important that HCPs are flexible, enabling people with PKU a choice of clinic options according to their individual clinical need and circumstances.
{"title":"Patient and carer perceptions of video, telephone and in-person clinics for Phenylketonuria (PKU).","authors":"Hannah McBride, Sharon Evans, Alex Pinto, Anne Daly, Catherine Ashmore, Fatma Ilgaz, Suzanne Ford, Sharon Buckley, Anita MacDonald","doi":"10.1186/s13023-024-03295-7","DOIUrl":"10.1186/s13023-024-03295-7","url":null,"abstract":"<p><strong>Background: </strong>In phenylketonuria (PKU), attending multidisciplinary clinic reviews is an important aspect of life-long care. Since the COVID-19 pandemic, video and telephone clinics are used as alternative methods for people with PKU to have contact with their care team. There is limited research concerning patient preference, experience and perceptions of alternative types of clinic review. Individuals from the UK with PKU and their caregivers were invited to complete an online questionnaire, hosted on the National Society for PKU (NSPKU) website and social media platform.</p><p><strong>Results: </strong>Data was available from 203 respondents. Forty one per cent of respondents (n = 49/119) preferred in-person clinics; 41% (n = 49) a hybrid of in-person, video and telephone clinics; 9% (n = 11) video clinics only, 6% (n = 7) telephone only and 3% (n = 3) were unsure. The main respondent obstacles to in-person clinics were costs, travel and time, but this was balanced by the benefits of a physical examination and better patient engagement/motivation. Twenty one per cent (n = 36/169) of respondents were uncomfortable with the number of healthcare professionals (HCPs) in a clinic room. Patients were less likely to consult with a doctor on video (64%, n = 91/143) or phone (50%, n = 59/119) reviews compared to in-person (80%, n = 146/183). Issues with video and telephone reviews included the shorter time length of review, distractions, technical issues and poor patient engagement.</p><p><strong>Conclusions: </strong>Online video and telephone clinic platforms were effective in overcoming the challenging circumstances in management, monitoring and treatment of patients with PKU during the COVID-19 pandemic. However, in-person clinics remain the preferred respondent option. It is important that HCPs are flexible, enabling people with PKU a choice of clinic options according to their individual clinical need and circumstances.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11337755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142009148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Madelung's disease (MD), alternatively referred to as benign symmetric lipomatosis, multiple symmetric lipomatosis, or Launois-Bensaude syndrome, is an uncommon benign disorder marked by symmetric proliferation of adipose tissue in the head, neck, and torso regions.
Case description: In this case, the patient was a female with the late middle-aged demographic, diagnosed with Type I MD. Notably, she exhibited no prior history of alcohol consumption, and there was no family history of MD. Subsequent to the clinical diagnosis, the patient underwent medical imaging assessments to delineate the surgical parameters. Post-surgery, she demonstrated a favorable recovery trajectory, marked by the absence of any surgical complications.
Result: The patient underwent successful surgical excision of the lipomatous mass. Postoperatively, she had an uneventful recovery with no complications and no recurrence observed during the follow-up period of seven months.
Conclusion: Timely diagnosis and early surgical intervention play a pivotal role in enhancing the quality of life for individuals with MD. Preoperative medical imaging examinations function as highly effective tools, contributing to heightened surgical safety and a decreased probability of encountering complications during the surgical procedure.
背景:马德龙病(Madelung's disease,MD)又称良性对称性脂肪瘤病、多发性对称性脂肪瘤病或劳努瓦-本绍德综合征,是一种不常见的良性疾病,其特征是头、颈和躯干部位的脂肪组织对称性增生:本病例中,患者为女性,中年后期,被诊断为 I 型 MD。值得注意的是,她之前没有饮酒史,也没有家族遗传史。临床诊断后,患者接受了医学影像评估,以确定手术参数。术后,她的恢复情况良好,没有出现任何手术并发症:结果:患者成功接受了脂肪瘤肿块切除手术。结果:患者成功接受了脂肪瘤肿块切除手术,术后恢复顺利,没有出现任何并发症,随访 7 个月也没有发现复发:结论:及时诊断和早期手术干预对提高 MD 患者的生活质量至关重要。术前医学影像检查是非常有效的工具,有助于提高手术安全性,降低手术过程中出现并发症的概率。
{"title":"A case report on Madelung's disease and comprehensive review of the literature.","authors":"Cheng Jiao, Wei Liu, Yiming Qiao, Shuai Qi, Yifei Shen","doi":"10.1186/s13023-024-03303-w","DOIUrl":"10.1186/s13023-024-03303-w","url":null,"abstract":"<p><strong>Background: </strong>Madelung's disease (MD), alternatively referred to as benign symmetric lipomatosis, multiple symmetric lipomatosis, or Launois-Bensaude syndrome, is an uncommon benign disorder marked by symmetric proliferation of adipose tissue in the head, neck, and torso regions.</p><p><strong>Case description: </strong>In this case, the patient was a female with the late middle-aged demographic, diagnosed with Type I MD. Notably, she exhibited no prior history of alcohol consumption, and there was no family history of MD. Subsequent to the clinical diagnosis, the patient underwent medical imaging assessments to delineate the surgical parameters. Post-surgery, she demonstrated a favorable recovery trajectory, marked by the absence of any surgical complications.</p><p><strong>Result: </strong>The patient underwent successful surgical excision of the lipomatous mass. Postoperatively, she had an uneventful recovery with no complications and no recurrence observed during the follow-up period of seven months.</p><p><strong>Conclusion: </strong>Timely diagnosis and early surgical intervention play a pivotal role in enhancing the quality of life for individuals with MD. Preoperative medical imaging examinations function as highly effective tools, contributing to heightened surgical safety and a decreased probability of encountering complications during the surgical procedure.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11330121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Chromosome 7 has regions enriched with low copy repeats (LCRs), which increase the likelihood of chromosomal microdeletion disorders. Documented microdeletion disorders on chromosome 7 include both well-known Williams syndrome and more rare cases. It is noteworthy that most cases of various microdeletions are characterized by phenotypic signs of neuropsychological developmental disorders, which, however, have a different genetic origin. The localization of the microdeletions, the genes included in the region, as well as the structural features of the sequences of these genes have a cumulative influence on the phenotypic characteristics of the individuals for each specific case and the severity of the manifestations of disorders. The consideration of these features and their detailed analysis is important for a correct and comprehensive assessment of the disease.
Results: The article describes a clinical case of 7p22.3 microdeletion in a patient with congenital heart defect and neurological abnormalities - epilepsy, combined with moderate mental and motor developmental delay.
Conclusions: Through detailed genetic analyses, we are improving the clinical description of the rare 7p22.3 microdeletion and thus creating a basis for future genetic counseling and research into targeted therapies.
{"title":"7p22.3 microdeletion: a case study of a patient with congenital heart defect, neurodevelopmental delay and epilepsy.","authors":"Liliya Skvortsova, Anastassiya Perfilyeva, Kira Bespalova, Yelena Kuzovleva, Nailya Kabysheva, Ozada Khamdiyeva","doi":"10.1186/s13023-024-03321-8","DOIUrl":"10.1186/s13023-024-03321-8","url":null,"abstract":"<p><strong>Background: </strong>Chromosome 7 has regions enriched with low copy repeats (LCRs), which increase the likelihood of chromosomal microdeletion disorders. Documented microdeletion disorders on chromosome 7 include both well-known Williams syndrome and more rare cases. It is noteworthy that most cases of various microdeletions are characterized by phenotypic signs of neuropsychological developmental disorders, which, however, have a different genetic origin. The localization of the microdeletions, the genes included in the region, as well as the structural features of the sequences of these genes have a cumulative influence on the phenotypic characteristics of the individuals for each specific case and the severity of the manifestations of disorders. The consideration of these features and their detailed analysis is important for a correct and comprehensive assessment of the disease.</p><p><strong>Results: </strong>The article describes a clinical case of 7p22.3 microdeletion in a patient with congenital heart defect and neurological abnormalities - epilepsy, combined with moderate mental and motor developmental delay.</p><p><strong>Conclusions: </strong>Through detailed genetic analyses, we are improving the clinical description of the rare 7p22.3 microdeletion and thus creating a basis for future genetic counseling and research into targeted therapies.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11330011/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background: Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients.
Methods: This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded.
Results: Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217).
Conclusions: Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration.
{"title":"Long-term safety and influence on growth in patients receiving sirolimus: a pooled analysis.","authors":"Yang-Yang Wang, Li-Ping Zou, Kai-Feng Xu, Wen-Shuai Xu, Meng-Na Zhang, Qian Lu, Xin-Lun Tian, Ling-Yu Pang, Wen He, Qiu-Hong Wang, Yang Gao, Li-Ying Liu, Xiao-Qiao Chen, Shu-Fang Ma, Hui-Min Chen, Shuo Dun, Xiao-Yan Yang, Xiao-Mei Luo, Lu-Lu Huang, Yu-Fen Li","doi":"10.1186/s13023-024-03243-5","DOIUrl":"10.1186/s13023-024-03243-5","url":null,"abstract":"<p><strong>Background: </strong>Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients.</p><p><strong>Methods: </strong>This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded.</p><p><strong>Results: </strong>Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217).</p><p><strong>Conclusions: </strong>Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration.</p><p><strong>Trial registration: </strong>Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11325711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-15DOI: 10.1186/s13023-024-03206-w
Jin Wu, Lijuan Huang, Yunyu Zhou, Yan Xie, Tong Mo, Ningdong Li
Objective: This study aimed to describe the clinical and genetic characteristics of Chinese patients with congenital fibrosis of the extraocular muscles (CFEOM), and to evaluate the phenotype-genotype correlations in these patients.
Methods: This was a retrospective study. Patients with CFEOM underwent detailed ophthalmic examinations and magnetic resonance imaging (MRI). Panel-based next-generation sequencing was performed to identify pathogenic variants of disease-causing genes.
Results: Sixty-two patients with CFEOM were recruited into this study. Thirty-nine patients were diagnosed with CFEOM1 and 23 with CFEOM3. Forty-nine of the 62 patients with CFEOM carried either KIF21A (41/49) or TUBB3 variants (8/49). Six known missense variants in the KIF21A and TUBB3 genes, and a novel variant (c.3906T > A, p.D1302E) in the KIF21A gene were detected. Most patients with CFEOM1 carrying the KIF21A mutation displayed isolated CFEOM, whereas patients with CFEOM3 carrying the TUBB3 mutation had a wide range of clinical manifestations, either CFEOM alone or syndromes. Nystagmus was also present in 12 patients with CFEOM. Furthermore, the MRI findings varied, ranging from attenuation of the extraocular muscles to dysgenesis of the cranial nerves and brain structure.
Conclusions: The novel variants identified in this study will further expand the spectrum of pathogenic variants in CFEOM-related genes. However, no phenotype-genotype correlations were established because of the diversity of the clinical characteristics of these patients.
{"title":"Clinical and genetic characteristics of Chinese patients with congenital fibrosis of the extraocular muscles.","authors":"Jin Wu, Lijuan Huang, Yunyu Zhou, Yan Xie, Tong Mo, Ningdong Li","doi":"10.1186/s13023-024-03206-w","DOIUrl":"10.1186/s13023-024-03206-w","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to describe the clinical and genetic characteristics of Chinese patients with congenital fibrosis of the extraocular muscles (CFEOM), and to evaluate the phenotype-genotype correlations in these patients.</p><p><strong>Methods: </strong>This was a retrospective study. Patients with CFEOM underwent detailed ophthalmic examinations and magnetic resonance imaging (MRI). Panel-based next-generation sequencing was performed to identify pathogenic variants of disease-causing genes.</p><p><strong>Results: </strong>Sixty-two patients with CFEOM were recruited into this study. Thirty-nine patients were diagnosed with CFEOM1 and 23 with CFEOM3. Forty-nine of the 62 patients with CFEOM carried either KIF21A (41/49) or TUBB3 variants (8/49). Six known missense variants in the KIF21A and TUBB3 genes, and a novel variant (c.3906T > A, p.D1302E) in the KIF21A gene were detected. Most patients with CFEOM1 carrying the KIF21A mutation displayed isolated CFEOM, whereas patients with CFEOM3 carrying the TUBB3 mutation had a wide range of clinical manifestations, either CFEOM alone or syndromes. Nystagmus was also present in 12 patients with CFEOM. Furthermore, the MRI findings varied, ranging from attenuation of the extraocular muscles to dysgenesis of the cranial nerves and brain structure.</p><p><strong>Conclusions: </strong>The novel variants identified in this study will further expand the spectrum of pathogenic variants in CFEOM-related genes. However, no phenotype-genotype correlations were established because of the diversity of the clinical characteristics of these patients.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11325808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-14DOI: 10.1186/s13023-024-03312-9
Najia Ahmadi, Michele Zoch, Oya Guengoeze, Carlo Facchinello, Antonia Mondorf, Katharina Stratmann, Khader Musleh, Hans-Peter Erasmus, Jana Tchertov, Richard Gebler, Jannik Schaaf, Lena S Frischen, Azadeh Nasirian, Jiabin Dai, Elisa Henke, Douglas Tremblay, Andrew Srisuwananukorn, Martin Bornhäuser, Christoph Röllig, Jan-Niklas Eckardt, Jan Moritz Middeke, Markus Wolfien, Martin Sedlmayr
Background: Given the geographical sparsity of Rare Diseases (RDs), assembling a cohort is often a challenging task. Common data models (CDM) can harmonize disparate sources of data that can be the basis of decision support systems and artificial intelligence-based studies, leading to new insights in the field. This work is sought to support the design of large-scale multi-center studies for rare diseases.
Methods: In an interdisciplinary group, we derived a list of elements of RDs in three medical domains (endocrinology, gastroenterology, and pneumonology) according to specialist knowledge and clinical guidelines in an iterative process. We then defined a RDs data structure that matched all our data elements and built Extract, Transform, Load (ETL) processes to transfer the structure to a joint CDM. To ensure interoperability of our developed CDM and its subsequent usage for further RDs domains, we ultimately mapped it to Observational Medical Outcomes Partnership (OMOP) CDM. We then included a fourth domain, hematology, as a proof-of-concept and mapped an acute myeloid leukemia (AML) dataset to the developed CDM.
Results: We have developed an OMOP-based rare diseases common data model (RD-CDM) using data elements from the three domains (endocrinology, gastroenterology, and pneumonology) and tested the CDM using data from the hematology domain. The total study cohort included 61,697 patients. After aligning our modules with those of Medical Informatics Initiative (MII) Core Dataset (CDS) modules, we leveraged its ETL process. This facilitated the seamless transfer of demographic information, diagnoses, procedures, laboratory results, and medication modules from our RD-CDM to the OMOP. For the phenotypes and genotypes, we developed a second ETL process. We finally derived lessons learned for customizing our RD-CDM for different RDs.
Discussion: This work can serve as a blueprint for other domains as its modularized structure could be extended towards novel data types. An interdisciplinary group of stakeholders that are actively supporting the project's progress is necessary to reach a comprehensive CDM.
Conclusion: The customized data structure related to our RD-CDM can be used to perform multi-center studies to test data-driven hypotheses on a larger scale and take advantage of the analytical tools offered by the OHDSI community.
{"title":"How to customize common data models for rare diseases: an OMOP-based implementation and lessons learned.","authors":"Najia Ahmadi, Michele Zoch, Oya Guengoeze, Carlo Facchinello, Antonia Mondorf, Katharina Stratmann, Khader Musleh, Hans-Peter Erasmus, Jana Tchertov, Richard Gebler, Jannik Schaaf, Lena S Frischen, Azadeh Nasirian, Jiabin Dai, Elisa Henke, Douglas Tremblay, Andrew Srisuwananukorn, Martin Bornhäuser, Christoph Röllig, Jan-Niklas Eckardt, Jan Moritz Middeke, Markus Wolfien, Martin Sedlmayr","doi":"10.1186/s13023-024-03312-9","DOIUrl":"10.1186/s13023-024-03312-9","url":null,"abstract":"<p><strong>Background: </strong>Given the geographical sparsity of Rare Diseases (RDs), assembling a cohort is often a challenging task. Common data models (CDM) can harmonize disparate sources of data that can be the basis of decision support systems and artificial intelligence-based studies, leading to new insights in the field. This work is sought to support the design of large-scale multi-center studies for rare diseases.</p><p><strong>Methods: </strong>In an interdisciplinary group, we derived a list of elements of RDs in three medical domains (endocrinology, gastroenterology, and pneumonology) according to specialist knowledge and clinical guidelines in an iterative process. We then defined a RDs data structure that matched all our data elements and built Extract, Transform, Load (ETL) processes to transfer the structure to a joint CDM. To ensure interoperability of our developed CDM and its subsequent usage for further RDs domains, we ultimately mapped it to Observational Medical Outcomes Partnership (OMOP) CDM. We then included a fourth domain, hematology, as a proof-of-concept and mapped an acute myeloid leukemia (AML) dataset to the developed CDM.</p><p><strong>Results: </strong>We have developed an OMOP-based rare diseases common data model (RD-CDM) using data elements from the three domains (endocrinology, gastroenterology, and pneumonology) and tested the CDM using data from the hematology domain. The total study cohort included 61,697 patients. After aligning our modules with those of Medical Informatics Initiative (MII) Core Dataset (CDS) modules, we leveraged its ETL process. This facilitated the seamless transfer of demographic information, diagnoses, procedures, laboratory results, and medication modules from our RD-CDM to the OMOP. For the phenotypes and genotypes, we developed a second ETL process. We finally derived lessons learned for customizing our RD-CDM for different RDs.</p><p><strong>Discussion: </strong>This work can serve as a blueprint for other domains as its modularized structure could be extended towards novel data types. An interdisciplinary group of stakeholders that are actively supporting the project's progress is necessary to reach a comprehensive CDM.</p><p><strong>Conclusion: </strong>The customized data structure related to our RD-CDM can be used to perform multi-center studies to test data-driven hypotheses on a larger scale and take advantage of the analytical tools offered by the OHDSI community.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11325822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}