European journal of medical genetics最新文献

{"title":"Long-term clinical evaluation of patients with alpha-mannosidosis – A multicenter study","authors":"Engin Köse ,&nbsp;Çiğdem Seher Kasapkara ,&nbsp;Aslı İnci ,&nbsp;Yılmaz Yıldız ,&nbsp;İlknur Sürücü Kara ,&nbsp;Ayça Burcu Kahraman ,&nbsp;Leyla Tümer ,&nbsp;Ali Dursun ,&nbsp;Fatma Tuba Eminoğlu","doi":"10.1016/j.ejmg.2024.104927","DOIUrl":"10.1016/j.ejmg.2024.104927","url":null,"abstract":"<div><h3>Background</h3><p>Alpha mannosidosis is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in the <em>MAN2B1</em> gene. It manifests with clinical features, including intellectual disability, hearing impairment, coarse facial appearance, skeletal anomalies, immunodeficiency, central nervous system involvement, psychiatric comorbidities, corneal opacity, and hepatosplenomegaly.</p><p>This multicenter study assesses the long-term outcomes of individuals diagnosed with alpha-mannosidosis, examining demographic, clinical, laboratory, and molecular characteristics.</p></div><div><h3>Method</h3><p>Sixteen patients diagnosed with alpha-mannosidosis who presented to four pediatric metabolic units were included in the study. The patients' medical records were analyzed and data on demographics, clinical presentation and laboratory findings were recorded.</p></div><div><h3>Results</h3><p>Of the 16 patients (6 females, 10 males) with alpha mannosidosis included in the study, the mean age at the time of diagnosis was 79.4 ± 56.1 (16–208) months, and the mean diagnosis delay time was 57.9 ± 51.9 (4–181) months.</p><p>Hearing loss was the primary manifestation found in seven out of 16 patients (43.8%), followed by speech delay in 37.8%. On clinical follow-up, 87.5% of patients experienced recurrent infections, mainly in the upper respiratory tract, with 12 requiring the use of a hearing aid. Hepatomegaly was found in six out of 13 patients who received abdominal ultrasonography; two out of 12 patients who underwent echocardiography were found to have mitral valve prolapse (16.6%).</p><p>Upon neurological evaluation, five patients displayed no neurological manifestation. Delayed language development was observed in nine (56.3%) patients, intellectual disability in eight (50%) patients, and hypertonicity was identified in one (6.3%) patient with the severe form of the disease.</p><p>Homozygous c.2477C&gt;A (p.Ser826Ter) and homozygous c.967G&gt;A (p.Glu323Lys) novel variants were detected in four patients and one patient, respectively. The most common variant observed in the study was c.2477C&gt;A (p.Ser826Ter).</p></div><div><h3>Conclusion</h3><p>The present study identified two novel <em>MAN2B1</em> variants. An evaluation of the long-term outcome of alpha-mannosidosis, in which the early initiation of enzyme replacement therapy (ERT) may lead to a better clinical outcome, can permit a better analysis of the effect of ERT on the natural progression of the disease.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104927"},"PeriodicalIF":1.9,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000193/pdfft?md5=e070835ad551252ae75c0c87c59ce9e2&pid=1-s2.0-S1769721224000193-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139926805","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}

{"title":"Imaging in osteogenesis imperfecta: Where we are and where we are going","authors":"S. Gazzotti ,&nbsp;R. Sassi ,&nbsp;M.P. Aparisi Gómez ,&nbsp;A. Moroni ,&nbsp;E. Brizola ,&nbsp;M. Miceli ,&nbsp;A. Bazzocchi","doi":"10.1016/j.ejmg.2024.104926","DOIUrl":"10.1016/j.ejmg.2024.104926","url":null,"abstract":"&lt;div&gt;&lt;p&gt;Osteogenesis imperfecta (OI) is a rare phenotypically and genetically heterogeneous group of inherited skeletal dysplasias. The hallmark features of OI include bone fragility and susceptibility to fractures, bone deformity, and diminished growth, along with a plethora of associated secondary features (both skeletal and extraskeletal). The diagnosis of OI is currently made on clinical grounds and may be confirmed by genetic testing. However, imaging remains pivotal in the evaluation of this disease. The aim of this article is to review the current role played by the various radiologic techniques in the diagnosis and monitoring of OI in the postnatal setting as well as to discuss recent advances and future perspectives in OI imaging. Conventional Radiography and Dual-energy X-ray Absorptiometry (DXA) are currently the two most used imaging modalities in OI. The cardinal radiographic features of OI include generalized osteopenia/osteoporosis, bone deformities, and fractures. DXA is currently the most available technique to assess Bone Mineral Density (BMD), specifically areal BMD (aBMD). However, DXA has important limitations and cannot fully characterize bone fragility in OI based on aBMD. Novel DXA-derived parameters, such as Trabecular Bone Score (TBS), may provide further insight into skeletal changes induced by OI, but evidence is still limited. Techniques like Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) can be useful as problem-solvers or in specific settings, including the evaluation of cranio-cervical abnormalities. Recent evidence supports the use of High-Resolution peripheral Quantitative Computed Tomography (HR-pQCT) as a promising tool to improve the characterization of bone fragility in OI. However, HR-pQCT remains a primarily research technique at present. Quantitative Computed Tomography (QCT) is an alternative to DXA for the determination of BMD at central sites, with distinct advantages but considerably higher radiation exposure. Quantitative Ultrasound (QUS) is a portable, inexpensive, and radiation-free modality that may complement DXA evaluation, providing information on bone quality. However, evidence of usefulness of QUS in OI is poor. Radiofrequency Echographic Multi Spectrometry (REMS) is an emerging non-ionizing imaging method that holds promise for the diagnosis of low BMD and for the prediction of fracture risk, but so far only one published study has investigated its role in OI. To conclude, several different radiologic techniques have proven to be effective in the diagnosis and monitoring of OI, each with their own specificities and peculiarities. Clinicians should be aware of the strategic role of the various modalities in the different phases of the patient care process. In this scenario, the development of international guidelines including recommendations on the role of imaging in the diagnosis and monitoring of OI, accompanied by continuous active research in the field, could significantly ","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104926"},"PeriodicalIF":1.9,"publicationDate":"2024-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000181/pdfft?md5=bbff8f6389bdde9f1e7b5cfab22fb19f&pid=1-s2.0-S1769721224000181-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899550","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}

{"title":"A rare skeletal dysplasia in the etiology of severe scoliosis: Diaphanospondylodysostosis","authors":"Tuğba Daşar ,&nbsp;Adalet Elçin Yıldız ,&nbsp;Gökhan Demirkıran ,&nbsp;Gülen Eda Utine ,&nbsp;Pelin Özlem Şimşek Kiper","doi":"10.1016/j.ejmg.2024.104924","DOIUrl":"https://doi.org/10.1016/j.ejmg.2024.104924","url":null,"abstract":"<div><p>Diaphanospondylodysostosis is a rare genetic skeletal disorder caused by biallelic variants in the <em>BMPER</em> gene. The term, diaphanospondylodysostosis, includes ischiospinal dysotosis, which was previously known as a distinct entity with milder clinical features. The clinical phenotype of diaphanospondylodysostosis is quite variable with mortality in early postnatal life in some patients. Main clinical and radiographic features are narrow thorax, vertebral segmentation defects, rib anomalies, ossification defects of vertebrae, ischium and sacrum, and renal cysts. In this study, we report on a 14-year-old girl patient with diaphanospondylodysostosis harbouring a novel <em>BMPER</em> mutation. The patient presented with severe scoliosis and severely hypoplastic/aplastic distal phalanges of the fingers and toes, findings yet hitherto not described in this syndrome.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104924"},"PeriodicalIF":1.9,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000168/pdfft?md5=4d9a1bcee3b7bb411f2a9626e2106322&pid=1-s2.0-S1769721224000168-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139733184","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}

{"title":"Genome sequencing identify chromosome 9 inversions disrupting ENG in 2 unrelated HHT families","authors":"M. Tusseau ,&nbsp;M. Eyries ,&nbsp;N. Chatron ,&nbsp;F. Coulet ,&nbsp;A. Guichet ,&nbsp;E. Colin ,&nbsp;B. Demeer ,&nbsp;H. Maillard ,&nbsp;J. Thevenon ,&nbsp;C. Lavigne ,&nbsp;V. Saillour ,&nbsp;C. Paris ,&nbsp;J.M. De Sainte Agathe ,&nbsp;M. Pujalte ,&nbsp;A. Guilhem ,&nbsp;S. Dupuis-Girod ,&nbsp;G. Lesca","doi":"10.1016/j.ejmg.2024.104919","DOIUrl":"10.1016/j.ejmg.2024.104919","url":null,"abstract":"<div><p>Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is a dominant inherited vascular disorder. The clinical diagnosis is based on the Curaçao criteria and pathogenic variants in the <em>ENG</em> and <em>ACVRL1</em> genes are responsible for most cases of HHT.</p><p>Four families with a negative targeted gene panel and selected by a multidisciplinary team were selected and whole-genome sequencing was performed according to the recommendations of the French National Plan for Genomic Medicine. Structural variations were confirmed by standard molecular cytogenetic analysis (FISH).</p><p>In two families with a definite diagnosis of HHT, we identified two different paracentric inversions of chromosome 9, both disrupting the <em>ENG</em> gene. These inversions are considered as pathogenic and causative for the HHT phenotype of the patients.</p><p>This is the first time structural variations are reported to cause HHT. As such balanced events are often missed by exon-based sequencing (panel, exome), structural variations may be an under-recognized cause of HHT. Genome sequencing for the detection of these events could be suggested for patients with a definite diagnosis of HHT and in whom no causative pathogenic variant was identified.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104919"},"PeriodicalIF":1.9,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000119/pdfft?md5=e8bd561a1b79324d6847166202353e14&pid=1-s2.0-S1769721224000119-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139734685","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}

{"title":"Beyond 'speech delay': Expanding the phenotype of BRPF1-related disorder","authors":"Lottie D. Morison ,&nbsp;Olivia Van Reyk ,&nbsp;Emma Baker ,&nbsp;Lyse Ruaud ,&nbsp;Nathalie Couque ,&nbsp;Alain Verloes ,&nbsp;David J. Amor ,&nbsp;Angela T. Morgan","doi":"10.1016/j.ejmg.2024.104923","DOIUrl":"10.1016/j.ejmg.2024.104923","url":null,"abstract":"<div><p>Pathogenic variants in <em>BRPF1</em> cause intellectual disability, ptosis and facial dysmorphism. Speech and language deficits have been identified as a manifestation of <em>BRPF1-</em>related disorder but have not been systematically characterized. We provide a comprehensive delineation of speech and language abilities in <em>BRPF1</em>-related disorder and expand the phenotype. Speech and language, and health and medical history were assessed in 15 participants (male = 10, median age = 7 years 4 months) with 14 <em>BRPF1</em> variants. Language disorders were common (11/12), and most had mild to moderate deficits across receptive, expressive, written, and social-pragmatic domains. Speech disorders were frequent (7/9), including phonological delay (6/9) and disorder (3/9), and childhood apraxia of speech (3/9). All those tested for cognitive abilities had a FSIQ ≥70 (4/4). Participants had vision impairment (13/15), fine (8/15) and gross motor delay (10/15) which often resolved in later childhood, infant feeding impairment (8/15), and infant hypotonia (9/15). We have implicated <em>BRPF1-</em>related disorder as causative for speech and language disorder, including childhood apraxia of speech. Adaptive behavior and cognition were strengths when compared to other monogenic neurodevelopmental chromatin-related disorders. The universal involvement of speech and language impairment is noteable, relative to the high degree of phenotypic variability in <em>BRPF1-</em>related disorder.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104923"},"PeriodicalIF":1.9,"publicationDate":"2024-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000156/pdfft?md5=381f1a56300a0473ef2d84a5ba13915a&pid=1-s2.0-S1769721224000156-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139722164","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}

{"title":"TBX5 variants and cardiac phenotype: A systematic review of the literature and a novel variant","authors":"Anne Kathrine Møller Nielsen ,&nbsp;Anna Maria Dehn ,&nbsp;Vibeke Hjortdal ,&nbsp;Lars Allan Larsen","doi":"10.1016/j.ejmg.2024.104920","DOIUrl":"10.1016/j.ejmg.2024.104920","url":null,"abstract":"<div><p>T-Box Transcription Factor 5 (<em>TBX5</em>) variants are associated with Holt-Oram syndrome. Holt-Oram syndrome display phenotypic variability, regarding upper limb defects, congenital heart defects, and arrhythmias. To investigate the genotype-phenotype relationship between <em>TBX5</em> variants and cardiac disease, we performed a systematic review of the literature. Through the systematic review we identified 108 variants in <em>TBX5</em> associated with a cardiac phenotype in 277 patients. Arrhythmias were more frequent in patients with a missense variant (48% vs 30%, p = 0.009) and upper limb abnormalities were more frequent in patients with protein-truncating variants (85% vs 64%, p = 0.0008). We found clustering of missense variants in the T-box domain. Furthermore, we present a family with atrial septal defects. By whole exome sequencing, we identified a novel missense variant p.Phe232Leu in <em>TBX5</em>. The cardiac phenotype included atrial septal defect, arrhythmias, heart failure, and dilated cardiomyopathy. Clinical examination revealed subtle upper limb abnormalities. Thus, the family corresponds to the diagnostic criteria of Holt-Oram syndrome.</p><p>We provide an overview of cardiac phenotypes associated with <em>TBX5</em> variants and show an increased risk of arrhythmias associated to missense variants compared to protein-truncating variants. We report a novel missense variant in <em>TBX5</em> in a family with an atypical Holt-Oram syndrome phenotype.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104920"},"PeriodicalIF":1.9,"publicationDate":"2024-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000120/pdfft?md5=79fb65ff0aca33731b5306bf7153af79&pid=1-s2.0-S1769721224000120-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139711795","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}

{"title":"Altered peripheral blood leukocyte subpopulations, function, and gene expression in children with Down syndrome: implications for respiratory tract infection","authors":"Kelley L. Colvin ,&nbsp;Kristine Wolter-Warmerdam ,&nbsp;Francis Hickey ,&nbsp;Michael E. Yeager","doi":"10.1016/j.ejmg.2024.104922","DOIUrl":"10.1016/j.ejmg.2024.104922","url":null,"abstract":"<div><h3>Objectives</h3><p>We tested the hypothesis that aberrant expression of Hsa21-encoded interferon genes in peripheral blood immune cells would correlate to immune cell dysfunction in children with Down syndrome (DS).</p></div><div><h3>Study design</h3><p>We performed flow cytometry to quantify peripheral blood leukocyte subtypes and measured their ability to migrate and phagocytose. In matched samples, we measured gene expression levels for constituents of interferon signaling pathways. We screened 49 children, of which 29 were individuals with DS.</p></div><div><h3>Results</h3><p>We show that the percentages of two peripheral blood myeloid cell subtypes (alternatively-activated macrophages and low-density granulocytes) in children with DS differed significantly from typical children, children with DS circulate a very different pattern of cytokines vs. typical individuals, and higher expression levels of type III interferon receptor Interleukin-10Rb in individuals with DS correlated with reduced migratory and phagocytic capacity of macrophages.</p></div><div><h3>Conclusions</h3><p>Increased susceptibility to severe and chronic infection in children with DS may result from inappropriate numbers and subtypes of immune cells that are phenotypically and functionally altered due to trisomy 21 associated interferonopathy.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104922"},"PeriodicalIF":1.9,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000144/pdfft?md5=8736f775e4024936e7613a8fe394e4ba&pid=1-s2.0-S1769721224000144-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139690168","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}

{"title":"Rapid exome sequencing for children with severe acute encephalopathy – A case series","authors":"Clair Habib ,&nbsp;Tamar Paperna ,&nbsp;Rinat Zaid ,&nbsp;Sarit Ravid ,&nbsp;Josef Ben Ari ,&nbsp;Galit Tal ,&nbsp;Karin Weiss ,&nbsp;Tova Hershkovitz","doi":"10.1016/j.ejmg.2024.104918","DOIUrl":"10.1016/j.ejmg.2024.104918","url":null,"abstract":"<div><p>Increasingly, next-generation sequencing (NGS) is becoming an invaluable tool in the diagnosis of unexplained acute neurological disorders, such as acute encephalopathy/encephalitis. Here, we describe a brief series of pediatric patients who presented at the pediatric intensive care unit with severe acute encephalopathy, initially suspected as infectious or inflammatory but subsequently diagnosed with a monogenic disorder.</p><p>Rapid exome sequencing was performed during the initial hospitalization of three unrelated patients, and results were delivered within 7–21 days. All patients were previously healthy, 1.5–3 years old, of Muslim Arab descent, with consanguineous parents. One patient presenting with acute necrotizing encephalopathy (ANEC). Her sister presented with ANEC one year prior.</p><p>Exome sequencing was diagnostic in all three patients. All were homozygous for pathogenic and likely-pathogenic variants associated with recessive disorders; MOCS2, NDUFS8 and DBR1. Surprisingly, the initial workup was not suggestive of the final diagnosis.</p><p>This case series demonstrates that the use of rapid exome sequencing is shifting the paradigm of diagnostics even in critical care situations and should be considered early on in children with acute encephalopathy. A timely diagnosis can direct initial treatment as well as inform decisions regarding long-term care.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104918"},"PeriodicalIF":1.9,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000107/pdfft?md5=4817e4a68c204c7ffedb6884840898f8&pid=1-s2.0-S1769721224000107-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139702181","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}

{"title":"Impressive clinical improvement and disappearance of neuropathic pain in an adult patient with hypophosphatasia treated with asfotase alfa","authors":"Zografia Zervou ,&nbsp;Roel Plooij ,&nbsp;Evert F.S. van Velsen ,&nbsp;Remco G.M. Timmermans ,&nbsp;Serwet Demirdas ,&nbsp;M. Carola Zillikens","doi":"10.1016/j.ejmg.2024.104915","DOIUrl":"10.1016/j.ejmg.2024.104915","url":null,"abstract":"<div><p>Hypophosphatasia (HPP) is a rare disorder, resulting from loss-of-function variants of the ALPL gene encoding non-tissue specific alkaline phosphatase (TNSALP). Presentation varies largely, with increased severity usually occurring with earlier disease onset. Here we describe the clinical improvement of a 57-year-old woman with childhood onset HPP, after initiating treatment with asfotase alfa (Strensiq®). This was started because of the rapid and progressive radiological deterioration of bone structure after placement of nails in both upper legs for spontaneous atypical femur fracture (AFF) - like fractures. Initiation of treatment, not only resulted in stabilization of bone structure on X-rays, but within a few weeks there was a dramatic reduction of burning pain sensations in the lower legs, attributed in retrospect to neuropathic pain, and also almost complete disappearance of headaches. Additionally, unhealed metatarsal fractures finally healed after almost 10 years. Drug efficacy was further evaluated through -quality of life questionnaires and multiple tests conducted by the physiotherapist, and showed clear improvements. Within 3 months after starting asfotase alfa, the patient was able to carry out her daily tasks indoors without relying on a walker and even started electric bike rides for 20 km/day. In conclusion, treatment with asfotase alfa, halted rapid radiological bone deterioration after bilateral intramedullary femoral pen placement and strongly increased quality of life, marked by rapid disappearance of neuropathic pain, reduction in headaches and musculoskeletal pains, and enhanced muscle strength and mobility. The quick and almost complete disappearance of neuropathic pain and headache suggests a relation with disturbed levels of metabolites in HPP.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104915"},"PeriodicalIF":1.9,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000077/pdfft?md5=f9ca4ebb87cb392455bfab7eb6de6900&pid=1-s2.0-S1769721224000077-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139702180","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}

{"title":"Development of a low-cost and accurate carrier screening method for spinal muscular atrophy in developing countries","authors":"Yu Jiang ,&nbsp;Zhenyu Luo ,&nbsp;Wenrong Wang ,&nbsp;Xingxiu Lu ,&nbsp;ZhongMin Xia ,&nbsp;Jieqiong Xie ,&nbsp;Mei Lu ,&nbsp;Lili Wu ,&nbsp;Yulin Zhou ,&nbsp;Qiwei Guo","doi":"10.1016/j.ejmg.2024.104921","DOIUrl":"10.1016/j.ejmg.2024.104921","url":null,"abstract":"<div><p>Heterozygous carriers of the survival of motor neuron 1 (<em>SMN1</em>) gene deletion in parents account for approximately 95% of neonatal spinal muscular atrophy cases. Given the severity of the disease, professional organizations have recommended periconceptional spinal muscular atrophy carrier screening to all couples, regardless of race or ethnicity. However, the prevalence of screening activities in mainland China remains suboptimal, mainly attributed to the limitations of the existing carrier screening methods. Herein, we aimed to develop a low-cost, accessible, and accurate carrier screening method based on duplex droplet digital PCR (ddPCR), to cover a wider population in developing countries, including China. The receiver operating characteristic curve was used to determine the cut-off value of <em>SMN1</em> copy numbers. Performance validation was conducted for linearity, precision, and accuracy. In total, 482 cases were considered to validate the concordance between the developed ddPCR assay and multiplex ligation-dependent probe amplification. Linear correlations were excellent between the expected concentration of the reference gene and the observed values (R² &gt; 0.99). Both the intra- and inter-assay precision of our ddPCR assays were less than 6.0%. The multiplex ligation-dependent probe amplification and ddPCR results were consistent in 480 of the 482 cases (99.6%). Two cases with multiplex ligation-dependent probe amplification, suggestive of two copies of <em>SMN1</em> exon 7, were classified into three copies by ddPCR analysis. The overall correct classification of the samples included in our ddPCR assay was 100%. This study demonstrates that an appropriate cut-off value is an important prerequisite for establishing a semi-quantitative method to determine the <em>SMN1</em> copy numbers. Compared to conventional methods, our ddPCR assay is low-cost, highly accurate, and has full potential for application in population spinal muscular atrophy carriers screening.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104921"},"PeriodicalIF":1.9,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000132/pdfft?md5=cfd4db4d64b8ec77a305d5a9bb260c49&pid=1-s2.0-S1769721224000132-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139702179","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}