Orphanet Journal of Rare Diseases最新文献

{"title":"Profiling of pathogenic variants in Japanese patients with sarcoglycanopathy.","authors":"Rui Shimazaki, Yoshihiko Saito, Tomonari Awaya, Narihiro Minami, Ryo Kurosawa, Motoyasu Hosokawa, Hiroaki Ohara, Shinichiro Hayashi, Akihide Takeuchi, Masatoshi Hagiwara, Yukiko K Hayashi, Satoru Noguchi, Ichizo Nishino","doi":"10.1186/s13023-024-03521-2","DOIUrl":"https://doi.org/10.1186/s13023-024-03521-2","url":null,"abstract":"<p><strong>Background: </strong>Sarcoglycanopathies (SGPs) are limb-girdle muscular dystrophies (LGMDs) that can be classified into four types, LGMDR3, LGMDR4, LGMDR5, and LGMDR6, caused by mutations in the genes, SGCA, SGCB, SGCG, and SGCD, respectively. SGPs are relatively rare in Japan. This study aims to profile the genetic variants that cause SGPs in Japanese patients.</p><p><strong>Methods: </strong>Clinical course and pathological findings were retrospectively reviewed in Japanese patients with SGP. Genetic analyses were performed using a combination of targeted resequencing with a hereditary muscle disease panel, whole genome sequencing, multiplex ligation-dependent probe amplification, and long-read sequencing. The structures of transcripts with aberrant splicing were also determined by RT-PCR, RNA-seq, and in silico prediction.</p><p><strong>Results: </strong>We identified biallelic variants in SGC genes in 53 families, including three families with LGMDR6, which had not been identified in Japan so far. SGCA was the most common causative gene, accounting for 56% of cases, followed by SGCG, SGCB, and SGCD, at 17%, 21%, and 6%, respectively. Missense variants in SGCA were very frequent at 78.3%, while they were relatively rare in SGCB, SGCG, and SGCD at 11.1%, 18.2%, and 16.6%, respectively. We also analyzed the haplotypes of alleles carrying three variants found in multiple cases: c.229C > T in SGCA, c.325C > T in SGCB, and exon 6 deletion in SGCG; two distinct haplotypes were found for c.229C > T in SGCA, while each of the latter two variants was on single haplotypes.</p><p><strong>Conclusions: </strong>We present genetic profiles of Japanese patients with SGPs. Haplotype analysis indicated common ancestors of frequent variants. Our findings will support genetic diagnosis and gene therapy.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"20 1","pages":"1"},"PeriodicalIF":3.4,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risdiplam utilization, adherence, and associated health care costs for patients with spinal muscular atrophy: a United States retrospective claims database analysis.","authors":"Anish Patel, Walter Toro, Min Yang, Wei Song, Raj Desai, Mingchen Ye, Nadia Tabatabaeepour, Omar Dabbous","doi":"10.1186/s13023-024-03399-0","DOIUrl":"10.1186/s13023-024-03399-0","url":null,"abstract":"<p><strong>Background: </strong>Spinal muscular atrophy (SMA) is a genetic neuromuscular disease associated with progressive loss of motor function. Risdiplam, a daily oral therapy, was approved in the United States for the treatment of SMA. Risdiplam's effectiveness depends on patient adherence to the treatment regimen. This retrospective claims database analysis assessed real-world treatment adherence and persistence, and all-cause health care costs by adherence status, for patients with SMA receiving risdiplam. Outcomes were summarized by SMA types (1-4) and age groups (0-2, 3-5, 6-17, and ≥ 18 years).</p><p><strong>Results: </strong>86 patients with ≥ 1 SMA diagnosis, risdiplam treatment, and ≥ 6 months of continuous enrollment after the index date (SMA diagnosis) were identified in the IQVIA PharMetrics^® Plus database (01/01/2020-06/30/2022). One patient had SMA type 1 (a 1-year-old boy), 18 had type 2 (mean ± SD age: 7.9 ± 5.7 years; 61% female), 47 had type 3 (17.3 ± 10.2 years; 55% female), and 20 had type 4 (38.2 ± 11.6 years; 55% female). The mean proportion of days covered (PDC) with risdiplam was 0.89 overall, ranging from 0.88 for SMA type 4 to 0.97 for type 1. The majority (83.7%) of patients were adherent to risdiplam (PDC ≥0.80), ranging from 75.0% for type 4 to 100% for type 1. Adherence ranged from 76.5% among 6-12-year-olds to 100% among 0-2-year-olds. Compared with adherent patients, nonadherent patients had higher median total health care costs by $335,049 for type 2, $41,204 for type 3, and $12,223 for type 4. Among adherent patients, patients with PDC between 0.90 and 1.00 had lower costs compared with patients with PDC between 0.80 and 0.90.</p><p><strong>Conclusions: </strong>Nonadherence to risdiplam was observed in the first year of treatment, especially for patients with SMA type 4 and patients aged 6-12 years. Nonadherence was associated with higher all-cause health care costs, with the most pronounced cost difference for SMA type 2. For adherent patients, those who were highly adherent incurred lower health care costs. These findings underscore the importance of treatment adherence and persistence for patients with SMA receiving risdiplam, particularly for younger children and those with greater disease severity.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"494"},"PeriodicalIF":3.4,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907456","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}

{"title":"Patient and parent knowledge, understanding, and concerns after a new diagnosis of Ehlers Danlos syndrome.","authors":"Jordan T Jones, Lora L Black, William R Black","doi":"10.1186/s13023-024-03517-y","DOIUrl":"10.1186/s13023-024-03517-y","url":null,"abstract":"<p><strong>Introduction: </strong>After diagnosis of Ehlers Danlos Syndrome (EDS), it is unclear what information patients and parents need and understand about EDS. The objective of this study is to characterize patient and parent knowledge and concerns about EDS after a diagnosis of EDS is made to determine patient and parent concerns and identify barriers that cause discomfort with the diagnosis.6 METHODS: A convenience sample of patient and parent dyads were recruited after new diagnosis of EDS. Patients and parents completed questionnaires that assessed knowledge, comfort, and barriers of EDS before and after diagnosis, EDS education materials accessed, and additional clinical needs and concerns.</p><p><strong>Results: </strong>Seventy-two dyads completed the survey.</p><p><strong>Conclusion: </strong>Many respondents actively seek information on the diagnosis and management of EDS. Parents and patients look for information about EDS differently. Parents have more concerns after diagnosis and both want well-constructed, empirically supported educational materials delivered via multiple modalities, which makes clinical guidelines more essential.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"493"},"PeriodicalIF":3.4,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907452","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}

{"title":"Safety and efficacy of omaveloxolone v/s placebo for the treatment of Friedreich's ataxia in patients aged more than 16 years: a systematic review.","authors":"Ankita Umrao, Monika Pahuja, Nabendu Sekhar Chatterjee","doi":"10.1186/s13023-024-03474-6","DOIUrl":"10.1186/s13023-024-03474-6","url":null,"abstract":"<p><strong>Background: </strong>Friedreich's ataxia (FA) is a rare genetic disorder caused by silencing of the frataxin gene (FXN), which leads to multiorgan damage. Nrf2 is a regulator of FXN, which is a modulator of oxidative stress in animals and humans. Omaveloxolone (Omav) is an Nrf2 activator and has been reported to have antioxidative potential in various disease conditions. The present review was conducted to determine the use of Omav, the only FDA-approved treatment for FA.</p><p><strong>Methods: </strong>Three electronic databases, Cochrane, PubMed and Google Scholar, were searched with terms such as 'Omaveloxolone', 'Friedreich ataxia', 'genetic diseases', 'autosomal recessive', and 'rare disorders' using various advanced search filters. Articles were screened, extracted, and assessed for quality, and a qualitative synthesis of the data was performed. The study protocol was registered in PROSPERO (CRD42024531449).</p><p><strong>Results: </strong>A total of 201 records were found, with very few published research articles on the topic. Only two randomized clinical trials published in a series of three research articles were included in the current systematic review. Peak load exercise and modified Friedreich's Ataxia Rating Scale (mFARS) values were considered the major outcome measures for determining the efficacy of 150 mg Omav capsules/day in FA. Exploratory outcome measures, such as low-contrast letter visual acuity test, exercise test, T25-FW, 9-HPT, health-related quality of life, and biochemical tests, were also assessed along with adverse events in all the studies.</p><p><strong>Conclusion: </strong>Although, the quality of the articles demonstrated low bias. However, the short duration, small sample size, and missing data, including the values of different measures of mFARS scores in patients, limit the generalizability of the results. Further studies with longer durations and in severe patients with foot deformities are needed to clearly define the efficacy of Omav in FA and to determine the optimal drug for FA patients in India.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"495"},"PeriodicalIF":3.4,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907459","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}

{"title":"VIPAS39 related arthrogryposis-renal dysfunction-cholestasis syndrome-case report and systematic review.","authors":"Jan Kafol, Barbara Gnidovec Strazisar, Ana Drole Torkar, Matjaz Homan, Sara Bertok, Matej Mlinaric, Jaka Sikonja, Jernej Kovač, Mirjana Perkovic Benedik, Tanja Kersnik Levart, Mojca Zerjav Tansek, Marina Praprotnik, Tadej Battelino, Maruša Debeljak, Urh Groselj","doi":"10.1186/s13023-024-03486-2","DOIUrl":"10.1186/s13023-024-03486-2","url":null,"abstract":"<p><strong>Background: </strong>Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome, a rare autosomal recessive disorder, exhibits genetic heterogeneity with the VIPAS39 gene pathological variants being a distinct contributor.</p><p><strong>Results: </strong>We present two related patients from Kosovo, describing the clinical, genetic, and therapeutic aspects of the syndrome. The identified novel VIPAS39 pathological variants (c.762G > A; c.1064_1082delinsAGTG) emphasize the complex phenotypic expression of ARC syndrome. A systematic literature review identified 8 VIPAS39-related ARC cases with notable variability in clinical features. Prognostically, patients fell into severe and milder groups, with some reaching adolescence. Our report aligns with others noting milder ARC courses and emphasizes the value of genetic testing, especially in atypical presentations. Challenges included incomplete literature data, early mortality affecting diagnostic workup, and limited VIPAS39-related ARC cases. Comparisons with the more prevalent VPS33B pathological variants revealed no distinct clinical differences.</p><p><strong>Conclusion: </strong>Our study expands understanding of ARC syndrome, highlighting its genetic diversity and clinical variability. Milder presentations underscore diagnostic challenges and the potential prevalence of undiagnosed cases. Increased awareness and comprehensive genetic testing are crucial for early and accurate diagnosis.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"496"},"PeriodicalIF":3.4,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142907462","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}

{"title":"Two-year follow-up after drug desensitization in mucopolysaccharidosis.","authors":"Federico Spataro, Roberto Ria, Nada Chaoul, Antonio Giovanni Solimando, Vanessa Desantis, Angelo Vacca, Danilo Di Bona, Attilio Di Girolamo, Luigi Macchia","doi":"10.1186/s13023-024-03516-z","DOIUrl":"10.1186/s13023-024-03516-z","url":null,"abstract":"<p><strong>Background: </strong>Mucopolysaccharidosis (MPS) type 1 S and type 2 are rare lysosomal storage disorders characterized by impaired enzyme production, resulting in glycosaminoglycans accumulation within lysosomes. Enzyme Replacement Therapy (ERT) with laronidase and idursulfase are first line treatments, respectively. However, infusion-related hypersensitivity reactions (HR) may lead to ERT discontinuation. Thus, desensitization can be performed to restore ERT.</p><p><strong>Methods: </strong>We report on a two-year follow-up after a combined desensitization approach in two MPS patients experiencing HR to ERT. This approach consists of intravenous rapid desensitization combined with the subcutaneous allergen immunotherapy-like desensitization with the culprit recombinant enzyme.</p><p><strong>Results: </strong>The first patient, suffering from MPS type I, underwent to the combined desensitization approach, and subsequently tolerated weekly standard laronidase infusions for 13 months when HR occurred again. Then, a monthly omalizumab (anti-IgE monoclonal antibody) administration was implemented allowing the patient to restore ERT. The second patient, diagnosed with MPS type 2, was subjected to a similar combined desensitization strategy with idursulfase, and achieved a total desensitization after one year, confirmed by negative skin tests. Thus, he continued standard ERT infusions without HR occurrence.</p><p><strong>Conclusion: </strong>The combined desensitization approach proved effective in conferring immunotolerance for at least one year in both MPS patients, also demonstrated by the negative skin tests in one patient. However, when immunotolerance to ERT is lost, omalizumab administration can be a valid option in restoring ERT.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"491"},"PeriodicalIF":3.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11673970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896661","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}

{"title":"When care hurts: parents' experiences of caring for a child with epidermolysis bullosa.","authors":"Elisabeth Daae, Kristin Billaud Feragen, Terje Naerland, Charlotte von der Lippe","doi":"10.1186/s13023-024-03502-5","DOIUrl":"10.1186/s13023-024-03502-5","url":null,"abstract":"<p><strong>Background: </strong>Epidermolysis bullosa (EB) comprises a group of genetically and clinically heterogeneous diseases characterized by skin fragility and blistering. EB is incurable, and treatment consists of preventing blisters in addition to painful and time consuming skin care, often performed by the parents, in addition to monitoring other symptoms in cases of severe EB.</p><p><strong>Results: </strong>The purpose of this study was to explore parental experiences of caring for a child with EB. Data were collected from semi-structured interviews, and analyzed through reflexive thematic analysis. The sample consisted of 15 parents. Our analysis revealed three main themes: Becoming a self-taught provider of home-based skin care; Balancing roles; and Ahead of every challenge. The results indicate aspects of caring for a child with EB that may be under-recognized by healthcare professionals (HCPs) and allied caretakers. Examples of this was extensive home care, learning skin care through trial-and-error, tension between illness-demands and the child's psychological needs, and parents being gatekeepers of their child's well-being.</p><p><strong>Conclusions: </strong>Caring for a child with EB may imply practical and emotionally demanding tasks for the parents, and possible unmet healthcare needs. It is important that HCPs recognize and understand the potential burden of extensive home care these parents experience as part of providing for their child with EB and the family.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"492"},"PeriodicalIF":3.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11681652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896662","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}

{"title":"Impact of enzyme replacement therapy on clinical manifestations in females with Fabry disease.","authors":"Malte Lenders, Albina Nowak, Markus Cybulla, Jessica Kaufeld, Anja Friederike Köhn, Nicole Maria Muschol, Christine Kurschat, Eva Brand","doi":"10.1186/s13023-024-03503-4","DOIUrl":"10.1186/s13023-024-03503-4","url":null,"abstract":"<p><strong>Background: </strong>The aim of our multicenter study was to investigate the implementation of the European Fabry guidelines on therapeutic recommendations in female patients with Fabry disease (FD) and to analyze the impact of enzyme replacement therapy (ERT) in treated and untreated females.</p><p><strong>Results: </strong>Data from 3 consecutive visits of 159 female FD patients from 6 Fabry centers were retrospectively analyzed. According to their treatment, patients were separated in 3 groups (untreated, n = 71; newly ERT-treated, n = 47; long-term ERT-treated, n = 41). Clinical presentation and laboratory data, including plasma globotriaosylsphingosine (lyso-Gb₃) levels were assessed. The observation time ranged from 49 to 62 months. ∼90% of female patients treated with ERT presented with at least one organ manifestation justifying treatment according to current European guidelines. Untreated females showed a less severe disease load with less FD-typical organ damage. All groups presented with a stable cardiac status (all p > 0.05) over time. ERT-treated females presented with a slight yearly loss of estimated glomerular filtration (eGFR) over time (both p < 0.05), which was comparable to the natural decline for this age. Plasma lyso-Gb₃ levels were higher in ERT-treated females and decreased by 0.95 [-4.44 to 4.08] ng/ml/year (p = 0.0002) in those who were newly ERT-treated.</p><p><strong>Conclusions: </strong>Severely affected females with FD who were treated with ERT, and less severely affected untreated females, showed a broadly stable disease course over 5 years. The treatment decisions were largely based on the European guidelines for FD. In untreated females, it is crucial to explore if organ involvement is FD-related in order to make the correct treatment decision.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"490"},"PeriodicalIF":3.4,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11673826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896659","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}

{"title":"A cross-sectional and longitudinal evaluation of serum creatinine as a biomarker in spinal muscular atrophy.","authors":"Xin Zhao, Zhenxiang Gong, Han Luo, Zehui Li, Rong Gao, Kangqin Yang, Wenhua Deng, Sirui Peng, Li Ba, Yang Liu, Min Zhang","doi":"10.1186/s13023-024-03515-0","DOIUrl":"10.1186/s13023-024-03515-0","url":null,"abstract":"<p><strong>Objective: </strong>Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by proximal muscle weakness and atrophy. The increasing availability of disease-modifying therapies has prompted the development of biomarkers to facilitate clinical assessments. We explored the association between disease severity and serum creatinine (Crn) levels in SMA patients undergoing up to two years of treatment with nusinersen.</p><p><strong>Methods: </strong>We measured serum Crn levels and assessed function performance using the Hammersmith Functional Motor Scale-Expanded (HFMSE), Medical Research Council Scale (MRC), 6-Minute Walk Test (6MWT), ulnar Compound Muscle Action Potential (CMAP), and forced vital capacity (FVC) in a cohort comprising 28 adolescent and adult patients with SMA. The association between Crn and disease severity was investigated through partial rank correlation analysis and linear mixed models while accounting for age, gender, and BMI. Linear models were employed to predict functional performance.</p><p><strong>Results: </strong>28 SMA patients and 28 gender- and age-matched healthy controls (HCs) were included, resulting in a dataset of 185 visits. Compared to HCs, SMA patients exhibited significantly lower Crn values ​​(67.4 ± 14 vs. 23.7 ± 14.8 umol/L, p<0.0001). After adjusting for age, sex, and BMI, Crn showed positive correlations with the HFMSE (p<0.0001, r = 0.884), MRC (p<0.0001, r = 0.827), FVC (p = 0.002, r = 0.730), and ulnar CMAP (p<0.0001, r = 0.807). Patients with SMN2 copy number ≥ 4 had nearly twice as high Crn levels as those with SMN2 copy number < 4 (34.1 ± 3.75 vs. 17.2 ± 2.52 umol/L, p = 0.00145). Ambulant SMA patients had more than double the Crn levels compared to non-ambulant ones (32 ± 2.33 vs. 12.9 ± 2.38 umol/L, p<0.0001). Furthermore, Crn explained that up to 83.5% of the variance in functional performance measured by HFMSE, MRC, and 6MWT was significantly higher than that of traditional biomarkers.</p><p><strong>Conclusions: </strong>These findings suggest that Crn may be a potential biomarker for assessing disease severity in adolescents and adults with SMA, demonstrating its promise in clinical applications.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"489"},"PeriodicalIF":3.4,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11670464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896650","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}

{"title":"Expanding the phenotypic and genetic spectrum of GTPBP3 deficiency: findings from nine Chinese pedigrees.","authors":"Yaojun Xie, Keyi Li, Li Yang, Xiaofei Zeng, Zhehui Chen, Xue Ma, Luyi Zhang, Yuwei Zhou, Liqin Jin, Yanling Yang, Xiaoting Lou","doi":"10.1186/s13023-024-03469-3","DOIUrl":"10.1186/s13023-024-03469-3","url":null,"abstract":"<p><strong>Background: </strong>GTPBP3 catalyzes τm⁵(s²) U biosynthesis at the 34th wobble position of mitochondrial tRNAs, the hypomodification of τm⁵U leads to mitochondrial disease. While twenty-three variants of GTPBP3 have been reported worldwide, the genetic landscape in China remains uncertain.</p><p><strong>Methods: </strong>By using whole-exome sequencing, the candidate individuals carrying GTPBP3 variants were screened and identified. Pathogenicity analysis of variants was biochemically verified by patients-derived immortalized lymphocytes and cell models.</p><p><strong>Results: </strong>Through whole-exome sequencing, thirteen variants associated with GTPBP3 were identified in nine Chinese pedigrees, with eight of these variants being newly reported. Affected individuals displayed classic neurologic phenotypes and heart complications including developmental delay, seizures, hypotonia, exercise intolerance, and hypertrophic cardiomyopathy. Additionally, they displayed new symptoms such as eye problems like strabismus and heart issues related to valve function. Studies conducted on patient-derived cells provided evidence of reduced levels of GTPBP3 and impairment in mitochondrial energetic biogenesis. Re-expressing GTPBP3 variants in knockout cell lines further defined the pathogenicity of the novel variants. Analysis of the genetic spectrum in the Chinese population highlighted a concentration in exons 4 and 6, with c.689A > C being the prominent hotspot.</p><p><strong>Conclusion: </strong>Our findings emphasize the extensive clinical and genetic implications of GTPBP3-related mitochondrial disorders, particularly within the Chinese population, but further investigations are needed to explore the phenotype-genotype correlation.</p>","PeriodicalId":19651,"journal":{"name":"Orphanet Journal of Rare Diseases","volume":"19 1","pages":"488"},"PeriodicalIF":3.4,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11668094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886138","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}