Molecular genetics and metabolism最新文献

{"title":"Newborn screening for spinal muscular atrophy: The potential of digital polymerase chain reaction technique","authors":"Jun Kido ,&nbsp;Ken Haruno ,&nbsp;Keishin Sugawara ,&nbsp;Kotaro Anan ,&nbsp;Yusuke Hattori ,&nbsp;Yusuke Noda ,&nbsp;Takaaki Sawada ,&nbsp;Kimitoshi Nakamura","doi":"10.1016/j.ymgme.2025.109114","DOIUrl":"10.1016/j.ymgme.2025.109114","url":null,"abstract":"<div><div>Spinal muscular atrophy (SMA) is a degenerative neuromuscular disorder caused by a homozygous <em>SMN1</em> loss-of-function variant. Early detection of SMA at the pre-symptomatic stage is essential for effective therapy. Consequently, Japan initiated newborn screening (NBS) for SMA in 2021 in the Kumamoto Prefecture, following global recommendations and implementations.</div><div>The current NBS protocol involves a two-step process: first, quantitative real-time polymerase chain reaction (qPCR) for <em>SMN1</em>, followed by <em>SMN1</em> and <em>SMN2</em> copy number analysis using multiplex ligation-dependent probe amplification (MLPA). However, this approach is time-intensive, and qPCR alone cannot distinguish a single copy of <em>SMN1</em> exon 7. The current NBS protocol is designed to detect approximately 96 % of SMA cases, specifically those with homozygous <em>SMN1</em> exon 7 deletions.</div><div>This study developed a digital PCR system for simultaneous analysis of <em>SMN1</em> and <em>SMN2</em> copy numbers to reduce the diagnostic time and improve diagnostic accuracy. Digital PCR was tested on dried blood spot (DBS) samples from 6 SMA patients (P-1 - P-6) and 386 healthy newborns. Additionally, the <em>SMN1</em> and <em>SMN2</em> copy numbers of the 6 patients were evaluated using MLPA.</div><div>The results demonstrate that digital PCR enables simultaneous analysis of <em>SMN1</em> and <em>SMN2</em> copy numbers, with the outcomes for all six patients matching those obtained through MLPA. Moreover, digital PCR was more cost-effective than qPCR.</div><div>Thus, digital PCR offers a practical and efficient alternative for SMA screening in NBS, enabling simultaneous analysis of <em>SMN1</em> and <em>SMN2</em> copy numbers while also improving the diagnostic speed and accuracy.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 2","pages":"Article 109114"},"PeriodicalIF":3.7,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of BOLA3 in the mitochondrial Fe-S cluster clarified by metabolomic analysis","authors":"Hiroyuki Iijima ,&nbsp;Atsuko Imai-Okazaki ,&nbsp;Yoshihito Kishita ,&nbsp;Ayumu Sugiura ,&nbsp;Masaru Shimura ,&nbsp;Kei Murayama ,&nbsp;Yasushi Okazaki ,&nbsp;Akira Ohtake","doi":"10.1016/j.ymgme.2025.109113","DOIUrl":"10.1016/j.ymgme.2025.109113","url":null,"abstract":"<div><div>BOLA3 is one of the proteins involved in the assembly and transport of [4Fe-4S] clusters, which are incorporated into mitochondrial respiratory chain complexes I and II, aconitase, and lipoic acid synthetase. Pathogenic variants in the <em>BOLA3</em> gene cause a rare condition known as multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, characterized by life-threatening lactic acidosis, nonketotic hyperglycinemia, and hypertrophic cardiomyopathy.</div><div>The aim of this study was to elucidate the biochemical characteristics of patients with <em>BOLA3</em> variants and to clarify the role of BOLA3 protein in humans. The characteristics, clinical course, and biochemical data of eight Japanese patients with <em>BOLA3</em> pathogenic variants were collected. In addition, metabolomic analyses were performed using capillary electrophoresis time-of-flight mass spectrometry, blue native polyacrylamide gel electrophoresis (BN-PAGE)/Western blot analysis of mitochondrial respiratory chain complexes, and in-gel enzyme staining of mitochondrial respiratory chain complexes of fibroblasts from all eight patients. Metabolomic data were compared between the eight patients with <em>BOLA3</em> variants and three control samples using Welch's <em>t</em>-test. In the metabolomic analysis, levels of lactic acid, pyruvic acid, alanine, tricarboxylic acid (TCA) cycle intermediates (such as α-ketoglutaric acid and succinic acid), branched-chain amino acids, and metabolites of lysine and tryptophan were significantly elevated in the <em>BOLA3</em> group. Data collected during the patients' lives showed increased lactic acid and glycine levels. In BN-PAGE/Western blot analysis and in-gel enzyme staining, bands for complexes I and II were barely detectable in all eight cases. These results indicate that <em>BOLA3</em> variants decrease the activity of lipoic acid-dependent proteins (pyruvate dehydrogenase complex, α-ketoglutarate dehydrogenase, 2-oxoadipate dehydrogenase, branched-chain ketoacid dehydrogenase, and the glycine cleavage system), as well as mitochondrial respiratory chain complexes I and II, but do not affect aconitase. Thus, it is believed that BOLA3 is involved in transporting [4Fe-4S] clusters to respiratory chain complexes I and II and lipoic acid synthetase, but does not interfere with aconitase. These findings suggest that while lipoic acid supplementation or vitamin cocktails may provide benefits, the impaired [4Fe-4S] cluster pathway itself should be targeted for treatment to improve the extensive metabolic abnormalities caused by BOLA3 deficiency.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 2","pages":"Article 109113"},"PeriodicalIF":3.7,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The value of MR spectroscopy and MR elastography in assessing hepatic involvement of chronic visceral acid sphingomyelinase deficiency in adults","authors":"Eline C.B. Eskes ,&nbsp;Sandra A.M. van den Berg-Faaij ,&nbsp;Nienke P.M. Wassenaar ,&nbsp;Carla E.M. Hollak ,&nbsp;Aart J. Nederveen ,&nbsp;Barbara Sjouke","doi":"10.1016/j.ymgme.2025.109107","DOIUrl":"10.1016/j.ymgme.2025.109107","url":null,"abstract":"<div><div>Hepatic involvement is one of the main visceral manifestations of Acid Sphingomyelinase Deficiency (ASMD). It can lead to liver fibrosis and liver failure in a subset of patients. Better understanding of the boundary between reversible and irreversible liver involvement is important to initiate enzyme replacement therapy at the right moment. Currently, liver enzymes and liver stiffness measured with transient elastography (TE) are used to assess liver involvement of ASMD. The aim of this study was to investigate whether magnetic resonance (MR) techniques such as MR spectroscopy (MRS) and MR elastography (MRE) are useful methods to measure liver involvement of ASMD and whether they are more useful than TE.</div><div>Thirteen therapy-naïve adult ASMD patients with the chronic visceral subtype and eleven age-, sex- and body mass index-matched healthy controls were recruited. All participants underwent MRS and MRE scans and had blood drawn for the measurement of liver enzymes. For patients data of TE and biochemical plasma markers for ASMD were collected.</div><div>Median fat fraction measured with MRS and median liver stiffness measured with MRE did not differ significantly between ASMD patients and healthy controls (respectively median PDFF 1.0 %, range 0.2–24.2 % for patients and median PDFF 0.7 %, range 0.2–8.4 % for healthy controls, <em>p</em> = 0.49 and median liver stiffness 1.2 m/s, range 0.9–1.4 m/s for patients and median liver stiffness 1.3 m/s, range 1.1–1.4 m/s for healthy controls, <em>p</em> = 0.86). A significant correlation was observed between liver stiffness measured with MRE and liver stiffness measured with TE (<em>R</em> = 0.74, <em>p</em> = 0.014). The MRS spectra showed no specific sphingomyelin peaks. At this moment, TE seems the best method to monitor liver stiffness for adult patients with chronic visceral ASMD.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 2","pages":"Article 109107"},"PeriodicalIF":3.7,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Letter to the editor: SSR4-CDG, an ultra-rare X-linked congenital disorder of glycosylation affecting the TRAP complex: Review of 22 affected individuals including the first adult patient","authors":"Ileana Trujillo ,&nbsp;Maria E. Aguirre-Flores ,&nbsp;Patrick Sarkis ,&nbsp;Mayowa A. Osundiji","doi":"10.1016/j.ymgme.2025.109106","DOIUrl":"10.1016/j.ymgme.2025.109106","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109106"},"PeriodicalIF":3.7,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143825542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA sequencing driven diagnosis expands the phenotypic spectrum of NBAS deficiency","authors":"Sarah Silverstein ,&nbsp;Thomas Cassini ,&nbsp;Jiayu Fu ,&nbsp;Barbara Pusey ,&nbsp;Ellen Macnamara ,&nbsp;F. Graeme Frost ,&nbsp;Charlotte Williams ,&nbsp;Yan Huang ,&nbsp;Cynthia J. Tifft ,&nbsp;Undiagnosed Diseases Network,&nbsp;William Gahl ,&nbsp;May-Christine Malicdan ,&nbsp;David R. Adams","doi":"10.1016/j.ymgme.2025.109105","DOIUrl":"10.1016/j.ymgme.2025.109105","url":null,"abstract":"<div><div>One in 10 individuals has a rare disease, with exome and genome sequencing yielding an overall diagnostic rate of approximately 30 %. RNA sequencing can augment genome analysis and improve diagnosis. We present a young woman with global developmental delay, poor growth, distinctive facial features, osteopenia, premature ovarian insufficiency, and ocular abnormalities who had non-diagnostic genome sequencing. RNAseq performed on her skin fibroblasts showed that <em>NBAS</em> gene expression was significantly reduced compared with controls. Manual inspection of the binary alignment map (BAM) files revealed compound heterozygous variants in <em>NBAS</em>: a rare deep intronic variant NM_015909.4:c.2423 + 403G &gt; C which creates a hypomorphic pseudoexon not seen in control samples (gnomad allele frequency (AF) 0.000006572); and a rare premature termination codon (PTC) NM_015909.4:c.4753C &gt; T; p.Arg1585Ter (gnomad AF 0.000006572). Both variants are predicted to cause nonsense mediated decay of transcripts, as the pseudoexon contains a PTC. Biallelic variants in <em>NBAS</em> are associated with two major phenotypes, i.e., infantile liver failure syndrome 2 (MIM # <span><span>616483</span><svg><path></path></svg></span>) and short stature, optic nerve atrophy, and Pelger-Huet anomaly (MIM # <span><span>614800</span><svg><path></path></svg></span>). Our patient, the first reported with one loss of function and one splice variant resulting in an out of frame transcript in <em>NBAS</em>, manifested a severe phenotype compared with previously reported individuals. This case demonstrates the utility of incorporating RNAseq to generate diagnostic candidates and expands the phenotypic spectrum of <em>NBAS</em> deficiency.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109105"},"PeriodicalIF":3.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Newborn screening follow-up for very long-chain acyl-CoA dehydrogenase deficiency in Colorado: Working towards a standardized protocol","authors":"M.M. Crenshaw ,&nbsp;O.M. D'Annibale ,&nbsp;A. Schechter ,&nbsp;M. Sethuraman ,&nbsp;C. Porter ,&nbsp;G. Bonn ,&nbsp;E. Wright ,&nbsp;T. Wood ,&nbsp;J. Vockley ,&nbsp;P.L. Hall ,&nbsp;McCandless SE","doi":"10.1016/j.ymgme.2025.109104","DOIUrl":"10.1016/j.ymgme.2025.109104","url":null,"abstract":"<div><div>Very long chain acyl-CoA dehydrogenase deficiency (VLCADD) is an autosomal recessive fatty acid β-oxidation disorder that has been identified by newborn screening (NBS) in most states since the early 2000s. Despite over 20 years of experience, there are aspects of VLCADD NBS that remain challenging. We conducted a retrospective chart review of abnormal NBS for VLCADD in Colorado between 2017 and 2023. We analyzed confirmatory plasma acylcarnitine profiles (P-ACP), genetic sequencing of <em>ACADVL</em>, Collaborative Laboratory Integrated Reports (CLIR) scores, patient enzyme analysis of VLCAD, and cell-based variant expression analysis. A real-world “Clinical Designation” was then compared to a variety of algorithms trialed on the data. Of the 67 infants with abnormal screens during this timeframe, 5 (7 %) had a Clinical Designation of affected, 4 (6 %) remained unclassified, and 58 (87 %) were discharged based on a designation of unaffected. A Kruskal-Wallis rank sum test showed the biomarker with the best discrimination between affected and unaffected individuals was C14:1/C12:1 [chi-squared 10.4 (<em>p</em> = 0.001)]. The highest performing algorithm was (Molecular testing + cell-based expression) + (P-ACP C14:1 OR P-ACP C14:1/C12:1). Excluding the missing data, this algorithm showed 96 % (46 of 48) agreement with the Clinical Designation. We conclude that there is not a single biomarker that can specifically discern affected from unaffected individuals who screen positive on NBS for VLCADD. Thus, we developed a standardized diagnostic approach to more accurately classify patients that starts with the molecular findings and requires at least one of the P-ACP C14:1 or P-ACP C14:1/C12:1 to agree with molecular findings. The algorithm needs to be trialed with a different data set, and will advance the conversation around maximizing benefits and minimizing harms for infants who screen positive for VLCADD.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109104"},"PeriodicalIF":3.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic insights into arimoclomol mediated effects on lysosomal function in Niemann-pick type C disease","authors":"Hadeel Shammas ,&nbsp;Cathrine Kloster Fog ,&nbsp;Pontus Klein ,&nbsp;Anja Koustrup ,&nbsp;Marianne Terndrup Pedersen ,&nbsp;Anne Sigaard Bie ,&nbsp;Travis Mickle ,&nbsp;Nikolaj Havnsøe Torp Petersen ,&nbsp;Thomas Kirkegaard Jensen ,&nbsp;Sven Guenther","doi":"10.1016/j.ymgme.2025.109103","DOIUrl":"10.1016/j.ymgme.2025.109103","url":null,"abstract":"<div><div>Niemann-Pick disease type C (NPC) is an ultra-rare, fatal neurodegenerative disease. It is characterized by lysosomal dysfunction with cytotoxic accumulation of unesterified cholesterol and glycosphingolipids in lysosomes, which causes neurodegeneration and peripheral organ dysfunction. Arimoclomol, an orally available small molecule, is the first FDA-approved treatment for NPC when used in combination with miglustat. Here, we present the results of a series of in vitro studies performed to explore the pathways by which arimoclomol targets the fundamentals of NPC etiology. While the precise cellular interactions of arimoclomol remain unclear, the increased translocation of the transcription factors EB and E3 (TFEB and TFE3) from the cytosol to the nucleus is a key initial step for triggering a cascade of downstream events that can rescue cellular functions. Activation of TFEB and TFE3 raises the expression rates of coordinated lysosomal expression and regulation (CLEAR) genes including <em>NPC1</em> that are essential for the regulation of lysosomal function. The subsequent upregulation of CLEAR network proteins combined with increased unfolded protein response activation was shown to enlarge the pool of matured NPC1 capable of reaching the lysosome to reduce cholesterol accumulation. By also amplifying expression of CLEAR genes associated with autophagy, arimoclomol has the potential to act on different pathways and improve cell viability independent of NPC1 protein levels and functionality.</div><div>In summary, the findings presented illustrate how arimoclomol improves lysosomal function and potentially autophagy flux to decrease lipid burden in NPC patient fibroblasts.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109103"},"PeriodicalIF":3.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and efficacy of migalastat in adolescent patients with Fabry disease: Results from ASPIRE, a phase 3b, open-label, single-arm, 12-month clinical trial, and its open-label extension","authors":"Uma Ramaswami ,&nbsp;Esperanza Font-Montgomery ,&nbsp;Ozlem Goker-Alpan ,&nbsp;Damara Ortiz ,&nbsp;Amarilis Sanchez-Valle ,&nbsp;Chester B. Whitley ,&nbsp;William R. Wilcox ,&nbsp;Hai Jiang ,&nbsp;Lee Ann Lawson ,&nbsp;Jennie Vosk ,&nbsp;Haichen Yang ,&nbsp;Robert J. Hopkin","doi":"10.1016/j.ymgme.2025.109102","DOIUrl":"10.1016/j.ymgme.2025.109102","url":null,"abstract":"<div><div>Fabry disease (FD) is a progressive, multisystemic, X-linked lysosomal disorder caused by reduced or absent α-galactosidase A activity due to galactosidase alpha (<em>GLA</em>) gene variants. Although clinical manifestations of FD often appear in childhood, approved treatments for the management of FD in children and adolescents are limited. ASPIRE (<span><span>NCT03500094</span><svg><path></path></svg></span>) was a phase 3b, two-stage, open-label, multicenter study evaluating the safety, pharmacokinetics, and efficacy of migalastat in adolescents 12 to &lt;18 years, ≥ 45 kg with FD and amenable <em>GLA</em> variants. Long-term outcomes were evaluated in the ongoing open-label extension (OLE) study (<span><span>NCT04049760</span><svg><path></path></svg></span>). Pharmacokinetic results (a primary objective of ASPIRE) were reported previously. Here, we report safety, efficacy, pharmacodynamic, and patient-reported outcome measures in adolescents treated with migalastat for up to 48 months across ASPIRE and the subsequent OLE. Outcome measures included treatment-emergent adverse events, estimated glomerular filtration rate, left ventricular mass index, plasma globotriaosylsphingosine (lyso-Gb3) levels, the Fabry-specific Pediatric Health and Pain Questionnaire (FPHPQ), and the Pediatric Quality of Life Inventory™. Overall, 21 patients (52.4 % female) received at least one dose of migalastat in ASPIRE, 11 of whom were enzyme replacement therapy experienced. Mean age at study entry was 14.7 years. Treatment with migalastat was well tolerated in this adolescent population with no new or unexpected safety findings observed. Renal and cardiac measures remained within the normal range for adolescent patients throughout ASPIRE and the OLE with no meaningful changes observed with migalastat treatment. Plasma lyso-Gb3 levels were stable. Pain related to heat or exertion (as measured by FPHPQ) improved with migalastat treatment, and other patient-reported measures of pain, gastrointestinal symptoms, and quality of life remained stable. These data show a benefit of long-term migalastat treatment in this adolescent patient population with amenable <em>GLA</em> variants.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109102"},"PeriodicalIF":3.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143816543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recruitment through empathy and education: The role of the clinical experience on workforce development","authors":"Rishisree Achanta ,&nbsp;Ashley Cannon ,&nbsp;Shayla R. Goldberg ,&nbsp;Ryan Ha ,&nbsp;Andriae LaCour ,&nbsp;Christine Maccia ,&nbsp;Deepika Burkardt ,&nbsp;Jennifer Micham ,&nbsp;Debra S. Regier","doi":"10.1016/j.ymgme.2025.109101","DOIUrl":"10.1016/j.ymgme.2025.109101","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109101"},"PeriodicalIF":3.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143808704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of Nitisinone for patients with alkaptonuria: A systematic review with metanalysis","authors":"Flávia Diniz Mayrink ,&nbsp;Gilson Dorneles ,&nbsp;Igor Martins da Silva ,&nbsp;Camila Alves Areda","doi":"10.1016/j.ymgme.2025.109099","DOIUrl":"10.1016/j.ymgme.2025.109099","url":null,"abstract":"<div><h3>Aim</h3><div>We conducted a systematic review to assess the efficacy and safety of nitisinone for the treatment of patients with alkaptonuria (AKU).</div></div><div><h3>Methods</h3><div>Randomized clinical trials that assessed the impact of nitisinone on urinary and serum homogentisic acid (HGA), quality of life, joint range of motion, and adverse events in AKU patients were retrieved from Pubmed and EMBASE up to May 2024. Risk of bias assessment was performed with RoB 2.0, and the GRADE approach assessed the certainty of evidence (CoE) of each main outcome.</div></div><div><h3>Results</h3><div>Four publications from three studies summarizing data of 218 patients with AKU were included in the review process. Nitisinone administration decreased the urinary HGA levels (mean difference [MD]: −38.98; 95 % confidence interval [95 %-CI]: −53.18 to −24.78; CoE: moderate) without changes in the range of motion of the worst hip joint (MD: -6.23; 95 %-CI: −13.91 to 1.44; CoE: High). On the other hand, large increases in tyrosine were observed associated with nitisinone treatment (MD: 708.77; 95 %-CI: 649.32 to 768.22; CoE: High). AKU patients treated with nitisinone presented increased general health perception (MD: 2.77; 95 %-CI: 0.62 to 4.91), mental health (MD: 1.03; 95 %-CI: 0.90 to 1.19) and mental role functioning (MD: 5.57; 95 %-CI: 0.47 to 10.66). No statistical increases in overall adverse events (Relative Risk [RR]: 1.03; 95 %-CI: 0.90 to 1.19; CoE: High) or serious adverse events (RR: 2.47; 95 %-CI: 0.24 to 25.91; CoE: low) were observed.</div></div><div><h3>Conclusion</h3><div>This systematic review identified significant potential for nitisinone to modify the natural history of AKU, considering the relevance of clinical changes induced by the treatment.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 1","pages":"Article 109099"},"PeriodicalIF":3.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}