Molecular Genetics and Metabolism Reports最新文献

{"title":"Unveiling alpha-mannosidosis in Iraqi children: A series of clinically and genetically characterized cases with novel MAN2B1 variant","authors":"Mays Riyadh Al Tai ,&nbsp;Nebal Waill Saadi ,&nbsp;Marwa Sabah Alothman ,&nbsp;Ikhlas Ali Ahmed ,&nbsp;Hala Sameh Arif ,&nbsp;Saja Baheer Abdulwahhab","doi":"10.1016/j.ymgmr.2025.101282","DOIUrl":"10.1016/j.ymgmr.2025.101282","url":null,"abstract":"<div><h3>Background</h3><div>Alpha-mannosidosis is a rare lysosomal storage disorder caused by <em>MAN2B1</em> mutations, leading to cognitive decline, hearing loss, infections, and skeletal abnormalities. Limited data exist from the Middle East; this study describes the clinical and genetic features of affected Iraqi children.</div></div><div><h3>Patients and methods</h3><div>This study was conducted at Children Welfare Teaching Hospital, and Al Emamayn Al Khadimiyan Medical City Baghdad, Iraq. We retrospectively reviewed children diagnosed with alpha-mannosidosis (2017–2025). Diagnosis was confirmed by enzyme assay and <em>MAN2B1</em> testing. Clinical and imaging data were collected from medical records.</div></div><div><h3>Results</h3><div>A total of nine children from five unrelated families were identified. The cohort included seven males and two females. The mean age at symptoms onset was 1.1 ± 0.5 years, while the mean age at diagnosis was 10.7 ± 7.6 years, indicating a diagnostic delay of approximately 9.6 ± 7.4 years. All the patients were born to consanguineous parents. The most common clinical features included psychomotor delay, sensorineural hearing loss and coarse facial features (100 % for each). Neuroimaging of the brain revealed variable findings, and skeletal radiographs showed dysostosis multiplex in 4/9 patients. Genetic testing revealed three pathogenic/likely pathogenic <em>MAN2B1</em> variants, including one novel variant [c.830C &gt; T (p.Pro277Leu)].</div></div><div><h3>Conclusion</h3><div>Our findings represent the first clinical and molecular characterization of alpha-mannosidosis in Iraqi children and reveal previously unreported genetic features in this population. It highlights that clinical and laboratory findings in our patients were largely consistent with previously published regional and international data. It demonstrates notable diagnostic delay and identified novel variants, expanding the mutational spectrum associated with the disease.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101282"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145929217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two adult sisters with untreated phenylketonuria: Strikingly discordant clinical phenotype","authors":"Didem Demirbas,&nbsp;Susan E. Waisbren,&nbsp;Olaf Bodamer,&nbsp;Christina Y. Hung,&nbsp;Farrah Rajabi ,&nbsp;Gerard Berry,&nbsp;Harvey L. Levy","doi":"10.1016/j.ymgmr.2026.101304","DOIUrl":"10.1016/j.ymgmr.2026.101304","url":null,"abstract":"<div><div>Intellectual disability is the cardinal clinical feature of untreated phenylketonuria (PKU). Nevertheless, there are rare individuals with untreated PKU who have had normal or near normal cognition despite having never been treated. We are reporting two adult sisters with untreated PKU who are strikingly discordant in cognition and the studies we conducted to determine whether there is a significant difference between the sisters that might explain the discordancy. The older sister has the expected moderate to severe cognitive disability while the younger sister is intellectually normal having graduated from college and serving as an executive secretary until retirement. Studies that include plasma phenylalanine (Phe) and other amino acids, urine organic acids, phenylalanine hydroxylase (<em>PAH</em>) genotype, <em>in vivo</em> PAH activity, brain MRI, and whole exome sequencing failed to reveal a significant difference between the sisters. The results of published studies comparing cognitively normal and abnormal individuals with untreated PKU also failed to reveal a significant difference with the exception of a single unconfirmed study reporting a lower brain Phe level in three adults with untreated PKU (Moller HE, Weglage J, Wiedermann D, Ullrich K, 1998). It is important to identify and study cognitively normal or near normal individuals with untreated PKU in search of a factor that might explain the discordancy in clinical outcome and lead to a further understanding of pathogenesis in PKU.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101304"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147397688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Newborn screening, genetic analysis, and long-term follow-up of 89 cases with short-chain acyl-CoA dehydrogenase deficiency (SCADD)","authors":"GuLing Qian ,&nbsp;Chen Liu ,&nbsp;YanHua Xu ,&nbsp;Duo Zhou ,&nbsp;Chi Chen ,&nbsp;BenQing Wu ,&nbsp;XinWen Huang","doi":"10.1016/j.ymgmr.2026.101292","DOIUrl":"10.1016/j.ymgmr.2026.101292","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to delineate the neonatal screening landscape, incidence, tandem mass spectrometry (MS/MS)-based metabolic signatures, ACADS gene variant spectrum, and long-term clinical outcomes of short-chain acyl-CoA dehydrogenase deficiency (SCADD) in newborns from Zhejiang Province, China.</div></div><div><h3>Methods</h3><div>A retrospective cohort study was conducted on 4,667,883 newborns in Zhejiang screened between November 2013 and August 2025. Acylcarnitine profiles in dried blood spots were analyzed by MS/MS. Urinary organic acids and ACADS gene variants were detected via gas chromatography–mass spectrometry (GC–MS) and high-throughput sequencing, respectively. Confirmed SCADD patients underwent longitudinal follow-up to evaluate growth, neurodevelopment, and biochemical parameters.</div></div><div><h3>Results</h3><div>Initial screening identified 500 infants with elevated butyrylcarnitine (C4) or C4/ propionylcarnitine (C3) ratios; 89 were confirmed as SCADD, corresponding to an incidence of 1 in 52,448 (1.9 per 100,000). All patients were asymptomatic during the neonatal period. Among the 26 patients who underwent urinary GC/MS, 25 (96.2%) presented with elevated ethylmalonic acid (EMA) levels. Fifty-one ACADS variants were identified, with missense variants (46/51, 90.2%) being the most prevalent; the top three variants were c.1031 A &gt; G (28.1%), c.164C &gt; T (13.5%), and c.1130C &gt; T (11.2%).</div></div><div><h3>Conclusions</h3><div>The incidence of SCADD in Zhejiang is 1 in 52,448, with c.1031 A &gt; G and c.164C &gt; T as the most frequent ACADS variants; and most screen-detected SCADD cases remain asymptomatic.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101292"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146169977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intermittent ketogenic fasting with medium-chain triglycerides improves ataxia in COQ8A-related coenzyme Q10 deficiency: A case report","authors":"Wiebke Hahn ,&nbsp;Karla Erffmeier ,&nbsp;Maximilian Schulze ,&nbsp;Felix Zahnert ,&nbsp;Susanne Knake ,&nbsp;Panagiota-Eleni Tsalouchidou","doi":"10.1016/j.ymgmr.2026.101296","DOIUrl":"10.1016/j.ymgmr.2026.101296","url":null,"abstract":"<div><h3>Background</h3><div>Mutations in COQ8A cause primary coenzyme Q10 deficiency, which can present clinically heterogeneously: Symptoms range from cerebellar ataxia, epilepsy, encephalomyopathy, macular degeneration to nephropathy. High-dose coenzyme Q10 supplementation is widely used, yet there is little evidence on complementary strategies, particularly for non-epileptic features such as cerebellar ataxia.</div></div><div><h3>Case presentation</h3><div>We report a 46-year-old female with genetically confirmed COQ8A-related coenzyme Q10 (CoQ10) deficiency, presenting with ataxia and epilepsy characterized by myoclonic and bilateral tonic–clonic seizures, who participated in a clinical protocol of ketogenic intermittent fasting, a method of intermittent fasting combined with medium-chain triglycerides (MCT) primarily designed for seizure management. The patient followed a 16:8 intermittent fasting regime combined with MCT intake for three months, followed by three months of all-alone intermittent fasting. Routine blood markers and brain MRI, including diffusion imaging were obtained before and after ketogenic fasting.</div></div><div><h3>Results</h3><div>During the study protocol, while no seizure reduction in myoclonic seizures could be observed, ataxia - quantified by the Scale for the Assessment and Rating of Ataxia (SARA) - improved significantly from 8.5 to 6.0 during the interventions. MRI showed a trend suggesting improved cerebellar microstructural integrity.</div></div><div><h3>Conclusions</h3><div>This case highlights the potential of ketogenic intermittent fasting as an adjunct therapy for mitochondrial ataxia. Ketogenic intermittent fasting was associated with clinically meaningful improvement of ataxia in a patient with COQ8A-related CoQ10 deficiency, suggesting that ketogenic dietary strategies may represent a promising adjunct therapeutic approach for mitochondrial ataxia. Future research should assess this intervention in larger patient cohorts to confirm its potential benefits.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101296"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146169978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Olipudase alfa treatment for pediatric acid sphingomyelinase deficiency in Egypt: A prospective, observational cohort study with an interventional subgroup","authors":"Nehal Abdelaziz Arafa ,&nbsp;Aml Mahfouz ,&nbsp;Shimaa Anwar ,&nbsp;Iman Marzouk","doi":"10.1016/j.ymgmr.2026.101293","DOIUrl":"10.1016/j.ymgmr.2026.101293","url":null,"abstract":"<div><h3>Objectives</h3><div>To present key features of pediatric acid sphingomyelinase deficiency (ASMD) and assess the clinical and safety outcomes of enzyme replacement therapy with olipudase alfa.</div></div><div><h3>Study design</h3><div>A prospective, observational cohort study of pediatric patients with ASMD that included an interventional subgroup treated with olipudase alfa. Patients presenting to the Alexandria University Children's Hospital in Egypt from June 2022 to May 2023 underwent clinical examination and genetic testing. Clinical and safety outcomes were assessed in patients who received biweekly infusions of olipudase alfa for 12 months.</div></div><div><h3>Results</h3><div>Fifteen pediatric patients with ASMD were included (10 were classified as type A or A/B and 5 were classified as type B). Patients with ASMD type A or A/B presented earlier and more severely, with a higher rate of mortality than patients with type B. Qualitative improvements in developmental and neurocognitive outcomes, clinical presentation, and laboratory parameters were observed among the patients with ASMD type A/B or type B treated with olipudase alfa (<em>n</em> = 6), with only mild safety events recorded. Treated patients with type B (<em>n</em> = 4) demonstrated significantly improved weight (<em>p</em> = 0.031, <em>η</em>² = 0.757) and height/length <em>Z</em>-scores (<em>p</em> = 0.009, <em>η</em>² = 0.707), and liver size (<em>p</em> = 0.025, <em>η</em>² = 0.839) compared with baseline.</div></div><div><h3>Conclusions</h3><div>This case series contributes to the clinical and biochemical understanding of ASMD and may help reduce diagnostic delays and improve clinical management. Olipudase alfa was generally well tolerated, and promising clinical improvements were observed.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101293"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146169976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular characterization of Alkaptonuria in Brazilian patients","authors":"Carolina Araújo Moreno ,&nbsp;Ruy Pires de Oliveira Sobrinho ,&nbsp;Josep Jorente ,&nbsp;Simone Appenzeller ,&nbsp;Nelma Gláucia Silva Meira ,&nbsp;Lucas Cadete Caldeira Costa ,&nbsp;Angelina Xavier Acosta ,&nbsp;The Brazilian Rare Genomes Project Consortium ,&nbsp;Mara Sanches Guaragna ,&nbsp;Carlos Eduardo Steiner","doi":"10.1016/j.ymgmr.2025.101288","DOIUrl":"10.1016/j.ymgmr.2025.101288","url":null,"abstract":"<div><h3>Objective</h3><div>Alkaptonuria is a rare inborn error of metabolism, with few reports from Brazil and typically lacking genotype descriptions in the Brazilian population.</div></div><div><h3>Methods</h3><div>A retrospective study of clinical and molecular data of individuals with alkaptonuria submitted to whole genome sequencing.</div></div><div><h3>Results</h3><div>Five individuals from four unrelated families were enrolled, with ages ranging from 8 months to 61 years at first evaluation and currently ranging from 26 to 65 years. All presented a history of dark urine since infancy and accentuated elevation of homogentisic acid excretion in urine samples. In two consanguineous families from the State of Bahia, the c.847 A &gt; T and c.899 T &gt; G variants were identified in homozygous status in the <em>HGD</em> gene; one of the individuals also had a history of infertility and presented the homozygous c.537 + 1G &gt; A variant in the <em>STX2</em> gene. The two remaining families without consanguinity, both from the State of São Paulo, presented with a combination of the heterozygous variants c.508G &gt; A and c.899 T &gt; G in one individual, and deletion of exon 13 of the <em>HGD</em> gene in trans with the c.1007-172 A &gt; G deep intronic variant as a possible causative variant in another patient.</div></div><div><h3>Conclusions</h3><div>Although small, the present series represents the first cohort of Brazilian individuals with alkaptonuria investigated by genomic sequencing, identifying a common variant (c.899 T &gt; G) in two families and three exonic and one deep intronic variant in the <em>HGD</em> gene, besides a possible double diagnosis comprising infertility due to a homozygous variant of uncertain significance in the <em>STX2</em> gene.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101288"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Multiple Sulfatase Deficiency (MSD) in newborn screening: A case study","authors":"Taraka R. Donti,&nbsp;James C. DiPerna,&nbsp;Madhuri R. Hegde,&nbsp;Revvity Omics, Inc","doi":"10.1016/j.ymgmr.2025.101285","DOIUrl":"10.1016/j.ymgmr.2025.101285","url":null,"abstract":"<div><div>A patient with multiple sulfatase deficiency (MSD) was identified through a lysosomal storage disorder enzyme analysis panel, based on a characteristic pattern of reduced activities across multiple sulfatases. Newborn screening laboratories implement various quality control protocols to assess the integrity of received samples. The quality control policy for identifying heat-denatured samples evaluates several enzyme activity levels to determine if a sample has been compromised by excessive heat. A new quality control policy has been established to differentiate heat-denatured samples from those affected by Multiple Sulfatase Deficiency.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101285"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical expert opinion on the role of elosulfase alfa in non-ambulatory individuals with Morquio A syndrome","authors":"Carolina F.M. de Souza ,&nbsp;Barbara K. Burton ,&nbsp;Philippe M. Campeau ,&nbsp;Roberto Giugliani ,&nbsp;Nathalie Guffon ,&nbsp;Christina Lampe ,&nbsp;Nicole Muschol ,&nbsp;Serap Sivri ,&nbsp;Martha Solano ,&nbsp;Karolina M. Stepien","doi":"10.1016/j.ymgmr.2026.101290","DOIUrl":"10.1016/j.ymgmr.2026.101290","url":null,"abstract":"<div><h3>Background</h3><div>Morquio A syndrome is associated with progressive loss of ambulatory capacity. The impact of elosulfase alfa enzyme replacement therapy (ERT), the approved treatment for Morquio A, remains understudied in non-ambulatory patients.</div></div><div><h3>Methods</h3><div>A modified Delphi study explored international expert opinions on drivers for using elosulfase alfa in non-ambulatory patients, potential treatment benefits in this population, and strategies for monitoring treatment impact. The study consisted of an initial exploratory virtual advisory board, anonymous voting on statements, and a survey to collect additional information.</div></div><div><h3>Results</h3><div>Ten physicians with expertise in managing patients with Morquio A participated in the study. The experts reached ≥70% agreement on 14 statements; nine statements achieved 100% agreement. They agreed that mobility should not drive decisions to initiate, continue or discontinue treatment. ERT should be considered or continued as long as the benefits outweigh the burden of treatment. The decision to discontinue ERT should be based on clinician and patient/family consensus considering clinical status, health-related quality of life, and treatment burden. Clinical experience suggests that patients who cannot complete the 6MWT can still benefit from ERT. In these patients, treatment success may be measured using assessments of pulmonary function, hand dexterity, general functionality and pain, patient-reported symptoms, and quality of life assessments.</div></div><div><h3>Conclusions</h3><div>This explorative study offers valuable insights into drivers of ERT use in non-ambulatory patients with Morquio A, its potential benefits, and strategies for monitoring treatment outcomes in clinical practice. These findings may guide patient management, optimize treatment, and inform future research for this population.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101290"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146024224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel homozygous CA5A gene deletion in carbonic anhydrase VA deficiency presenting as developmental delay without metabolic crisis","authors":"Maryam F. Bin Hadyan ,&nbsp;Mohammed A. Saleh ,&nbsp;Saad Aldalaqan ,&nbsp;Aziza M. Mushiba ,&nbsp;Ali M. Alasmari ,&nbsp;Eissa A. Faqeih ,&nbsp;Abdul A. Peer-Zada","doi":"10.1016/j.ymgmr.2026.101294","DOIUrl":"10.1016/j.ymgmr.2026.101294","url":null,"abstract":"<div><h3>Background</h3><div>Carbonic anhydrase VA deficiency is a rare autosomal recessive disorder caused by biallelic mutations in the CA5A gene. Patients present with acute metabolic decompensation including hyperammonemia in infancy albeit a good outcome.</div></div><div><h3>Objective</h3><div>We report three children from the same Saudi tribe with a novel homozygous deletion in CA5A gene, manifesting predominantly as developmental delay without hyperammonemia and major metabolic crises.</div></div><div><h3>Methods</h3><div>Diagnostic work-up included clinical, biochemical, neuroimaging, and genetic analyses through WES and WGS with family segregation analysis.</div></div><div><h3>Results</h3><div>The first patient, a 3-year-old girl, presented with global developmental delay, corpus callosum thinning, and mild periventricular leukomalacia on brain MRI. The second patient, a 7-year-old girl born to consanguineous parents, had delayed motor and language milestones with persistent speech delay, microcephaly, and mild to moderate intellectual disability, but normal metabolic and neuroimaging findings. Her younger sister, aged 4 years, showed mild speech delay without additional clinical abnormalities with biochemical investigations in both siblings unremarkable. None presented with classic neonatal hyperammonemia. A pathogenic homozygous loss of 16.5 kb (exons 3–7) in CA5A gene (chr16:87921735–87,938,510 NM_001739.2) was identified in all the three children with the parents and healthy siblings carrying the variant in heterozygous state.</div></div><div><h3>Conclusion</h3><div>CA-VA deficiency may present with non-specific neurodevelopmental delay without metabolic decompensation. Genetic analysis remains the cornerstone for identifying atypical cases with novel mutations in a rare disease and recognition of this atypical presentation is essential for awareness of the disease.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101294"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147284104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biochemical characterization of the FH variant p.Lys414Glu reveals loss of enzymatic function and disrupted multimerization","authors":"Connor J. Huck ,&nbsp;Isabella Devaprasad ,&nbsp;Blake R. Wilde","doi":"10.1016/j.ymgmr.2025.101287","DOIUrl":"10.1016/j.ymgmr.2025.101287","url":null,"abstract":"<div><div>Variants of uncertain significance (VUS) in fumarate hydratase (<em>FH</em>) complicate the diagnosis of hereditary leiomyomatosis and renal cell carcinoma (HLRCC). The FH VUS p.Lys414Glu has been reported in patients with HLRCC features but additional evidence is needed to support an interpretation of pathogenicity. Here we show that p.Lys414Glu is completely inactive, supporting a classification of pathogenic and providing critical evidence for clinical care and surveillance of patients with germline FH p.Lys414Glu.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"46 ","pages":"Article 101287"},"PeriodicalIF":1.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145898012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}