Molecular Genetics and Metabolism Reports最新文献

{"title":"SCYL1 deficiency and intrafamilial variability: Two cases from Kuwait","authors":"Laila Kazem ,&nbsp;Wafaa Al-Qabandi ,&nbsp;Buthaina Albash ,&nbsp;Reem Elshafie ,&nbsp;Miao He ,&nbsp;Hind Alsharhan","doi":"10.1016/j.ymgmr.2025.101269","DOIUrl":"10.1016/j.ymgmr.2025.101269","url":null,"abstract":"<div><h3>Introduction</h3><div>Biallelic pathogenic variants in <em>SCYL1</em> have been reported in 22 individuals to date. Also referred to as CALFAN syndrome (cholestasis, acute liver failure, and neurodegeneration), this condition is characterized by recurrent episodic acute liver failure (ALF) with low-GGT cholestasis and variable neurological manifestations. <em>SCYL1</em> deficiency disrupts intracellular vesicular trafficking, leading to hepatopathy and, in some cases, abnormal glycosylation.</div></div><div><h3>Results</h3><div>We report two Kuwaiti siblings homozygous for a pathogenic splice site variant in <em>SCYL1</em>(NM_020680.4):c.1386 + 1G &gt; A p.?. The younger sibling, an 8-year-old female presented at 16 months with ALF, hepatosplenomegaly, global developmental delay, hypotonia, and gait instability. During liver crises, she demonstrated biochemical features including low-GGT cholestasis, coagulopathy, and transient glycosylation abnormalities. Liver biopsy revealed peri-sinusoidal fibrosis and mild steatosis. She experienced two additional ALF episodes at 26 months and 3 years, both resolving completely. Follow-up biochemical testing at age 5.5 years showed normalization of glycosylation patterns following hepatic recovery. In contrast, her 9-year-old brother, who carries the same homozygous variant, remains asymptomatic, with normal development, liver function and imaging.</div></div><div><h3>Conclusion</h3><div>To our knowledge, this is the first description of an asymptomatic individual homozygous for a pathogenic <em>SCYL1</em> variant. Our findings highlight striking intrafamilial variability in <em>SCYL1</em>-deficiency and emphasize the reversibility of glycosylation abnormalities and liver dysfunction upon clinical recovery.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101269"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145325208","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":"Siblings of FBXL4-related mitochondrial DNA depletion syndrome, leading to fatal fulminant pneumonia","authors":"Takato Akiba ,&nbsp;Shino Shimada ,&nbsp;Shimpei Matsuda ,&nbsp;Shoji Ishida ,&nbsp;Yosuke Baba ,&nbsp;Atsushi Yamashita ,&nbsp;Hiromichi Shoji ,&nbsp;Yasushi Okazaki ,&nbsp;Kei Murayama","doi":"10.1016/j.ymgmr.2025.101266","DOIUrl":"10.1016/j.ymgmr.2025.101266","url":null,"abstract":"<div><div>The F-box and leucine-rich repeat protein 4 (<em>FBXL4</em>) is a nuclear encoded mitochondrial protein essential for mitochondrial DNA (mtDNA) maintenance. Biallelic variants in <em>FBXL4</em> cause FBXL4-related mitochondrial DNA depletion syndrome (FBXL4-MTDPS), characterized by lactic acidosis and developmental delay. We report two siblings diagnosed with FBXL4-MTDPS who died of fulminant pneumonia in infancy; autopsy revealed extensive pulmonary inflammation consistent with severe bacterial infection. FBXL4-MTDPS may involve intrinsic defects in pulmonary infection defense, increasing susceptibility to fatal infection such as pneumonia.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101266"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145266534","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":"Profiling glycosphingolipid changes in mouse and human cellular models of lysosomal free sialic acid storage disorder","authors":"Marya S. Sabir ,&nbsp;Kostantin Dobrenis ,&nbsp;Allisandra K. Rha ,&nbsp;Laura Pollard ,&nbsp;Petcharat Leoyklang ,&nbsp;Mariah Marrero ,&nbsp;Carla Ciccone ,&nbsp;Mary E. Hackbarth ,&nbsp;Marjan Huizing ,&nbsp;Raymond Y. Wang ,&nbsp;William A. Gahl ,&nbsp;Frances M. Platt ,&nbsp;May Christine V. Malicdan","doi":"10.1016/j.ymgmr.2025.101275","DOIUrl":"10.1016/j.ymgmr.2025.101275","url":null,"abstract":"<div><div>Free sialic acid storage disorder (FSASD) is an autosomal recessive lysosomal storage disease caused by biallelic pathogenic variants in <em>SLC17A5</em>, which encodes the lysosomal sialic acid transporter, sialin. FSASD is characterized by excessive lysosomal free sialic acid accumulation, leading to either a severe, early-onset lethal phenotype or a progressive neurodegenerative course. To characterize biochemical alterations in FSASD models, we performed comprehensive profiling of glycosphingolipids (GSLs), including sialylated species (i.e., gangliosides), in mouse embryonic fibroblasts (MEFs) derived from Slc17a5-R39C/R39C and Slc17a5-KO/KO mouse models, as well as in human SLC17A5-deficient HEK-293 T cells generated via CRISPR-Cas9-mediated non-homologous end joining. HPLC-based analyses demonstrated GM3 ganglioside accumulation in MEFs and significant reductions in a-series GSLs—including GM2, GM1a, and GD1a—in SLC17A5-deficient HEK-293 T cells. Analysis of neuraminidase 1/3/4 activities revealed consistently elevated activity across all cell models, while cytosolic neuraminidase 2 showed only a modest increase in Slc17a5-R39C/R39C MEFs. Preliminary quantification showed elevated free sialic acid across all models, consistent with the characteristic biochemical defect observed in FSASD and supporting their relevance for mechanistic studies. These findings highlight that free sialic acid storage leads to changes in GSL homeostasis in FSASD mouse (MEFs) and human (SLC17A5-deficient HEK-293T) cellular models, underscoring their utility as models for studying FSASD pathogenesis.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101275"},"PeriodicalIF":1.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145465582","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":"Development of an automated quality control and assay performance management system for biochemical genetics laboratory","authors":"P. Tanpaiboon,&nbsp;D. Salazar,&nbsp;M. Pan,&nbsp;L. Xu,&nbsp;R. Sharma","doi":"10.1016/j.ymgmr.2025.101247","DOIUrl":"10.1016/j.ymgmr.2025.101247","url":null,"abstract":"<div><h3>Objectives</h3><div>Quality control (QC) in clinical laboratory is critical to ensuring quality and accuracy of patient results. However, QC monitoring is complicated in the multi-analyte, multi-instrument assays common to biochemical genetics laboratories. Comprehensive off-the-shelf QC management systems optimized for such highly complex assays and platforms are relatively scarce. A manual QC review process can impact laboratory productivity and increase risk of errors. Here we describe a novel software application that integrates, processes, and displays QC statistical parameters from multiple instruments in near real-time results by automated processor.</div></div><div><h3>Methods</h3><div>A customizable, cloud-based software application was developed to centralize the information, automate an extra review step in the QC review process and increase clinical utility. We monitored time spent on each step of QC review and QC range assignments before and one year after implementing the program and documented quality improvements.</div></div><div><h3>Results</h3><div>This QC program has modules for different assay platforms. The program's functions include automated collection and assay data analysis, Levey-Jennings charts with integrated data from multiple instruments, graphical data visualization, instrument data centralization, assay monitoring, and a QC audit trail. The program also generates email notifications for QC lot expiration, QC review reminder, and critical results alert enabling prompt communication to providers. After the first year, this program provided 81 %-time reduction of hands-on time.</div></div><div><h3>Conclusion</h3><div>This program improves assay quality and provides considerable time savings. One benefit of this software is the ease of updating program capabilities and customizing them to meet specific and changing needs, especially for high-complexity testing.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"Article 101247"},"PeriodicalIF":1.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144878157","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":"Iron metabolism and hematological abnormalities in adult patients affected with mucopolysaccharidoses","authors":"Gabija Kaciulyte ,&nbsp;Goknur Yorulmaz ,&nbsp;Reena Sharma ,&nbsp;Simon A. Jones ,&nbsp;Robert Wynn ,&nbsp;Heather Church ,&nbsp;Karen Tylee ,&nbsp;Muzaffer Bilgin ,&nbsp;Ana Jovanovic ,&nbsp;Peter Woolfson ,&nbsp;Karolina M. Stepien","doi":"10.1016/j.ymgmr.2025.101243","DOIUrl":"10.1016/j.ymgmr.2025.101243","url":null,"abstract":"<div><div>Mucopolysaccharidoses are a heterogeneous group of rare lysosomal storage disorders (LSDs) caused by genetic mutations resulting in the deficiency of lysosomal enzymes responsible for the degradation of glycosaminoglycans (GAGs). The potential association of hematological abnormalities and clinical manifestations in MPS disorder highlights the importance of exploring the role of regular iron studies and hematological tests in at risk MPS patients as undiagnosed anemia has been shown to worsen clinical outcomes. In this study, therefore, we aimed to describe the hematological abnormalities and iron studies in adult patients with MPS disorders in the context of their therapies. Ninety-seven patients with MPS types I, II, III, IV and VI were included in the study (46 % females). The overall prevalence of iron deficiency anemia is 38 % in adult MPS cohort and affects 63 % of MPS III and 50 % of MPS I patients. It is more common in females with MPS I and IVA than males, post cardiac valve surgery and in patients with gastrointestinal dysfunction. There was high variability in Hb, mean corpuscular volume, serum iron and transferrin saturation among all the MPS subgroups, with results being higher in the HSCT and ERT group as compared to treatment naïve patients. The urine GAGs/creatine ratio negatively correlated with several critical parameters, including iron saturation (−0.07), serum iron (−0.06), Hb (−0.16), and hematocrit (−0.08). It was more pronounced among MPS III patients. Pancytopenia in treatment naive MPS III is associated with 7 to 20 fold increase of urine GAGs excretion. It is important to take into consideration hematological and iron study abnormalities in the management of MPS patients, as special approaches may be required for both intestinal health and anemia treatment.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"Article 101243"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144633977","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":"Overview of genetic mutations causing adrenoleukodystrophy: A case-series study","authors":"Mohadeseh Fathi ,&nbsp;Sheyda Khalilian ,&nbsp;Arezou Sayad ,&nbsp;Parvaneh Karimzadeh ,&nbsp;Farzad Ahmadabadi ,&nbsp;Soudeh Ghafouri-Fard ,&nbsp;Mohammad Miryounesi","doi":"10.1016/j.ymgmr.2025.101237","DOIUrl":"10.1016/j.ymgmr.2025.101237","url":null,"abstract":"<div><div>X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder resulted from mutations in the <em>ABCD1</em> gene located at the Xq28 locus. This gene encodes a transporter protein responsible for importing very-long-chain fatty acids into peroxisomes. This research seeks to elucidate the clinical manifestations linked to various mutations in the <em>ABCD</em> gene among Iranian patients with X-ALD, considering the diverse severity of symptoms observed in this disease. Totally, six variants, including a novel variant (c.1781-47G &gt; A) were identified in the <em>ABCD1</em> gene in the patients. All but one variant were classified as pathogenic or likely pathogenic; the remaining variant, c.1781-47G &gt; A, was identified as a variant of uncertain significance. This study broadens the spectrum of <em>ABCD1</em> mutations among Iranian patients, providing applicable information for appropriate genetic counseling in the affected families.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"Article 101237"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144470215","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":"Hand stiffness not only a rheumatological sign: A case of early onset mucolipidosis III-gamma with literature review","authors":"Alessandro La Rosa ,&nbsp;Alessia Pepe ,&nbsp;Barbara Tappino ,&nbsp;Fabio Corsolini ,&nbsp;Andrea Chiaro ,&nbsp;Annalisa Madeo","doi":"10.1016/j.ymgmr.2025.101246","DOIUrl":"10.1016/j.ymgmr.2025.101246","url":null,"abstract":"<div><h3>Background</h3><div>Mucolipidosis (ML) is a rare autosomal recessive lysosomal disorder with variable onset and severity: MLII, characterized by early onset and rapid progression, and MLIII, milder with late onset and prolonged survival. ML is due to mutations in the Golgi enzyme uridine diphosphate-<em>N</em>-acetylglucosamine-1-phosphotransferase, whose subunits are encoded by <em>GNPTAB</em> and <em>GNPTG</em> genes. This report presents a particular case of infantile early-onset MLIII-gamma and emphasizes that articular manifestations can be a sign of a metabolic disease rather than a rheumatological or orthopedic one.</div></div><div><h3>Case report</h3><div>A 5.7-years-old girl presented with progressive hand stiffness and joint pain, exhibiting symptoms from 6 months of age. She displayed claw-hand deformity and joint stiffness but normal growth and neurodevelopment. Biochemical testing revealed normal activities of alpha-L-iduronidase and arylsulfatase-B in leukocytes, excluding mucopolysaccharidosis I and VI, while beta-hexosaminidase and alpha-L-fucosidase activities in plasma were elevated, suggesting ML. Genetic analysis of <em>GNPTAB</em> and <em>GNPTG</em> identified two pathogenic variants in the <em>GNPTG</em> gene, confirming MLIII-gamma diagnosis. Despite early onset, the patient exhibited a less severe skeletal phenotype and showed mild cardiac and ocular involvement, occasionally described in classic MLIII-gamma.</div></div><div><h3>Discussion</h3><div>The natural history of MLIII remains poorly understood and mainly based on sporadic case reports/series. Our case presents a typical MLIII-gamma phenotype but with an unexpectedly early onset, expanding the clinical spectrum of this disease. It emphasizes the need for increased awareness among pediatric rheumatologists regarding metabolic disorders. Further case studies are essential to enhance understanding and improve diagnostic and therapeutic approaches for ML.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"Article 101246"},"PeriodicalIF":1.9,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144829086","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":"GNE myopathy with premature ovarian failure: Case report and review of the literature","authors":"Shangyi Yang,&nbsp;Jine Yang","doi":"10.1016/j.ymgmr.2025.101240","DOIUrl":"10.1016/j.ymgmr.2025.101240","url":null,"abstract":"<div><div>GNE myopathy (GNE-M) is an ultra-rare disease characterized by muscle weakness in the extremities. The main etiology is that a pathogenic variation in the <em>GNE</em> gene leads to a reduction in sialic acid synthesis. However, whether it is associated with premature ovarian failure (POF) isunknown. Here we report a case of GNE-M with premature ovarian failure (GNE-M-POF). The clinical data of a case of GNE-M-POF in our hospital were collected. The historical trajectory, molecular features, diagnosis and treatment were analyzed retrospectively, and the literature was reviewed. Over the course of 12 years, the patient presents with a slow and progressively worsening clinical manifestation. She was amenorrheic at the age of 35 and never conceived. Her calf muscles, and some of her thigh muscles were severely atrophied, leaving her unable to walk on her own. POF may be an extra-muscular manifestation of GNE-M, and further research is needed to verify the association.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"Article 101240"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144518672","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":"TANGO2 deficiency disorder in a 61-year-old male with episodic weakness, rhabdomyolysis, myotonia, and a novel missense variant","authors":"Henry Skocy ,&nbsp;Amber McFerren ,&nbsp;Daniel Cairns ,&nbsp;H. Mark Kenney ,&nbsp;Eran Tallis ,&nbsp;Amit S. Dhamoon ,&nbsp;Ellie Garbade ,&nbsp;Samuel J. Mackenzie","doi":"10.1016/j.ymgmr.2025.101241","DOIUrl":"10.1016/j.ymgmr.2025.101241","url":null,"abstract":"<div><div>TANGO2 Deficiency Disorder (TDD) is an autosomal recessive condition, most commonly diagnosed in childhood. Clinical features may include episodic movement disorders, seizures, cognitive impairment, hypothyroidism, and metabolic crises marked by rhabdomyolysis and life-threatening cardiac symptoms. A small number of adults, thought to largely represent the milder end of the phenotypic spectrum, have received a diagnosis of TDD in their 30's or 40's, though no genotype-phenotype correlations have been established to date. In this case report, we present a 61-year-old man with mild intellectual disability and recurrent muscle weakness who was diagnosed with TDD during an inpatient hospitalization for diverticulitis, prostatitis, and muscle weakness, ultimately attributed to rhabdomyolysis. Genetic testing revealed a deletion of exons 3–9 in <em>TANGO2</em> along with a novel missense variant (c.187G &gt; T; p.Gly63Cys) on the other allele. The patient was started on vitamin B-complex with additional pantothenic acid (500 mg daily) and subsequently noted improvement in his speech and energy levels. To our knowledge, this case describes the oldest known individual living with TDD by two decades. Additionally, the patient's relatively mild symptom profile and previously unreported missense variant in <em>TANGO2</em> may represent the first known example of genotype-phenotype correlation in TDD.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"Article 101241"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144550056","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":"Diagnostic challenges in ornithine transcarbamylase deficiency lacking genetic confirmation: liver biopsy versus human induced pluripotent stem cell technology","authors":"Alexander Laemmle ,&nbsp;Niklas Naef","doi":"10.1016/j.ymgmr.2025.101239","DOIUrl":"10.1016/j.ymgmr.2025.101239","url":null,"abstract":"","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"Article 101239"},"PeriodicalIF":1.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144492152","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}