Molecular genetics and metabolism最新文献

{"title":"Atypical free sialic acid storage disorder associated with tissue specific mosaicism of SLC17A5.","authors":"Marwan Shinawi, Daniel J Wegner, Alexander J Paul, William Buchser, Robert Schmidt, Jaiprakash Sharma, Marco Sardiello, Kathleen Sisco, Linda Manwaring, Margaret Reynolds, Robert Fulton, Catrina Fronick, Andrew Shaver, Tina Y Huang, Ashley Carroll, Kyria Roessler, Aaron L Halpern, Patricia I Dickson, Jennifer A Wambach","doi":"10.1016/j.ymgme.2024.109004","DOIUrl":"10.1016/j.ymgme.2024.109004","url":null,"abstract":"<p><p>Free sialic acid storage disorder (FSASD) is a rare autosomal recessive lysosomal storage disease caused by pathogenic SLC17A5 variants with variable disease severity. We performed a multidisciplinary evaluation of an adolescent female with suspected lysosomal storage disease and conducted comprehensive studies to uncover the molecular etiology. The proband exhibited intellectual disability, a storage disease gestalt, and mildly elevated urine free sialic acid levels. Skin electron micrographs showed prominent cytoplasmic vacuolation. Clinical exome and genome sequencing identified a maternally-inherited SLC17A5 variant: c.533delC;p.Thr178Asnfs*34. RNASeq of proband skin fibroblasts revealed exon 3 skipping, which was not detected in RNA from proband blood or parental fibroblasts. Targeted deep sequencing of proband fibroblast DNA revealed a 184 bp deletion in ∼15 % of reads, encompassing the 3' end of exon 3. Illumina Complete Long Read sequencing confirmed the deletion was in the paternally-inherited allele and found in a mosaic state in proband fibroblasts and muscle but not in blood or buccal cells. Functional studies, including SLC17A5 knockout cells and transient transfections of mutated SLC17A5 demonstrated pathogenicity of the identified variants. We report an adolescent female with atypical FSASD with tissue-specific mosaicism for an intragenic deletion in SLC17A5, explaining the atypical clinical course, mild biochemical abnormalities, and long diagnostic process.</p>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 1","pages":"109004"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915130","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":"Clinical and biochemical abnormalities in a feline model of GM2 activator deficiency.","authors":"Sidney J Beecy, Amanda L Gross, Anne S Maguire, Leah M K Hoffman, Elise B Diffie, Paul Cuddon, Pamela Kell, Xuntian Jiang, Heather L Gray-Edwards, Douglas R Martin","doi":"10.1016/j.ymgme.2024.108615","DOIUrl":"10.1016/j.ymgme.2024.108615","url":null,"abstract":"<p><p>Though it has no catalytic activity toward GM2 ganglioside, the GM2 activator protein (GM2A) is essential for ganglioside hydrolysis by facilitating the action of lysosomal ß-N-acetylhexosaminidase. GM2A deficiency results in death in early childhood due to rapid central nervous system deterioration similar to the related GM2 gangliosidoses, Tay-Sachs disease and Sandhoff disease. This manuscript further characterizes a feline model of GM2A deficiency with a focus on clinical and biochemical parameters that may be useful as benchmarks for translational therapeutic research. The GM2A deficient cat has clinical features consistent with the human condition, including isointensity of gray and white matter of the brain on T2-weighted MRI; MR spectroscopic changes of brain metabolites consistent with gliosis, neuronal injury and demyelination; rhythmical slowing of cerebral cortical activation on electroencephalography; and elevation of aspartate aminotransferase and lactate dehydrogenase in cerebrospinal fluid. Biochemically, the brain of GM2A deficient cats has storage of GM2 and GA2 ganglioside coincident with increased hexosaminidase activity toward a standard synthetic substrate. Also, the brain of GM2A deficient cats has increased levels of lyso-platelet activating factor and lyso-phosphatidylcholine, which may serve as novel biomarkers of disease progression and provide insights into pathogenic mechanisms.</p>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 1","pages":"108615"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791573","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":"Characterization of gallbladder disease in metachromatic leukodystrophy across the lifespan.","authors":"Sylvia Mutua, Anjana Sevagamoorthy, Sarah Woidill, Paul J Orchard, Francesco Gavazzi, Suzanne P MacFarland, Pierre Russo, Adeline Vanderver, Laura A Adang","doi":"10.1016/j.ymgme.2024.109003","DOIUrl":"10.1016/j.ymgme.2024.109003","url":null,"abstract":"<p><p>Metachromatic leukodystrophy (MLD) is a progressive demyelinating disorder resulting from the toxic accumulation of sulfatides. The stereotyped neurodegeneration of MLD is well understood, and cases are categorized into subtypes by age at neurologic onset: late infantile (LI), juvenile (J), and adult. The systemic burden of disease, such as gallbladder involvement, however, is less well characterized. It is important to understand the longitudinal trajectory of gallbladder complications in MLD and its relationship with neurologic progression as this has the potential to identify cases of active disease before neurologic onset. Additionally, as newborn screening is established in MLD, it will inform clinical care during the presymptomatic period. To address this knowledge gap, we leveraged a retrospective natural history study of MLD and published cases in the medical literature. Medical records from subjects consented to a natural history study were used to collect information of disease course, including gallbladder abnormality. Neurologic function was retrospectively assessed using the gross motor function classification scale (GMFC-MLD). Additionally, a comprehensive review identified published cases of MLD with subject-level information around gallbladder disease. Data was summarized using descriptive statistics, Fisher's exact test for significance, and survival analysis with log rank test. The natural history cohort includes 40 subjects with gallbladder reports (imaging or pathology). The first gallbladder evaluation occurred after neurologic onset in 35/40 cases. Gallbladder abnormalities were noted in 36 subjects, often within the initial evaluation (97.2 %). There was no difference in the time to first gallbladder abnormality (log rank: p = 0.4170) and risk of polyps or higher (log rank: p = 0.6414) between the LI- and non-LI subtypes. The level of gallbladder involvement does not correlate with GMFC-MLD score (Fisher's exact: p = 0.321). A review of the literature identified 87 additional cases of MLD with mention of gallbladder status across 40 published studies. Gallbladder involvement was noted in 74 cases and occurred at similar rates across subtypes (X² = 4.68, p = 0.7925). Overall, the study showed a high prevalence of gallbladder complications in MLD. Gallbladder abnormalities were commonly found at first evaluation, even in pre- or early symptomatic disease. Since gallbladder disease has the potential to progress to malignancy, this supports the integration of regular gallbladder monitoring as clinical care and its potential as a predictive biomarker supporting disease onset.</p>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 1","pages":"109003"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903479","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":"Digital microfluidic platform for dried blood spot newborn screening of lysosomal storage diseases in Campania region (Italy): Findings from the first year pilot project.","authors":"Melania Scarcella, Simona Fecarotta, Marianna Alagia, Ferdinando Barretta, Fabiana Uomo, Valeria De Pasquale, Hari S Patel, Pietro Strisciuglio, Giancarlo Parenti, Giulia Frisso, Luigi Michele Pavone, Margherita Ruoppolo","doi":"10.1016/j.ymgme.2024.109008","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.109008","url":null,"abstract":"<p><strong>Background: </strong>Newborn screening (NBS) is a simple, non-invasive test that allows for the early identification of genetic diseases within the first days of a newborn's life. The aim of NBS is to detect potentially fatal or disabling conditions in newborns as early as possible, before the onset of disease symptoms. Early diagnosis enables timely treatments and improves the quality of life for affected patients.</p><p><strong>Results: </strong>A pilot project for dried blood spot (DBS) NBS of lysosomal storage diseases (LSDs), including Mucopolysaccharidosis I (MPSI, IDUA α-L-iduronidase deficiency), Pompe disease (GAA α-glucosidase acid deficiency), Gaucher disease (GBA β-glucosidase deficiency) and Fabry disease (GLA α-galactosidase deficiency), was conducted using the digital microfluidic (DMF) technique. DBS were analyzed in a multiplexed assays for the enzymatic activities of four lysosomal enzymes (IDUA, GAA, GBA, GLA), and subjects identified as deficient in any of these enzymes were referred to the clinical reference center for diagnosis confirmation. From June 6th, 2022, to May 12th, 2023, a total of 7650 newborns were analyzed and 1 subject affected by Pompe disease was identified together with two additional subjects, suspected of Pompe and Fabry disease respectively, for whom continued follow-up is mandatory to determine the phenotype.</p><p><strong>Conclusions: </strong>The pilot project for DBS NBS of four LSDs in Campania Region validated the effectiveness of DMF method, established enzymatic activity cut-offs, and identified newborns referred to the clinical center for integrated diagnostics, including genetic analyses. The results suggest that this technique can effectively detect potentially affected newborns, who will require further diagnostic confirmation and clinical follow-up. This diagnostic flow chart provides the opportunity to initiate early treatments and improve LSD patients' life span.</p>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":" ","pages":"109008"},"PeriodicalIF":3.7,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952004","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":"Untargeted metabolomics analysis as a potential screening tool for 3-methylglutaconic aciduria syndromes.","authors":"Charles R DiFalco, Charul Gijavanekar, Yue Wang, Alexandra N Grace, Keren Machol, Lisa Emrick, Ning Liu, Elizabeth Mizerik, Laura Mackay, Hongzheng Dai, Liesbeth Vossaert, Fan Xia, Sarah H Elsea, Fernando Scaglia","doi":"10.1016/j.ymgme.2024.109009","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.109009","url":null,"abstract":"<p><p>The 3-methylglutaconic aciduria (3-MGA-uria) syndromes comprise a heterogeneous group of inborn errors of metabolism defined biochemically by detectable elevation of 3-methylglutaconic acid (3-MGA) in the urine. In type 1 (or primary) 3-MGA-uria, distal defects in the leucine catabolism pathway directly cause this elevation. Secondary 3-MGA-uria syndromes, however, are unrelated to leucine metabolism-specific defects but share a common biochemical phenotype of elevated 3-MGA. It is currently thought that this accumulation is due to an underlying buildup of acetyl-CoA in the mitochondria from impaired function of the TCA cycle with ensuing formation of trans-3-methylglutaconyl CoA and its subsequent byproducts, including 3-MGA. In these disorders, urine 3-MGA levels are known to be fluctuant and at times undetectable by standard urine organic acid analysis (UOA), thereby reducing the utility of this biochemical screening method. Here, we retrospectively evaluated a cohort of nine patients with confirmed 3-MGA-uria syndromes. It was observed that UOA analysis obtained from three separate patients did not identify detectable 3-MGA levels. This inherent limitation highlights the need for a more sensitive clinical modality. Untargeted metabolomics profiling is a rapidly emerging technology that is being used to detect and characterize biochemical abnormalities in many inborn errors of metabolism. Untargeted metabolomics profiling performed on plasma samples in this cohort identified significant elevations of 3-MGA in all nine individuals. This high degree of clinical sensitivity demonstrates the promising potential for untargeted metabolomics analysis as both an effective biochemical screening tool for 3-MGA-uria syndromes and a functional method to assist with validation of genomic variants of uncertain significance in these disorders.</p>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 3","pages":"109009"},"PeriodicalIF":3.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951234","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":"Breath biopsy in inborn errors of metabolism: A proof-of-principle study in propionic acidemia.","authors":"Oleg A Shchelochkov, Huw Davies, Robert P Mohney, Ace Hatch, Owen Birch, Susan Ferry, Carol Van Ryzin, Camryn Hall, Samantha McCoy, Jerry Vockley, Mickey J M Kuo, Irini Manoli, Jennifer L Sloan, Charles P Venditti","doi":"10.1016/j.ymgme.2024.109005","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.109005","url":null,"abstract":"<p><strong>Background: </strong>Impaired oxidation of branched chain amino acids may give rise to volatile organic compounds (VOCs). We hypothesized that VOCs will be present in exhaled breath of participants with propionic acidemia (PA), and their relative abundance would correlate with clinical and biochemical characteristics of the disease.</p><p><strong>Methods: </strong>We enrolled 5 affected participants from a natural history study of PA (ClinicalTrials.gov ID NCT02890342) plus five age- and sex-matched unaffected controls. We collected exhaled breath using a non-invasive breath sampling platform paired with thermal desorption-gas chromatography-mass spectrometry. Clinical and biochemical parameters were correlated with the relative abundance of VOCs.</p><p><strong>Results: </strong>Unbiased screening identified several candidate VOC biomarkers of PA. One candidate putatively identified as 3-pentanone was the most abundant (45-fold higher in cases vs. controls, p-value <0.05). 3-Pentanone abundance positively correlated with plasma propionylcarnitine (p = 0.01), plasma 2-methylcitrate (p < 0.05), 3-OH-propionate (p < 0.01), full scale IQ (p < 0.01), and showed a statistical trend with height z-scores (p = 0.08). It inversely correlated with the whole-body in vivo oxidation of 1-¹³C-propionate (p < 0.05). In a participant who received an orthotopic liver transplant, 3-pentanone levels were lower and segregated with \"mild\" PA.</p><p><strong>Conclusion: </strong>Non-invasive breath sampling is a promising method to identify and quantitate VOCs that correlate with the clinical and biochemical parameters of PA. Our proof-of-principle findings may have wide implications for the diagnosis and severity stratification of inborn errors of metabolism affecting oxidation of amino acids which might be monitored in a similar fashion.</p><p><strong>Synopsis: </strong>A proof-of-principle study putatively identifies 3-pentanone in exhaled breath as a correlate of the clinical and biochemical outcomes in propionic acidemia.</p>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"144 3","pages":"109005"},"PeriodicalIF":3.7,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951048","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":"Cover 2 / Ed. Board","authors":"","doi":"10.1016/S1096-7192(24)00501-8","DOIUrl":"10.1016/S1096-7192(24)00501-8","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 4","pages":"Article 108617"},"PeriodicalIF":3.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142759505","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":"Corrigendum to “Evaluating change in diet with pegvaliase treatment in adults with phenylketonuria: Analysis of phase 3 clinical trial data” [Molecular Genetics and Metabolism 141, Issue 3 (2024) 108122]","authors":"Fran Rohr ,&nbsp;Barbara Burton ,&nbsp;Anne Dee ,&nbsp;Cary O. Harding ,&nbsp;Joshua Lilienstein ,&nbsp;Kristin Lindstrom ,&nbsp;Erin MacLeod ,&nbsp;Sarah Rose ,&nbsp;Rani Singh ,&nbsp;Sandra van Calcar ,&nbsp;Kaleigh Whitehall","doi":"10.1016/j.ymgme.2024.108613","DOIUrl":"10.1016/j.ymgme.2024.108613","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"143 4","pages":"Article 108613"},"PeriodicalIF":3.7,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High precision newborn screening for mucopolysaccharidosis type I by enzymatic activity followed by endogenous, non-reducing end glycosaminoglycan analysis.","authors":"Zackary M Herbst, Francyne Kubaski, Laura Pollard, Khaja Basheeruddin, Barbara Burton, Joseph Orsini, Matthew Henderson, Pranesh Chakraborty, Michael H Gelb","doi":"10.1016/j.ymgme.2024.108612","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.108612","url":null,"abstract":"<p><p>Measurement of enzymatic activity in newborn dried blood spots (DBS) is the preferred first-tier method in newborn screening (NBS) for mucopolysaccharidosis (MPS) disorders. However, false positives are observed due mainly to the presence of pseudodeficiencies. Our previous publications on glycosaminoglycan (GAG) biomarker levels in dried blood spots (DBS) for mucopolysaccharidoses demonstrated that second-tier GAG biomarker analysis can dramatically reduce the false positive rate in NBS. In the present study, we extend this approach to the analysis of a large number of false positives for MPS-I obtained from the Illinois, New York, and Tennessee NBS programs and from Greenwood Genetics Center. Results show that GAG levels measured by the Endogenous-Non-Reducing End method (Endogenous-NRE) are in the normal reference range for all samples. In a second study, we analyzed 166 samples that showed below-cutoff MPS-I enzymatic activity level after testing 384,144 newborns in the Ontario, Canada NBS program. Both genotype and Endogenous-NRE GAG levels were determined for all 166 samples. Newborns at high risk for MPS-I based on genotype also showed elevated GAG levels and were clinically confirmed to be symptomatic for MPS-I. All newborns with pseudodeficiency or carrier status by genotyping all showed normal levels of the appropriate GAG biomarker. Samples found to be inconclusive based on one or more variants of unknown significance (VUS) all showed normal GAG biomarker levels and were found to be clinically normal during follow-up. These studies show that the Endogenous-NRE GAG second-tier NBS method is preferred over second-tier DNA analysis for the NBS of MPS-I with minimal false positives.</p>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":" ","pages":"108612"},"PeriodicalIF":3.7,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792094","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":"Imaging improvement in acid sphingomyelinase deficiency on enzyme replacement therapy.","authors":"William L Simpson, Jaya Ganesh","doi":"10.1016/j.ymgme.2024.108611","DOIUrl":"https://doi.org/10.1016/j.ymgme.2024.108611","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":" ","pages":"108611"},"PeriodicalIF":3.7,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687522","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}