Molecular Genetics and Metabolism Reports最新文献

{"title":"Homozygous slc25a20 zebrafish mutant reveals insights into carnitine-acylcarnitine translocase deficiency pathogenesis","authors":"Ryuichi Hishida ,&nbsp;Kohei Ishiguro ,&nbsp;Tomoyuki Yamanaka ,&nbsp;Shinya Toyokuni ,&nbsp;Hideaki Matsui","doi":"10.1016/j.ymgmr.2024.101165","DOIUrl":"10.1016/j.ymgmr.2024.101165","url":null,"abstract":"<div><div>The <em>SLC25A20</em> gene encodes carnitine-acylcarnitine translocase (CACT), facilitating the transport of long-chain acylcarnitine required for energy production via β-oxidation into the mitochondria. Loss-of-function mutations in this gene lead to CACT deficiency, a rare autosomal recessive disorder of fatty acid metabolism characterized by severe symptoms including cardiomyopathy, hepatic dysfunction, rhabdomyolysis, hypoketotic hypoglycemia, and hyperammonemia, often resulting in neonatal mortality. Here, we utilized CRISPR/Cas9 gene editing to isolate <em>slc25a20</em> mutant zebrafish. Homozygous mutants displayed significant lethality, with the majority succumbing before reaching maturity. However, we identified a notably rare homozygous individual that survived into adulthood, prompting a histological examination. Firstly, we observed adipose tissue accumulation at various sites in the homozygous mutant. The mutant heart exhibited hypertrophy, along with degenerated myocardial and muscle cells containing numerous eosinophilic nuclei. Additionally, we found no large oil droplet vacuoles in the mutant liver; however, the hepatocytes displayed numerous small vacuoles resembling lipid droplets. Iron deposition was evident in the spleen and parts of the liver. Overall, our <em>slc25a20</em> zebrafish mutant displayed tissue pathologies analogous to human CACT deficiency, suggesting its potential as a pathological model contributing to the elucidation of pathogenesis and the improvement/development of therapies for CACT deficiency.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101165"},"PeriodicalIF":1.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142704532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cognition and wellbeing in middle-aged early treated people with phenylketonuria: Preliminary results and methodological lessons","authors":"Lucie Thomas ,&nbsp;Lynne Aitkenhead ,&nbsp;Karolina M. Stepien ,&nbsp;Alison Woodall ,&nbsp;Anita Macdonald ,&nbsp;Cristina Romani","doi":"10.1016/j.ymgmr.2024.101160","DOIUrl":"10.1016/j.ymgmr.2024.101160","url":null,"abstract":"<div><div>The first cohort of early-treated adults with phenylketonuria (PKU) is reaching middle-age and moving towards old age. We do not know if and how the effects of an aging brain may interact with the effect of PKU. This study compared wellbeing and cognition in 19 middle-aged adults with PKU (age 40+ mean = 45.8) and in a younger adult PKU group (age 18–36 mean = 26.7). The middle-aged PKU group demonstrated more anxiety and depression, and more negative effects of the COVID-19 pandemic, compared to age-matched controls. They also demonstrated a steep deterioration of quality of life compared to younger adults with PKU. These last results confounded age with the effects of the pandemic, since only the older participants were tested during the COVID-19 pandemic, but taken together, results consistently point to AwPKU being less resilient to age and other life stressors affecting wellbeing. Regarding cognition, the older PKU group demonstrated significantly worse performance than the younger group, and within the middle-age groups, the effect of age was stronger in the PKU group than in the control, even though this was not statistically significant. In contrast, size of impairment relative to an age-matched control group was numerically smaller in older, middle-age PKU group. We discuss possible methodological confounders related to this last result. Our study points to the challenges of using cross-sectional results to track performance across the lifespan and to the need to acquire more corroborating evidence before concluding there is no accelerating brain aging in PKU.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101160"},"PeriodicalIF":1.8,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142703989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mannose phosphate isomerase-congenital disorder of glycosylation leads to asymptomatic hypoglycemia","authors":"Cheng Luo ,&nbsp;Danxia Peng ,&nbsp;Yanyan Li ,&nbsp;Shuping Liu ,&nbsp;Qiong Wu ,&nbsp;Xuan Xu ,&nbsp;Jie Wen","doi":"10.1016/j.ymgmr.2024.101162","DOIUrl":"10.1016/j.ymgmr.2024.101162","url":null,"abstract":"<div><h3>Background</h3><div>Mannose phosphate isomerase deficiency-congenital glycosylation disorders (MPI-CDG) is a rare autosomal recessive disorder caused by pathogenic variants in the <em>MPI</em> gene and characterized by digestive, hepatic, and endocrine-related symptoms. Herein, we reported a case of a 4-month-old baby with MPI-CDG confirmed by genetic testing.</div></div><div><h3>Case summary</h3><div>Based on the age of the child and the present clinical symptoms (feeding difficulties, intractable diarrhea, vomiting, hepatosplenomegaly, recurrent hypoglycemia, coagulation disorder, and hypoproteinemia under the premise of anti-infection therapy), congenital glycosylation disorder was suspected, which was then confirmed by genetic testing. Her father carried a heterozygous deletion variant of exons 1–2 of the <em>MPI</em> gene, while her mother carried a heterozygous variant of C. 422C &gt; T variant. It was suspected that a biallelic pathogenic variant of the <em>MPI</em> gene caused the CDG.</div></div><div><h3>Conclusion</h3><div>MPI-CDG should be considered in infancy with unexplained hypoglycemia and recurrent digestive and endocrine system involvement. Also, if evident symptoms are present, a gene examination should be performed, as this could speed up the diagnosis assuring timely treatment.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101162"},"PeriodicalIF":1.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142703990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Propionic Acidemia diagnosed in Amish adults and pregnancy outcomes: A case series","authors":"Ethan M. Scott ,&nbsp;Brandon Smith ,&nbsp;Joseph Liu ,&nbsp;Karlee Hoffman ,&nbsp;Jennifer Hershberger ,&nbsp;Andew Crosby ,&nbsp;Emma L. Baple ,&nbsp;Olivia K. Wenger","doi":"10.1016/j.ymgmr.2024.101161","DOIUrl":"10.1016/j.ymgmr.2024.101161","url":null,"abstract":"<div><h3>Background</h3><div>Propionic acidemia (PA) is an inborn error of metabolism (IEM) that typically presents in the newborn. The Amish of North America have an increased prevalence of PA due to a founder variant in the <em>PCCB</em> gene. The Amish PA phenotype is variable, and some individuals remain asymptomatic and undiagnosed until adulthood. Additionally, there are limited reports of pregnancy outcomes in Amish individuals with PA.</div></div><div><h3>Methods</h3><div>A retrospective single center chart review was completed on sixty Amish individuals with PA to identify individuals diagnosed as adults (18 years or older) and pregnancy outcomes. We assessed age at diagnosis, reason for PA testing, medical history prior to diagnosis including developmental delay, seizure, protein intolerance, cardiac symptoms, and anxiety. Following the diagnosis, we assessed the prevalence of prolonged QTc and dilated cardiomyopathy. We assessed our cohort for number of pregnancies, pregnancy outcomes, and peripartum complications.</div></div><div><h3>Results</h3><div>Nine out of sixty individuals (15 %) were diagnosed with PA as adults. A family member with PA was the most common reason to prompt genetic testing. Cardiac symptoms were present in six of nine individuals prior to diagnosis. Three individuals diagnosed as adults had dilated cardiomyopathy and one underwent cardiac transplant. There were twenty-one pregnancies in six women with eighteen successful deliveries and three miscarriages. Two women developed peripartum cardiomyopathy. There were no acute maternal decompensations.</div></div><div><h3>Conclusion</h3><div>Our work supports the consideration that all Amish newborns be screened for PA with molecular testing to enable early diagnosis. The stark difference in peripartum outcomes requires further prospective work to ensure appropriate monitoring throughout pregnancy while respecting individual values and autonomy.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101161"},"PeriodicalIF":1.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142704530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel frameshift variant in the SLC2A1 gene causing a mild phenotype of GLUT1 deficiency syndrome: case report","authors":"Lívia Maria Ferreira Sobrinho ,&nbsp;Thiago Oliveira Silva ,&nbsp;Lilia Farret Refosco ,&nbsp;Soraia Poloni ,&nbsp;Fabiano Oliveira Poswar ,&nbsp;Carolina Fischinger Moura de Souza ,&nbsp;Fernanda Sperb-Ludwig ,&nbsp;Ida Vanessa Doederlein Schwartz","doi":"10.1016/j.ymgmr.2024.101164","DOIUrl":"10.1016/j.ymgmr.2024.101164","url":null,"abstract":"<div><div>Glucose transporter type 1 deficiency syndrome (GLUT1) is a genetic condition, most often of autosomal dominant inheritance, and corresponds to a broad spectrum of signs and symptoms due to hypoglycorrhachia, which include seizures, delay in neuropsychomotor development, intellectual disability, movement disorders, dysarthria and postnatal microcephaly. The severity of symptoms are variable. Symptomatic treatment consists of the ketogenic diet, which allows energy supply to the brain through sustained and continuous ketosis. In this study, we report a novel heterozygous frameshift variant (c.855_856insTT; p.Gly286Leufs*55) in the <em>SLC2A1</em> gene in a preschool Brazilian child with atypical phenotype of GLUT1 deficiency syndrome, characterized by ataxia and mild speech delay. Our study enriches the <em>SLC2A1</em> gene mutation spectrum and emphasizes the importance of molecular genetic studies for screening patients with neuropsychomotor developmental delay.</div><div><strong>Sentence take-home message (synopsis) of the article</strong>: The study enriches the <em>SLC2A1</em> gene mutation spectrum and emphasizes the importance of molecular genetic studies for screening patients with neuropsychomotor developmental delay.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101164"},"PeriodicalIF":1.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142704533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"D-glyceric aciduria due to GLYCTK mutation: Disease or non-disease?","authors":"Sandra D.K. Kingma ,&nbsp;Laura K.M. Steinbusch ,&nbsp;Sietse M. Aukema ,&nbsp;Margje Sinnema ,&nbsp;Bianca Panis ,&nbsp;Joost Nicolai ,&nbsp;Estela Rubio-Gozalbo","doi":"10.1016/j.ymgmr.2024.101159","DOIUrl":"10.1016/j.ymgmr.2024.101159","url":null,"abstract":"<div><div>D-glyceric aciduria (DGA) is caused by D-glycerate-2-kinase deficiency due to biallelic pathogenic variants in <em>GLYCTK.</em> It is associated with variable neurological symptoms. DGA is extremely rare, and genetic variants are only known in 7 previously described patients. We report a new patient with DGA and a novel homozygous <em>GLYCTK</em> variant.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101159"},"PeriodicalIF":1.8,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142650670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A case series of Cypriot patients with CblC defect: Clinical, biochemical and molecular characteristics","authors":"Theodoros Georgiou ,&nbsp;Olga Grafakou ,&nbsp;Anna Malekkou ,&nbsp;Emilia Athanasiou ,&nbsp;Ioannis Ioannou ,&nbsp;Vivi Choleva ,&nbsp;Maria Dionysiou ,&nbsp;Gabriella Mavrikiou ,&nbsp;Anthi Demetriadou ,&nbsp;Violetta Anastasiadou ,&nbsp;Anthi Drousiotou ,&nbsp;Petros P. Petrou","doi":"10.1016/j.ymgmr.2024.101158","DOIUrl":"10.1016/j.ymgmr.2024.101158","url":null,"abstract":"<div><div>Methylmalonic aciduria and homocystinuria, CblC type, is an inborn error of intracellular vitamin B12 (cobalamin) metabolism caused, in the majority of cases, by mutations in the <em>MMACHC</em> gene. Five Cypriot patients (four males and one female) were diagnosed with a CblC defect. Age at diagnosis ranged from 10 days to 9 months. We present here the clinical, biochemical and molecular findings of these patients. Our retrospective study indicates that all patients were carriers of the known p.Arg91LysfsTer14 variant in either a homozygous or compound heterozygous state with other known <em>MMACHC</em> pathogenic variants. Out of three patients sharing the same genotype the one diagnosed and initiated treatment in the neonatal period displayed an improved clinical outcome.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101158"},"PeriodicalIF":1.8,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142650669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel disease-causing variant associated with a milder phenotype of AARS2-related leukodystrophy — A case report","authors":"Joana Fernandes ,&nbsp;João Moura ,&nbsp;João Tarrio ,&nbsp;Jorge Oliveira ,&nbsp;Ana Lopes ,&nbsp;João Parente Freixo ,&nbsp;Gonçalo Videira","doi":"10.1016/j.ymgmr.2024.101157","DOIUrl":"10.1016/j.ymgmr.2024.101157","url":null,"abstract":"<div><h3>Background and objectives</h3><div>Adult-onset leukodystrophies are a rare group of neurological disorders characterized by progressive degeneration of the cerebral white matter. One of these diseases is caused by biallelic pathogenic variants in the <em>AARS2</em> gene. We describe a patient with late-onset <em>AARS2</em>-related leukoencephalopathy, a milder phenotype and a novel disease-causing variant.</div></div><div><h3>Methods</h3><div>The patient was characterized during routine clinical practice.</div></div><div><h3>Results</h3><div>A 40-year-old male was evaluated for chronic headaches. Six years before, he was hospitalized for a major depression with psychotic features. The first neurological examination was normal, except for a slow downbeat nystagmus. Brain MRI revealed significant hyperintensities in T2 and T2-FLAIR bilaterally in the frontal lobes, with periventricular and corpus callosum involvement, and without restricted diffusion. A multigene panel for leukodystrophies based on whole-exome sequencing identified two heterozygous variants in the <em>AARS2</em> gene: one previously reported in the literature, already classified as pathogenic, NM_020745.4:c.595C &gt; T (p.(Arg199Cys)), and one novel variant c.730G &gt; A (p.(Val244Ile)), later reclassified as likely pathogenic. Nine years have passed since the first symptoms without clear clinical progression.</div></div><div><h3>Discussion</h3><div>This case underlines that adult-onset leukodystrophy caused by variants in <em>AARS2</em> may have a wide range of phenotypes and patterns of progression. The new variant c.730G &gt; A (p.(Val244Ile)) herein described may induce a milder clinical picture and a less severe radiological pattern.</div></div><div><h3>Practical implications</h3><div>Adult-onset leukoencephalopathies may present with milder clinical signs than what is generally perceived, and novel disease-causing variants are being identified.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101157"},"PeriodicalIF":1.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142553122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review","authors":"Mahmood Noori ,&nbsp;Omar Jarrah ,&nbsp;Aisha Al Shamsi","doi":"10.1016/j.ymgmr.2024.101156","DOIUrl":"10.1016/j.ymgmr.2024.101156","url":null,"abstract":"<div><h3>Background</h3><div>Protein metabolism and urea production maintain protein and amino acid homeostasis in normal status. Ammonia results from amino acid turnover and is produced by intestinal urease-positive bacteria. Ammonia must be detoxified, and the urea cycle converts ammonia into urea. CPS1 is an enzyme in the urea cycle that catalyzes ammonia and bicarbonate condensation. CPS1 deficiency presents in the neonatal period with hyperammonemia, resulting in death or neurological sequelae if patients survive.</div></div><div><h3>Objectives/aims</h3><div>To share the experience of patients with CPS1 deficiency from Tawam Hospital and to shed light on the spectrum of variants found in those patients.</div></div><div><h3>Methods</h3><div>A retrospective chart review was done. All patients with CPS1 deficiency admitted to Tawam Hospital from 2010 to 2023 were included. Collected data included age and ammonia level at presentation, the time needed to drop ammonia level below 100 μmol/L, acute management modality provided, long-term neurological sequelae, sequence variants, severity, and duration of hyperammonemia encephalopathy, age at last follow-up, and, if applicable, survival for at least six months.</div></div><div><h3>Results</h3><div>Only five patients with CPS1 deficiency over 13 years were found; two males and three females. Three patients are doing relatively well at 18 months, 7, and 9 years of age. The presented age was in the neonatal period except in one patient. One patient was found to have frameshift, resulting in a premature stop codon in the <em>CPS1</em> gene, had a devastating course that ended with death. One patient had recurrent hyperammonemia episodes in her first year of life, which led to microcephaly and global developmental delay. One patient underwent hemodialysis, and one patient underwent peritoneal dialysis. All patients except one were on Carglumic acid which could contribute to their survival and disease control. All variants reported here are novel except one.</div></div><div><h3>Conclusion</h3><div>Although the presentation was different in severity, three patients are doing relatively well and approaching their developmental milestones. Thus, early recognition, prompt actions to drop high ammonia level, and good follow-up plans are emphasized. Further studies are needed to correlate the genotype-phenotype of reported variants here, which can help predict the severity of CPS1 deficiency.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101156"},"PeriodicalIF":1.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142522471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isolated methylmalonic acidemia in Mexico: Genotypic spectrum, report of two novel MMUT variants and a possible synergistic heterozygosity effect","authors":"Cynthia Fernández-Lainez ,&nbsp;Marcela Vela-Amieva ,&nbsp;Miriam Reyna-Fabián ,&nbsp;Liliana Fernández-Hernández ,&nbsp;Sara Guillén-López ,&nbsp;Lizbeth López-Mejía ,&nbsp;Miguel Ángel Alcántara-Ortigoza ,&nbsp;Ariadna González-del Angel ,&nbsp;Rosa Itzel Carrillo-Nieto ,&nbsp;Enrique Ortega-Valdez ,&nbsp;Mauricio Rojas-Maruri ,&nbsp;Cecilia Ridaura-Sanz","doi":"10.1016/j.ymgmr.2024.101155","DOIUrl":"10.1016/j.ymgmr.2024.101155","url":null,"abstract":"<div><div>Isolated methylmalonic acidemia (iMMA) is a group of monogenic metabolic disorders affecting methylmalonate and cobalamin metabolism. Five iMMA-responsible genes have been described to date: <em>MMUT</em> (MIM *609058), <em>MMAA</em> (MIM *607481, <em>MMAB</em> (MIM *607568), <em>MMADHC</em> (MIM *611935), and <em>MCEE</em> (MIM *608419). Although iMMA is the most common form of organic acidemia reported in Mexico, its genotypic spectrum is still largely unknown. We performed a clinical exome analysis on 42 unrelated Mexican patients with iMMA. <em>MMUT</em> deficiency accounted for 73.8 % of all cases, followed by <em>MMAA</em> (14.2 %), <em>MMAB</em> (7.2 %), and <em>MMADHC</em> (2.4 %) deficiencies. One patient presented <em>MMUT</em> and <em>MMAA</em> double heterozygosity, which should be further experimentally confirmed to prove that synergistic heterozygosity could be another inheritance mechanism in iMMA. The most frequent <em>MMUT</em> genotype involved the Hispanic variant NM_000255.4:c. [322C &gt; T];[322C &gt; T] or p.[Arg108Cys];[Arg108Cys] (14.3 %). Two novel <em>MMUT</em> variants, NM_000255.4:c.589G &gt; A or p.(Ala197Thr) and c.1476C &gt; A or p.(Tyr492*), were identified in a deceased newborn presenting the neonatal-onset severe form of the disease. <em>In silico</em> protein modeling of the p.(Arg108Cys) and novel p.(Ala197Thr) <em>MMUT</em> variants suggested disruption of the substrate-binding and catalytic domains of the protein, respectively. This study expands the current knowledge on the molecular spectrum of iMMA in the Mexican population and reinforces the importance of genetic analysis in guiding clinical management.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"41 ","pages":"Article 101155"},"PeriodicalIF":1.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}