Molecular Genetics and Metabolism Reports最新文献

{"title":"Improving sapropterin administration efficacy in PKU: Clinical practice case studies","authors":"Martina Tosi ,&nbsp;Anne Daly ,&nbsp;Catherine Ashmore ,&nbsp;Alex Pinto ,&nbsp;Suresh Vijay ,&nbsp;Elvira Verduci ,&nbsp;Sharon Evans ,&nbsp;Anita MacDonald","doi":"10.1016/j.ymgmr.2025.101252","DOIUrl":"10.1016/j.ymgmr.2025.101252","url":null,"abstract":"<div><div>In patients with phenylketonuria (PKU), sapropterin dihydrochloride (sapropterin) lowers blood phenylalanine (Phe) and may enhance Phe tolerance in sapropterin responsive patients. Attention to its administration, particularly the timing, and giving it with food with appropriate macronutrient composition, is important. We describe two boys with PKU who improved their Phe tolerance and metabolic control when they adjusted their method of sapropterin administration. Case 1: aged 7.2<del>5</del> years with mild PKU experienced a 40 % reduction in blood Phe after a 30-day sapropterin trial (20 mg/kg). Initially, he took sapropterin once daily dissolved in water. This increased his protein tolerance from 26 g to 50 g/day and reduced his protein equivalent from protein substitute to 20 g/day. His blood Phe was a median of 230 μmol/L (range: 130–300). After six months, twice-daily dosing further improved his protein tolerance to 60 g/day, with a lower median blood Phe (130 μmol/L, range: 80–220). By age 8 years, he swallowed tablets intact with meals, ate an unrestricted protein intake (∼80 g/day), stopped protein substitute, maintained excellent metabolic control with perceived cognitive improvement. Case 2: a boy who aged 4.9<del>92</del> years with mild PKU had a 33 % reduction in blood Phe after a 30-day sapropterin (20 mg/kg) trial. Initially, he took sapropterin once daily dissolved in water, increasing his protein tolerance from 14 g to 55 g/day, and reducing protein equivalent from protein substitute to 20 g/day. Median blood Phe was 240 μmol/L (range: 120–320). At age 6.9<del>2</del> years, twice-daily dosing and swallowing intact tablets further lowered his blood Phe, to a mean of 130 μmol/L (range: 100–130). He stopped dietary protein restriction and protein substitute intake. These case studies showed clinical and dietary benefits with adjustment of sapropterin administration. It was unclear if the improvements observed were associated with twice daily sapropterin administration, attention to taking it with fat containing meals, swallowing the tablets intact, or a combination of these. Further research to monitor the efficacy and safety of administration change is necessary.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101252"},"PeriodicalIF":1.9,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096334","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":"Mitochondrial dysfunction in methylmalonic acidemia: A pilot study using Seahorse technology in peripheral blood","authors":"Sinziana Stanescu ,&nbsp;Olatz Villate ,&nbsp;Fernando Andrade ,&nbsp;Domingo Gonzalez-Lamuño ,&nbsp;Amaya Bélanger-Quintana ,&nbsp;Francisco Arrieta ,&nbsp;Maria-Luz Couce ,&nbsp;Alfonso Muriel ,&nbsp;Luis Aldamiz-Echevarria","doi":"10.1016/j.ymgmr.2025.101251","DOIUrl":"10.1016/j.ymgmr.2025.101251","url":null,"abstract":"<div><h3>Introduction</h3><div>Isolated methylmalonic acidemia (MMA) is an inborn error of metabolism due to the deficiency of the methylmalonic mutase enzyme. Many patients develop chronic complications such as basal ganglia lesions or kidney impairment. A growing body of evidence supports secondary mitochondrial dysfunction as the main cause for the development of these long-term complications, even in patients with good metabolic control. Currently, available methods to study mitochondrial function are often invasive, such as muscular or skin biopsy.</div></div><div><h3>Objectives</h3><div>This pilot study is aimed to develop a safe, non-invasive method to assess mitochondrial and glycolytic function in isolated MMA patients using lymphocytes.</div></div><div><h3>Materials and methods</h3><div>Mitochondrial bioenergetics and glycolysis were evaluated in lymphocytes from two <em>mut</em>^<em>0</em> MMA patients and two age- and sex-matched controls using Seahorse technology. <em>In vitro</em> treatments with triheptanoin, citrate, and resveratrol were performed.</div></div><div><h3>Results</h3><div>MMA lymphocytes showed significant impairment in mitochondrial respiration and glycolysis compared to healthy controls. Triheptanoin exposure improved ATP production and glycolytic flux (ECAR), but no significant changes were observed in oxygen consumption (OCR). Citrate and resveratrol had no measurable impact on bioenergetic parameters.</div></div><div><h3>Conclusions</h3><div>This exploratory study suggests that Seahorse technology can detect mitochondrial dysfunction in MMA lymphocytes. Further studies in larger cohorts are required to validate these findings and explore their clinical relevance.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101251"},"PeriodicalIF":1.9,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045619","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":"Application of high-resolution mass spectrometry profiling towards the diagnosis and acute management of maple syrup urine disease","authors":"Rafael Garrett ,&nbsp;Sara Pickett ,&nbsp;Melinda J. Peters ,&nbsp;Khadija Belhassan ,&nbsp;Adam S. Ptolemy ,&nbsp;Roy W.A. Peake","doi":"10.1016/j.ymgmr.2025.101250","DOIUrl":"10.1016/j.ymgmr.2025.101250","url":null,"abstract":"<div><div>The current approach for investigating patients with suspected inborn errors of metabolism (IEMs) involves traditional targeted biochemical assays such as amino/organic acid analyses. Although highly effective for confirmatory testing, they are less effective in identifying disorders not included in newborn screening (NBS) panels, and for patients with non-classical clinical presentations. Targeted assays analyze a narrow range of metabolites and are conducted across different analytical platforms, often requiring more than one specimen type. In contrast, comprehensive metabolic profiling using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) provides significantly more information from a single specimen, eliminating the need for multiple and time-consuming analyses across different platforms. We describe the use of LC-HRMS metabolic profiling in two patients with decompensated maple syrup urine disease (MSUD). In the first patient, a previously healthy 3-month-old infant presenting with altered mental status, apnea, and seizures, LC-HRMS analysis of plasma before treatment showed increased levels of branched-chain amino acids and their related 2-keto and hydroxy acids. The diagnosis of MSUD was confirmed by targeted amino acid analysis. Additionally, the treatment course, which included dialysis and nutritional management, was monitored using LC-HRMS. This approach was successfully applied to a second patient, a 1-week-old infant with classical MSUD identified through NBS. In conclusion, comprehensive metabolic profiling by LC-HRMS is a valuable investigative tool for patients with both classic and non-specific neurometabolic clinical phenotypes, providing additional insights into metabolite perturbations during acute management.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101250"},"PeriodicalIF":1.9,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145045620","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":"Comment on: Lee J.Z.C. et al. Case report: Hepatocellular carcinoma in a patient with Pyridoxamine 5-phosphate oxidase (PNPO) deficiency undergoing pyridoxal 5-phosphate (PLP) treatment. Mol Genet Metab Rep. 2025;9;43:101224.","authors":"P. De Liso ,&nbsp;R. Webster ,&nbsp;B. Plecko ,&nbsp;F. Vigevano","doi":"10.1016/j.ymgmr.2025.101248","DOIUrl":"10.1016/j.ymgmr.2025.101248","url":null,"abstract":"","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101248"},"PeriodicalIF":1.9,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896732","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":"Acute profound lactic alkalosis associated with NDUFV1 compound heterozygosity in a previously healthy 6-year-old female","authors":"Stephen G. Kaler ,&nbsp;William Fyke ,&nbsp;Angela Lignelli-Dipple ,&nbsp;Valentina Emmanuele ,&nbsp;Eun Bi Lee ,&nbsp;Hyein Kathy Lee ,&nbsp;Adiel Munk ,&nbsp;Jose Andres Morales Corado ,&nbsp;Alejandro Iglesias ,&nbsp;Priyanka Mehrotra","doi":"10.1016/j.ymgmr.2025.101249","DOIUrl":"10.1016/j.ymgmr.2025.101249","url":null,"abstract":"<div><div><em>NDUFV1</em> encodes NADH: ubiquinone oxidoreductase core subunit V1, a key component of mitochondrial Complex 1. Biallelic pathogenic variants in this gene produce a broad and variable phenotypic spectrum in affected individuals, including ophthalmoplegia, developmental delays, brain imaging abnormalities, and recurrent episodes of emesis and lactic acidemia. We report female siblings compound heterozygous for two missense variants (Arg40Gln, Val245Met) in <em>NDUFV1</em> with unusual presentations of this condition. The 6-year-old proband showed normal growth and neurodevelopment until recently when weight loss and recurrent vomiting were noticed and brain imaging abnormalities consistent with Complex 1 deficiency were documented. She developed lactic acidemia without a clear precipitating factor and that, incongruously, was associated with profound alkalosis with blood pH as high as 7.83. We describe management of her acute illness during a hospital admission with aggressive sodium bicarbonate and sodium acetate replacement, and eventual recognition that anxiety-related hyperventilation contributed substantially to her transient profound alkalosis. We review the complex interplay of lactic acidemia due to mitochondrial Complex 1 deficiency, metabolic acidosis from acute loss of bicarbonate, respiratory alkalosis from hyperventilation and hypocapnia, and other concomitant medical issues, as well as her distinctive neuroradiological findings. Her 14-year-old sister was diagnosed retrospectively despite an earlier initial presentation, and manifests greater neurocognitive effects, similar neuroradiological signs, but no history of acute metabolic decompensation. These cases expand the phenotypic spectrum of this rare inherited illness, provide new information about its presentation and intrafamilial variability, and offer insight relevant to management of life-threatening metabolic crises associated with this disorder.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"45 ","pages":"Article 101249"},"PeriodicalIF":1.9,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144896731","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":"2025-08-21","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":"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":"2025-08-13","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":"Thiamine-responsive maple syrup urine disease missed by newborn screen: A case report.","authors":"Jariya Upadia, Grace Noh, Kea Crivelly, Jennifer Smith, Hans C Andersson","doi":"10.1016/j.ymgmr.2025.101244","DOIUrl":"10.1016/j.ymgmr.2025.101244","url":null,"abstract":"<p><p>Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder caused by a deficiency of the branched-chain α-ketoacid dehydrogenase (BCKAD) complex. It is classified into four subtypes: classic, intermediate, intermittent, and thiamine-responsive. We report a case of a female infant who presented with global developmental delay at 8 months of age. Plasma amino acid analysis revealed markedly elevated levels of leucine (1863 μmol/L), isoleucine (790 μmol/L), valine (1011 μmol/L), and alloisoleucine (427 μmol/L). The patient demonstrated marked improvement in biochemical markers, increased tolerance of dietary leucine intake, and developmental progress following thiamine supplementation. This case highlights a novel thiamine-responsive MSUD genotype and emphasizes the importance of recognizing this treatable subtype, the therapeutic potential of high-dose thiamine, and the possibility of false-negative results in newborn screening.</p>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"101244"},"PeriodicalIF":1.9,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12351175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874113","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":"Evaluation of <i>GLA</i> variants detected in newborn screening for Fabry disease using biomarker analysis.","authors":"Takaaki Sawada, Jun Kido, Takahiro Tsukimura, Keishin Sugawara, Tomoko Shiga, Seiji Saito, Tadayasu Togawa, Takahito Inoue, Yoriko Watanabe, Junpei Hamada, Hitoshi Sakuraba, Kimitoshi Nakamura","doi":"10.1016/j.ymgmr.2025.101245","DOIUrl":"10.1016/j.ymgmr.2025.101245","url":null,"abstract":"<p><p>Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the <i>GLA</i> gene, resulting in deficient or dysfunctional α-galactosidase A (AGAL) activity. Newborn screening (NBS) enables early detection and management; however, ascertaining the pathogenicity of unknown <i>GLA</i> variants remains a diagnostic challenge. This study aimed to evaluate the clinical significance of <i>GLA</i> gene variants detected through NBS in Japan, utilizing biochemical, genetic, and structural analyses. A total of 22 individuals, including newborns and their relatives carrying <i>GLA</i> gene variants, were analyzed. Plasma AGAL activity, plasma globotriaosylsphingosine (Lyso-Gb3), and urinary globotriaosylceramide levels were measured. <i>In silico</i> predictions, structural modeling, and variant classification databases were employed to assess pathogenicity. Significant reductions in AGAL activity and elevated Lyso-Gb3 levels were observed in variants, such as p.R112H and p.K391E, suggesting a high likelihood of being pathogenic variants. Variants like p.W209R, p.I242T, p.M267T, and p.R356Q demonstrated mild biochemical abnormalities, indicating limited pathogenic potential or non-pathogenicity. Variants, such as p.E66Q and c.-10C > T, showed no significant biochemical effects, indicating that they are benign. This study underscores the diverse pathogenicity of <i>GLA</i> gene variants identified through NBS, emphasizing the need for integrated diagnostic strategies, including biomarker analysis, structural assessments, and long-term clinical follow-up. These findings contribute to improving genotype-phenotype correlations and optimizing diagnostic precision for FD.</p>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"101245"},"PeriodicalIF":1.9,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12351176/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144874201","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":"Outcome of two siblings with late-onset Krabbe disease following allogeneic hematopoietic stem cell transplantation: And review of literature","authors":"Montaha Almudhry ,&nbsp;Chitra Prasad ,&nbsp;Keng Yow Tay ,&nbsp;C. Anthony Rupar ,&nbsp;Harold Atkins ,&nbsp;Asuri N. Prasad","doi":"10.1016/j.ymgmr.2025.101242","DOIUrl":"10.1016/j.ymgmr.2025.101242","url":null,"abstract":"<div><h3>Objectives</h3><div>To compare delayed-onset Krabbe disease (KD) and outcomes between two siblings in relation to allogeneic hematopoietic stem cell transplantation (HSCT).</div></div><div><h3>Methods</h3><div>We provide a descriptive report on two siblings with late-onset KD and their clinical course before and after HSCT.</div></div><div><h3>Results</h3><div>The index case presented with neurological symptoms that were presumptively diagnosed with multiple sclerosis (MS). Despite treatment with immunotherapy, the patient continued to decline progressively, prompting reassessment in the neurometabolic clinic 17 years after symptom onset. Symmetrical white matter changes in the pyramidal tract and optic radiation on MRI, absence of GALC enzyme activity in the blood, and identification of a pathogenic and likely pathogenic <em>GALC</em> variants confirmed the diagnosis of late-onset KD. After the proband's diagnosis, late-onset KD was also confirmed in his two siblings. In contrast to the index case, the younger sibling underwent HSCT with milder symptoms, stabilizing neurocognitive status, and imaging findings. Despite advanced disease, the proband's condition has stabilized following HSCT.</div></div><div><h3>Discussion</h3><div>Late-onset KD is clinically heterogeneous in presentation. Recognizing its progressive course, variable clinical features, positive family history (if present), and characteristic imaging can enable timely recognition. Earlier intervention with HSCT may modify the outcome.</div></div>","PeriodicalId":18814,"journal":{"name":"Molecular Genetics and Metabolism Reports","volume":"44 ","pages":"Article 101242"},"PeriodicalIF":1.8,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657236","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}