Preliminary observations of glucose metabolism dysregulation in pediatric Huntington’s disease
BackgroundPediatric Huntington’s disease (PHD), a rare and severe form of juvenile-onset Huntington’s disease (JOHD), is associated with highly expanded CAG repeats in the HTT gene and a rapidly progressive neurodegenerative course. Recent studies have suggested that glucose metabolism may be impair...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2025.1626275/full |
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| author | Federica Graziola Federica Rachele Danti Martina Penzo Antonio Spagarino Eleonora Minacapilli Marco Moscatelli Federica Zibordi Caterina Mariotti Giovanna Zorzi Giovanna Zorzi |
| author_facet | Federica Graziola Federica Rachele Danti Martina Penzo Antonio Spagarino Eleonora Minacapilli Marco Moscatelli Federica Zibordi Caterina Mariotti Giovanna Zorzi Giovanna Zorzi |
| author_sort | Federica Graziola |
| collection | DOAJ |
| description | BackgroundPediatric Huntington’s disease (PHD), a rare and severe form of juvenile-onset Huntington’s disease (JOHD), is associated with highly expanded CAG repeats in the HTT gene and a rapidly progressive neurodegenerative course. Recent studies have suggested that glucose metabolism may be impaired in PHD due to reduced expression of glucose transporters in the brain, resembling aspects of GLUT1 Deficiency Syndrome (GLUT1DS).MethodsWe investigated glucose metabolism in two pediatric patients with genetically confirmed PHD (CAG repeats: 76 and 79) referred to our tertiary care center. Clinical, neuroimaging, and neuropsychological data were collected alongside metabolic assessments, including cerebrospinal fluid (CSF) and plasma glucose and lactate levels, CSF-to-serum glucose ratio, and red blood cell GLUT1 expression using the METAglut1 test. 18F-FDG PET imaging and brain MRI were performed to assess cerebral metabolism and structural changes.ResultsBoth patients exhibited progressive motor and cognitive decline with dystonia-parkinsonian features, learning disabilities, and behavioral disturbances. Brain MRI showed caudate and putaminal atrophy, while PET imaging demonstrated severely reduced glucose uptake in the basal ganglia. CSF/plasma glucose ratios were within or near the lower end of the normal range (0.51 and 0.6), and GLUT1 expression in red blood cells was within normal limits. No significant biochemical alterations consistent with GLUT1DS were detected.ConclusionOur findings confirm localized cerebral hypometabolism in the basal ganglia of PHD patients, consistent with previous neuropathological reports. However, systemic biochemical indicators of glucose transport deficiency, including erythrocyte GLUT1 function and CSF glucose, were not significantly altered. While glucose dysregulation appears to be a feature of PHD brain pathology, our results do not support the use of metabolic interventions such as the ketogenic diet in the absence of confirmed GLUT1 dysfunction. Further studies in larger cohorts are warranted to better characterize the metabolic profile of PHD and guide therapeutic strategies. |
| format | Article |
| id | doaj-art-40596bea7c2a40b990adc79bacb22f09 |
| institution | Kabale University |
| issn | 1664-2295 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Neurology |
| spelling | doaj-art-40596bea7c2a40b990adc79bacb22f092025-08-20T13:55:31ZengFrontiers Media S.A.Frontiers in Neurology1664-22952025-08-011610.3389/fneur.2025.16262751626275Preliminary observations of glucose metabolism dysregulation in pediatric Huntington’s diseaseFederica Graziola0Federica Rachele Danti1Martina Penzo2Antonio Spagarino3Eleonora Minacapilli4Marco Moscatelli5Federica Zibordi6Caterina Mariotti7Giovanna Zorzi8Giovanna Zorzi9Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyDepartment of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyDepartment of Biomedical and Clinical Sciences, Postgraduate School of Child Neuropsychiatry, University of Milan, Milan, ItalyPediatric Section, Department of Medical Sciences, University of Ferrara, Ferrara, ItalyDepartment of Biomedical and Clinical Sciences, Postgraduate School of Child Neuropsychiatry, University of Milan, Milan, ItalyNeuroradiology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyDepartment of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyMedical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyDepartment of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyDepartment of Biomedical and Clinical Sciences, Postgraduate School of Child Neuropsychiatry, University of Milan, Milan, ItalyBackgroundPediatric Huntington’s disease (PHD), a rare and severe form of juvenile-onset Huntington’s disease (JOHD), is associated with highly expanded CAG repeats in the HTT gene and a rapidly progressive neurodegenerative course. Recent studies have suggested that glucose metabolism may be impaired in PHD due to reduced expression of glucose transporters in the brain, resembling aspects of GLUT1 Deficiency Syndrome (GLUT1DS).MethodsWe investigated glucose metabolism in two pediatric patients with genetically confirmed PHD (CAG repeats: 76 and 79) referred to our tertiary care center. Clinical, neuroimaging, and neuropsychological data were collected alongside metabolic assessments, including cerebrospinal fluid (CSF) and plasma glucose and lactate levels, CSF-to-serum glucose ratio, and red blood cell GLUT1 expression using the METAglut1 test. 18F-FDG PET imaging and brain MRI were performed to assess cerebral metabolism and structural changes.ResultsBoth patients exhibited progressive motor and cognitive decline with dystonia-parkinsonian features, learning disabilities, and behavioral disturbances. Brain MRI showed caudate and putaminal atrophy, while PET imaging demonstrated severely reduced glucose uptake in the basal ganglia. CSF/plasma glucose ratios were within or near the lower end of the normal range (0.51 and 0.6), and GLUT1 expression in red blood cells was within normal limits. No significant biochemical alterations consistent with GLUT1DS were detected.ConclusionOur findings confirm localized cerebral hypometabolism in the basal ganglia of PHD patients, consistent with previous neuropathological reports. However, systemic biochemical indicators of glucose transport deficiency, including erythrocyte GLUT1 function and CSF glucose, were not significantly altered. While glucose dysregulation appears to be a feature of PHD brain pathology, our results do not support the use of metabolic interventions such as the ketogenic diet in the absence of confirmed GLUT1 dysfunction. Further studies in larger cohorts are warranted to better characterize the metabolic profile of PHD and guide therapeutic strategies.https://www.frontiersin.org/articles/10.3389/fneur.2025.1626275/fullHuntington’s diseasepediatric Huntington’s diseasejuvenile-onset HDGLUT-1 deficiency syndromeGLUT1 |
| spellingShingle | Federica Graziola Federica Rachele Danti Martina Penzo Antonio Spagarino Eleonora Minacapilli Marco Moscatelli Federica Zibordi Caterina Mariotti Giovanna Zorzi Giovanna Zorzi Preliminary observations of glucose metabolism dysregulation in pediatric Huntington’s disease Frontiers in Neurology Huntington’s disease pediatric Huntington’s disease juvenile-onset HD GLUT-1 deficiency syndrome GLUT1 |
| title | Preliminary observations of glucose metabolism dysregulation in pediatric Huntington’s disease |
| title_full | Preliminary observations of glucose metabolism dysregulation in pediatric Huntington’s disease |
| title_fullStr | Preliminary observations of glucose metabolism dysregulation in pediatric Huntington’s disease |
| title_full_unstemmed | Preliminary observations of glucose metabolism dysregulation in pediatric Huntington’s disease |
| title_short | Preliminary observations of glucose metabolism dysregulation in pediatric Huntington’s disease |
| title_sort | preliminary observations of glucose metabolism dysregulation in pediatric huntington s disease |
| topic | Huntington’s disease pediatric Huntington’s disease juvenile-onset HD GLUT-1 deficiency syndrome GLUT1 |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2025.1626275/full |
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