Itay Tokatly Latzer, Henry H C Lee, Edward Yang, Cesar Alves, Mariarita Bertoldi, Caitlyn Fung, Spencer V Steele, Eren Kule, Zijie Jin, Alexander Rotenberg, Jean-Baptiste Roullet, Phillip L Pearl
{"title":"ssadh缺乏的人和小鼠中枢性髓鞘发育异常。","authors":"Itay Tokatly Latzer, Henry H C Lee, Edward Yang, Cesar Alves, Mariarita Bertoldi, Caitlyn Fung, Spencer V Steele, Eren Kule, Zijie Jin, Alexander Rotenberg, Jean-Baptiste Roullet, Phillip L Pearl","doi":"10.1002/acn3.70148","DOIUrl":null,"url":null,"abstract":"<p><strong>Objectives: </strong>Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder characterized by an accumulation of γ-aminobutyric (GABA). In addition to its synaptic role as an inhibitory neurotransmitter, GABA also plays an important role in myelination. We aimed to investigate the relationship between GABA and myelination abnormalities in SSADHD patients and the mouse model.</p><p><strong>Methods: </strong>Brain MRIs performed on 44 individuals (23 with SSADHD and 21 healthy controls) were independently reviewed by two neuroradiologists and scored using a disease-specific myelination scoring system. Inter-rater reliability (IRR) was assessed by the intraclass correlation coefficient. Myelination scores of SSADHD individuals were correlated with clinical, biochemical, magnetic resonance spectroscopy, and genetic data. Additionally, we investigated the expression of myelin-related genes in a mouse SSADHD model.</p><p><strong>Results: </strong>Dysmyelination in SSADHD patients was overall mild, but significantly greater than in healthy controls (p < 0.001). In SSADHD patients, lower myelination scores were significantly correlated with younger age (R = 0.775, p < 0.001) and higher plasma GABA (R = -0.722, p < 0.001) and γ-hydroxybutyric acid (GHB) (R = -0.683, p = 0.001). In SSADH-deficient mice, there was reduced expression of genes encoding myelin basic protein (p = 0.001), myelin-associated oligodendrocyte basic protein (p = 0.001), and mitochondrial aspartate transporter (p = 0.025).</p><p><strong>Interpretation: </strong>Excessive GABA and GHB, which characterize SSADHD and are further pronounced in younger SSADHD individuals, may account for delayed oligodendrocyte maturation and altered myelination dynamics in this disorder. Studying the properties of dysmyelination in this unique disorder enhances our understanding of GABA's mediating role on myelination and may contribute to monitoring disease progression and managing other white-matter neurological disorders.</p><p><strong>Trial registration: </strong>NCT03758521.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9000,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Central Dysmyelination in SSADH-Deficient Humans and Mice.\",\"authors\":\"Itay Tokatly Latzer, Henry H C Lee, Edward Yang, Cesar Alves, Mariarita Bertoldi, Caitlyn Fung, Spencer V Steele, Eren Kule, Zijie Jin, Alexander Rotenberg, Jean-Baptiste Roullet, Phillip L Pearl\",\"doi\":\"10.1002/acn3.70148\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objectives: </strong>Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder characterized by an accumulation of γ-aminobutyric (GABA). In addition to its synaptic role as an inhibitory neurotransmitter, GABA also plays an important role in myelination. We aimed to investigate the relationship between GABA and myelination abnormalities in SSADHD patients and the mouse model.</p><p><strong>Methods: </strong>Brain MRIs performed on 44 individuals (23 with SSADHD and 21 healthy controls) were independently reviewed by two neuroradiologists and scored using a disease-specific myelination scoring system. Inter-rater reliability (IRR) was assessed by the intraclass correlation coefficient. Myelination scores of SSADHD individuals were correlated with clinical, biochemical, magnetic resonance spectroscopy, and genetic data. Additionally, we investigated the expression of myelin-related genes in a mouse SSADHD model.</p><p><strong>Results: </strong>Dysmyelination in SSADHD patients was overall mild, but significantly greater than in healthy controls (p < 0.001). In SSADHD patients, lower myelination scores were significantly correlated with younger age (R = 0.775, p < 0.001) and higher plasma GABA (R = -0.722, p < 0.001) and γ-hydroxybutyric acid (GHB) (R = -0.683, p = 0.001). In SSADH-deficient mice, there was reduced expression of genes encoding myelin basic protein (p = 0.001), myelin-associated oligodendrocyte basic protein (p = 0.001), and mitochondrial aspartate transporter (p = 0.025).</p><p><strong>Interpretation: </strong>Excessive GABA and GHB, which characterize SSADHD and are further pronounced in younger SSADHD individuals, may account for delayed oligodendrocyte maturation and altered myelination dynamics in this disorder. Studying the properties of dysmyelination in this unique disorder enhances our understanding of GABA's mediating role on myelination and may contribute to monitoring disease progression and managing other white-matter neurological disorders.</p><p><strong>Trial registration: </strong>NCT03758521.</p>\",\"PeriodicalId\":126,\"journal\":{\"name\":\"Annals of Clinical and Translational Neurology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":3.9000,\"publicationDate\":\"2025-07-31\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Clinical and Translational Neurology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/acn3.70148\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Clinical and Translational Neurology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/acn3.70148","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Central Dysmyelination in SSADH-Deficient Humans and Mice.
Objectives: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder characterized by an accumulation of γ-aminobutyric (GABA). In addition to its synaptic role as an inhibitory neurotransmitter, GABA also plays an important role in myelination. We aimed to investigate the relationship between GABA and myelination abnormalities in SSADHD patients and the mouse model.
Methods: Brain MRIs performed on 44 individuals (23 with SSADHD and 21 healthy controls) were independently reviewed by two neuroradiologists and scored using a disease-specific myelination scoring system. Inter-rater reliability (IRR) was assessed by the intraclass correlation coefficient. Myelination scores of SSADHD individuals were correlated with clinical, biochemical, magnetic resonance spectroscopy, and genetic data. Additionally, we investigated the expression of myelin-related genes in a mouse SSADHD model.
Results: Dysmyelination in SSADHD patients was overall mild, but significantly greater than in healthy controls (p < 0.001). In SSADHD patients, lower myelination scores were significantly correlated with younger age (R = 0.775, p < 0.001) and higher plasma GABA (R = -0.722, p < 0.001) and γ-hydroxybutyric acid (GHB) (R = -0.683, p = 0.001). In SSADH-deficient mice, there was reduced expression of genes encoding myelin basic protein (p = 0.001), myelin-associated oligodendrocyte basic protein (p = 0.001), and mitochondrial aspartate transporter (p = 0.025).
Interpretation: Excessive GABA and GHB, which characterize SSADHD and are further pronounced in younger SSADHD individuals, may account for delayed oligodendrocyte maturation and altered myelination dynamics in this disorder. Studying the properties of dysmyelination in this unique disorder enhances our understanding of GABA's mediating role on myelination and may contribute to monitoring disease progression and managing other white-matter neurological disorders.
期刊介绍：
Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.
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