Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder
Abstract Background Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children’s Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natur...
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2024-04-01
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| Series: | Journal of Neurodevelopmental Disorders |
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| Online Access: | https://doi.org/10.1186/s11689-024-09538-9 |
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| author | Itay Tokatly Latzer Jean-Baptiste Roullet Wardiya Afshar-Saber Henry H. C. Lee Mariarita Bertoldi Gabrielle E. McGinty Melissa L. DiBacco Erland Arning Melissa Tsuboyama Alexander Rotenberg Thomas Opladen Kathrin Jeltsch Àngels García-Cazorla Natalia Juliá-Palacios K. Michael Gibson Mustafa Sahin Phillip L. Pearl |
| author_facet | Itay Tokatly Latzer Jean-Baptiste Roullet Wardiya Afshar-Saber Henry H. C. Lee Mariarita Bertoldi Gabrielle E. McGinty Melissa L. DiBacco Erland Arning Melissa Tsuboyama Alexander Rotenberg Thomas Opladen Kathrin Jeltsch Àngels García-Cazorla Natalia Juliá-Palacios K. Michael Gibson Mustafa Sahin Phillip L. Pearl |
| author_sort | Itay Tokatly Latzer |
| collection | DOAJ |
| description | Abstract Background Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children’s Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy. Methods SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy. Results The 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4–14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder’s clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in vitro neuronal model of SSADHD and express the neuronal marker microtubule-associated protein 2 (MAP2), as well as GABA. GABA-metabolism in induced GABAergic neurons could be reversed using CRISPR correction of the pathogenic variants or mRNA transfection and SSADHD iPSCs were associated with excessive glutamatergic activity and related synaptic excitation. Conclusions Findings from the SSADHD Natural History Study converge with iPSC and animal model work focused on a common disorder within our IDDRC, deepening our knowledge of the pathophysiology and longitudinal clinical course of a complex neurodevelopmental disorder. This further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy. |
| format | Article |
| id | doaj-art-cb335a1bff7e48c685c43cab55795ad8 |
| institution | Kabale University |
| issn | 1866-1955 |
| language | English |
| publishDate | 2024-04-01 |
| publisher | BMC |
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| series | Journal of Neurodevelopmental Disorders |
| spelling | doaj-art-cb335a1bff7e48c685c43cab55795ad82025-01-19T12:10:46ZengBMCJournal of Neurodevelopmental Disorders1866-19552024-04-0116111510.1186/s11689-024-09538-9Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorderItay Tokatly Latzer0Jean-Baptiste Roullet1Wardiya Afshar-Saber2Henry H. C. Lee3Mariarita Bertoldi4Gabrielle E. McGinty5Melissa L. DiBacco6Erland Arning7Melissa Tsuboyama8Alexander Rotenberg9Thomas Opladen10Kathrin Jeltsch11Àngels García-Cazorla12Natalia Juliá-Palacios13K. Michael Gibson14Mustafa Sahin15Phillip L. Pearl16Department of Neurology, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State UniversityRosamund Stone Zander Translational Neuroscience Center, Boston Children’s HospitalRosamund Stone Zander Translational Neuroscience Center, Boston Children’s HospitalDepartment of Neuroscience, Biomedicine and Movement Sciences, University of VeronaF.M. Kirby Neurobiology Center, Boston Children’s HospitalDepartment of Neurology, Boston Children’s Hospital, Harvard Medical SchoolInstitute of Metabolic Disease, Baylor Scott & White Research InstituteDepartment of Neurology, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Neurology, Boston Children’s Hospital, Harvard Medical SchoolDivision of Neuropediatrics & Metabolic Medicine, University Children’s Hospital HeidelbergDivision of Neuropediatrics & Metabolic Medicine, University Children’s Hospital HeidelbergNeurometabolic Unit, Neurology Department, Institut de Recerca, Hospital Sant Joan de DéuNeurometabolic Unit, Neurology Department, Institut de Recerca, Hospital Sant Joan de DéuDepartment of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State UniversityDepartment of Neurology, Boston Children’s Hospital, Harvard Medical SchoolDepartment of Neurology, Boston Children’s Hospital, Harvard Medical SchoolAbstract Background Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children’s Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy. Methods SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy. Results The 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4–14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder’s clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in vitro neuronal model of SSADHD and express the neuronal marker microtubule-associated protein 2 (MAP2), as well as GABA. GABA-metabolism in induced GABAergic neurons could be reversed using CRISPR correction of the pathogenic variants or mRNA transfection and SSADHD iPSCs were associated with excessive glutamatergic activity and related synaptic excitation. Conclusions Findings from the SSADHD Natural History Study converge with iPSC and animal model work focused on a common disorder within our IDDRC, deepening our knowledge of the pathophysiology and longitudinal clinical course of a complex neurodevelopmental disorder. This further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy.https://doi.org/10.1186/s11689-024-09538-9Succinic semialdehyde dehydrogenaseNeurotransmittersGABADevelopment |
| spellingShingle | Itay Tokatly Latzer Jean-Baptiste Roullet Wardiya Afshar-Saber Henry H. C. Lee Mariarita Bertoldi Gabrielle E. McGinty Melissa L. DiBacco Erland Arning Melissa Tsuboyama Alexander Rotenberg Thomas Opladen Kathrin Jeltsch Àngels García-Cazorla Natalia Juliá-Palacios K. Michael Gibson Mustafa Sahin Phillip L. Pearl Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder Journal of Neurodevelopmental Disorders Succinic semialdehyde dehydrogenase Neurotransmitters GABA Development |
| title | Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder |
| title_full | Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder |
| title_fullStr | Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder |
| title_full_unstemmed | Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder |
| title_short | Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder |
| title_sort | clinical and molecular outcomes from the 5 year natural history study of ssadh deficiency a model metabolic neurodevelopmental disorder |
| topic | Succinic semialdehyde dehydrogenase Neurotransmitters GABA Development |
| url | https://doi.org/10.1186/s11689-024-09538-9 |
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