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Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder.
Tokatly Latzer, Itay; Roullet, Jean-Baptiste; Afshar-Saber, Wardiya; Lee, Henry H C; Bertoldi, Mariarita; McGinty, Gabrielle E; DiBacco, Melissa L; Arning, Erland; Tsuboyama, Melissa; Rotenberg, Alexander; Opladen, Thomas; Jeltsch, Kathrin; García-Cazorla, Àngels; Juliá-Palacios, Natalia; Gibson, K Michael; Sahin, Mustafa; Pearl, Phillip L.
Afiliação
  • Tokatly Latzer I; Department of Neurology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.
  • Roullet JB; School of Medicine, Faculty of Medical and Health Sciences, Tel-Aviv University, Tel Aviv, Israel.
  • Afshar-Saber W; Department of Pharmacotherapy, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA.
  • Lee HHC; Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, MA, 02115, USA.
  • Bertoldi M; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA.
  • McGinty GE; Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, MA, 02115, USA.
  • DiBacco ML; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA.
  • Arning E; Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
  • Tsuboyama M; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA.
  • Rotenberg A; Department of Neurology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.
  • Opladen T; Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, USA.
  • Jeltsch K; Department of Neurology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.
  • García-Cazorla À; Department of Neurology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA, 02115, USA.
  • Juliá-Palacios N; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA.
  • Gibson KM; Division of Neuropediatrics & Metabolic Medicine, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
  • Sahin M; Division of Neuropediatrics & Metabolic Medicine, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
  • Pearl PL; Neurometabolic Unit, Neurology Department, Institut de Recerca, Hospital Sant Joan de Déu, Barcelona, Spain.
J Neurodev Disord ; 16(1): 21, 2024 Apr 24.
Article em En | MEDLINE | ID: mdl-38658850
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Deficiências do Desenvolvimento / Succinato-Semialdeído Desidrogenase / Células-Tronco Pluripotentes Induzidas / Erros Inatos do Metabolismo dos Aminoácidos Limite: Adolescent / Animals / Child / Child, preschool / Female / Humans / Male Idioma: En Revista: J Neurodev Disord Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Deficiências do Desenvolvimento / Succinato-Semialdeído Desidrogenase / Células-Tronco Pluripotentes Induzidas / Erros Inatos do Metabolismo dos Aminoácidos Limite: Adolescent / Animals / Child / Child, preschool / Female / Humans / Male Idioma: En Revista: J Neurodev Disord Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Reino Unido