Rory J Tinker1, Marni J Falk2, Amy Goldstein2, Ibrahim George-Sankoh1, Rui Xiao3, Laura Adang4, Rebecca Ganetzky5. 1. Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 2. Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 3. Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, USA. 4. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 5. Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: ganetzkyr@chop.edu.
Abstract
BACKGROUND: Leigh spectrum syndrome (LSS) is a primary mitochondrial disorder characterized by neurodevelopmental regression and metabolic stroke typically in early life. Developmental delay (DD) is known to follow episodes of neurologic regression in LSS, although primary developmental delay (pDD) has been rarely reported. We hypothesized that pDD precedes regression in a broader subset of LSS individuals and may associate with worse long-term educational outcomes. METHODS: From a retrospective cohort, subjects with pathogenic variant(s) in a nuclear or mitochondrial gene associated with LSS and consistent clinical manifestations and neuroradiological findings. Detailed developmental histories and neurologic outcomes were extracted. RESULTS: Of 69 LSS subjects, 47 (68.1%) had a history of pDD and 53 (76.8%) had neurodevelopmental regression. We identified 3 distinct developmental phenotypes: [1] pDD followed by regression (N = 31/69, 44.9%), [2] pDD without subsequent regression (16/69, 23.2%), [3] regression without pDD (N = 22/69, 31.9%). A history of pDD was associated with earlier disease onset (p = 0.0003) and worse educational outcomes (OR 22.14). CONCLUSION: LSS is associated with multiple developmental phenotypes and pDD is associated with negative educational outcomes. pDD occurring prior to neurologic regression suggests that mitochondrial energetics impact developmental trajectories prior to acute metabolic failure and regression, providing an opportunity for earlier diagnosis and/or therapeutic intervention.
BACKGROUND: Leigh spectrum syndrome (LSS) is a primary mitochondrial disorder characterized by neurodevelopmental regression and metabolic stroke typically in early life. Developmental delay (DD) is known to follow episodes of neurologic regression in LSS, although primary developmental delay (pDD) has been rarely reported. We hypothesized that pDD precedes regression in a broader subset of LSS individuals and may associate with worse long-term educational outcomes. METHODS: From a retrospective cohort, subjects with pathogenic variant(s) in a nuclear or mitochondrial gene associated with LSS and consistent clinical manifestations and neuroradiological findings. Detailed developmental histories and neurologic outcomes were extracted. RESULTS: Of 69 LSS subjects, 47 (68.1%) had a history of pDD and 53 (76.8%) had neurodevelopmental regression. We identified 3 distinct developmental phenotypes: [1] pDD followed by regression (N = 31/69, 44.9%), [2] pDD without subsequent regression (16/69, 23.2%), [3] regression without pDD (N = 22/69, 31.9%). A history of pDD was associated with earlier disease onset (p = 0.0003) and worse educational outcomes (OR 22.14). CONCLUSION: LSS is associated with multiple developmental phenotypes and pDD is associated with negative educational outcomes. pDD occurring prior to neurologic regression suggests that mitochondrial energetics impact developmental trajectories prior to acute metabolic failure and regression, providing an opportunity for earlier diagnosis and/or therapeutic intervention.
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