The first-ever prospective natural history study to comprehensively clinically phenotype individuals affected by KCNT1-related epilepsy is initiated, presenting the study design and methods and several challenges that arose in its implementation and discusses various solutions implemented in this medically complex population.
Abstract
Background and Objectives KCNT1-related epilepsy is an ultra-rare pediatric-onset developmental and epileptic encephalopathy with a broad clinical phenotype ranging from, most commonly, severe infantile-onset epilepsy and global developmental delay to, less commonly, milder phenotypes including sleep-related seizures, autism spectrum disorder, and learning disability. We initiated the first-ever prospective natural history study to comprehensively clinically phenotype individuals affected by this disorder. Methods The primary aim of this study was to characterize seizures in individuals with KCNT1-related epilepsy. Secondary and exploratory aims included characterization of the full spectrum of disease symptoms, understanding caregiver burden, and collection of blood and urine samples for biomarker exploration. All study activities were conducted remotely (e.g., home-based assessments, telehealth visits). Results Thirty-five participants (n = 20 male, 15 female) were enrolled in this study. The average age at the baseline visit was 76.0 months (s.d. = 75.5). This article presents the study design and methods and several challenges that arose in its implementation and discusses various solutions implemented in this medically complex population. Discussion Future work will apply the lessons from this study in the planning and design of clinical trials for KCNT1-related epilepsy and possibly other developmental and epileptic encephalopathies.
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CASK-related disorders may present with severe neurodevelopmental impairment and cerebral palsy–like phenotypes, even in the absence of characteristic neuroimaging findings, which should raise suspicion for CASK-related disorders.
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“hemiconvulsion-hemiplegia-epilepsy syndrome” is identified as a distinct feature and potential prognostic indicator for middle domain variants in DNM1L variants, which are predominantly missense, with the middle domain as a hotspot.
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BACKGROUND
TTC19-related mitochondrial disease is a rare mitochondrial disorder of respiratory chain Complex III (CIII), typically associated with neurodegeneration and Leigh syndrome. However, its clinical presentation is variable, which complicates diagnosis and management.
OBJECTIVE
To characterize the clinical and neuroimaging features of pediatric patients with TTC19 variants, focusing on disease course and outcomes.
METHODS
We conducted a multicentric retrospective study of 11 patients diagnosed with TTC19 variants in France. Data were collected from patients'medical records from multiple mitochondrial disease reference centers, encompassing demographic, clinical, neuroimaging, and genetic information. Brain MRIs were reviewed by a sole neuroradiologist expert to standardize findings. All patients had genetic confirmation of TTC19-related mitochondrial disease.
RESULTS
The cohort consisted of 6 families, with a mean age at onset of 5.7 years (range: 0.8-15 years). Patients exhibited two distinct clinical patterns: progressive neurodegenerative disease (chronic Leigh syndrome) and acute/subacute Leigh syndrome. Neuroimaging consistently revealed striatal lesions in all patients and brainstem involvement in almost all of them. Additional findings included cerebellar atrophy and lactate peak on MR spectroscopy. Clinical manifestations were predominantly neurological, with motor involvement including, dystonia, cerebellar ataxia, and orofacial apraxia and frequently cognitive impairments. Acute Leigh episodes were observed in many patients, leading to sudden deterioration. The disease progression varied, with patients experiencing progressive decline, stepwise declines and others remaining stable between episodes.
CONCLUSION
TTC19-related mitochondrial disease leads to a severe neurodegenerative phenotype, characterized by early-onset motor and cognitive delays, with a consistent neuroimaging signature involving the striatum and brainstem. This study expands the understanding of TTC19-related mitochondrial disease and underscores the importance of neuroimaging in diagnosis and management.
Claire-Marine Bérat, G. Barcia, P. Gaignard et al.· Molecular Genetics and Metab...· 0 citations
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