Neurofibromatosis type 1 (NF1) is associated with cognitive dysfunction and structural brain abnormalities such as an enlarged corpus callosum. This study aimed to determine the relationship between corpus callosum morphology and cognitive function in children with neurofibromatosis type 1 using quantitative neuroanatomic imaging techniques. Children with neurofibromatosis type 1 (n = 46) demonstrated a significantly larger total corpus callosum and corpus callosum index compared with control participants (n = 30). A larger corpus callosum index in children with neurofibromatosis type 1 was associated with significantly lower IQ, reduced abstract concept formation, reduced verbal memory, and diminished academic ability, specifically reading and math. Our results suggest an enlarged corpus callosum in children with neurofibromatosis type 1 is associated with cognitive impairment and may provide an early structural marker for the children at risk of cognitive difficulties. Cognitive deficits associated with structural brain abnormalities in neurofibromatosis type 1 are unlikely to be reversible and so may not respond to proposed pharmacological therapies for neurofibromatosis type 1-related cognitive impairments.
We compared cognitive functioning, academic ability, and the predictors of academic underachievement in children with neurofibromatosis type 1 (NF1) (n = 132), children with NF1 and comorbid attention deficit hyperactivity disorder (NF1 + ADHD) (n = 60), and unaffected controls (n = 52). Results indicate the presence of ADHD burdens some aspects of cognitive functioning and learning in NF1. Inattention and executive dysfunction are general characteristics of the NF1 cognitive phenotype and significantly undermine academic achievement across children with NF1.
Variants in SLC18A3, vesicular acetylcholine transporter, cause congenital myasthenic syndrome ABSTRACT Objective: To describe the clinical and genetic characteristics of presynaptic congenital myasthenic syndrome secondary to biallelic variants in SLC18A3.Methods: Individuals from 2 families were identified with biallelic variants in SLC18A3, the gene encoding the vesicular acetylcholine transporter (VAChT), through whole-exome sequencing.Results: The patients demonstrated features seen in presynaptic congenital myasthenic syndrome, including ptosis, ophthalmoplegia, fatigable weakness, apneic crises, and deterioration of symptoms in cold water for patient 1. Both patients demonstrated moderate clinical improvement on pyridostigmine. Patient 1 had a broader phenotype, including learning difficulties and left ventricular dysfunction. Electrophysiologic studies were typical for a presynaptic defect. Both patients showed profound electrodecrement on low-frequency repetitive stimulation followed by a prolonged period of postactivation exhaustion. In patient 1, this was unmasked only after isometric contraction, a recognized feature of presynaptic disease, emphasizing the importance of activation procedures.
Conclusions:VAChT is responsible for uptake of acetylcholine into presynaptic vesicles. The clinical and electrographic characteristics of the patients described are consistent with previously reported mouse models of VAChT deficiency. These findings make it very likely that defects in VAChT due to variants in SLC18A3 are a cause of congenital myasthenic syndrome in humans.
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