Epilepsy in inherited neurotransmitter disorders: Spotlights on pathophysiology and clinical management
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REVIEW ARTICLE
Epilepsy in inherited neurotransmitter disorders: Spotlights onpathophysiology and clinical management Mario Mastrangelo 1 Received: 23 April 2020 / Accepted: 16 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Inborn errors of neurotransmitter metabolism are ultrarare disorders affecting neurotransmitter biosynthesis, breakdown or transport or their essential cofactors. Neurotransmitter dysfunctions could also result from the impairment of neuronal receptors, intracellular signaling, vesicle release or other synaptic abnormalities. Epilepsy is the main clinical hallmark in some of these diseases (e.g. disorders of GABA metabolism, glycine encephalopathy) while it is infrequent in others (e.g. all the disorders of monoamine metabolism in exception for dihydropteridine reductase deficiency). This review analyzes the epileptogenic mechanisms, the epilepsy phenotypes and the principle for the clinical management of epilepsy in primary and secondary inherited disorders of neurotransmitter metabolism (disorders of GABA, serine and glycine metabolism, disorders of neurotransmitter receptors and secondary neurotransmitter diseases). Keywords Epileptic and developmental encephalopathies . Neurotransmission . GABA . Glycine encephalopathy . Serine metabolism disorders . Biogenic amine . Children
Background Neurotransmitters are a heterogeneous group of chemical messengers, modulating neuronal communications (Brennenstuli et al. 2019). They include amino acids (glutamate, glycine, serine and gamma aminobutyric acid), peptides, purines, acetylcholine and monoamines (including epinephrine, norepinephrine, dopamine and serotonin) (Opladen et al. 2016). Inborn errors of neurotransmitter metabolism are ultrarare disorders affecting neurotransmitter biosynthesis, breakdown or transport or their essential cofactors (Table 1; Pearl et al. 2007). A severe functional impairment of neurotransmitter may also be due to abnormalities of neuronal receptors (e.g. genetic syndromes associated to GABAA subunits and GRINpathies), vesicle release (e.g. STXBP1 encephalopathy, VMAT 2 deficiency), intracellular signaling and other secondary neurotransmitter
* Mario Mastrangelo [email protected] 1
Child Neurology and Psychiatry Unit-Department of Human Neuroscience, Sapienza Università di Roma-Umberto I Policlinico di Roma, Via dei Sabelli, 108 - 00141, Roma, Italy
diseases (e.g. Rett syndrome, cerebral folate deficiency etc.). (Tables 1 and 2; McTague et al. 2016; Van Karnebeek et al. 2018). The clinical presentation may include a variable spectrum of symptoms such as developmental delay or regression, movement disorders, muscle tone abnormalities and autonomic signs (Pearl et al. 2005). The present review analyzes epileptogenic mechanisms, the main epilepsy phenotypes and the principles for the clinical management of primary and secondary disorders of neurotransmitter metabolism. Epilepsy is the predominant hallmark in some cases (e.g. disorders of GABA metabolism, glycine
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