Clinical Features and Pharmacotherapy of Childhood Monoamine Neurotransmitter Disorders

Abstract

Childhood neurotransmitter disorders are increasingly recognised as an expanding group of inherited neurometabolic syndromes. They are caused by disturbance in synthesis, metabolism, and homeostasis of the monoamine neurotransmitters, including the catecholamines (dopamine, norepinephrine, and epinephrine) and serotonin. Disturbances in monoamine neurotransmission will lead to neurological symptoms that often overlap with clinical features of other childhood neurological disorders (such as hypoxic ischaemic encephalopathy, cerebral palsy, other movement disorders, and paroxysmal conditions); consequently, neurotransmitter disorders are frequently misdiagnosed. The diagnosis of neurotransmitter disorders is made through detailed clinical assessment, analysis of cerebrospinal fluid neurotransmitters, and further supportive diagnostic investigations. Early and accurate diagnosis of neurotransmitter disorders is important, as many are amenable to therapeutic intervention. The principles of treatment for monoamine neurotransmitter disorders are mainly directly derived from understanding these metabolic pathways. In disorders characterized by enzyme deficiency, we aim to increase monoamine substrate availability, boost enzyme co-factor levels, reduce monoamine breakdown, and replace depleted levels of monoamines with pharmacological analogs as clinically indicated. Most monoamine neurotransmitter disorders lead to reduced levels of central dopamine and/or serotonin. Complete amelioration of motor symptoms is achievable in some disorders, such as Segawa’s syndrome, and, in other conditions, significant improvement in quality of life can be attained with pharmacotherapy. In this review, we provide an overview of the clinical features and current treatment strategies for childhood monoamine neurotransmitter disorders.

GRIN1 mutations cause encephalopathy with infantile‐onset epilepsy, and hyperkinetic and stereotyped movement disorders

“…Of note, two patients showed dystonic eye movements resembling oculogyric crises; therefore, we suspected monoamine neurotransmitter disorders. In addition, extrapyramidal symptoms, sleep abnormalities, lack of eye pursuit, and feeding problems, which are common in the four patients with GRIN1 mutations, overlap with clinical features of monoamine metabolism disorders . On the other hand, two patients were suspected as having Rett syndrome, since they showed Rett‐like stereotypic hand movements and one of the features of Rett syndrome such as bruxism, inappropriate crying and laughter, hyperventilation, sleep abnormalities, and no purposeful hand skills.…”

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

“…Indeed, many of the coding variants have been reported to have altered function or regulation (25,28,29,31,34,35), but a systematic comparison of the coding DAT variants associated with psychiatric disease is lacking. Since obligate carriers of 'loss of function' mutations do not appear to be predisposed to psychiatric disease (36,37), a key question is if and how coding variants in psychiatric patients may impose pathophysiological disturbances, and not least if the variants share structural or functional changes. Our findings herein reveal novel aberrant phenotypes for several rare, diseaseassociated coding DAT variants, and identifies changes in transporter ion conductances as a potential common mechanism through which functional variants may cause dopaminergic dyshomeostasis.…”

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“…This may be related to some similarity in effect of pyridoxine; which is converted to active Pyridoxal phosphate that's involved as coenzyme for number of decarboxylases enzymes used in the synthesis of monoamine neurotransmitters such as serotonin, dopamine; gamma -aminobutyric acid, and norepinephrine 10 . Supplement of pyridoxine may elevate the brain level of these neurotransmitters, except norepinephrine 11 .…”