Monoamine neurotransmitter disorders present predominantly with neurologic features, including dystonic or dyskinetic cerebral palsy and movement disorders. Genetic conditions that lead to secondary defects in the synthesis, catabolism, transport, and metabolism of biogenic amines can lead to neurotransmitter abnormalities, which can present with similar features. Eleven patients with secondary neurotransmitter abnormalities were enrolled between 2011 and 2015. All patients underwent research-based whole exome and/or whole genome sequencing (WES/WGS). A trial of treatment with levodopa/carbidopa and 5-hydroxytryptophan was initiated. In six families with abnormal neurotransmitter profiles and neurological phenotypes, variants in known disease-causing genes (KCNJ6, SCN2A, CSTB in 2 siblings, NRNX1, KIF1A and PAK3) were identified, while one patient had a variant of uncertain significance in a candidate gene (DLG4) that may explain her phenotype. In 3 patients, no compelling candidate genes were identified. A trial of neurotransmitter replacement therapy led to improvement in motor and behavioral symptoms in all but two patients. The patient with KCNJ6 variant did not respond to L-dopa therapy, but rather experienced increased dyskinetic movements even at low dose of medication. The patient’s symptoms harboring the NRNX1 deletion remained unaltered. This study demonstrates the utility of genome-wide sequencing in further understanding the etiology and pathophysiology of neurometabolic conditions, and the potential of secondary neurotransmitter deficiencies to serve as novel therapeutic targets. As there was a largely favorable response to therapy in our case series, a careful trial of neurotransmitter replacement therapy should be considered in patients with cerebrospinal fluid (CSF) monoamines below reference range.

单胺类神经递质疾病主要表现为神经系统特征，包括肌张力障碍或运动障碍性脑瘫和运动障碍。导致生物胺的合成、分解代谢、运输和代谢中的继发性缺陷的遗传条件可导致神经递质异常，其可能具有相似的特征。2011 年至 2015 年间，11 名继发性神经递质异常患者入组。所有患者均接受了基于研究的全外显子组和/或全基因组测序 (WES/WGS)。开始了用左旋多巴/卡比多巴和 5-羟色氨酸治疗的试验。在 6 个神经递质谱和神经表型异常的家族中，已知致病基因的变异（2 个兄弟姐妹中的KCNJ6、SCN2A、CSTB ，NRNX1、KIF1A和PAK3 ) 被鉴定，而一名患者的候选基因 ( DLG4 ) 具有不确定意义的变异，这可能解释她的表型。在 3 名患者中，未鉴定出令人信服的候选基因。除两名患者外，一项神经递质替代疗法试验导致所有患者的运动和行为症状得到改善。具有KCNJ6变异的患者对左旋多巴治疗没有反应，但即使在低剂量药物下也经历了运动障碍增加。携带NRNX1的患者症状删除保持不变。这项研究证明了全基因组测序在进一步了解神经代谢疾病的病因和病理生理学方面的效用，以及继发性神经递质缺乏作为新治疗靶点的潜力。由于在我们的病例系列中对治疗有很大的反应，因此应考虑在脑脊液 (CSF) 单胺低于参考范围的患者中仔细试验神经递质替代疗法。