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Secondary biogenic amine deficiencies: genetic etiology, therapeutic interventions, and clinical effects


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.

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Fig. 1
Fig. 2



5-Hydroxyindoleacetic acid




Aromatic amino acid decarboxylase


American College of Medical Geneticists

BH4 :



Dopamine transporter


Cerebral palsy


Extracellular signal-regulated kinase


Homovanillic acid


Intellectual and developmental disabilities


Incidental finding


International Working Group on Neurotransmitter Related Disorders


Mitochondrial DNA




P21-activated kinase


Parkinson’s disease


Protein kinase C


Rapidly accelerated fibrosarcoma


Rat sarcoma


Serotonin transporter


Tyrosine hydroxylase


Tryptophan hydroxylase


Variant of uncertain significance


Whole exome sequencing


Whole genome sequencing


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We are indebted to all patients and their families for participation in this study; our colleagues in the Departments of Pediatrics and Medical Genetics, University of British Columbia (Canada) for clinical management of patients; and other colleagues at BC Children’s Hospital and Vancouver General Hospital contributing to the diagnoses and management of these patients.


This study is supported by funding from the B.C. Children’s Hospital Foundation (Treatable Intellectual Disability Endeavour in British Columbia: 1st Collaborative Area of Innovation; Genome BC (SOF-195 grant to CvK); BC Clinical Genomics Network (#00032 grant to CvK); Rare Diseases Foundation (microgrants to CvK & GH), Canadian Institutes of Health Research (#301221 grant to CvK, RDMM), Michael Smith Foundation for Health Research Scholar Award (to CvK), Genome Canada (ABC4DE Project to WW; RDMM); CIHR New Investigator Award (to CR); CFRI Fellowship to AM; CFRI PhD award to JL and Alberta Children’s Hospital Research Institute Foundation.

The CAUSES Study was funded by the BC Children’s Hospital Foundation (Mining for Miracles) and GenomeBC; investigators include Shelin Adam, Christele Du Souich, Alison Elliott, Anna Lehman, Jill Mwemifumbo, Tanya Nelson, Clara van Karnebeek and Jan Friedman. Bioinformatics support was provided to CAUSES by the laboratory of Wyeth Wasserman.

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All authors made substantial contributions to the conception or design of the work (GAH, MTG, CvK) and the acquisition, analysis, or interpretation of data (MTG, IBH, AM, VA, MP, BD, CS, JL, JM, AG, SS, JMF, AL, CR, WW). GAH, MTG, IBH drafted the manuscript. CvK, JMF, AL revised it critically for important intellectual content, and all authors approved the current version to be published.

Corresponding authors

Correspondence to Maja Tarailo-Graovac or Gabriella A. Horvath.

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Supplemental Table 3

Presenting symptoms of patients. (DOCX 16 KB)

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van Karnebeek, C.D., Blydt-Hansen, I., Matthews, A.M. et al. Secondary biogenic amine deficiencies: genetic etiology, therapeutic interventions, and clinical effects. Neurogenetics 22, 251–262 (2021).

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  • Next generation sequencing
  • Neurotransmitters
  • Biogenic amines