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

• Published in: Neurogenetics 2021-10, Vol.22 (4), p.251-262
• Main Authors: van Karnebeek, Clara D., Blydt-Hansen, Ingrid, Matthews, Allison M., Avramovic, Vladimir, Price, Magda, Drogemoller, Britt, Shyr, Casper, Lee, Jessica, Mwenifumbo, Jill, Ghani, Aisha, Stockler, Sylvia, Friedman, Jan M., Lehman, Anna, Ross, Colin J., Wasserman, Wyeth W., Tarailo-Graovac, Maja, Horvath, Gabriella A.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Amines; Biogenic amines; Biogenic Amines - metabolism; Biomedical and Life Sciences; Biomedicine; Carbidopa - metabolism; Cerebrospinal fluid; Child; Child, Preschool; Drug Combinations; Etiology; Female; Genomes; Human Genetics; Humans; Kinesins - metabolism; Levodopa; Levodopa - genetics; Levodopa - metabolism; Levodopa - therapeutic use; Male; Molecular Medicine; Monoamines; Movement disorders; Neurology; Neurosciences; Neurotransmitter Agents - cerebrospinal fluid; Original Article; p21-Activated Kinases - deficiency; p21-Activated Kinases - metabolism; Paralysis; Pathophysiology; Patients; Phenotypes; Therapeutic applications; Therapeutic targets; Whole genome sequencing; Young Adult
• ISSN: 1364-6745; 1364-6753
• DOI: 10.1007/s10048-021-00652-7

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.