Views & Reviews CME Aromatic L-amino acid decarboxylase deficiency Clinical features, treatment, and prognosis R. Pons, MD; B. Ford, MD; C.A. Chiriboga, MD; P.T. Clayton, MD; V. Hinton, PhD; K. Hyland, PhD; R. Sharma, PhD; and D.C. De Vivo, MD Abstract—Background: Deficiency of aromatic L-amino acid decarboxylase (AADC) is associated with severe developmen- tal delay, oculogyric crises (OGC), and autonomic dysfunction. Treatment with dopamine agonists and MAO inhibitors is beneficial, yet long-term prognosis is unclear. Objective: To delineate the clinical and molecular spectrum of AADC deficiency, its management, and long-term follow-up. Results: The authors present six patients with AADC deficiency and review seven cases from the literature. All patients showed reduced catecholamine metabolites and elevation of 3-O- methyldopa in CSF. Residual plasma AADC activity ranged from undetectable to 8% of normal. Mutational spectrum was heterogeneous. All patients presented with hypotonia, hypokinesia, OGC, and signs of autonomic dysfunction since early life. Diurnal fluctuation or improvement of symptoms after sleep were noted in half of the patients. Treatment response was variable. Two groups of patients were detected: Group I (five males) responded to treatment and made developmental progress. Group II (one male, five females) responded poorly to treatment, and often developed drug-induced dyskinesias. Conclusions: The molecular and clinical spectrum of AADC deficiency is heterogeneous. Two groups, one with predomi- nant male sex and favorable response to treatment, and the other with predominant female sex and poor response to treatment, can be discerned. NEUROLOGY 2004;62:1058 –1065 Disorders of monoamine neurotransmitter metabo- lism have been increasingly recognized. Mono- amines, also called biogenic amines, include serotonin and the two catecholamines dopamine and norepinephrine. These compounds have numerous roles including modulation of psychomotor function; hormone secretion; cardiovascular, respiratory, and gastrointestinal control; sleep mechanisms; body temperature; and pain. 1 The starting substrate for the formation of cat- echolamines is tyrosine and for serotonin is trypto- phan. Specific tetrahydrobiopterin-dependent amino acid hydroxylases convert tyrosine to levodopa and tryptophan to 5-hydroxytryptophan (5-HTP). Levo- dopa and 5-HTP then undergo decarboxylation through the action of the pyridoxine-dependent aro- matic L-amino acid decarboxylase (AADC), which leads to the formation of dopamine and serotonin. Within noradrenergic neurons dopamine is converted to norepinephrine using dopamine -hydroxylase and within the pineal gland, serotonin is methylated to melatonin (figure). Monoamine catabolism involves the action of monoamine oxidase (MAO) and catechol-O-methyl- transferase, with the formation of homovanillic acid (HVA) from dopamine and 5-hydroxyindolacetic acid (5-HIAA) from serotonin (see the figure). The levels of these metabolites in CSF reflect the turnover of monoamines within the brain. 1 Several enzyme defects leading to individual or combined deficiencies of monoamine neurotransmit- ters have been described. 1 In 1992, Hyland et al. described the first patients with AADC deficiency. 2 These twin boys presented with motor, extrapyrami- dal, and autonomic symptoms. CSF monoamine me- tabolites pointed to a deficiency in the synthesis of catecholamines and serotonin, and enzyme assay in plasma confirmed the AADC deficiency. 2 Since that first description, seven more patients have been de- scribed in detail 3-7 and five more as short communi- From the Departments of Neurology and Pediatrics (Drs. Pons, Ford, Chiriboga, Hinton, and De Vivo), College of Physicians and Surgeons of Columbia University, New York, NY; Biochemistry Endocrinology and Metabolism Unit (Dr. Clayton), Institute of Child Health at Great Ormond Street Hospital, University College London, UK; Institute of Metabolic Disease (Drs. Hyland and Sharma), Baylor University Medical Center, Dallas, TX; and Universitat Autonoma de Barcelona (Dr. Pons), Spain. Received June 17, 2003. Accepted in final form November 24, 2003. Address correspondence and reprint requests to Dr. Darryl C. De Vivo, Neurological Institute, 710 West 168 th Street, New York, NY 10032; e-mail: dcd1@columbia.edu 1058 Copyright © 2004 by AAN Enterprises, Inc.