Kinetic Analyses Guide the Therapeutic Decision in a Novel Form of Moderate Aromatic Acid Decarboxylase Deficiency

Abstract

Background: Aromatic amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder resulting in a combined dopamine and serotonin deficiency. About 50% of the cases set in the neonatal period. Here, we report an atypical clinical presentation with moderate symptoms.Patient: At 10 months old, the patient presented paroxysmal eye movements without seizures, and feeding difficulties which were attributed to gastroesophageal reflux. She was investigated at the age of 7 years, because of orofacial dyspraxia, hypomimie, axial hypotonia and focal segmental dystonia, bilateral ptosis, without evidence for cognitive impairment.Results: HVA [110 nM; (reference value (rv): 202-596)] and HIAA (12 nM; rv: 87-366) decreased, OMD (520 nM; rv: 5-60) and 5-HTP (56 nM; rv: 2-16) increased in CSF. We confirmed the diagnosis of AADC deficiency because the activity in plasma was low: 4 pmol/min/ml; rv: 16-137. The kinetic analysis revealed a sixfold increase in the apparent affinity for L-dopa (4.26 mM; control ¼ 0.71), but the V max was unchanged (37.5 pmol dopamine/min/ml; control ¼ 39.1), suggesting a modification in the substrate binding-site. Molecular analysis revealed two heterozygous mutations in the DDC gene: c1040G > A; pR347Q already described, and a novel mutation c478C > T, pR160W.Conclusion: (1) CSF neurotransmitters metabolites suggested a moderate AADC deficiency; (2) The initial velocity saturation curve for L-dopa displayed a cooperative ligand binding behavior, in keeping with the modifications of the three-dimensional structure, induced by the amino acid substitutions (3) The treatment combination of L-dopa with pyridoxine dramatically improved the quality of life, the fatigability, and the paroxysmal eye movements. Abbreviations 3DThree dimensional 3-OMD 3-Ortho-methyldopa 5-HIAA 5-Hydroxyindolacetic acid 5-HT 5-Hydroxytryptamine 5-HTP 5-Hydroxytryptophan AADC Aromatic L-amino acid decarboxylase CSF Cerebral spinal fluid DA Dopamine JIMD Reports

Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency

“…Six cases could be classified as mild (reported in [5, 18, 19, 35, 43]), 15 as moderate (reported in [2, 5, 7, 20, 22, 31, 35, 40, 44, 45]), and 82 as severe. For 14 cases, insufficient information about the clinical picture was available.…”

“…Three siblings, extensively represented in the literature, with a homozygous p.[G102S], c.[304G > A] variant became able to walk independently ( n  = 1) or with assistance ( n  = 2) and showed improvement of dystonia, truncal hypotonia and speech after L-Dopa treatment was started [7, 40, 47]. More recently, a patient with other variants affecting the L-Dopa binding site p.[R347Q];[R160W], c.[1040G > A];[478C > T], also showed a good response to L-Dopa [19]. Currently, therapeutic implications of other DDC gene variants in AADCD are being investigated [48].…”

“…In both patients, 3-OMD and -5-HTP were increased and MHPG was decreased [5]. In only one patient, normal MHPG was reported, with decreased HVA and 5-HIAA [19]. Normal CSF pterins (neopterin, dihydrobiopterin and tetrahydrobiopterin) are essential to differentiate AADCD from the tetrahydrobiopterin disorders [6].…”

“…However, in 4 patients with variants at the L-Dopa binding site, a sustained effect of L-Dopa was seen (see part I). Reported side effects (diarrhea and restlessness) in these patients were minimal and dose-dependent [19]. No improvement was reported in 3 cases [40, 42], and in 3 cases response was not described [2].…”

Aromatic L-amino acid decarboxylase deficiency: perspectives on diagnosis and management

“…30 This patient was treated with L-dopa and pyridoxine and showed marked improvement in terms of quality of life, fatigability, and paroxysmal eye movements (OGCs). This illustrates the fact that certain mutations may significantly affect enzyme kinetics, and substrate supplementation (L-dopa) may result in markedly improved clinical function.…”