Aromatic L-amino Acid Decarboxylase (AADC)
Aromatic L-amino acid decarboxylase is a pyridoxine dependent enzyme that decarboxylates L-dopa and 5-HTP to make dopamine and serotonin respectively. Patients with this disorder typically present in the first few months of life with dystonia or intermittent limb spasticity, axial and truncal hypotonia, oculogyric crises, autonomic symptoms, and ptosis.15 Neonatal symptoms including poor suck and feeding difficulties, ptosis, lethargy, and hypothermia are common. Neurologic signs and symptoms are clearly evident within the first few months of life in all patients reported to date. These patients demonstrate multi-systemic involvement with a wide array of neurologic difficulties including problems with sleep, attention, emotional regulation, and cognitive function that extend well beyond their motor difficulties. As they get older, gross motor delays with fluctuating tone, ataxia and expressive speech impairment are prominent features, even in the patients with the best outcomes.
The phenomenology of the movement disorder is remarkably similar among the cases, and not surprisingly shares a number of features in common with children with BH4 deficiency disorders such as PTS and DHPR deficiency, and the autosomal recessive form of GTP cyclohydrolase deficiency. Intermittent oculogyric crises and limb dystonia, generalized athetosis, and an overall paucity of voluntary movement become evident between 1 to 6 months of age. Tongue thrusting, ocular convergence spasm (figure 2), myoclonic jerks, and episodes of sudden loss of head control or episodes resembling flexor spasms are common, and frequently lead to a clinical diagnosis of epilepsy.
Oculogyric crises, orofacial dystonia, torticollis, limb tremor with attempted voluntary movement, and blepharospasm are often the most compelling evidence supporting a defect in dopaminergic transmission. Breath-holding or apneic spells, paroxysmal sweating, nasal congestion, sudden respiratory or cardiorespiratory arrest, unresponsiveness associated with hypoglycemia, intermittent hypothermia, and feeding and gastrointestinal issues are manifestations of the often profound autonomic dysfunction these patients demonstrate.
CSF neurotransmitter metabolites show a characteristic pattern with low HVA and 5-HIAA, markedly elevated 3-O-methyldopa, 5-hydroxytryptophan and L-dopa, and normal biopterin and neopterin levels. Plasma L-dopa is markedly elevated. Urine catecholamines may be reduced or elevated.
While some children have demonstrated benefit in terms of the underlying movement disorder, treatment is complex, and these patients are vulnerable to an array of medication-related side effects. Instead of replacement of neurotransmitter precursors, as in the BH4 deficiency related disorders, the use of neurotransmitter receptor agonists or strategies to hinder reuptake or metabolism of endogenously produced neurotransmitters is necessary.
Reported benefit has been noted in a subset of patients with monoamine oxidase inhibitors, dopamine receptor agonists, anticholinergic agents, pyridoxine and in rare cases associated with a defect in the AADC gene at the dopa-binding site, L-dopa.19 However, in spite of a variety of treatment interventions directed at ameliorating the effects of the associated neurotransmitter deficiency state, overall clinical outcomes in AADC deficiency remains poor.
All patients reported to date have had some degree of cognitive impairment, and there is increasing evidence of a gender dependent discrepancy in severity, with females demonstrating the most severe phenotypes.
