Aromatic L-amino acid decarboxylase deficiency: a systematic review

Abstract

Aim: To gain greater knowledge regarding the natural history of aromatic L-amino acid decarboxylase (AADC) deficiency, a genetic disorder that causes severe deficits in motor and cognitive development. Materials & methods: A systematic literature review was performed of all case reports and clinical studies published through December 2019 of patients with AADC deficiency. The data were summarized descriptively. Results: The search identified 94 publications that described 237 unique patients. Mean (standard deviation) age at diagnosis was 3.2 (±5.7) years and 16 deaths were reported. Most patients (57%) received the standard of care therapies, which showed limited efficacy in this patient population. Conclusion: AADC deficiency is a devastating disease and prospectively defined natural history studies are warranted to further understand this disease.

Clinical Features in Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: A Systematic Review

“…An improvement in vitamin B6 was reported only in 38% of patients. This literature review thus confirms previous knowledge that drug treatment is not satisfactory, that response to medications is better in mild-to-moderate compared to severe cases, and that dopamine agonists and MAO inhibitors show better results than vitamin B6 [ 8 , 18 , 55 , 56 ]. Adeno-associated viral vector-mediated (AAV2) gene transfer of the human AADC gene into the putamina was performed for the first time in 2012 [ 57 ].…”

“…Adeno-associated viral vector-mediated (AAV2) gene transfer of the human AADC gene into the putamina was performed for the first time in 2012 [ 57 ]. All patients undergoing gene therapy, 4% of this review population, improved cognitive and motor performances [ 7 , 55 ]. Motor improvements were also reported in the 10 patients described by Chien and colleagues; however, they were not included in this database due to their nontraceability [ 12 ].…”

Patient selection considerations for AADC deficiency gene therapy

“…1,2,6,7 Impaired monoamine neurotransmitter synthesis caused by AADC deficiency generally manifests as global motor and intellectual disabilities, orthopedic and cardiopulmonary sequelae, and premature death. 2,6,[8][9][10] Reductions in dopamine are associated with abnormal motor control and regulation (e.g., movement disorders such as hypotonia, dystonia, and oculogyric crisis [OGC]), cognitive function, emotional regulation, and endocrine-mediated functions. 6 Autonomic nervous system symptoms in AADC deficiency may also arise, owing to impaired epinephrine and norepinephrine synthesis consequent to reduced dopamine levels 6 ; these symptoms include ptosis, hyperhidrosis, temperature dysregulation, hypoglycemia, gastrointestinal symptoms, and cardiopulmonary dysregulation.…”

“…6,11 The symptomatic presentation of AADC deficiency is varied; whereas some patients may have subtle clinical presentations, others have profound impairment. 2,8,[12][13][14][15] Until recently, treatment options for AADC deficiency offered partial symptomatic improvement either by maintaining existing monoamine levels through catabolic inhibition or by mimicking endogenous monoaminemediated signal effects with receptor agonists. 2,10,11 However, these treatments are of limited efficacy in many patients and do not address the underlying cause of the disease.…”

“…Impaired monoamine neurotransmitter synthesis caused by AADC deficiency generally manifests as global motor and intellectual disabilities, orthopedic and cardiopulmonary sequelae, and premature death 2,6,8–10 . Reductions in dopamine are associated with abnormal motor control and regulation (e.g., movement disorders such as hypotonia, dystonia, and oculogyric crisis [OGC]), cognitive function, emotional regulation, and endocrine‐mediated functions 6 .…”