Search for a rare disease
Other search option(s)
Aromatic L-amino acid decarboxylase deficiency
A rare, severe, genetic neurometabolic disorder associated with clinical manifestations related to impaired synthesis of dopamine, noradrenaline, adrenaline and serotonin. Clinical manifestations are typically characterized by early-onset muscular hypotonia, movement disorders (oculogyric crisis, dystonia), developmental delay, ptosis and non-motor symptoms (sleep disturbance, irritability, excessive sweating, and nasal congestion).
ORPHA:35708Classification level: Disorder
The global incidence of aromatic L-amino acid decarboxylase deficiency (AADC) deficiency is unknown. Since the initial description more than 150 patients have been described in the medical literature.
AADC deficiency typically presents in infancy with muscular hypotonia, oculogyric crises, and developmental delay. Thermoregulation disturbances, autonomic dysfunction, sleep disorders, dystonia, nasal congestion, feeding problems and intellectual disability are additional disease features. Age of onset of initial symptoms ranges from neonatal period to 12 months (mean 2-3 months). The majority of published patients have severe phenotype with profound motor developmental impairment while some present mild to moderate phenotype with ability to walk independently and having functional independence in daily activities. It has been suggested that symptoms can evolve with age.
Aromatic L-amino acid decarboxylase (AADC), coded by the DDC gene (7p12.2-p12.1), is the final enzyme in the biosynthesis of the monoamine neurotransmitters serotonin and dopamine; dopamine is the precursor for norepinephrine and epinephrine. Subsequently, AADC enzyme deficiency results in a severe combined deficiency of serotonin, dopamine, norepinephrine and epinephrine.
The diagnosis is established by determination of biogenic amines in cerebrospinal fluid (CSF), enzyme activity essay in plasma and mutational analysis. Additionally, measurement of 3-O-methyldopa (3-OMD) in dried blood spot in new born screening programs is proposed and already implemented in some programs.
AADC deficiency can show clinical symptoms overlapping with other primary disorders of biogenic amines of tetrahydrobiopterin (BH4) metabolism that should be differentiated via biochemical investigation of the CSF in the first step. PNPO (pyridoxamine 5'-phosphate oxidase) deficiency can show a similar biochemical pattern in CSF but presents a different clinical picture.
A biochemical prenatal diagnosis of AADC deficiency might be possible by measuring 3-OMD, 5-HTP and L-Dopa in amniotic fluid or fetal plasma but if both disease-causing genetic variants are known, the most reliable method of prenatal diagnostic approach is genetic analysis of chorionic villi or amniotic fluid cells. This option should be offered to carriers of mutations of AADC deficiency, especially in case of a known index patient.
The pattern if inheritance is autosomal recessive; where both parents are unaffected carriers, there is a 25% risk of transmitting the disease to offspring. Genetic counseling about inheritance, risk of reoccurrence and disease is very important for affected families.
Management and treatment
The treatment of AADC deficiency is challenging since symptoms are refractory particularly in severe cases. A complex treatment regimen including dopamine agonists, monoamine oxidase inhibitors, pyridoxine phosphate, anticholinergic and antiepileptic drugs are required. Various supportive therapeutic approaches (physiotherapy, speech therapy) are recommended. In clinical trials, gene therapy has demonstrated clinical improvement (reduced frequency of oculogyric crises, weight recovery, and improvement in the ability to sit, walk, and talk over a five-year period). The treatment is pending approval in Europe.
The prognosis mainly depends on the disease severity. There is no clear genotype-phenotype correlation but some mutations are associated with severe phenotype. It has been described that there is a significant childhood mortality risk for patients with severe disease course.
- Clinical practice guidelines
- English (2017)