Aromatic L-amino acid decarboxylase deficiency

Georg F Hoffmann MD (Dr. Hoffmann of the University Center for Child and Adolescent Medicine in Heidelberg has no relevant financial relationships to disclose.)
Barry Wolf MD PhD, editor. (Dr. Wolf of Henry Ford Hospital has no relevant financial relationships to disclose.)
Originally released November 28, 1994; last updated October 1, 2015; expires October 1, 2018

This article includes discussion of aromatic L-amino acid decarboxylase deficiency, AADC deficiency, L-dopa decarboxylase deficiency, and 5-hydroxytryptophan decarboxylase deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Aromatic L-amino acid decarboxylase (AADC) deficiency was identified as an autosomal recessively inherited disorder of biogenic amine metabolism resulting in combined generalized deficiency of serotonin and all catecholamines. The main clinical features are progressive developmental delay, hypokinesia, truncal muscular hypotonia, often combined with limb rigidity, a progressive extrapyramidal movement disorder, especially parkinsonism-dystonia and chorea, and oculogyric crises. Because the products of the defective enzyme cannot pass through the blood-brain barrier, aromatic L-amino acid decarboxylase deficiency is 1 of the most difficult neurotransmitter disorders to treat. Gene therapy may provide a superior means of treatment in addition to current pharmaceutical interventions. Adeno-associated virus vector-mediated gene delivery of aromatic L-amino acid decarboxylase into the putamen of individuals with Parkinson disease initially demonstrated the safety and efficacy of this form of therapy in 4 affected children.

An international support group, the AADC Research Trust Children's Charity, has been established as a nonprofit organization that has been instrumental in helping to provide information and linking families and professionals involved in diagnosis, care, and research. The association's board of directors and medical and scientific advisory board reviews contents, resources, and medical information posted on the website located at http://www.aadcresearch.org.

Key points

 

• Aromatic L-amino acid decarboxylase deficiency presents with progressive developmental and severe neurologic dysfunction.

 

• Aromatic L-amino acid decarboxylase deficiency is inherited in an autosomal recessive manner.

 

• Aromatic L-amino acid decarboxylase deficiency leads to severe deficiency of serotonin and catecholamine neurotransmitters.

 

• Diagnosis relies on the measurement of neurotransmitters in CSF.

 

• Gene therapy may provide a means of treating aromatic L-amino acid decarboxylase deficiency.

Historical note and terminology

Disorders leading to severe deficiencies of biogenic amines (essentially, serotonin, dopamine, and norepinephrine) in infants and children were for many years exclusively associated with biochemical defects of tetrahydrobiopterin metabolism (Opladen et al 2012). Tetrahydrobiopterin is the cofactor for tyrosine hydroxylase and tryptophan hydroxylase, the rate-limiting enzymes required for dopamine and serotonin biosynthesis. Fortunately, children with these disorders are often detected early because tetrahydrobiopterin is also the cofactor for phenylalanine hydroxylase, which causes hyperphenylalaninemia and is detected in newborn screening programs. The next step in the biosynthesis is the decarboxylation by aromatic L-amino acid decarboxylase encoded by the DDC gene. Autosomal recessively inherited mutations in the DDC gene impair the synthesis of both serotonin and the catecholamines. Over 50 different pathogenic mutations have been published: http://www.biopku.org.

In 1988, monozygotic twins presented at the Hospital for Sick Children, Great Ormond Street in London, with the neurologic symptoms of biogenic amine deficiency. A central and peripheral neurotransmitter deficiency was confirmed, but the children were not hyperphenylalaninemic, nor did they have any abnormality of tetrahydrobiopterin metabolism. The next step after tyrosine hydroxylase and tryptophan hydroxylase in the biosynthetic pathway for dopamine and serotonin is common to both pathways and involves the vitamin B6 (pyridoxal 5'-phosphate) dependent decarboxylation of levodopa and 5-hydroxytryptophan to form dopamine and serotonin, respectively. The reactions are catalyzed by a single enzyme, aromatic L-amino acid decarboxylase (Lovenberg et al 1962). This enzyme is often named according to the substrate being metabolized (ie, levodopa decarboxylase or 5-hydroxytryptophan decarboxylase). Confirmation of a deficiency of the enzyme in the twins was established by measurement of levodopa decarboxylase activity in plasma and levodopa and 5-hydroxytryptophan decarboxylase activity in a liver biopsy (Hyland and Clayton 1990; Hyland et al 1992).

Since the initial description of aromatic L-amino acid decarboxylase deficiency, over 100 cases have been tabulated in a database of pediatric neurotransmitter disorders (http://www.biopku.org) (Haavik et al 2008; Brun et al 2010), and several reviews have been published (Swoboda et al 2003; Pons et al 2004; Manegold et al 2009; Brun et al 2010). It is likely that many other cases exist, but diagnosis has not been made because of the absence of easily recognized markers in normal metabolic evaluations.

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