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  • Updated 09.08.2020
  • Released 11.28.1994
  • Expires For CME 09.08.2023

Aromatic L-amino acid decarboxylase deficiency

Introduction

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 developmental delay, hypokinesia, truncal muscular hypotonia, often combined with limb rigidity, a progressive extrapyramidal movement disorder, especially parkinsonism-dystonia and chorea, oculogyric crises, as well as autonomic symptoms. 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. Adeno-associated virus vector-mediated gene delivery of the dopa decarboxylase (DCC) gene bilaterally into the putamen of individuals with aromatic L-amino acid decarboxylase deficiency demonstrated safety and efficacy in first affected children. Two further clinical trials of gene therapy confirmed the promising results. It is to be hoped that with early detection by newborn screening and followed by optimized therapy (ie, gene therapy), the outlook of this often-devastating disorder will be changed.

The International Working Group on Neurotransmitter related Disorders has been instrumental in these positive developments and hopefully the next breakthroughs will be the first international, longitudinal patient registry and evidence-based guidelines for diagnosis and treatment (http://www.intd-online.org).

An international support group, the AADC Research Trust Children’s Charity, a nonprofit organization, has also 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 severe developmental and neurologic dysfunction. It should be considered in infants and children with features suggestive of dystonic or athetoid cerebral palsy, hypotonia, developmental delay, and autonomic symptoms of unknown etiology.

• Aromatic L-amino acid decarboxylase deficiency leads to severe deficiency of serotonin as well as all catecholamines.

• Diagnosis relies on the measurement of neurotransmitters in CSF.

• Aromatic L-amino acid decarboxylase deficiency is inherited in an autosomal recessive manner, and some genotype-phenotype correlations have been described.

• Gene therapy is showing promising results.

Historical note and terminology

For many years, disorders leading to severe deficiencies of biogenic amines (serotonin, dopamine, epinephrine, and norepinephrine) in infants and children were exclusively associated with biochemical defects of tetrahydrobiopterin metabolism (35). 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 80 different pathogenic mutations have been published: http://www.biopku.org.

In 1988, monozygotic twins presented at the Hospital for Sick Children, Great Ormond Street, London, with the neurologic symptoms of biogenic amine deficiency, reminiscent of defects of tetrahydrobiopterin metabolism. Central and peripheral neurotransmitter deficiency was confirmed, but the children were not hyperphenylalaninemic, nor did they have any abnormality of tetrahydrobiopterin metabolism. The 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. These reactions are catalyzed by a single enzyme, aromatic L-amino acid decarboxylase (28). 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 liver biopsy (20; 22).

Since the initial description of aromatic L-amino acid decarboxylase deficiency, about 200 cases have been tabulated in a database of pediatric neurotransmitter disorders (http://www.biopku.org) (16; 08), and several reviews have been published (37; 30; 08; 17). Additional patients are known, and it is most likely that many more cases exist, but diagnosis has not been made because of the absence of easily recognized markers in normal metabolic evaluations.

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