Widening Phenotypic Spectrum of AADC Deficiency, a Disorder of Dopamine and Serotonin Synthesis

Abstract

Objectives: Aromatic amino acid decarboxylase deficiency presents with prominent extrapyramidal and autonomic features and CSF monoamine deficiency with increased 3-O-methyldopa, a by-product of accumulated L-DOPA. Less than 100 cases have been identified. The disease is typically associated with a severe phenotype and worse prognosis in females. Gene transfer technology has been implemented using an adeno-associated virus encoding AADC in the putamen bilaterally.

Methods: We describe the phenotype/genotype in a cohort of five cases showing a heterogeneous phenotype and variably intact response to pharmacologic therapy.

Results: Five patients (age range 2–10 years, mean 5 years, 3M/2F) with confirmed AADC deficiency are described. Four (3M/1F) have had improvement on combinations of dopaminergic agonists, MAO inhibitors, pyridoxine/P5P, and folinic acid. Each presented with hypotonia, decreased voluntary movement, dystonia, irritability, and oculogyric crises. Two (1M/1F) are independently ambulatory and are not dependent on gastrostomy tube feedings; the 9-year-old girl is reading single words. One female has a severe phenotype including recurrent hypoglycemic events associated with bradycardia, although the latter have resolved with chronic anticholinergic therapy. One Taiwanese boy had the common homozygous mutation, and otherwise we describe five new DDC mutations.

Conclusions: We report a wider phenotypic spectrum including intact response to pharmacologic management and milder outcome in a female, as well as five new mutations. Four of five patients have improved on combination therapy including a dopamine agonist, MAO inhibitor, pyridoxal-5′-phosphate, and folinic acid. The advent of viral-mediated gene therapy in AADC deficiency renders expanded knowledge of the outcome increasingly important.

Competing interests: None declared

An erratum to this chapter is available at 10.1007/8904_2014_327

An erratum to this chapter can be found at http://dx.doi.org/10.1007/978-3-662-44578-5_344

Appendices

Synopsis

Aromatic amino acid decarboxylase deficiency is a rare disorder with a heterogeneous phenotypic spectrum that must be taken into account in evaluating prospective gene transfer technologies.

Compliance with Ethics Guidelines

The authors, Guy Helman, Maria Belen Pappa, and Phillip Pearl, report no conflicts of interest. All patients were evaluated in good clinical practice. IRB approval was obtained (BCH protocol 3660). Guy Helman was responsible for data review and manuscript preparation and submission. Maria Belen Pappa provided data and manuscript review. Phillip Pearl was responsible for data collection and analysis, manuscript oversight, and ethical conduct oversight.