(PDE) Pyridoxine dependent epilepsy and antiquitin deficiency

Disorder Overview

The underlying genetic defect remained unknown for a long time and diagnosis was limited to the demonstration of seizure remission and relapse after a controlled trial of pyridoxine administration and withdrawal [2]. Due to the lack of a biological diagnostic marker, diagnosis may have been missed in many cases. The variation in diagnostic hits is reflected in the considerable heterogeneity of published prevalence data, ranging from 1:20.000 in a German center with a pyridoxine trial routinely performed in all patients with epileptic encephalopathy, [3] to 1:400.000 in a survey focusing on diagnosed cases in Dutch neuropediatric clinics, [4] and 1:600.000 in the UK [5]. In a hospital based study 7.4% (6 out of 81) children with intractable seizures below 3 years of age, showed a clear response to pyridoxine [6]. Notably, despite the clear response of seizures to high dosages of vitamin B6, patients with PDE do not have biochemical evidence of vitamin B6 deficiency [7,8].

For a long time deficiency of glutamic acid decarboxylase (GAD), catalyzing the conversion of glutamate to GABA and requiring vitamin B6 (pyridoxal-phosphate) as cofactor, was considered the underlying cause of PDE [9]. However, conflicting results of glutamate and GABA studies in CSF [8,10,11] and negative linkage studies to the two GAD isoforms in the brain (Gad1 and Gad2) [12,13] made clear that GAD deficiency is not the primary cause of PDE. Following the description of pipecolic acid as a first diagnostic marker of PDE [14] mutations in the gene for α-aminoadipicsemialdehyde dehydrogenase and resultant enzyme deficiency were identified as the major underlying genetic cause of PDE [15]. Since then this association has been confirmed in numerous cases ascertained clinically with PDE [16–27]. α-Aminoadipic-semialdehyde dehydrogenase (also known as ALDH7A1 or antiquitin, ATQ) is encoded by the ALDH7A1 or ATQ gene, and its function lies in the catabolism of lysine.

The direct link to amino acid metabolism provides new insights into the pathophysiology of PDE and clues for improved diagnostic and therapeutic options for this condition. We reviewed the current state and new developments in diagnosis and treatment of PDE and ATQ deficiency. This article provides an overview of the current knowledge of clinical, biochemical, and molecular genetic characteristics of ATQ deficiency and summarizes recommendations for diagnosis and management.