PDE — Pyridoxine dependent epilepsy and antiquitin deficiency

Pyridoxine dependent epilepsy (PDE) (MIM#266100) is an autosomal recessive epileptic encephalopathy characterized by a therapeutic response to pharmacological dosages of vitamin B6 and resistance to conventional antiepileptic treatment. PDE was first described in 1954 in an infant with therapy-resistant seizures who showed prompt cessation of seizures after the administration of a multivitamin cocktail containing vitamin B6 [1]. Since then, over 200 patients have been described in the literature.

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.
 Research study for patients with PDE or GA I 
We are recruiting patients and families for the CHARLIE metabolism Project (CHAnging Rare disorder of LysINe metabolism). This is an international collaboration focused on developing novel therapies for patients with pyridoxine-dependent epilepsy (PDE) and glutaric aciduria type I (GA I).  Both substrate reduction therapy (an upstream block of lysine metabolism) and gene replacement therapy will be trialed in model systems such as neuronal stem cells, mouse, and zebrafish models.  The CHARLIE project is led by Professor Clara van Karnebeek at the University of Amsterdam UMC in the Netherlands. 
Although this is a basic-research focused project, we also want to work closely with patients and families in order to describe the needs and wishes of families and to define goals of care that are essential to improve quality of life. This project (referred to as “patients in the lead”) is led by Hanna Dekker who is the director of the VKS (a Dutch patient support organization).  https://www.stofwisselingsziekten.nl/
If you are interested in more information or in participating, please contact Dr. Curtis Coughlin II at the University of Colorado (Curtis.Coughlin@cuanschutz.edu, 303.724.3839)


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