Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)

Abstract

Pyridoxine-dependent epilepsy was recently shown to be due to mutations in the ALDH7A1 gene, which encodes antiquitin, an enzyme that catalyses the nicotinamide adenine dinucleotide-dependent dehydrogenation of l-α-aminoadipic semialdehyde/l-Δ1-piperideine 6-carboxylate. However, whilst this is a highly treatable disorder, there is general uncertainty about when to consider this diagnosis and how to test for it. This study aimed to evaluate the use of measurement of urine l-α-aminoadipic semialdehyde/creatinine ratio and mutation analysis of ALDH7A1 (antiquitin) in investigation of patients with suspected or clinically proven pyridoxine-dependent epilepsy and to characterize further the phenotypic spectrum of antiquitin deficiency. Urinary l-α-aminoadipic semialdehyde concentration was determined by liquid chromatography tandem mass spectrometry. When this was above the normal range, DNA sequencing of the ALDH7A1 gene was performed. Clinicians were asked to complete questionnaires on clinical, biochemical, magnetic resonance imaging and electroencephalography features of patients. The clinical spectrum of antiquitin deficiency extended from ventriculomegaly detected on foetal ultrasound, through abnormal foetal movements and a multisystem neonatal disorder, to the onset of seizures and autistic features after the first year of life. Our relatively large series suggested that clinical diagnosis of pyridoxine dependent epilepsy can be challenging because: (i) there may be some response to antiepileptic drugs; (ii) in infants with multisystem pathology, the response to pyridoxine may not be instant and obvious; and (iii) structural brain abnormalities may co-exist and be considered sufficient cause of epilepsy, whereas the fits may be a consequence of antiquitin deficiency and are then responsive to pyridoxine. These findings support the use of biochemical and DNA tests for antiquitin deficiency and a clinical trial of pyridoxine in infants and children with epilepsy across a broad range of clinical scenarios.

Seizures Due to a KCNQ2 Mutation: Treatment with Vitamin B6

“…Typically patients present with antiepileptic drug-resistant seizures in the neonatal period that respond dramatically to pyridoxine (PN) and remain seizure-free on this treatment. This metabolic defect has been shown to be due to a deficiency of a-aminoadipic semialdehyde (a-AASA) dehydrogenase, an enzyme on the lysine catabolic pathway (Mills et al 2010). The accumulating upstream metabolite, L-D 1 -piperideine-6-carboxylate (P6C), forms an adduct with pyridoxal 5 0 -phosphate (PLP), the active form of vitamin B 6 , rendering it inactive as a cofactor.…”

Vitamin B6 is essential for serine de novo biosynthesis

“…Glycine levels have also been reported to be slightly raised in the CSF of patients with mutations in PROSC prior to B6-supplementation (Darin et al 2016). In patients with mutations in ALDH7A1, however, CSF glycine levels have been reported to be normal (Hoffmann et al 2007) or just slightly elevated (Mills et al 2010). Interestingly few studies report on serine levels leading us to assume that serine is kept within normal values in the CSF of vitamin B6 deficient patients.…”

Lysine-Restricted Diet as Adjunct Therapy for Pyridoxine-Dependent Epilepsy: The PDE Consortium Consensus Recommendations

“…The Consortium recognizes that, aside from potential neurotoxic damage, the ID seen in PDE could be explained by the role of ATQ in neuronal migration (Jansen et al 2013), as well as the increased rate of fetal distress leading to premature birth and/or associated pathology (Mills et al 2010). Additionally, an association between delay in diagnosis and poor development has been reported (Bok et al 2012).…”

“…The potential neurotoxicity of permanently raised AASA or other metabolites could have a substantial impact on neurodevelopmental outcomes. In a cohort of 32 PDE patients, no clear genotype-phenotype correlation could be established (Mills et al 2010). Lysine restriction should, therefore, be initiated as early as possible in newly diagnosed PDE patients to optimize developmental outcomes, and be maintained over an extended period of time.…”

“…Pyridoxine-dependent epilepsy (PDE, MIM #266100) is an autosomal recessive epileptic encephalopathy characterized by resistance to conventional anti-epileptic drugs but responsiveness to pharmacological dosages of pyridoxine (Mills et al 2010). In 2006, the underlying genetic defect was identified as deficiency of a-aminoadipic semialdehyde dehydrogenase (antiquitin), which is involved in cerebral lysine catabolism (MIM #107323) (Mills et al 2006).…”