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-alpha-aminoadipic semialdehyde/L-Delta1-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-alpha-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-alpha-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.

Figure 1

Analysis of urinary α-AASA for patients with mutations in ALDH7A1 and age-matched controls. Number of controls measured: age <6 months = 95; age 6–12 months = 61; age >12 months = 93. Patient F2 had two measurements of urinary α-AASA while under 6 months of age and Patient F16 had α-AASA measured once when <6 months and once when 6–12 months of age.

Figure 2

Urinary α-AASA concentrations of controls. All of these controls were measured in the laboratory in London. Number of controls measured: age <6 months =  95; age 6–12 months =  61; age >12 months = 93. Solid line represents the mean. Dotted line indicates the lowest measurement of α-AASA in age-related patients with PDE in whom at least one mutation in ALDH7A1 has been demonstrated. Using the Dunn’s multiple comparison test, the three control groups are found to be significantly different from each other (P < 0.001). The asterisk indicates that Patient F19 had a urine excretion <2 but was measured in the laboratory in Amsterdam and we have found one ALDH7A1 mutation (see Supplementary material).