Abstract
Pyridoxine monotherapy in PDE-ALDH7A1 often results in adequate seizure control, but neurodevelopmental outcome varies. Detailed long-term neurological outcome is unknown. Here we present the cognitive and neurological features of the Dutch PDE-ALDH7A1 cohort. Neurological outcome was assessed in 24 patients (age 1-26 years); classified as normal, complex minor neurological dysfunction (complex MND) or abnormal. Intelligence quotient (IQ) was derived from standardized IQ tests with five severity levels of intellectual disability (ID). MRI's and treatments were assessed. Ten patients (42%) showed unremarkable neurological examination, 11 (46%) complex MND, and 3 (12%) cerebral palsy (CP). Minor coordination problems were identified in 17 (71%), fine motor disability in 11 (46%), posture/muscle tone deviancies in 11 (46%) and abnormal reflexes in 8 (33%). Six patients (25%) had an IQ>85, 7 (29%) borderline, 7 (29%) mild, 3 (13%) moderate, and 1 severe ID. Cerebral ventriculomegaly on MRI was progressive in 11. Three patients showed normal neurologic exam, IQ, and MRI. Eleven patients were treated with pyridoxine only and 13 by additional lysine reduction therapy (LRT). LRT started at age <3 years demonstrated beneficial effect on IQ results in 3 patients. Complex MND and CP occurred more frequently in PDE-ALDH7A1 (46% and 12%) than in general population (7% and 0.2%, Peters et al., 2011, Schaefer et al., 2008). Twenty-five percent had a normal IQ. Although LRT shows potential to improve outcomes, data are heterogeneous in small patient numbers. More research with longer follow-up via the International PDE Registry (www.pdeonline.org) is needed.
Highlights
Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a rare epileptic encephalopathy
In the Netherlands, 28 patients with PDE-ALDH7A1 were born between January 1991 and January 2018
We propose three possible explanations here: a) Inactivation of pyridoxal 50-phosphate (PLP) leading to a pyridoxine deficiency [15]: Pyridoxine is a cofactor to >160 enzymes, most in the CNS, required for the biosynthesis of several neurotransmitters, including dopamine, which is of importance via the nigrostriatal circuitry for the coordination of movements [41,42]
Summary
Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a rare epileptic encephalopathy. Recent estimated incidence based on international genomic data is 1:64.352 births [1]. In the Netherlands, the estimated incidence is around 1:276.000, primarily based on clinical criteria This would mean that every three years, two children in the Netherlands are born with PDE-ALDH7A1 [2]. Pyridoxine monotherapy in PDE-ALDH7A1 often results in adequate seizure control, but neurodevelopmental outcome varies. We present the cognitive and neurological features of the Dutch PDE-ALDH7A1 cohort. Methods: Neurological outcome was assessed in 24 patients (age 1e26 years); classified as normal, complex minor neurological dysfunction (complex MND) or abnormal. Results: Ten patients (42%) showed unremarkable neurological examination, 11 (46%) complex MND, and 3 (12%) cerebral palsy (CP). Three patients showed normal neurologic exam, IQ, and MRI.
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