The corpus callosum is the largest white matter bundle and plays a crucial role in the interhemispheric transfer of information from associative cortices to coordinate and integrate bilateral functionality for diverse motor and cognitive functions. Excitation and inhibition are the basic physiological effects. The corpus callosum increases with age and shows age-dependent, region-specific growth. Developmental defects of the corpus callosum are frequently encountered in individuals with inborn errors of metabolism.
In pyridoxine-dependent epilepsy (PDE), corpus callosum thinning and other developmental defects of the nervous system have been reported in several case reports. Friedman et al. systematically evaluated the magnetic resonance imaging features and the corpus callosum morphology in a wide age range (birth to 48y) of individuals with PDE. The authors demonstrate a consistent reduction in the size of the posterior callosum in the youngest and a progressive reduction of the other corpus callosum regions in the older individuals.
The pathological mechanism behind this progressive reduction of corpus callosum regions is unknown. Various prenatal brain abnormalities have been reported in individuals with PDE and have been shown in 17 of 30 study participants. The early disturbance of the brain development might have a secondary impact on the later corpus callosum development. Delayed pyridoxine treatment does not play a significant role as shown in the study. An ongoing disease, as supposed by the authors, seems quite possible with respect to the genetic background and untreated abnormal lysine metabolism. Recently, Jansen et al. found a reduced antiquitin protein expression and an accumulation of α-aminoadipic semialdehyde (α-AASA), Δ1-piperideine-6-carboxylate (P6C), and pipecolic acid in the brain of a patient with PDE. According to the authors, accumulation of toxic metabolites, lack of other critical activities of antiquitin, and dysfunction of pyridoxal phosphate dependent enzymes could be the causes of the abnormal brain morphology in PDE.
The aim of pyridoxine treatment is to compensate the pyridoxal phosphate deficiency caused by condensation with P6C. Pyridoxal phosphate is the biologically active form of pyridoxine and a cofactor for more than 140 enzymatic activities and essential for the formation of several neurotransmitters. Insufficient availability of pyridoxal phosphate can impair the cell-to-cell signalling, which could result in abnormal corpus callosum development. A pyridoxine dosage oriented on suppression of seizures might not be sufficient to compensate the whole spectrum of P6C-induced pyridoxal phosphate deficiency. In addition, pyridoxine treatment has a limited influence on the elevations of α-AASA and P6C and does not prevent accumulation of α-AASA, P6C, and pipecolic acid in the brain.
Several studies on abnormal corpus callosum development indicate a relationship between the extent of the corpus callosum abnormalities and cognitive deficits. In the study of Friedman et al. the cognitive status of their patients is not reported and further studies are needed to determine the relationship between corpus callosum abnormalities and clinical parameters in individuals with PDE. Neurodevelopmental disabilities are regularly seen in PDE, even when treatment was started early and the individuals are seizure free.
The important question is: can we influence cognition and corpus callosum development by better treatment? In an early study by Baxter et al. a better intellectual performance in seizure-free participants with PDE was achieved when the pyridoxine dose was increased. The optimal dosage is still a matter of debate and limited by potential side effects of pyridoxine. Usually the pyridoxine dose (15–30mg/kg/d) is orientated on the suppression of seizures and up to now we have no biochemical parameter as a reference point for an optimal pyridoxine dose. Lysine restricted diet seems to be another promising approach to reduce the potentially toxic lysine metabolites and to improve developmental outcome.