Pyridoxine-Dependent Epilepsy: An Expanding Clinical Spectrum.

Clara D M van Karnebeek, Sylvia A Tiebout, Jikkemien Niermeijer, Bwee Tien Poll-The, Aisha Ghani, Curtis R Coughlin, Johan L K Van Hove, Jost Wigand Richter, Hans Juergen Christen, Renata Gallagher, Hans Hartmann, Sylvia Stockler-Ipsiroglu

Journal: Pediatric neurology 2017;59():6-12

PMID: 26995068

Full Text on Elsevier Science View on PubMed

Abstract

BACKGROUND

Pyridoxine-dependent epilepsy is a rare autosomal recessive epileptic encephalopathy caused by antiquitin (ALDH7A1) deficiency. In spite of adequate seizure control, 75% of patients suffer intellectual developmental disability. Antiquitin deficiency affects lysine catabolism resulting in accumulation of α-aminoadipic semialdehyde/pyrroline 6' carboxylate and pipecolic acid. Beside neonatal refractory epileptic encephalopathy, numerous neurological manifestations and metabolic/biochemical findings have been reported.

METHODS AND RESULTS

We present a phenotypic spectrum of antiquitin deficiency based on a literature review (2006 to 2015) of reports (n = 49) describing the clinical presentation of confirmed patients (n > 200) and a further six patient vignettes. Possible presentations include perinatal asphyxia; neonatal withdrawal syndrome; sepsis; enterocolitis; hypoglycemia; neuroimaging abnormalities (corpus callosum and cerebellar abnormalities, hemorrhage, white matter lesions); biochemical abnormalities (lactic acidosis, electrolyte disturbances, neurotransmitter abnormalities); and seizure response to pyridoxine, pyridoxal-phosphate, and folinic acid dietary interventions.

DISCUSSION

The phenotypic spectrum of pyridoxine-dependent epilepsy is wide, including a myriad of neurological and systemic symptoms. Its hallmark feature is refractory seizures during the first year of life. Given its amenability to treatment with lysine-lowering strategies in addition to pyridoxine supplementation for optimal seizure control and developmental outcomes, early diagnosis of pyridoxine-dependent epilepsy is essential. All infants presenting with unexplained seizures should be screened for antiquitin deficiency by determination of α-aminoadipic semialdehyde/pyrroline 6' carboxylate (in urine, plasma or cerebrospinal fluid) and ALDH7A1 molecular analysis.

Address: Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada; Treatable Intellectual Disability Endeavor in British Columbia (TIDE-BC), Vancouver, British Columbia, Canada. Electronic address: [email protected].; Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.; Department of Neurology, St Elisabeth Twee Steden Hospital, Tilburg, The Netherlands.; Department of Pediatric Neurology, Emma Children's Hospital, University of Amsterdam, AMC, Amsterdam, The Netherlands.; Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Treatable Intellectual Disability Endeavor in British Columbia (TIDE-BC), Vancouver, British Columbia, Canada.; Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, Colorado.; Department of Pediatrics, Children's Hospital auf der Bult, Hannover, Germany; Department of Neuropediatrics, Children's Hospital auf der Bult, Hannover, Germany.; Department of Medical Genetics, University of California San Francisco, San Francisco, California.; Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.; Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada; Treatable Intellectual Disability Endeavor in British Columbia (TIDE-BC), Vancouver, British Columbia, Canada. Electronic address: [email protected].

DOI: 10.1016/j.pediatrneurol.2015.12.013