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 2nd; Johan L K Van Hove; Jost Wigand Richter; Hans Juergen Christen; Renata Gallagher; Hans Hartmann; Sylvia Stockler-Ipsiroglu

doi:10.1016/j.pediatrneurol.2015.12.013

Pyridoxine-Dependent Epilepsy: An Expanding Clinical Spectrum

Pediatr Neurol. 2016 Jun:59:6-12. doi: 10.1016/j.pediatrneurol.2015.12.013. Epub 2016 Jan 11.

Affiliations

¹ 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: cvankarnebeek@cw.bc.ca.
² Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
³ Department of Neurology, St Elisabeth Twee Steden Hospital, Tilburg, The Netherlands.
⁴ Department of Pediatric Neurology, Emma Children's Hospital, University of Amsterdam, AMC, Amsterdam, The Netherlands.
⁵ 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.
⁶ Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado, Aurora, Colorado.
⁷ Department of Pediatrics, Children's Hospital auf der Bult, Hannover, Germany; Department of Neuropediatrics, Children's Hospital auf der Bult, Hannover, Germany.
⁸ Department of Medical Genetics, University of California San Francisco, San Francisco, California.
⁹ Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
¹⁰ 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: sstockler@cw.bc.ca.

PMID: 26995068
DOI: 10.1016/j.pediatrneurol.2015.12.013

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.

Keywords: B6 vitamer; lysine catabolism; metabolic epilepsy; neonatal encephalopathy; seizures; treatment.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Epilepsy / diagnosis
Epilepsy / genetics
Epilepsy / physiopathology*
Epilepsy / therapy
Humans
Phenotype

Supplementary concepts

Pyridoxine-dependent epilepsy