NORD gratefully acknowledges Sidney M Gospe, Jr, MD, PhD, Herman and Faye Sarkowsky Endowed Chair Emeritus of Child Neurology, Professor Emeritus of Neurology and Pediatrics, University of Washington School of Medicine, for assistance in the preparation of this report.
Patients with the classic neonatal PDE experience seizures soon after birth. In retrospect, many mothers describe rhythmic movements in the uterus (womb) that may start in the late second trimester and which likely represent fetal seizures. Affected neonates frequently have periods of irritability, unusual eye and facial movements, fluctuating tone, and poor feeding (encephalopathy) that precede the onset of clinical seizures. Abnormal Apgar scores (which measure heart rate, respiration, muscle tone, reflex irritability and color at birth plus one minute and at birth plus five minutes) and cord blood gases may also be seen. Under such conditions, it is not uncommon for these infants to be diagnosed initially as laboring under insufficient oxygen with consequent damage to the nervous system. Similar periods of encephalopathy may be seen in older infants with PDE, particularly prior to the onset of a recurrence of clinical seizures. Pyridoxine-treated patients who have been lax in taking their medicine (non-compliant) or those patients whose daily vitamin requirement may have increased due to growth or an intercurrent infection (particularly fever or gastroenteritis) may also experience recurrent seizures.
Many atypical presentations of PDE have been described. These include late onset seizures (up to two years of age, and in very rare instances into adolescence), seizures which initially respond to anticonvulsant drugs and then become intractable, seizures during early life which do not respond to pyridoxine but which then come under control with pyridoxine several months later, and patients with prolonged seizure-free intervals (up to 5.5 months) which occur after discontinuing pyridoxine.
Patients with PDE may have various types of clinical seizures. While dramatic presentations consisting of prolonged seizures and/or recurrent episodes of shorter seizures associated with a long-lasting loss of consciousness (status epilepticus) are considered to be the typical feature of affected individuals, PDE patients may also have recurrent self-limited events including partial seizures, generalized seizures, atonic seizures, myoclonic events and infantile spasms. On EEG, patients with PDE may also have electrographic seizures without clinical correlates.
A variable degree of intellectual disability is common in these patients. Patients whose seizures appear earlier in life are more likely to show diminished cognitive function. Some clinical reports conclude that the length of the delay in diagnosis and initiation of effective pyridoxine treatment may be related to increased handicaps. Future cognitive function is also likely related to the type of genetic mutation underlying PDE in a particular patient, as well as any associated abnormalities in brain development. Few formal psychometric assessments in patients with PDE have been performed. The limited studies performed to date indicate that in these patients verbal intellectual function is more impaired than non-verbal skills. While significant neurodevelopmental disabilities and psychiatric disorders may be present in some PDE patients, it is important that parents know that patients with PDE may have normal intellectual function.
Mutations in the antiquitin gene (ALDH7A1) were identified in 2006 as the cause of PDE. Antiquitin is an enzyme that plays a role in the metabolism of lysine, an amino acid. Abnormal function of antiquitin secondarily results in elevations of the chemical alpha-aminoadipic semialdehyde (α-AASA) which leads to reduced activity of several enzymes in the brain that regulate the transmission of signals between neurons as well as brain development.
PDE is a familial (genetic) disorder that follows autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
All individuals carry 4- 5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
PDE is considered to be a rare disease, and only a few epidemiologic studies have been published. For example, a study from the United Kingdom and the Republic of Ireland reported a point prevalence of 1:687,000 for definite and probable cases of PDE, while a survey conducted in the Netherlands reported an estimated birth incidence of 1:396,000. PDE is quite likely under-diagnosed and a higher birth incidence is suspected. This notion is supported by a study from a German center where pyridoxine administration is part of a standard treatment protocol for neonatal seizures and a birth incidence of probable cases of 1:20,000 was reported. Recently, an international genetics study of 185 PDE subjects together with the analysis of population-based genomic databases concluded that the birth incidence of PDE is approximately 1:64,000 live births.
Until the third year of life, PDE must be considered as a possible cause of intractable seizures in any patient. In particular, this diagnosis needs to be investigated in any newborn (neonate) with encephalopathy and seizures when there is no convincing evidence of oxygen deprivation, brain hemorrhage, other identifiable underlying metabolic disturbance or brain malformation. PDE must also be suspected in all young patients with intractable seizures with a history of a similar disorder in a sibling. Prior to the discovery of the abnormal gene and biochemical markers, the diagnosis could only be made on a clinical basis by observing over the course of days to weeks a patient’s response to pyridoxine therapy. Importantly, there are no definitive EEG or imaging features that will confirm a diagnosis of PDE. A clinical diagnosis may be made on an acute basis in patients experiencing prolonged or very frequent seizures by administering 100 mg of pyridoxine intravenously while monitoring the EEG, oxygen saturation and vital signs. In most patients with PDE, clinical seizures will cease and a corresponding change in the EEG will be noted. If a response is not demonstrated, the dose should be repeated up to a maximum of 500 mg. In some patients with PDE, significant neurologic and cardiorespiratory adverse effects followed this trial; therefore, close systemic monitoring is essential. For patients who are experiencing shorter seizures which occur at least daily, the diagnosis can be made by administering 30 mg/kg/day of pyridoxine orally. Patients with PDE who are treated in this fashion should stop having clinical seizures within a week. In either case, to confirm the diagnosis of PDE, a patient whose seizures stop after the use of pyridoxine should have blood or urine tested for α-AASA, or a test of the ALDH7A1 gene. With the development of multi-gene “epilepsy panels” and whole exome sequencing, PDE may be an unanticipated diagnosis in patients with intractable epilepsy and its discovery should lead to an immediate change in management.
While the effective treatment of patients with PDE requires lifelong pharmacologic supplements of pyridoxine, given the rarity of this disorder there have been no controlled studies to determine the optimal dose. The RDA for pyridoxine is 0.5 mg for infants and 2 mg for adults. Patients with PDE generally have had excellent seizure control when treated with 50 – 100 mg of pyridoxine per day; some patients may be controlled on much smaller doses while others need higher doses. Some recent studies suggest that higher doses may enhance the intellectual development of these patients, and a dose of 15 – 30 mg/kg/day may be optimal. Particular patients with PDE who have associated abnormalities in brain development such as hydrocephalus or heterotopia (forms of birth defects in brain structure) may not have all of their seizures controlled with pyridoxine alone, and these patients require the use of one or more anticonvulsant drugs. However, the excessive use of pyridoxine must be avoided, as pyridoxine may damage the peripheral nervous system (neurotoxicity) manifesting as a reversible sensory neuropathy. While pyridoxine neurotoxicity has been reported primarily in adults who received “mega-vitamin therapy”, one adolescent with possible PDE who received 2 grams of pyridoxine per day has been reported with a non-disabling sensory neuropathy. Therefore, it is recommended that doses remain in the 15 – 30 mg/kg/day range, not exceed 500 mg per day.
Physicians interested in obtaining clinical and/or therapeutic information on pyridoxine-dependent epilepsy may wish to contact:
Sidney M. Gospe, Jr, MD, PhD
Professor Emeritus of Neurology and Pediatrics
University of Washington
e-mail: [email protected]
Physicians and patients interested in obtaining additional information regarding the management of pyridoxine-dependent epilepsy and current clinical research may contact the PDE Consortium:
Daily supplementation with pharmacologic doses of pyridoxine is the accepted treatment for this disorder. Cases of intractable seizures that did not respond to pyridoxine but did respond to P5P have been reported, and these were found to be due to a different genetic disorder (PNPO deficiency). While pyridoxal phosphate will also treat PDE, clinical research is required to determine the safety and effectiveness of treatment of PDE with pyridoxal phosphate.
As antiquitin is involved in the metabolism of the amino acid lysine, it has been suggested that dietary therapy designed to limit the amount of lysine consumed by a PDE patient may be beneficial. A small number of PDE patients treated with a “lysine restricted diet” have been reported in the medical literature and have shown improved developmental outcomes in response to this experimental therapy. The lysine-restricted diet has not yet been formally studied in a rigorous fashion. Another method of reducing lysine consumption is to supplement the diet of PDE patients with the amino acid L-arginine. The clinical response of a small number of PDE patients treated in this fashion has been reported in the medical literature. While research focused on these dietary therapies continues, the International PDE Consortium now recommends that all newborns and infants with PDE should be treated with lysine reduction therapies and that this form of therapy should be considered in certain older PDE patients. Parents of patients with PDE who would like to have their child treated with either of these special medical diets should consult a biochemical geneticist or other specialist in metabolic disorders.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
REVIEW ARTICLES and EXPERT CONSENSUS GUIDELINES
Coughlin CR 2nd, Tseng LA, Abdenur JE, et al. Consensus guidelines for the diagnosis and management of pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency. J Inherit Metab Dis. 2020 Nov 16. doi: 10.1002/jimd.12332. Epub ahead of print. PMID: 33200442.
van Karnebeek CD, Tiebout SA, Niermeijer J, et al. Pyridoxine-Dependent Epilepsy: An Expanding Clinical Spectrum. Pediatr Neurol. 2016;59:6-12
Alghamdi M, Bashiri FA, Abdelhakim M, et al. Phenotypic and molecular spectrum of pyridoxamine-5′-phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine-5′-phosphate oxidase deficiency. Clin Genet. 2021;99:99-110.
Coughlin CR 2nd, Swanson MA, Spector E, et al. The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: A common epileptic encephalopathy. J Inherit Metab Dis. 2019;42:353-361.
Johnstone DL, Al-Shekaili HH, Tarailo-Graovac M, et al. PLPHP deficiency: clinical, genetic, biochemical, and mechanistic insights. Brain. 2019;142:542-559.
de Rooy RLP, Halbertsma FJ, Struijs EA, et al. Pyridoxine dependent epilepsy: Is late onset a predictor for favorable outcome? Eur J Paediatr Neurol. 2018;22:662-666.
Coughlin CR, 2nd, van Karnebeek CD, Al-Hertani W, et al. Triple therapy with pyridoxine, arginine supplementation and dietary lysine restriction in pyridoxine-dependent epilepsy: Neurodevelopmental outcome. Mol Genet Metab. 2015;116:35-43.
Mercimek-Mahmutoglu S, Cordeiro D, Cruz V, et al. Novel therapy for pyridoxine dependent epilepsy due to ALDH7A1 genetic defect: L-arginine supplementation alternative to lysine-restricted diet. Eur J Paediatr Neurol. 2014;18:741-6.
van Karnebeek CD, Stockler-Ipsiroglu S, Jaggumantri S, et al. Lysine-restricted diet as adjunct therapy for pyridoxine-dependent epilepsy: The PDE Consortium consensus recommendations. JIMD Reports. 2014;15:1-11.
van Karnebeek, CDM, Hartmann, H, Jaggumantri, S, et al. Lysine-restricted diet for pyridoxine-dependent epilepsy: First evidence and future trials. Mol Genet Metab. 2012;107:335-344.
Scharer G, Brocker C, Vasiliou V, et al. The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1. J Inherit Metab Dis. 2010;33:571-581.
Mills PB, Footitt EJ, Mills KA, et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain. 2010;133:2148-2159.
Basura GJ, Hagland SP, Wiltse AM, et al. Clinical features and the management of pyridoxine-dependent and pyridoxine-responsive seizures: review of 63 North American cases submitted to a patient registry. Eur J Pediatr. 2009;168:697-704.
Rankin PM, Harrison S, Chong WK, et al. Pyridoxine-dependent seizures: a family phenotype that leads to severe cognitive deficits, regardless of treatment regime. Dev Med Child Neurol. 2007;49:300-305.
Mills PB, Struys E, Jakobs C, et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med. 2006;12:307-309.
Been JV, Bok JA, Andriessen P, et al. Epidemiology of pyridoxine-dependent seizures in The Netherlands. Arch Dis Child. 2005;90:1293-1296.
Baynes K, Tomaszewski Farias S, Gospe SM, Jr. Pyridoxine-dependent seizures and cognition in adulthood. Dev Med Child Neurol. 2003;45:782-785.
Grillo E, da Silva EJM, Barbata JH, Jr. Pyridoxine-dependent seizures responding to extremely low-dose pyridoxine. Dev Med Child Neurol. 2001;43:413-415.
Baxter P. (1999) Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK. Arch Dis Child. 1999;81:431-433.
Ebinger M, Schutze C, Konig S. Demographics and diagnosis of pyridoxine-dependent seizures. J Pediatr. 1999;134:795-796.
Ohtsuka Y, Hattori J, Ishida T, et al. Long-term follow-up of an individual with vitamin B6-dependent seizures. Dev Med Child Neurol. 1999;41:203-20
Bass NE, Wyllie E, Cohen B, Joseph SA. Pyridoxine-dependent epilepsy: the need for repeated pyridoxine trials and the risk of severe electrocerebral suppression with intravenous pyridoxine infusion. J Child Neurol 1996;11:422-424.
Baxter P, Griffiths P, Kelly T, et al. Pyridoxine-dependent seizures: demographic, clinical, MRI and psychometric features, and effect of dose on intelligence quotient. Dev Med Child Neurol. 1996;38:998-1006.
McLachlan RS, Brown WF. Pyridoxine dependent epilepsy with iatrogenic sensory neuronopathy. Can J Neurol Sci. 1995;22:50-51.
Coker S. Postneonatal vitamin B6-dependent epilepsy. Pediatrics. 1992;90:221-223.
Haenggeli C-A, Girardin E, Paunier L. Pyridoxine-dependent seizures, clinical and therapeutic aspects. Eur J Pediatr. 1991;150:452-455.
Goutières F, Aicardi J. Atypical presentations of pyridoxine-dependent seizures: a treatable cause of intractable epilepsy in infants. Ann Neurol. 1985;17:117-120.
Bankier A, Turner M, Hopkins IJ. Pyridoxine dependent seizures–a wider clinical spectrum. Arch Dis Child 1983;58:415-418.
Gospe SM Jr. Pyridoxine-Dependent Epilepsy. 2001 Dec 7 [Updated 2017 Apr 13]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1486/. Accessed January 24, 2021.
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