Last updated:
2/11/2025
Years published: 2003, 2007, 2011, 2014, 2017, 2021, 2025
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, and Adjunct Professor of Pediatrics, Duke University, for assistance in the preparation of this report.
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Pyridoxine-dependent epilepsy (PDE) is a rare cause of stubborn, difficult to control, (intractable) seizures appearing in newborns, infants and occasionally older children. PDE presents in a variety of forms with variable signs and symptoms (phenotypically heterogeneous). The one clinical feature characteristic of all patients with PDE is intractable seizures that are not controlled with antiseizure drugs, but do respond both clinically and usually on EEG (electroencephalographically) to large daily supplements of pyridoxine. These patients are not pyridoxine deficient. They are metabolically dependent on the vitamin. In other words, even though they get the recommended daily allowance (RDA) of pyridoxine from their normal diet, they require substantially more of the vitamin than an otherwise normal individual. People with PDE require pyridoxine therapy for life. Affected individuals have improved outcomes when dietary therapy is started in the first months of life, so an early diagnosis is essential.
Since the first clinical description of PDE in 1954, over 300 clinical and scientific papers have been published concerning the natural history and treatment of PDE and its underlying biochemical and genetic mechanisms with over 70% of these publications having appeared since 2005. Importantly, it is now established that there are at least three different forms of PDE. The most common and best studied form is due to an inherited loss of function of the enzyme antiquitin. This Rare Disease Report will focus on this form of PDE which has been reported in more than 200 people and is now formally designated as PDE-ALDH7A1.
Patients with the classic neonatal-onset form of PDE-ALDH7A1 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-ALDH7A1, 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-ALDH7A1 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 antiseizure 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-ALDH7A1 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, people with PDE-ALDH7A1 may also have recurrent self-limited events including partial seizures, generalized seizures, atonic seizures, myoclonic events and infantile spasms. On EEG, people with PDE-ALDH7A1 may also have electrographic seizures without clinical correlations.
A variable degree of intellectual disability is common. People 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 medical problems. Future cognitive function is also likely related to the type of gene changes (pathogenic variants) underlying PDE-ALDH7A1 in a particular person, as well as any associated abnormalities in brain development. Few formal psychometric assessments in people with PDE-ALDH7A1 have been performed. The studies performed to date indicate that verbal intellectual function is typically more impaired than non-verbal skills. While significant neurodevelopmental disabilities and psychiatric disorders may be present in some people with PDE-ALDH7A1, it is important that parents know that people with PDE-ALDH7A1 may have normal intellectual function.
Pathogenic variants in the antiquitin gene (ALDH7A1) were identified in 2006 as the cause of PDE-ALDH7A1. 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. The detection of increased levels of α-AASA in the urine or blood is supportive of a diagnosis of PDE-ALDH7A1. This chemical is therefore considered as a biomarker for the disorder, and several commercial and university laboratories can perform an assay for α-AASA. Other biomarkers have also been discovered.
PDE-ALDH7A1 follows autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
PDE-ALDH7A1 is considered to be a rare disease, and only a few epidemiologic studies have been published. An international genetics study of 185 people with PDE-ALDH7A1 together with the analysis of population-based genomic databases concluded that the birth incidence is approximately 1:64,000 live births. A recent study from Norway has estimated an incidence of 1:35,990 births.
Until the third year of life, PDE-ALDH7A1 must be considered as a possible cause of intractable seizures in any patient. 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-ALDH7A1 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 ALDH7A1 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-ALDH7A1, 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-ALDH7A1, 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.
To confirm the diagnosis of PDE-ALDH7A1, a patient whose seizures stop after the use of pyridoxine should have blood or urine tested for α-AASA, or molecular genetic testing for variants in the ALDH7A1 gene. With the development of multi-gene “epilepsy panels” and whole exome sequencing, PDE-ALDH7A1 is now commonly diagnosed via these laboratory tests and, therefore, may be an unanticipated diagnosis in patients with intractable epilepsy. No matter how PDE-ALDH7A1 is diagnosed, its discovery should lead to an immediate change in management.
Treatment
While the effective treatment of patients with PDE-ALDH7A1 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-ALDH7A1 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. Patients with PDE-ALDH7A1 who have associated abnormalities in brain development such as hydrocephalus or heterotopia (forms of birth defects in brain structure) may not have all their seizures controlled with pyridoxine alone and these patients require the use of one or more antiseizure 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 (neither a diagnosis of PDE-ALDH7A1 nor of one of the other two forms of PDE was made) 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.
As antiquitin is involved in the metabolism of the amino acid lysine, it has been proposed that in addition to daily pyridoxine supplementation, dietary therapy designed to limit the amount of lysine consumed by a PDE-ALDH7A1 patient (lysine reduction) may be beneficial. Several studies have been conducted to determine the effectiveness of lysine reduction in improving seizure control and cognitive development. Lysine reduction may be accomplished by limiting daily lysine intake (via protein restriction) and supplementing the diet with a lysine free protein supplement. An alternate approach to reducing lysine consumption is to supplement the diet of PDE-ALDH7A1 patients with the amino acid L-arginine, which interferes with the absorption of lysine in the gut. Sometimes these two methods of lysine reduction are used together, and this treatment has been termed “triple therapy” (pyridoxine supplementation, lysine restricted diet and L-arginine supplementation). It has now been demonstrated that if lysine reduction is started within the first few months of life there is a significant impact on the neurodevelopmental outcome of the patient. The International PDE Consortium now recommends that all newborns and infants with PDE-ALDH7A1 should be treated with lysine reduction therapies and that this form of therapy should be considered in certain older PDE patients. Parents of children with PDE-ALDH7A1 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.
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:
Web Site: www.pdeonline.org
e-mail: [email protected]
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 can also be used to treat PDE-ALDH7A1, clinical research is required to determine the safety and effectiveness of treatment of PDE-ALDH7A1 with pyridoxal phosphate.
In addition to α-AASA, several additional chemicals have been detected in blood and urine of PDE-ALDH7A1 patients and therefore may serve as biomarkers. As PDE-ALDH7A1 is a treatable metabolic disease, with improved outcomes when dietary therapy is started in the first months of life, an early diagnosis is essential. Therefore, several studies have been conducted to develop methods to screen for PDE-ALDH7A1 in blood specimens obtained shortly after birth (newborn screening). This research has demonstrated a “proof of principle” and now current studies are focused on improving laboratory methodology and conducting prospective population-based screening to determine the feasibility of adding PDE-ALDH7A1 to newborn screening programs.
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:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
REVIEW ARTICLES and EXPERT CONSENSUS GUIDELINES
Coughlin, CM II, Gospe SM, Jr. Pyridoxine-dependent epilepsy: Current perspectives and questions for future research. Ann Child Neurol Soc 2023;1:24-37.
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. 2021;44:178–192.
van Karnebeek CD, Tiebout SA, Niermeijer J, et al. Pyridoxine-Dependent Epilepsy: An Expanding Clinical Spectrum. Pediatr Neurol. 2016;59:6-12.
JOURNAL ARTICLES
Pauly K, Woontner M, Abdenur JE, et al. Feasibility of newborn screening for pyridoxine-dependent epilepsy. Mol Genet Metab. 2025;144(1):109002. doi:10.1016/j.ymgme.2024.109002
Jamali A, Kristensen E, Tangeraas T, et al. The spectrum of pyridoxine dependent epilepsy across the age span: A nationwide retrospective observational study. Epilepsy Res. 2023; 190:107099.
Coughlin, CR, Tseng, LA, Bok, LA, et al. Association between lysine reduction therapies and cognitive outcomes in patients with pyridoxine-dependent epilepsy. Neurology 2022;99:e2627-2636.
Tseng, LA, Abdenur, JE, Andrews A, et al. Timing of therapy and neurodevelopmental outcomes in 18 families with pyridoxine-dependent epilepsy. Mol Genet Metab 2022;135,:350–356.
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.
Engelke, U F, van Outersterp, RE, Merx, J, et al. Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy. J Clin Invest 2021;131: 148272.
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.
Wempe, MF, Kumar, A, Kumar, V, et al. Identification of a novel biomarker for pyridoxine-dependent epilepsy: Implications for newborn screening. J. Inherit. Metab. Dis. 2019;42:565–574.
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.
Jung S, Tran NT, Gospe SM Jr, Hahn SH. Preliminary investigation of the use of newborn dried blood spots for screening pyridoxine-dependent epilepsy by LC-MS/MS. Mol Genet Metab. 2013;110(3):237-240. doi:10.1016/j.ymgme.2013.07.017
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.
Mills PB, Footitt EJ, Mills KA, et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain. 2010;133:2148-2159.
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.
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.
Mills PB, Struys E, Jakobs C, et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med. 2006;12:307-309.
Mills PB, Struys E, Jakobs C, et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med. 2006;12:307-309.
Baynes K, Tomaszewski Farias S, Gospe SM, Jr. Pyridoxine-dependent seizures and cognition in adulthood. Dev Med Child Neurol. 2003;45:782-785.
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.
McLachlan RS, Brown WF. Pyridoxine dependent epilepsy with iatrogenic sensory neuronopathy. Can J Neurol Sci. 1995;22:50-51.
INTERNET
Al-Shekaili H, Ciapaite J, van Karnebeek C, et al. PLPBP Deficiency. 2023 Feb 16. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK589231/ Accessed Jan 30, 2025.
Gospe SM Jr. Pyridoxine-Dependent Epilepsy – ALDH7A1. 2001 Dec 7 [Updated 2022 Sep 22]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1486/ Accessed Jan 30, 2025.
Plecko B, Mills P. PNPO Deficiency. 2022 Jun 23. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK581452/ Accessed Jan 30, 2025.
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