NORD gratefully acknowledges Sidney M Gospe, Jr, MD, PhD, Herman and Faye Sarkowsky Endowed Chair of Child Neurology, Head, Division of Pediatric Neurology, Professor 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, 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 (hypoxic-ischemic encephalopathy). 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), seizures which initially respond to antiepileptic 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.
Some intellectual disability is common in these patients. Some clinicians believe that patients whose seizures appear earlier in life are more likely to show diminished cognitive function. Some physicians also maintain 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. It is important that patients and families know that some patients with PDE 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 (a-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 ALDH7A1 gene is located on chromosome 5q31.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered form 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further subdivided into many bands that are numbered. For example, chromosome 5q31 refers to band 31 on the long arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
PDE is a familial (genetic) disorder, and it is transmitted via autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits an abnormal gene for a particular trait from each parent. If an individual receives one normal gene and one 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 a defective 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 normal genes from both parents and be genetically normal for that particular trait 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.
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 (hypoxic-ischemic encephalopathy), 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 a-AASA, or a test of the ALDH7A1 gene.
Treatment
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. 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. Some patients require higher daily doses of pyridoxine. In 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 antiepileptic 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., M.D., Ph.D.
Seattle Children’s Hospital
4800 Sand Point Way NE
Neurology, MB.7.420
Seattle, WA 98105
e-mail: sgospe@uw.edu
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: pde@cw.bc.ca
Daily supplementation with pharmacologic doses of pyridoxine is the accepted treatment for this disorder. Recently, it was discovered that another rare cause of intractable neonatal seizures known as folinic acid-responsive seizures is also due to mutations in the ALDH7A1 gene. It is not known if the use of folinic acid together with pyridoxine will provide a better long-term prognosis in children with PDE. 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. 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: prpl@cc.nih.gov
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
van Karnebeek CD, Tiebout SA, Niermeijer J, et al. Pyridoxine-Dependent Epilepsy: An Expanding Clinical Spectrum. Pediatr Neurol. 2016;59:6-12
Stockler, S, Plecko, B, Gospe, SM, Jr., et al. Pyridoxine-dependent epilepsy and antiquitin deficiency: Clinical and molecular characteristics, and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab. 2011;104:48-60.
Gospe SM, Jr. Neonatal vitamin-responsive epileptic encephalopathies. Chang Gung Med J. 2010;33:1-12.
Baxter P. Pyridoxine dependent and pyridoxine responsive seizures. vitamin responsive Conditions in paediatric neurology. London, MacKeith Press: 2001:109-165.
Baxter P. Pyridoxine-dependent and pyridoxine-responsive seizures. Dev Med Child Neurol 2001;43:416-420.
JOURNAL ARTICLES
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.
Gallagher RC, Van Hove JL, Scharer G, et al. Folinic acid-responsive seizures are identical to pyridoxine-dependent epilepsy. Ann Neurol. 2009;65:550-556.
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. (1999) 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.
Clarke TA, Saunders BS. Pyridoxine-dependent seizures requiring high doses of pyridoxine for control. Am J Dis Child. 1979;133:963-965.
Bejovec M, Kulenda Z, Ponca E. Familial intrauterine convulsions in pyridoxine dependency. Arch Dis Child. 1967;42:201-207.
INTERNET
Gospe SM Jr. Pyridoxine-Dependent Epilepsy. 2001 Dec 7 [Updated 2014 Jun 19]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1486/. Accessed December 7, 2016.
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