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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, of which more than 200 cases have now been reported in the medical literature. 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 antiepileptic drugs but which 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. Patients with PDE require pyridoxine therapy for life.
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, and amino acid. Abnormal function of antiquitin secondarily results in elevations of the chemical a-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 the same abnormal gene for the same 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 the 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.
While pyridoxine-dependency should be considered when evaluating possible causes of intractable seizures in young patients, other more common causes must be ruled out, including a variety of brain malformation syndromes, serious acquired disorders of the central nevous system (such as hemorrhagic conditions and infections), and other inborn errors of metabolism. A closely related neonatal metabolic epilepsy is PNPO deficiency. Babies with this genetic disorder also have intractable seizures, but the seizures in these patients respond to pyridoxal-5'-phosphate (P5P, the biologically active form of pyridoxine) but do not respond to pyridoxine. Other genetic pyridoxine-dependency states have been described (e.g. pyridoxine-dependent anemia and pyridoxine-dependent forms of homocystinuria, xanthurenic aciduria and cystathioninuria), but these conditions are not genetically related to PDE, and intractable seizures are not a feature of these other disorders.
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.
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
Seattle, WA 98105
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. Parents of patients with PDE who would like to have their child treated with this special diet 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
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For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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Gospe SM (Updated 6/7/2012). Pyridoxine-Dependent Epilepsy. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1486/ Accessed Feb 24, 2014.
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