About pyridoxine-dependent seizures
What is pyridoxine-dependent seizures?
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 anticonvulsants 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.
What are the symptoms for pyridoxine-dependent seizures?
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.
What are the causes for pyridoxine-dependent seizures?
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.
What are the treatments for pyridoxine-dependent seizures?
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.
What are the risk factors for pyridoxine-dependent seizures?
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.
Is there a cure/medications for pyridoxine-dependent seizures?
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.