What Is Epilepsy?
While epilepsy is a common condition, it is also highly unique to each individual who experiences it. The severity and frequency of seizures can vary greatly, as can the symptoms that occur during seizures. Additionally, the causes of epilepsy are diverse and can include genetic factors, brain injuries, and certain medical conditions. Although it can be a lifelong condition, the management and treatment of epilepsy are also unique to each person and may involve medication, lifestyle changes, and/or surgical interventions. Despite the challenges it presents, many individuals with epilepsy are able to lead full and fulfilling lives with proper management and support.
What Is Pyridoxine-Dependent Epilepsy?
Pyridoxine-dependent epilepsy is a condition characterized by prolonged seizures that can lead to muscle rigidity, convulsions, and loss of consciousness. Unlike other forms of epilepsy, anticonvulsant drugs are ineffective in controlling seizures in individuals with pyridoxine-dependent epilepsy. Instead, treatment involves large daily doses of pyridoxine, a type of vitamin B6 found in food. Without proper treatment, this condition can lead to severe brain dysfunction and developmental delays. Although controlling seizures with pyridoxine is possible, individuals with this condition may still experience long-term neurological problems.
Pyridoxine dependence is a rare condition that can cause neonatal seizures and irreversible intellectual disability if not treated promptly. Previous studies have reported rapid clinical seizure control within seconds to minutes and EEG control within minutes to days. Due to its rarity, the absence of a specific laboratory test, and the limited information on EEG response to treatment, the diagnosis of pyridoxine dependence may be overlooked by clinicians.
What Causes Pyridoxine-Dependent Epilepsy?
It is caused by mutations in the ALDH7A1 gene, which provides instructions for making an enzyme called α-aminoadipic semialdehyde (α-AASA) dehydrogenase, also known as antiquitin. This enzyme is responsible for breaking down the amino acid lysine in the brain. When there is a deficiency of antiquitin, a molecule that interferes with vitamin B6 function builds up in various tissues.
Pyridoxine is involved in various processes in the body, such as the breakdown of amino acids and the production of neurotransmitters, which transmit signals in the brain. It is still unknown how a lack of pyridoxine leads to the seizures that are characteristic of this condition.
Although mutations in the ALDH7A1 gene are the primary cause of pyridoxine-dependent epilepsy, some individuals with this condition do not have identified mutations in this gene.
What Are the Alternative Names for Pyridoxine-Dependent Epilepsy?
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Pyridoxine dependency with seizures.
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Pyridoxine-dependent seizures.
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Epilepsy, pyridoxine-dependent.
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PDE (pyridoxine-dependent epilepsy).
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Vitamin B6-dependent seizures.
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Pyridoxine dependency.
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EPD (epilepsy, pyridoxine-dependent).
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AASA dehydrogenase deficiency.
What Are the Symptoms of Pyridoxine-Dependent Epilepsy?
The clinical characteristics of pyridoxine-dependent epilepsy - ALDH7A1 (PDE-ALDH7A1) are distinct and involve seizures that are not well-controlled by conventional anti-seizure medication. However, these seizures can be clinically and electrographically responsive to high daily doses of pyridoxine (vitamin B6), regardless of whether the patient presents with classic or atypical PDE-ALDH7A1. Those with classic PDE-ALDH7A1 usually experience untreated seizures within the first few weeks or months of life, including prolonged seizures and recurrent episodes of status epilepticus.
Atypical PDE-ALDH7A1, on the other hand, may present with later onset seizures, seizures that respond to anti-seizure medication but become intractable. Electrographic seizures may occur without clinical symptoms.
Clinical Features:
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Some of the indications for seizure disorder in infants and children include seizures in any child under one year of age without any apparent brain malformation or acquired brain injury.
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In neonates, the phenotype may indicate hypoxic-ischemic encephalopathy, making seizures difficult to control.
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Signs of encephalopathy such as irritability, restlessness, abnormal crying, and vomiting may precede or follow the actual seizures.
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In previously healthy infants, cryptogenic seizures may occur without an abnormal gestational or perinatal history.
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Seizures that are only partially responsive to anti-seizure medication, especially when accompanied by developmental delay and intellectual disability, can also be present in infants and children.
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A history of seizures that were either transient or unclearly responsive to pyridoxine may also be noted.
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Focal or unilateral seizures that are difficult to treat with anti-seizure medications, and are often associated with partial preservation of consciousness, may also be observed.
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Additionally, seizures that are responsive to folinic acid may be present in infants and children.
How Is Pyridoxine-Dependent Epilepsy Diagnosed?
When a patient shows a positive response to pyridoxine treatment and has elevated levels of alpha-aminoadipic semialdehyde (α-AASA) in urine or plasma, pyridoxine-dependent epilepsy (PDE-ALDH7A1) is usually suspected. A confirmed diagnosis of PDE-ALDH7A1 is made when the patient has clinical features consistent with the condition and carries two pathogenic (or likely pathogenic) mutations in the ALDH7A1 gene, which can be detected through molecular genetic testing.
How Is Pyridoxine-Dependent Epilepsy Treated?
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Pyridoxine Supplements- To manage PDE-ALDH7A1, there is currently no cure available. The only treatment option is lifelong supplementation of Pyridoxine, which requires targeted therapy. The optimal dose of Pyridoxine has not been studied due to the rarity of the condition. The International PDE Consortium recommends Pyridoxine doses according to age, ranging from 100 mg/day for newborns to a maximum of 500 mg/day for adults. Additionally, dietary modifications targeting the reduction of lysine intake are recommended.
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Supportive Care- Supportive care for developmental delay and intellectual disability follows standard practice. The treating neurologist should regularly assess the control of epilepsy via targeted therapy with Pyridoxine, the need for anti-seizure medication, and signs of sensory neuropathy. Furthermore, the individual's developmental progress and educational needs should be evaluated regularly.
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Risk Assessment- To evaluate relatives at risk, prenatal molecular genetic testing of fetuses can be performed to inform maternal pyridoxine supplementation during pregnancy and facilitate the initiation of treatment at birth. In cases where prenatal testing is not pursued, the neonate should receive therapeutic doses of Pyridoxine until molecular genetic testing for the family-specific ALDH7A1 variants has been completed.
PDE-ALDH7A1 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ALDH7A1 pathogenic variant, each sibling of an affected individual has a 25 % chance of being affected, a 50 % chance of being an asymptomatic carrier, and a 25 % chance of being unaffected and not a carrier. Carrier testing for relatives at risk, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for PDE-ALDH7A1 are possible. Genetic counseling is recommended to guide individuals and families affected by this condition.
Conclusion
Pyridoxine-dependent epilepsy is a genetic disorder. It is caused by mutations in the ALDH7A1 gene, which is inherited in an autosomal recessive pattern. Seizures in this condition usually begin in infancy or, in rare instances, before birth. The seizures are characterized by muscle rigidity, convulsions, and tonic-clonic seizures, which can last for several minutes and result in a loss of consciousness.
