ALDH7A1. This is the Epilepsiome page for ALDH7A1, which is associated with Pyridoxine-dependent epilepsy (PDE), a rare neurometabolic disease that generally presents with intractable neonatal seizures treatable with pyridoxine (vitamin B6) supplementation. Pathogenic ALDH7A1 variants can also cause Folinic acid-responsive seizures.
Here are the most recent blogs that mention ALDH7A1 or PDE
- Precision medicine in genetic epilepsies – three criteria to consider
- Hidden neurometabolic disorders – the expanding spectrum of PNPO deficiency
- Standing on the shoulders of giants: the EPICURE GWAS on Idiopathic Generalized Epilepsy
- Antiquitin mutations in folinic-acid responsive seizures
In a nutshell. Pyridoxine-dependent epilepsy (PDE) is an autosomal recessive neurometabolic disorder characterized by neonatal intractable seizures that are not well controlled by antiepileptic drugs but are responsive to daily pyridoxine (vitamin B6) supplementation. Since first being described in the 1950s, a clinical diagnosis of pyridoxine-dependent epilepsy has generally been established by monitoring a patient’s seizure activity during the administration of intravenous pyridoxine. In patients with this diagnosis, seizures generally stop shortly after pyroxidine administration. Despite good seizure control, many affected individuals still have intellectual disability. In 2006, Mills and colleagues discovered that pyridoxine-dependent epilepsy is caused by biallelic (homozygous or compound heterozygous) disease-causing variants in the ALDH7A1 gene. Patients generally have elevated α-aminoadipic semialdehyde (α-AASA) levels in urine and plasma. This accumulation leads to inactivation of pyridoxal phosphate (PLP), and some individuals also develop elevation of pipecolic acid in plasma and cerebral spinal fluid.
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Overview. Classic pyridoxine-dependent epilepsy generally presents with prolonged seizures and/or recurrent status epilepticus soon after birth or even prenatally. However, seizure type is variable and can also include recurrent self-limited seizures, such as partial, generalized or atonic seizures, as well as myoclonic events and infantile spasms. Clinical seizures can be preceded by periods of epileptic encephalopathy, presenting with irritability, crying, fluctuating tone, and/or poor feeding, and some patients also have facial grimacing and abnormal eye movements during seizures, as well as gastrointestinal symptoms, such as emesis and abdominal distention. Many individuals also have mild to severe developmental delay and intellectual disability including delayed or abnormal expressive language, although some maintain normal cognitive functioning.
Atypical pyridoxine-dependent epilepsy. Although most affected individuals present with intractable neonatal seizures that are unresponsive to anticonvulsants, some individuals present with later onset of seizures in infancy or early childhood (≤ 3). In addition, some individuals show initial responsiveness to antiepileptic drugs and later develop intractable seizures, while others initially present with seizures that are not controlled by pyridoxine but show a response several months later. Some patients who stop pyridoxine treatment can be seizure free for extended periods of time. ALDH7A1 mutations can also be identified in patients with neonatal seizures and other phenotypic presentations such as neonatal sepsis. In a previous publication by Mills and collaborators, some cases were described that would not have been screened for ALDH7A1 mutations in the first place. We also described one patient with atypical ALDH7A1 deficiency with a phenotypic presentation resembling Dravet Syndrome.
Folinic acid-responsive seizures. Some patients who present with intractable seizures that are responsive to folinic acid were previously diagnosed with folinic acid-responsive seizures but later studies found that these patients had biallelic ALDH7A1 variants and were responsive to pyridoxine.
EEG and Neuroimaging. EEG abnormalities are variable and non-specific and therefore are not useful in diagnosis. They can be present even after initiation of pyridoxine. In addition, patients have been shown to have different anomalies on brain imaging, particularly thinning/alteration of the corpus callosum. Friedman and colleagues found that younger individuals have changes in the posterior callosum while older individuals also have changes in the anterior region, leading them to hypothesize that evolving callosal alterations may contribute to symptoms not completely improved by therapy.
Phenotype categorization. Phenotypes are often divided in to 3 groups: 1) patients with complete control of seizures with pyridoxine treatment and normal development, 2) patients with complete control of seizures with pyridoxine treatment but with developmental delay, and 3) patients with incomplete control of seizures and developmental delay with pyridoxine treatment.
Mutation spectrum. Over 100 different disease-causing variants have been reported in ALDH7A1. Most variants are homozygous or compound heterozygous missense variants, but splice site and nonsense variants, as well as small insertions/deletions and exonic deletions, have also been identified. Disease-causing variants have been reported throughout the gene. Some pathogenic ALDH7A1 variants are unique to a single patient or family, but multiple recurrent variants have also been reported. The missense variant p.Glu399Gln in exon 14 is particularly common, and may be found in as many as 30% of patients according to Scharer and colleagues.
Genotype-Phenotype Correlation. No definite genotype-phenotype correlations have been established for ALDH7A1-related epilepsy thus far. The same variants have been identified in patients with both neonatal and late-onset of seizures. Variants that allow for residual enzyme activity, such as missense variants, have been proposed to lead to a better developmental outcome, but some patients with relatively normal intellectual functioning have variants without known residual activity.
General Considerations for Variant interpretation. When reviewing a genetic variant to determine its significance for a given patient, it is important to weigh multiple pieces of evidence:
Considerations for gene level interpretation. First, it is important to establish the strength of the evidence showing that the gene is associated with epilepsy. Some genes may only have one variant reported in a single individual with epilepsy, while other genes may have multiple variants reported in many large families with an autosomal dominant pattern of epilepsy. For ALDH7A1, there is very strong evidence for its role in human epilepsy.
Considerations for variant level interpretation. When reviewing the significance of a variant, it is important to consider the impact on the gene and the presence of the variant in previously described patient and control populations. Many clinical genetic testing laboratories classify genetic variants into different categories, ranging from benign to pathogenic. Variants that are common in control populations and would not be predicted to have a major impact on the gene/protein are generally classified as benign. Variants are more likely to be classified as pathogenic if the variants are rare or not present in the control population, reported in multiple individuals or families with disease, and likely to have a higher impact on the gene/protein based on the type of mutation or functional studies. Variants with uncertain or limited available evidence may be classified as variants of uncertain significance (VUS), indicating that further information is required in order for the variant to be further defined. In some cases, testing additional family members can be helpful, as it allows the lab to determine whether or not the variant was inherited (versus de novo) and how the variant segregates with disease in the family. Parental testing for novel ALDH7A1 variants can confirm biallelic inheritance, lending more support to the possibility that the novel variant/s could be disease-causing. Sometimes further classification of a VUS requires waiting for the identification of additional patients or families with similar or nearby variants.
Inheritance, Penetrance & Prevalence. ALDH7A1 related-epilepsy is inherited in an autosomal recessive pattern: biallelic (homozygous or compound heterozygous) variants are generally inherited from both of a patient’s unaffected parents who are carriers of a single ALDH7A1 disease-causing variant. ALDH7A1-related epilepsy is completely penetrant, so all individuals with biallelic disease-causing variants are symptomatic if untreated. Variable expressivity can occur, even with the same variant, particularly in age of onset, seizure types and degree of developmental issues. The exact worldwide prevalence of ALDH7A1-related epilepsy is unknown, however, studies in several European countries suggest that the prevalence of pyridoxine-dependent epilepsy may range from approximately 1/20,000 to 1/700,000.
Mechanism. ALDH7A1 encodes antiquitin, an α-aminoadipic semialdehyde (α-AASA) dehydrogenase in the pipecolic acid pathway of lysine catabolism. Antiquitin deficiency leads to accumulation of Δ1-piperideine-6-carboxylate (P6C), which then condenses with pyridoxal 5’-phosphate (PLP) resulting in inactivation of PLP. PLP is essential for normal neurotransmitter metabolism. The abnormalities in the pipecolic pathway result in elevation of α-AASA in cerebrospinal fluid, plasma, and urine, as well as elevation of pipecolic acid in cerebrospinal fluid and plasma.
Mice and Zebrafish. There are currently no mouse or zebrafish models for ALDH7A1-related epilepsy. An ALDH7A1-related epilepsy mouse or zebrafish model could help further elucidate the underlying mechanism of disease. Zebrafish with knockdown of ALDH7A1 have abnormalities of the eye and skeletal system.
Recurrence risk & testing of family members. ALDH7A1-related epilepsy is inherited in an autosomal recessive pattern. If both parents are carriers of a disease-causing variant, then each of their future children has a 25% (1 in 4) chance of inheriting both disease-causing variants and thus being affected with pyridoxine-dependent epilepsy. Each pregnancy has a 50% (1 in 2) of inheriting a single disease-causing variant from one of the parents and thus being an unaffected carrier.
Pyridoxine. Patients with PDE are generally treated with lifelong pyridoxine supplementation. The exact dosage recommendations are not well established and the dosage needs can vary between patients. Long-term oral therapy appears to be safe, although higher doses can result in sensory or motor neuropathy. Breakthrough seizures can occur during febrile illness, potentially requiring temporarily increased pyridoxine dosage. Although pyridoxine provides good seizure control for most patients, the vast majority of patients still have long-term issues, particularly with neurodevelopment. Concurrent treatment with antiepileptic drugs is sometimes needed for patients for whom pyridoxine does not completely control seizures. More recent studies are investigating the potential of alternative or concurrent therapies, such as pyridoxal phosphate, folinic acid, or a lysine-restricted diet.
Prenatal treatment. Some studies suggest that prenatal treatment of an affected or at-risk pregnancy can be beneficial by eliminating prenatal seizures and improving developmental outcomes. However, some affected individuals treated prenatally have still developed cognitive delay, indicating that prenatal treatment will not completely abolish all symptoms. In addition, some at-risk infants treated with pyridoxine immediately after birth have developed seizures, which have improved with removal of pyridoxine once PDE was ruled out, indicating that pyridoxine treatment should be overseen carefully and discontinued as soon as possible if a diagnosis of PDE is excluded.
Research studies, patient registries, and family connections. The Epilepsiome team is happy to facilitate if you have questions or a specific interest in this gene. There are a number of groups/websites that provide relevant information and support for individuals and families with pyridoxine-dependent epilepsy, including the groups listed below.
- American Epilepsy Society
- Epilepsy Foundation
- Epilepsy Action UK
- CLIMB: Children Living with Inherited Metabolic Diseases
- National Organization for Rare Disorders (NORD)
In addition, ALDH7A1 community has a registry to gather information about individuals with ALDH7A1 variants.