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Pyridoxine-Dependent Epilepsy

Synonyms: Pyridoxine Dependency, Pyridoxine-Dependent Seizures, Vitamin B6-Dependent Seizures
, MD, PhD
Herman and Faye Sarkowsky Endowed Chair of Child Neurology
Professor, Neurology and Pediatrics
University of Washington School of Medicine
Seattle, Washington

Initial Posting: ; Last Update: June 19, 2014.


Clinical characteristics.

Pyridoxine-dependent epilepsy is characterized by intractable seizures that are not controlled with antiepileptic drugs but that respond both clinically and electrographically to large daily supplements of pyridoxine (vitamin B6). Multiple types of clinical seizures have been reported in individuals with pyridoxine-dependent epilepsy. Dramatic presentations consisting of prolonged seizures and recurrent episodes of status epilepticus are typical; recurrent self-limited events including partial seizures, generalized seizures, atonic seizures, myoclonic events, and infantile spasms also occur. Affected individuals may have electrographic seizures without clinical correlates. Infants with the classic neonatal presentation begin to experience seizures soon after birth. Atypical features include: late-onset seizures (age ≤3 years); seizures that initially respond to antiepileptic drugs and then become intractable; seizures during early life that do not respond to pyridoxine but that are then controlled with pyridoxine several months later; and prolonged seizure-free intervals (≤5 1/2 months) that occur after pyridoxine discontinuation. Intellectual disability is common.


The diagnosis of pyridoxine-dependent epilepsy is typically made on clinical grounds and may be confirmed through biochemical and/or molecular genetic testing. Diagnosis may be made in individuals experiencing status epilepticus or repetitive clinical seizures that are not controlled with antiepileptic drugs by concurrently administering 100 mg of pyridoxine intravenously while monitoring the EEG, oxygen saturation, and vital signs. In individuals with pyridoxine-dependent epilepsy, clinical seizures generally cease over several minutes. If a clinical response is not demonstrated, the dose should be repeated up to a maximum of 500 mg. A corresponding change should be observed in the EEG, although it may be delayed by several hours. Alternatively, in children who experience frequent antiepileptic drug-resistant self-limited seizures, oral pyridoxine at a dose of 30 mg/kg/day may be initiated. Children who are pyridoxine dependent should have a resolution of their clinical seizures within three to seven days.

Elevated concentration of α-aminoadipic semialdehyde (α-AASA) in urine and plasma is a strong biomarker of the disorder; pipecolic acid may also be elevated in plasma and cerebrospinal fluid. ALDH7A1 is the only gene in which pathogenic variants are known to cause pyridoxine-dependent epilepsy.


Treatment of manifestations: Pyridoxine-dependent epilepsy is initially controlled with the addition of daily supplements of pyridoxine; subsequently, in the majority of patients all antiepileptic drugs can be withdrawn and seizure control continued with daily pyridoxine monotherapy in pharmacologic doses. To prevent exacerbation of clinical seizures and/or encephalopathy during an acute illness, the daily dose of pyridoxine may be doubled for several days. Special education programs are offered to affected individuals.

Prevention of secondary complications: Overzealous use of pyridoxine can cause a reversible sensory neuropathy.

Surveillance: Monitoring for development of clinical signs of a sensory neuropathy and regular assessments of intellectual function.

Evaluation of relatives at risk: If the pathogenic variants in the family are known: molecular genetic testing of at-risk newborn sibs of a proband for early diagnosis and treatment to reduce morbidity and mortality. If the pathogenic variants in the family are not known, and the at-risk sib is experiencing clinical seizures or encephalopathy: administer pyridoxine acutely (under EEG monitoring) for diagnostic and therapeutic purposes.

Genetic counseling.

Pyridoxine-dependent epilepsy is inherited in an autosomal recessive manner. At conception, each sib 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 at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both pathogenic variants in a family are known.


The diagnosis of pyridoxine-dependent epilepsy is established in a proband showing a clinical response to pyridoxine administration followed by biochemical testing showing the presence of biomarkers and/or molecular genetic testing that detects biallelic pathogenic variants in ALDH7A1, the only gene known to be associated with pyridoxine-dependent epilepsy.

Suggestive Findings

Pyridoxine-dependent epilepsy should be suspected in individuals with intractable seizures in the following situations [Goutières & Aicardi 1985]:

  • Cryptogenic seizures in a previously normal infant without an abnormal gestational or perinatal history
  • The occurrence of long-lasting focal or unilateral seizures, often with partial preservation of consciousness
  • Irritability, restlessness, crying, and vomiting preceding the actual seizures
  • A history of a severe convulsive disorder in a sib, often leading to death during status epilepticus
  • Parental consanguinity

In order not to miss milder and atypical presentations, Stockler et al [2011] recommend considering a diagnosis of pyridoxine-dependent epilepsy in the following categories of patients:

  • Infants and children with seizures that are partially responsive to antiepileptic drugs, in particular if associated with developmental delay and intellectual disability
  • Neonates with hypoxic ischemic encephalopathy and difficult-to-control seizures
  • Patients with a history of transient or unclear response to pyridoxine
  • Patients with a history of response to folinic acid and/or with the characteristic chromatographic pattern of folinic acid-responsive seizures on cerebrospinal fluid monoamine analysis
  • Seizures in any child under age one year without an apparent brain malformation as the cause of the epilepsy

A clinical diagnosis may be made:

  • On an acute basis in individuals experiencing clinical seizures by concurrently administering 100 mg of pyridoxine intravenously while monitoring the EEG, oxygen saturation, and vital signs [Baxter 2001, Gospe 2002, Stockler et al 2011]:
    • In individuals with pyridoxine-dependent epilepsy, clinical seizures generally cease over a period of several minutes.
    • If a clinical response is not demonstrated, the dose should be repeated up to a maximum of 500 mg.
    • A corresponding change should be observed in the EEG; in some circumstances, the change may be delayed by several hours.
    • In some individuals with pyridoxine-dependent epilepsy, significant neurologic and cardiorespiratory depression follows this trial, making close systemic monitoring essential.
  • By administering 30 mg/kg/day of pyridoxine orally. In individuals with pyridoxine-dependent epilepsy, clinical seizures should cease within three to five days [Baxter 2001, Gospe 2006, Stockler et al 2011].

In either of the above situations, the clinical diagnosis of pyridoxine-dependent epilepsy is confirmed by withdrawing antiepileptic drugs, followed by withdrawal of daily pyridoxine supplementation. The clinical diagnosis of pyridoxine-dependent epilepsy is established if seizures recur and are again controlled by pyridoxine monotherapy. Note: Screening of patients whose seizures respond to pyridoxine administration via measurement of biomarkers in urine, plasma, or cerebrospinal fluid has become more available and the confirmatory clinical step of pyridoxine supplementation withdrawal is now typically omitted.

Confirmatory Laboratory Testing

Testing for Biomarkers

Pipecolic acid. Elevated concentrations of pipecolic acid in plasma and cerebral spinal fluid have been demonstrated in several individuals with pyridoxine-dependent epilepsy both before and after long-term treatment with pyridoxine [Plecko et al 2000, Plecko et al 2005]. However, in some cases pipecolic acid concentrations have been shown to normalize after many years of therapy. Therefore, pipecolic acid must be considered as a nonspecific diagnostic marker for this disorder [Plecko et al 2005].

Alpha-aminoadipic semialdehyde (α-AASA). Elevated urinary concentration of α-AASA is a more sensitive biomarker than pipecolic acid for pyridoxine-dependent epilepsy [Mills et al 2006, Struys & Jakobs 2007]. Elevated plasma concentrations of α-AASA are also present [Sadilkova et al 2009]. While α-AASA was first thought to be a specific biomarker for PDE, recent research has demonstrated that α-AASA is also elevated in patients with molybdenum cofactor deficiency and isolated sulfite oxidase deficiency [Mills et al 2012]. In patients with elevated levels of α-AASA, these latter two conditions may be differentiated from PDE by measuring urinary sulfite, sulfocysteine, and xanthine levels.

Analysis of cerebrospinal fluid monoamine metabolites. As part of a comprehensive evaluation for neonatal or infantile epileptic encephalopathy, an analysis of cerebrospinal fluid monoamines via HPLC with electrochemical detection may be conducted. The chromatographic pattern characteristic of pyridoxine-dependent epilepsy contains two peaks of unknown identity [Gallagher et al 2009].

Newborn screening. The biomarker AASA has been shown to be present in blood specimens (newborn blood spots) from neonates subsequently diagnosed with pyridoxine-dependent epilepsy [Jung et al 2013]. Newborn screening for pyridoxine-dependent epilepsy is currently not available on a clinical basis.

Molecular Genetic Testing

One genetic testing strategy is molecular genetic testing of ALDH7A1, the only gene in which pathogenic variants are known to cause pyridoxine-dependent epilepsy [Mills et al 2006] (see Table 1). Sequence analysis of ALDH7A1 should be conducted. If neither or only one pathogenic variant is identified by sequence analysis, deletion/duplication analysis can be performed.

An alternative genetic testing strategy is use of a multi-gene panel that includes ALDH7A1 and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Table 1.

Summary of Molecular Genetic Testing Used in Pyridoxine-Dependent Epilepsy

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
ALDH7A1Sequence analysis 2117/122 3
Deletion/duplication analysis 43 individuals with exonic deletions 3, 5
Unknown 6NANA

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


113/122 families with patients with seizures responsive to pyridoxine had two identifiable pathogenic variants (three of which were exonic deletions), five had only one identifiable pathogenic variant associated with elevated plasma pipecolic acid concentration or urinary α-AASA concentration, and four had no pathogenic variants and a normal plasma pipecolic acid concentration [Mills et al 2006, Kanno et al 2007, Plecko et al 2007, Bennett et al 2009, Mills et al 2010, Scharer et al 2010, Bok et al 2012, Tlili et al 2013, Pérez et al 2013]. Click here (pdf) for more information on these studies involving the molecular diagnosis of pyridoxine-dependent epilepsy.


Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Two individuals who were compound heterozygotes (with one variant detected by sequence analysis while the second was an exonic deletion) [Kanno et al 2007, Plecko et al 2007] and one individual who was homozygous for a 23 kb deletion encompassing numerous exons [Pérez et al 2013].


Evidence for locus heterogeneity: (1) Assignment to the chromosome 5q31 pyridoxine-dependent epilepsy locus was excluded on the basis of haplotype analysis in one of the six North American pyridoxine-dependent epilepsy pedigrees. The affected children in the family had late-onset infantile spasms responsive to pyridoxine therapy [Bennett et al 2005]. A later study failed to detect ALDH7A1 pathogenic variants in these children and in two additional children presenting with pyridoxine-responsive late-onset infantile spasms [Bennett et al 2009]; (2) Very late-onset pyridoxine-dependent epilepsy presented in a female age eight years in whom linkage to the 5q31 locus was excluded by haplotype analysis [Kabakus et al 2008].

Clinical Characteristics

Clinical Description

The one clinical feature characteristic of all individuals with pyridoxine-dependent epilepsy is intractable seizures that are not controlled with antiepileptic drugs but that respond both clinically and electrographically to large daily supplements of pyridoxine.

Classic pyridoxine-dependent epilepsy. Multiple types of clinical seizures have been reported in individuals with pyridoxine-dependent epilepsy. Although dramatic presentations consisting of prolonged seizures and recurrent episodes of status epilepticus are typical, recurrent self-limited events including partial seizures, generalized seizures, atonic seizures, myoclonic events, and infantile spasms also occur. Affected individuals may have electrographic seizures without clinical correlates.

Newborns with the classic neonatal presentation begin to experience seizures soon after birth.

  • In retrospect, many mothers recount unusual intrauterine movements that may have started in the late second trimester and that likely represent fetal seizures [Baxter 2001].
  • Affected neonates frequently have periods of encephalopathy (irritability, crying, fluctuating tone, poor feeding) that precede the onset of clinical seizures. Low Apgar scores, abnormal cord blood gases, and other abnormalities of blood chemistries may also be observed. For this reason, it is not uncommon for these newborns to be diagnosed with hypoxic-ischemic encephalopathy [Haenggeli et al 1991, Baxter 1999, Mills et al 2010].
  • Clinical seizures may be associated with facial grimacing and abnormal eye movements [Schmitt et al 2010].

Similar periods of encephalopathy may be seen in older infants with pyridoxine-dependent epilepsy, particularly prior to recurrence of clinical seizures, which occur in children treated with pyridoxine whose vitamin requirement may have increased because of growth or intercurrent infection, particularly gastroenteritis.

Intellectual disability, particularly with expressive language, is common in individuals with pyridoxine-dependent epilepsy.

  • It has been suggested that an earlier onset of clinical seizures corresponds to a worse prognosis for cognitive function, and the length of the delay in diagnosis and initiation of effective pyridoxine treatment correlates with increased handicaps [Baxter 2001, Kluger et al 2008, Basura et al 2009].
  • Seizures in some individuals with molecularly confirmed pyridoxine-dependent epilepsy are incompletely controlled with pyridoxine, and concurrent treatment with one or more antiepileptic drugs is required. Significant intellectual disability is present in these individuals [Basura et al 2009, Scharer et al 2010].
  • Some affected individuals with normal intellectual function have been reported [Haenggeli et al 1991, Ohtsuka et al 1999, Basura et al 2009, Bok et al 2012].
  • Few formal psychometric assessments in individuals with pyridoxine-dependent epilepsy have been performed. These limited studies have inconsistent findings. Two earlier studies indicate that verbal skills are more impaired than nonverbal skills [Baxter et al 1996, Baynes et al 2003] while a more recent report suggests that verbal IQ is slightly (but not significantly) higher than performance IQ [Bok et al 2012].

Atypical pyridoxine-dependent epilepsy. Late-onset and other atypical features of this phenotypically heterogeneous disorder have been described [Goutières & Aicardi 1985, Coker 1992, Grillo et al 2001, Basura et al 2009]. These include:

  • Late-onset seizures (age ≤3 years)
  • Seizures that initially respond to anticonvulsants and then become intractable
  • Seizures during early life that do not respond to pyridoxine but that are then controlled with pyridoxine several months later
  • Prolonged seizure-free intervals (age ≤5 1/2 months) that occur after pyridoxine discontinuation.

EEG/neuroimaging. While a variety of EEG abnormalities have been described in individuals with pyridoxine-dependent epilepsy, none is pathognomonic for this disorder [Mikati et al 1991, Nabbout et al 1999, Naasan et al 2009, Bok et al 2010b, Mills et al 2010, Schmitt et al 2010]. Similarly, several imaging abnormalities have been reported in patients with pyridoxine-dependent epilepsy [Baxter et al 1996; Gospe & Hecht 1998; Mills et al 2010; Friedman et al, in press]. Thinning of the corpus callosum (greatest in the isthmus and more rostral callosum) is universally seen [Friedman et al, in press] and mega cisterna magma has been reported in a number of instances [Baxter et al 1996, Mills et al 2010].

Genotype-Phenotype Correlations

More than 80 ALDH7A1 sequence alterations have been documented in both neonatal-onset and late-onset cases; however, no firm genotype-phenotype correlations are known [Mills et al 2006, Kanno et al 2007, Plecko et al 2007, Rankin et al 2007, Salomons et al 2007, Bennett et al 2009, Striano et al 2009, Mills et al 2010, Scharer et al 2010, Stockler et al 2011, Bok et al 2012, Tlili et al 2013, Pérez et al 2013, Van Karnebeek & Gospe 2014].

The “common” p.Glu399Gln pathogenic variant in exon 14 (see Molecular Genetics, Pathogenic allelic variants) is responsible for approximately 30% of the mutated alleles. This missense mutation has been observed in both neonatal- and late-onset cases [Bennett et al 2009].

Missense mutations that result in residual enzyme activity may be associated with a more favorable developmental phenotype [Scharer et al 2010].


First described by Hunt et al [1954], pyridoxine-dependent epilepsy is generally considered to be a rare cause of intractable neonatal seizures. Prior to the discovery of the biochemical and genetic abnormalities underlying pyridoxine-dependent epilepsy, approximately 100 affected individuals had been reported [Baxter 1999]. Subsequently, ALDH7A1 sequence analysis has been conducted and reported on many of these individuals along with several others.

Only a few epidemiologic studies of this condition have been conducted.

  • In the northern part of the United Kingdom, the prevalence of pyridoxine-dependent epilepsy in children younger than age 16 years was estimated at 1:100,000 [Baxter et al 1996].
  • National studies in the United Kingdom and the Republic of Ireland noted a prevalence of approximately 1:700,000 [Baxter 1999].
  • A survey conducted in the Netherlands estimated a birth incidence of 1:396,000 [Been et al 2005].
  • A study conducted in Germany, where pyridoxine administration is part of a standard treatment protocol for neonatal seizures, reported a birth incidence of probable cases of 1:20,000 [Ebinger et al 1999].

Differential Diagnosis

Pyridoxine-dependent epilepsy should be considered as a cause of intractable seizures presenting in neonates, infants, and children up to the third year of life for which an underlying lesion (i.e., symptomatic epilepsy) has not been identified. In particular, this diagnosis needs to be investigated in any neonate who presents with encephalopathy and seizures and in whom there is no convincing evidence of hypoxic-ischemic encephalopathy or other identifiable underlying metabolic disturbance [Baxter 1999, Gospe 2002, Stockler et al 2011].

Neonatal and Childhood Epilepsy Conditions

Other causes of neonatal intractable seizures include the following:

Pyridoxine-responsive seizures. Some children with intractable seizures may have only partial improvement in seizure control with the addition of pyridoxine. In this situation, or in instances in which seizures recur after antiepileptic drugs are withdrawn and pyridoxine is continued, individuals who have not had molecular confirmation should not be diagnosed with pyridoxine-dependent epilepsy, but rather with "pyridoxine-responsive seizures" [Baxter 1999, Basura et al 2009].

Inborn pyridoxine dependency states. While other inborn pyridoxine dependency states have been described (e.g., pyridoxine-dependent anemia and pyridoxine-dependent forms of homocystinuria, xanthurenic aciduria, and cystathioninuria), these conditions are not genetically related to pyridoxine-dependent epilepsy.

Pyridoxal phosphate-responsive epilepsy (PNPO associated). A rare form of neonatal epileptic encephalopathy associated with pathogenic variants in PNPO, the gene that encodes pyridox(am)ine 5'-phosphate oxidase, an enzyme that interconverts the phosphorylated forms of pyridoxine and pyridoxamine to the biologically active pyridoxal phosphate (PLP), has recently been characterized. The initial reports of PNPO deficiency described infants with pharmacoresistant epileptic encephalopathy in whom the seizures responded to PLP but not to pyridoxine, suggesting that this disorder is clinically distinct from pyridoxine-dependent epilepsy [Mills et al 2005, Hoffmann et al 2007, Bagci et al 2008]. However, it was subsequently demonstrated that seizures in some patients with PNPO deficiency actually responded to pyridoxine rather than to PLP [Pearl et al 2013, Mills et al 2014, Plecko et al 2014]. Therefore, patients with an epileptic encephalopathy responsive to pyridoxine who do not have mutation of ALDH7A1 should have PNPO molecular genetic testing.

Other forms of pyridoxal phosphate-responsive epilepsy. Other children with intractable epilepsy who show a clinical response to pyridoxal phosphate rather than to pyridoxine have been reported [Wang et al 2005]. The biochemical basis of the epileptic condition in these children has not been established [Baxter 2005, Gospe 2006].


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with pyridoxine-dependent epilepsy, the following are appropriate:

  • Developmental assessment
  • Medical genetics consultation

Treatment of Manifestations

In the majority of patients with pyridoxine-dependent epilepsy, once seizures come under control with the addition of daily supplements of pyridoxine (see Prevention of Primary Manifestations), all antiepileptic drugs can be withdrawn, and seizure control will continue with daily pyridoxine monotherapy in pharmacologic doses.

Special education programs should be offered.

Prevention of Primary Manifestations

The effective treatment of individuals with pyridoxine-dependent epilepsy requires lifelong pharmacologic supplements of pyridoxine; the rarity of the disorder has precluded controlled studies to evaluate the optimal dose.

The recommended daily allowance (RDA) for pyridoxine is 0.5 mg for infants and 2 mg for adults. In general, individuals with pyridoxine-dependent epilepsy have excellent seizure control when treated with 50-100 mg of pyridoxine per day. Seizures in some individuals are controlled on much smaller doses and others require somewhat higher doses [Haenggeli et al 1991, Grillo et al 2001, Basura et al 2009, Stockler et al 2011].

Affected individuals may have exacerbations of clinical seizures and/or encephalopathy during an acute illness, such as gastroenteritis or a febrile respiratory infection. To prevent such an exacerbation in these circumstances, the daily dose of pyridoxine may be doubled for several days until the acute illness resolves.

Studies have indicated that higher doses may enhance intellectual development; it has been suggested that a dose of 15-30 mg/kg/day may be optimal [Baxter 2001, Stockler et al 2011] and that the dosage should not exceed 500 mg/day [Gospe 2002, Stockler et al 2011].

Such therapy is required for life; affected individuals are metabolically dependent on the vitamin, rather than pyridoxine deficient. Compliance with pyridoxine supplementation is critical: status epilepticus may develop within days of pyridoxine discontinuation.

Prevention of Secondary Complications

The overzealous use of pyridoxine must be avoided, as a reversible sensory neuropathy (ganglionopathy) caused by pyridoxine neurotoxicity can develop. While primarily reported in adults who have received "megavitamin therapy" with pyridoxine, sensory neuropathy has been reported in two persons with pyridoxine-dependent epilepsy [McLachlan & Brown 1995, Rankin et al 2007], one of whom was an adolescent who developed a secondary cause of epilepsy and received a pyridoxine dose of 2 g/day [McLachlan & Brown 1995].


Affected individuals should be followed for the development of clinical signs of a sensory neuropathy, including regular assessments of joint-position sense, ankle jerks, gait, and station [Baxter 2001, Stockler et al 2011].

Regular assessments of intellectual function should be offered.

Evaluation of Relatives at Risk

Empiric treatment of the affected individual’s newborn sibling with pyridoxine supplementation should be offered until testing has been completed.

If the ALDH7A1 pathogenic variants in the family are known, molecular genetic testing is appropriate.

If the pathogenic variants are not known, the following is recommended:

  • If a younger sib of a proband presents with encephalopathy or a seizure, pyridoxine should be administered acutely (ideally under EEG monitoring) for both diagnostic and therapeutic purposes.
  • α-AASA is a sensitive biomarker for pyridoxine-dependent epilepsy while pipecolic acid is an indirect and less sensitive biomarker. If elevated plasma biomarker concentrations have been demonstrated in the proband, a similar elevation in a younger sib would support a diagnosis of pyridoxine-dependent epilepsy.

Note: It would be unlikely for the proband's older sibs who have not experienced seizures to be pyridoxine dependent.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

As recurrence risk for couples who have a child with this disorder is 25%, there is justification to treat the mother empirically with supplemental pyridoxine at a dose of 50-100 mg per day throughout the last half of her subsequent pregnancies and to treat the newborn with supplemental pyridoxine to prevent seizures and reduce the risk of neurodevelopmental disability [Baxter & Aicardi 1999, Gospe 2002, Bok et al 2010a]. It is important to emphasize, however, that at least one severe phenotype has been described in a family in which prenatal treatment of an at-risk sib did not result in an improved neurodevelopmental outcome [Rankin et al 2007]. Molecular genetic testing of ALDH7A1 can be performed after birth; if both pathogenic variants are present, pyridoxine treatment should be continued; if not, treatment can be withdrawn.

Therapies Under Investigation

As ALDH7A1 encodes the enzyme α-aminoadipic semialdehyde dehydrogenase (antiquitin), which is involved in cerebral lysine catabolism, it has been proposed that persons with pyridoxine-dependent epilepsy may benefit from a lysine-restricted diet. A small number of individuals have been treated in this fashion; improvements in development and behavior along with decreased biomarker levels have been described [Stockler et al 2011, Van Karnebeek et al 2012]. A protocol for controlled therapeutic trials of lysine restriction in pyridoxine-dependent epilepsy has recently been proposed [Van Karnebeek et al 2014].

A cellular proof-of-concept for antisense therapy of pyridoxine-dependent epilepsy has recently been reported [Pérez et al 2013]. Specifically, the silent nucleotide change c.75C>T, a novel splicing mutation creating a new donor splice site in exon 1, could be rescued in a lymphoblast cell line via antisense therapy.

Search for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Pyridoxine-dependent epilepsy is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.
  • Even if the sibs of a proband are asymptomatic, molecular genetic testing to determine their genetic status should be considered for the purpose of early diagnosis and treatment of those who have inherited both pathogenic variants (see Management, Evaluation of Relatives at Risk).

Offspring of a proband

  • Adults diagnosed with the disorder are being followed, but the fertility status of these individuals is not known, and there are no published reports concerning the offspring of individuals with pyridoxine-dependent epilepsy.
  • The genetic status of the offspring will depend on the genetic status of the reproductive partner of the proband.
    • If the reproductive partner is not affected and not a carrier, all offspring will be carriers.
    • If the reproductive partner is a carrier of an ALDH7A1 pathogenic variant, each child will have a 50% chance of being affected and a 50% chance of being a carrier.
    • If the reproductive partner is also affected, all offspring will be affected.
  • Heterozygotes (carriers) are asymptomatic.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of an ALDH7A1 pathogenic variant.

Carrier Detection

Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the ALDH7A1 pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the ALDH7A1 pathogenic variants have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Epilepsy Society (AES)
  • Epilepsy Foundation
    8301 Professional Place East
    Suite 200
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
  • Pyridoxine-Dependent Seizures Registry
    Seattle Children's Hospital
    4800 Sand Point Way NE
    Neurology, MB.7.420
    Seattle WA 98105
    Phone: 206-987-2078
    Fax: 206-987-2649

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Pyridoxine-Dependent Epilepsy: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Pyridoxine-Dependent Epilepsy (View All in OMIM)


Molecular Genetic Pathogenesis

For many years, it was hypothesized that pyridoxine-dependent epilepsy was caused by an abnormality of the enzyme glutamic acid decarboxylase (GAD), which uses PLP as a cofactor. GAD converts glutamic acid, an excitatory neurotransmitter, into gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter. Both of these neurotransmitters play important roles in the control of epileptic processes. A number of clinical neurochemical studies indirectly supported this hypothesis. However, several laboratories failed to document genetic linkage of the phenotype to either isoform of GAD [Kure et al 1998, Battaglioli et al 2000, Cormier-Daire et al 2000].

A genome-wide linkage scan utilizing five families of North African descent (4 of whom were consanguineous) mapped a locus for pyridoxine-dependent epilepsy at chromosome 5q31 [Cormier-Daire et al 2000]. The recently identified gene ALDH7A1 maps to this region. Pathogenic variants in ALDH7A1 have been demonstrated to cause pyridoxine-dependent epilepsy. ALDH7A1 encodes the protein α-aminoadipic semialdehyde dehydrogenase (also referred to as antiquitin), an aldehyde dehydrogenase with a previously unknown physiologic substrate [Lee et al 1994]. It has now been demonstrated that antiquitin functions as a Δ1-piperideine-6-carboxylate (P6C)-α-AASA dehydrogenase. Abnormal activity of this enzyme results in increased levels of P6C, which is the cyclic Schiff base of α-AASA; these two substances are in equilibrium with one another. P6C, in turn, inactivates PLP by condensing with the cofactor, likely resulting in abnormal metabolism of neurotransmitters [Mills et al 2006]. Antiquitin has been shown to localize to radial glia, astrocytes, and ependymal cells but not to neurons. Deficiency of this protein in pyridoxine-dependent epilepsy is associated with neuronal migration abnormalities and other forms of brain dysgenesis, such as thinning of the corpus callosum [Jansen et al 2014; Friedman et al, in press]. These neurodevelopmental aspects of antiquitin deficiency are not reversible with pyridoxine treatment or lysine restriction.

Gene structure. ALDH7A1 has 1809 bases and comprises 18 exons that range from 42 bp to 352 bp in size. The coding region is 1533 bp in length. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Pathogenic variants have been documented in more than 100 affected families (see Table 1). These include a variety of missense mutations, single-base deletions, nonsense mutations (probably leading to nonsense-mediated mRNA decay), splice site mutations (predicted to cause exon skipping), and exonic deletions. Individuals who are either homozygous for a particular pathogenic variant or compound heterozygous for two pathogenic variants have been reported [Mills et al 2006, Plecko et al 2007, Rankin et al 2007, Salomons et al 2007, Bennett et al 2009, Gallagher et all 2009, Striano et al 2009, Mills et al 2010, Scharer et al 2010, Bok et al 2012, Tlili et al 2013].

Nine pathogenic variants represent 61% of disease alleles and several studies have demonstrated that the glutamine 399 residue is mutated at a frequency of 33%, with the p.Glu399Gln (NM_001182.2:c.1195G>C) pathogenic variant being most common [Plecko et al 2007, Salomons et al 2007, Bennett et al 2009, Mills et al 2010, Scharer et al 2010, Bok et al 2012].

Normal gene product. ALDH7A1 encodes a protein with 510 amino-acid residues [Mills et al 2006]. The deduced molecular weight of the encoded Δ1-piperideine-6-carboxylate (P6C)-α-AASA dehydrogenase protein (antiquitin) is 55285 [Lee et al 1994].

Abnormal gene product. In one study, the two missense mutations, one nonsense mutation, and the one documented single-base deletion all result in absent α-AASA dehydrogenase enzyme activity while the second nonsense mutation resulted in α-AASA dehydrogenase enzyme activity that was 1.8% of normal [Mills et al 2006]. The effect of selected ALDH7A1 mutations on antiquitin function has been studied by expressing human antiquitin cDNA in E. coli with reduced or absent enzyme activity being demonstrated [Coulter-Mackie et al 2012, Coulter-Mackie et al 2014]. This experimental system may help characterize the pathogenicity of ALDH7A1 variants. Molecular modeling indicates that missense mutations are divided into three categories [Scharer et al 2010]:

  • Mutations that affect NAD+ cofactor binding or catalysis;
  • Mutations that alter the substrate binding pocket; and
  • Mutations that potentially disrupt dimer or tetramer assembly of the antiquitin protein.


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Chapter Notes

Author Notes

Pyridoxine-Dependent Seizures Patient Registry

For diagnosed patients in the United States and Canada, operated through Seattle Children's Hospital in Seattle, WA. The registry may be contacted through the author or at gro.snerdlihcelttaes@enixodiryp.

Revision History

  • 19 June 2014 (me) Comprehensive update posted live
  • 7 June 2012 (sg) Revision: Table 1 updated
  • 26 April 2012 (sg) Revision: additions to molecular genetic testing table (Table 1); references added
  • 1 March 2012 (me) Comprehensive update posted live
  • 10 November 2009 (me) Comprehensive update posted live
  • 24 July 2007 (cd) Revision: clinical testing available: analyte and sequence analysis; prenatal diagnosis
  • 9 June 2006 (sg) Revision: mutations in ALDH7A1 found to be causative
  • 8 March 2006 (me) Comprehensive update posted to live Web site
  • 18 December 2003 (me) Comprehensive update posted to live Web site
  • 7 December 2001 (me) Review posted to the live Web site
  • 17 September 2001 (sg) Original submission
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