DiagnosisClinical DiagnosisAs recommended by Goutières & Aicardi [1985], pyridoxine dependency should be considered as the cause of intractable seizures in the following situations: 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 disabilityNeonates with hypoxic ischemic encephalopathy and difficult-to-control seizuresPatients with a history of transient or unclear response to pyridoxinePatients with a history of response to folinic acid and/or with the characteristic chromatographic pattern of folinic acid-responsive seizures on cerebrospinal fluid monoamine analysisSeizures in any child under age one year without an apparent brain malformation as the cause of the epilepsyA 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 medications, 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. Screening of at-risk persons via measurement of biomarkers in urine, plasma, or cerebrospinal fluid is becoming more available and this confirmatory clinical step is now frequently omitted (see Testing). TestingPipecolic 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 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]. Molecular Genetic Testing Gene. ALDH7A1 is the only gene in which mutations are known to cause pyridoxine-dependent epilepsy [Mills et al 2006].Evidence for locus heterogeneityAssignment 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]. ALDH7A1 mutations were not detected in these children, or in two other children presenting with pyridoxine-responsive late-onset infantile spasms responsive to pyridoxine [Bennett et al 2009]. 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 testingTable 1. Summary of Molecular Genetic Testing Used in Pyridoxine-Dependent EpilepsyView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityClassic Early-Onset SeizuresLate-Onset SeizuresALDH7A1Sequence analysisSequence variants 278/84 3, 4, 55/8 5, 6, 7ClinicalDeletion / duplication analysis 8Exonic or whole-gene deletions / duplications2 individuals with exonic deletions have been reported 3, 9Unknown; none reported 91. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. 78/84 families with early-onset seizures had two identifiable mutations (2 of which were exonic deletions), five had only one identifiable mutation associated with elevated plasma pipecolic acid concentration or urinary α-AASA concentration, and one had no mutations 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]. 4. Mills et al [2006], Plecko et al [2007], and Scharer et al [2010] studied 39 families with "classic neonatal pyridoxine-dependent epilepsy," all of whom were determined to be homozygous or compound heterozygous for mutations in ALDH7A. These include a variety of missense mutations, nonsense mutations, single base deletions, and splice site mutations. One of the mutated alleles was a deletion of exon 7 [Plecko et al 2007]. No individuals with atypical presentation were included in the three studies. Kanno et al [2007] reported five individuals with neonatal-onset pyridoxine-dependent epilepsy that was clinically proven by pyridoxine withdrawal. Four were compound heterozygotes for mutations in ALDH7A1; one of these mutated alleles was a deletion of exon 17. In one individual, mutations were not detected. This individual had normal plasma levels of pipecolic acid, and therefore it is unlikely that mutations in ALDH7A1 are responsible for the seizures that are clinically pyridoxine-dependent. Bennett et al [2009] studied 18 kindreds with pyridoxine dependency. Of 12 with classic neonatal-onset seizures, 11 were either homozygous or compound heterozygous for mutations in ALDH7A1; one had one mutated allele along with a significant elevation in plasma pipecolic acid concentration. 5. Mills et al [2010] studied an additional 30 families with pyridoxine-dependent epilepsy, two of whom had late-onset seizures developing at ages eight and 14 months. Twenty-seven of the families were either homozygous or compound heterozygous for mutations in ALDH7A1. Only one mutated allele was detected in the remaining three families.6. 4/8 familes with late-onset seizures had two identifiable mutations, while one had only one mutation [Bennett et al 2009, Mills et al 2010].7. Bennett et al [2009] studied 18 kindreds with pyridoxine dependency. Of six with late-onset pyridoxine-dependent epilepsy, three were either homozygous or compound heterozygous for mutations in ALDH7A1; three had no detectable ALDH7A1 mutations.8. Testing that identifies deletions/duplications not readily 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.9. Two individuals with neonatal-onset pyridoxine-dependent epilepsy have been reported with compound heterozygote mutations. One mutation was detected by sequence analysis; the second was demonstrated to be an exonic deletion [Kanno et al 2007, Plecko et al 2007]. No deletions or duplications involving ALDH7A1 have been reported to cause late-onset pyridoxine-dependent epilepsy. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband. Once a clinical diagnosis of pyridoxine dependency has been established by demonstrating cessation of seizures after the addition of pyridoxine to the treatment regimen, biochemical and molecular confirmation is recommended. 1.Measurement of plasma or urinary α-AASA concentration should be conducted. Alternatively, measurement of plasma levels of the indirect biomarker pipecolic acid can be considered. Elevated levels would be strongly supportive of a diagnosis of pyridoxine-dependent epilepsy. 2.Sequence analysis of ALDH7A1 should then be conducted.
Note: No deletions or duplications involving ALDH7A1 have been reported to cause pyridoxine-dependent epilepsy. Thus, the usefulness of deletion/duplication analysis is unknown. Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Predictive testing for at-risk newborn sibs requires prior identification of the disease-causing mutations in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersA small number of infants with intractable seizures either unresponsive or partially responsive to pyridoxine but responsive to folinic acid (folinic acid- responsive seizures) have been described [Hyland et al 1995, Torres et al 1999, Nicolai et al 2006]. Elevated levels of α-AASA and mutations in ALDH7A1 have now been demonstrated in these children, indicating that folinic acid-responsive seizures are allelic to pyridoxine-dependent epilepsy [Gallagher et al 2009].}

Natural HistoryThe one clinical feature characteristic of all individuals with pyridoxine-dependent epilepsy is intractable seizures that are not controlled with antiepileptic medications 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. Some affected individuals with normal intellectual function have been reported [Haenggeli et al 1991, Ohtsuka et al 1999, Basura et al 2009]. It has been suggested that an earlier onset of clinical seizures has 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 medications is required. Significant intellectual disability is present in these individuals [Basura et al 2009, Scharer et al 2010].Prenatal (maternal) treatment of an at-risk fetus with supplemental pyridoxine may improve neurodevelopmental outcome [Baxter & Aicardi 1999, Bok et al 2010a]. However, this may not always be the case: in one family, affected children had severe neurodevelopmental disability despite fetal and early postnatal treatment [Rankin et al 2007]. Few formal psychometric assessments in individuals with pyridoxine-dependent epilepsy have been performed. These limited studies indicate that verbal skills are more impaired than nonverbal skills [Baxter et al 1996, Baynes et al 2003]. 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 (up to 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; and Prolonged seizure-free intervals (up to age 5 1/2 months) that occur after pyridoxine discontinuation. While some late-onset cases have been demonstrated to have mutations in ALDH7A1, other cases have not shown sequence alterations, elevated levels of biochemical markers, or linkage to the 5q31 locus [Bennett et al 2005, Kabakus et al 2008, Bennett et al 2009] (see Differential Diagnosis).EEG/neuroimaging. While a variety of EEG [Mikati et al 1991, Nabbout et al 1999, Naasan et al 2009, Bok et al 2010b, Mills et al 2010, Schmitt et al 2010] and imaging abnormalities [Baxter et al 1996, Gospe & Hecht 1998, Mills et al 2010] have been described in individuals with pyridoxine-dependent epilepsy, none is pathognomonic for this disorder.

Genotype-Phenotype CorrelationsMore than 60 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]. Nine mutations represent 61% of disease alleles, with the “common” p.Glu399Gln (see Molecular Genetics, Pathologic allelic variants) mutation being 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].

Differential DiagnosisPyridoxine-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]. Genetic heterogeneity for pyridoxine-dependent epilepsy has been established; see Molecular Genetic Testing, Evidence for locus heterogeneity. 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 anticonvulsants are withdrawn and pyridoxine is continued, individuals who have not had biochemical or molecular confirmation should not be diagnosed with pyridoxine-dependent epilepsy, but rather with "pyridoxine-responsive seizures" [Baxter 1999, Basura et al 2009]. Of note, one such individual with intractable epilepsy only partially responsive to pyridoxine has been demonstrated to have ALDH7A1 mutations, indicating that a secondary cause of epilepsy likely developed [Bennett et al 2009].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.A rare form of neonatal epileptic encephalopathy that responds to pyridoxal phosphate (PLP), but not pyridoxine, has been reported. Affected individuals have mutations in PNPO, the gene that encodes pyridox(am)ine 5'-phosphate oxidase, an enzyme that interconverts the phosphorylated forms of pyridoxine and pyridoxamine to PLP [Mills et al 2005, Hoffmann et al 2007, Bagci et al 2008]. The seizures in infants with this condition do not respond to pyridoxine; therefore, this disorder is clinically distinct from pyridoxine-dependent 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]. Other causes of neonatal intractable seizures include the following:"Folinic acid-responsive seizures," a rare and poorly characterized condition. Affected neonates respond to daily folinic acid (citrovorum factor) supplementation [Hyland et al 1995, Torres et al 1999, Nicolai et al 2006]. Folinic acid-responsive seizures have been demonstrated to be allelic with pyridoxine-dependent epilepsy [Gallagher et al 2009]. (See Genetically Related Disorders.)Lissencephaly or other brain malformations that are distinguishable by the presence of structural brain malformations. (See Fukuyama Congenital Muscular Dystrophy, DCX-Related Disorders, and LIS1-Associated Lissencephaly/Subcortical Band Heterotopia.) Other rare inborn errors of metabolism that are identified by elevated ammonia, lactate, or anion gap on laboratory testing Severe acquired neurologic disorders such as intracerebral hemorrhage or infectious diseases (meningitis, encephalitis) Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with pyridoxine-dependent epilepsy, developmental assessment is appropriate.Treatment of ManifestationsIn 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 medications can be withdrawn, and seizure control will continue with daily pyridoxine monotherapy in pharmacologic doses. Special education programs should be offered.Prevention of Primary ManifestationsThe 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 15-18 mg/kg/day may be optimal [Baxter 2001] and that the dosage should not exceed 500 mg/day [Gospe 2002]. 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 ComplicationsThe 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]. SurveillanceAffected 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].Regular assessments of intellectual function should be offered.Evaluation of Relatives at RiskEmpiric treatment of the newborn with pyridoxine supplementation should be offered until testing has been completed.If the disease-causing mutations in the family are known, molecular genetic testing is appropriate. If the mutations 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 ManagementAs 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]. Molecular genetic testing of ALDH7A1 can be performed after birth; if both disease-causing mutations are present, pyridoxine treatment should be continued; if not, treatment can be withdrawn. 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].Therapies Under InvestigationAs 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. Fewer than ten individuals have been treated in this fashion; improvements in development and behavior along with decreased biomarker levels have been described [Stockler et al 2011]. Protocols for controlled therapeutic trials of lysine restriction are currently under development.Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDALDH7A15q23​.2Alpha-aminoadipic semialdehyde dehydrogenaseBIOMDB: Database of Mutations Causing Tetrahyrdobiopterin Deficiencies
Aldehyde Dehydrogenase Gene Superfamily Resource
ALDH7A1 homepage - Mendelian genesALDH7A1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name 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) View in own window 107323ALDEHYDE DEHYDROGENASE 7 FAMILY, MEMBER A1; ALDH7A1 266100EPILEPSY, PYRIDOXINE-DEPENDENT; EPDMolecular Genetic PathogenesisFor 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. Mutations 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]. Normal allelic variants. 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. Pathologic allelic variants. Mutations have been documented in more than 70 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 mutation or compound heterozygous for two mutations 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]. 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) mutation being most common [Plecko et al 2007, Salomons et al 2007, Bennett et al 2009, Mills et al 2010, Scharer et al 2010]. 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. 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]. 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; andMutations that potentially disrupt dimer or tetramer assembly of the antiqutin protein.