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Pyridoxine-Dependent Epilepsy – ALDH7A1

Synonyms: AASADH Deficiency, ALDH7A1 Deficiency, Alpha Aminoadipic Semialdehyde (α-AASA) Dehydrogenase Deficiency, Antiquitin (ATQ) Deficiency, PDE-ALDH7A1

, MD, PhD.

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Initial Posting: ; Last Update: July 29, 2021.

Estimated reading time: 30 minutes

Summary

Clinical characteristics.

Pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) is characterized by seizures not well controlled with anti-seizure medications that are responsive clinically and electrographically to large daily supplements of pyridoxine (vitamin B6). This is true across a phenotypic spectrum that ranges from classic to atypical PDE-ALDH7A1. Intellectual disability is common, particularly in classic PDE-ALDH7A1.

  • Classic PDE-ALDH7A1. Untreated seizures begin within the first weeks to months of life. Dramatic presentations 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. Electrographic seizures can occur without clinical correlates.
  • Atypical PDE-ALDH7A1. Findings in untreated individuals can include late-onset seizures beginning between late infancy and age three years, seizures that initially respond to anti-seizure medications and then become intractable, seizures during early life that do not respond to pyridoxine but are subsequently controlled with pyridoxine several months later, and prolonged seizure-free intervals (≤5 months) that occur after discontinuation of pyridoxine.

Diagnosis/testing.

The diagnosis of PDE-ALDH7A1 is suspected in a proband with seizures responsive to pyridoxine administration and increased concentration of α-aminoadipic semialdehyde (α-AASA) in urine and/or plasma. The diagnosis is established in a proband with suggestive clinical findings and biallelic pathogenic variants in ALDH7A1 identified by molecular genetic testing.

Management.

Treatment of manifestations: The International PDE Consortium has published clinical practice guidelines for PDE-ALDH7A1. Effective treatment requires lifelong pharmacologic supplements of pyridoxine; the rarity of the disorder has precluded controlled studies to evaluate the optimal dose. The guidelines recommend the following doses by age: newborns 100 mg/day; infants 30 mg/kg/day with a maximum of 300 mg/day; and children, adolescents, and adults 30 mg/kg/day with a maximum of 500 mg/day. To prevent exacerbation of clinical seizures and/or encephalopathy during an acute illness, the daily dose of pyridoxine may be doubled for several days.

Developmental delay and/or intellectual disability are managed per standard practice.

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

Surveillance: Monitoring for development of clinical signs of a sensory neuropathy; regular assessments of developmental progress and educational needs.

Evaluation of relatives at risk: Prenatal molecular genetic testing of fetuses at risk may be performed to inform maternal pyridoxine supplementation during pregnancy and facilitate initiation of treatment at birth. If prenatal testing has not been performed on a pregnancy at risk, empiric pyridoxine supplementation should be offered the neonate until molecular genetic testing for the family-specific ALDH7A1 variants has been completed.

Pregnancy management: Maternal supplemental pyridoxine at a dose of 50-100 mg/day throughout the last half of pregnancy and after birth may be considered if the fetus is known to be affected or, if diagnostic prenatal testing is not pursued, in an at-risk fetus and neonate, until the diagnosis has been ruled out.

Genetic counseling.

PDE-ALDH7A1 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ALDH7A1 pathogenic variant, each sib of an affected individual has at conception 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. Once the ALDH7A1 pathogenic variants have been identified in an affected family member, carrier testing for relatives at risk, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for PDE-ALDH7A1 are possible.

Diagnosis

Suggestive Findings

Pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) should be suspected in individuals with the following clinical findings, supportive laboratory findings, and family history.

Clinical features

  • Seizures in any child younger than age one year without an apparent brain malformation or acquired brain injury as the cause of the epilepsy
  • Cryptogenic seizures in a previously normal infant without an abnormal gestational or perinatal history
  • Neonates with a phenotype suggestive of hypoxic ischemic encephalopathy and with difficult-to-control seizures
  • The occurrence of long-lasting focal or unilateral seizures, resistant to anti-seizure medications, often with partial preservation of consciousness
  • Infants and children with seizures that are partially responsive to anti-seizure medications, in particular if associated with developmental delay and intellectual disability
  • Signs of encephalopathy including irritability, restlessness, abnormal crying, and vomiting preceding and/or following the actual seizures
  • Individuals with a history of transient or unclear response of seizures to pyridoxine
  • Infants and children with a history of seizures responsive to folinic acid

Aclinical diagnosis of pyridoxine-dependent epilepsy may be made:

  • On an acute basis in individuals experiencing prolonged clinical seizures (i.e., status epilepticus) by concurrently administering 100 mg of pyridoxine intravenously while monitoring the EEG, oxygen saturation, and vital signs [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. Note: 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 to individuals with pyridoxine-dependent epilepsy presenting with frequent seizures; clinical seizures should cease within three to five days [Baxter 2001, Stockler et al 2011].

Note: In the past, the clinical diagnosis of pyridoxine-dependent epilepsy was confirmed by withdrawing anti-seizure medications, followed by the withdrawal of daily pyridoxine supplementation and then successfully treating a recurrence of seizures with pyridoxine. Now that measurement of the biomarker α-AASA in urine and/or plasma – supportive of a diagnosis of pyridoxine-dependent epilepsy – is clinically available, this sequence of therapeutic changes is not necessary. In an individual with a clinical phenotype suggestive of pyridoxine-dependent epilepsy, daily pyridoxine supplementation should be continued while biomarker testing is pursued.

Supportive laboratory findings

  • Elevated plasma and urinary levels of alpha-aminoadipic semialdehyde (α-AASA)
  • Elevated concentrations of pipecolic acid in plasma and cerebral spinal fluid
    Note: Pipecolic acid concentrations may normalize after many years of therapy [Plecko et al 2005].
  • Analysis of cerebrospinal fluid monoamine metabolites via HPLC with electrochemical detection demonstrating a pattern characteristic of pyridoxine-dependent epilepsy and folinic acid-responsive seizures containing two peaks of unknown identity [Gallagher et al 2009]

Family history

  • Consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.
  • A severe convulsive disorder in a sib, often leading to death during status epilepticus

Treatment with pharmacologic doses of pyridoxine should begin immediately when concern for PDE-ALDH7A1 has been raised while additional testing is being performed to establish the genetic diagnosis. Specifically, newborns should receive 100 mg/day of pyridoxine, infants should receive 30 mg/kg/day with a maximum of 300 mg/day, and children and adolescents should receive 30 mg/kg/day with a maximum dose of 500 mg/day [Coughlin et al 2021].

Establishing the Diagnosis

The diagnosis of PDE-ALDH7A1 is established in a proband with suggestive findings and biallelic pathogenic variants in ALDH7A1 identified by molecular genetic testing (see Table 1).

Note: Previously when deletion/duplication analysis was not widely available, a diagnosis of PDE-ALDH7A1 could be made in an individual with one ALDH7A1 pathogenic variant detected by sequence analysis, clinical features consistent with PDE, and unequivocal elevation of the biomarker α-AASA in urine and/or plasma (i.e., the requirements for registration in the International PDE registry).

Note: Identification of biallelic ALDH7A1 variants of uncertain significance (or identification of one known ALDH7A1 pathogenic variant and one ALDH7A1 variant of uncertain significance) does not establish or rule out a diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing).

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of PDE-ALDH7A1 has not been considered or who had normal results on a multigene panel are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

A multigene panel (e.g., comprehensive epilepsy panel, infantile epilepsy panel, epilepsy advanced sequencing evaluation, or epileptic encephalopathy panel) that includes ALDH7A1 and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensivegenomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used [Costain et al 2019]; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Pyridoxine-Dependent Epilepsy – ALDH7A1

Gene 1MethodProportion of Pathogenic Variants 2 Detectable by Method
ALDH7A1 Sequence analysis 3>95% 4, 5
Gene-targeted deletion/duplication analysis 6<5% 4
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

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

4.

Data derived from Coughlin et al [2019] and the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017].

5.

Deep intronic variants may be missed by sequence analysis that includes exons and flanking regions only. ALDH7A1 variant c.696-502G>C results in introduction of a cryptic acceptor splice site, activation of a cryptic donor splice site, and introduction of a pseudoexon between exons 7 and 8 [Milh et al 2012].

6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

The one clinical feature characteristic of all individuals with pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) is seizures that are not well controlled with anti-seizure medications but that respond to large daily supplements of pyridoxine (vitamin B6). This is true across the phenotypic spectrum that ranges from classic to atypical PDE-ALDH7A1. Intellectual disability is common.

Classic PDE-ALDH7A1

Seizures. Newborns with the classic neonatal presentation begin to experience seizures soon after birth. However, 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].

Multiple types of clinical seizures have been reported in untreated infants and children. While dramatic presentations consisting of prolonged seizures and recurrent episodes of status epilepticus are typical, recurrent self-limited events including partial, generalized, and atonic seizures, myoclonic events, and infantile spasms also occur. Affected individuals may have electrographic seizures without clinical correlates. Clinical seizures may be associated with facial grimacing and abnormal eye movements [van Karnebeek et al 2016].

Untreated affected neonates frequently have periods of encephalopathy (irritability, crying, fluctuating tone, poor feeding) that precede the onset of clinical seizures. Low Apgar scores, abnormal umbilical 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 initially diagnosed with hypoxic-ischemic encephalopathy [Mills et al 2010, van Karnebeek et al 2016].

Similar periods of encephalopathy may be seen in older infants, particularly prior to recurrence of clinical seizures that occur in children treated with pyridoxine whose vitamin B6 requirement may have increased because of growth and/or intercurrent infection, particularly gastroenteritis.

Intellectual function. Intellectual disability, particularly with expressive language, is common. It has been suggested that an earlier onset of clinical seizures corresponds to a worse prognosis for cognitive function, and that the length of the delay in diagnosis and initiation of effective pyridoxine treatment correlates with increased risk for intellectual disability [Baxter 2001, Basura et al 2009, de Rooy et al 2018].

Individuals in whom seizures are incompletely controlled with pyridoxine require concurrent treatment with one or more anti-seizure medications and have significant intellectual disability [Basura et al 2009, van Karnebeek et al 2016].

Some affected individuals with normal intellectual function have been reported [Basura et al 2009, Bok et al 2012, van Karnebeek et al 2016, de Rooy et al 2018].

The few formal psychometric assessments that have been performed have had inconsistent findings. Two early studies indicated that verbal skills were more impaired than nonverbal skills [Baxter et al 1996, Baynes et al 2003] whereas a more recent report suggests that verbal IQ is slightly (but not significantly) higher than performance IQ [Bok et al 2012].

Atypical PDE-ALDH7A1

Late-onset and other atypical features of PDE-ALDH7A1 can include the following [Basura et al 2009, van Karnebeek et al 2016].

Seizures

  • Late-onset seizures (i.e., beginning after age 2 months). Some individuals present after one year of age and as late as adolescence.
  • Seizures that initially respond to anti-seizure medications but then become intractable
  • Seizures during early life that do not respond to pyridoxine but are controlled with pyridoxine several months later
  • Prolonged seizure-free intervals (age ≤5 months) that occur after pyridoxine discontinuation
  • Folinic acid-responsive seizures. A small number of infants have intractable seizures that are either unresponsive or partially responsive to pyridoxine but responsive to folinic acid. Elevated levels of α-AASA and biallelic pathogenic variants in ALDH7A1 in these children indicate that folinic acid-responsive seizures are part of the phenotypic continuum of PDE-ALDH7A1 [Gallagher et al 2009].

Intellectual function. Variable degrees of intellectual disability have been described in individuals with atypical PDE-ALDH7A1. The more favorable cognitive outcome more commonly observed in persons with the late-onset phenotype may be due to a combination of factors, most notably the lack of neonatal seizure-induced brain injury [de Rooy et al 2018].

Classic PDE-ALDH7A1 and Atypical PDE-ALDH7A1

EEG. While a variety of EEG abnormalities have been described, none is pathognomonic for PDE-ALDH7A1 [Mills et al 2010, Schmitt et al 2010]. For infants with status epilepticus who receive intravenous pyridoxine while undergoing EEG monitoring, an electrographic response to the vitamin is commonly recorded but is not specific for the disease [Bok et al 2010].

Neuroimaging. MRI abnormalities (Figure 1) reported include the following:

Figure 1.

Figure 1.

Mid-sagittal magnetic resonance image of the brain from an adult male with PDE-ALDH7A1 demonstrating both thinning of the isthmus of the corpus callosum (red arrow) and mega cisterna magma (blue arrow)

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

The common p.Glu427Gln pathogenic variant in exon 14 accounts for approximately 33% of pathogenic variants [Coughlin et al 2019]. Homozygous p.Glu427Gln variants have been observed in both neonatal- and late-onset PDE-ALDH7A1 [Bennett et al 2009].

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

Nomenclature

Pyridoxine-responsive seizures. Children with findings suggestive of pyridoxine-dependent epilepsy (i.e., children with intractable seizures who have only partially improved seizure control with the addition of pyridoxine and children in whom seizures recur after anti-seizure medications are withdrawn and pyridoxine is continued) who have not had molecular confirmation of one of the three pyridoxine-dependent epilepsies should be diagnosed with "pyridoxine-responsive seizures" rather than pyridoxine-dependent epilepsy (see Differential Diagnosis).

Prevalence

First described by Hunt et al [1954], pyridoxine-dependent epilepsy is generally considered to be a rare cause of intractable neonatal seizures. In addition to PDE-ALDH7A1, two other genetic causes of pyridoxine-dependent epilepsy (PDE-PLPBP and PDE-PNPO) have been characterized (see Differential Diagnosis).

As of 2019, 185 individuals with PDE-ALDH7A1 have been reported, with an estimated incidence of 1:64,352 live births [Coughlin et al 2019].

Differential Diagnosis

Pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) should be considered as a cause of intractable seizures presenting in neonates, infants, children, and adolescents for which an underlying lesion (i.e., symptomatic epilepsy) has not been identified. In particular, this diagnosis needs to be investigated in any neonate with encephalopathy and seizures in whom there is no convincing evidence of hypoxic-ischemic encephalopathy or other identifiable underlying metabolic disturbance [Baxter 1999, Stockler et al 2011, van Karnebeek et al 2016].

Pyridoxine-Dependent Epilepsies

Pyridoxine-dependent epilepsy – PLPBP (PDE-PLPBP) (OMIM 617290), also referred to as PLP binding protein deficiency, is caused by biallelic pathogenic variants in PLPBP (formerly PROSC), which encodes a protein involved in the intracellular homeostatic regulation of pyridoxal 5'-phosphate (PLP), the biologically active form of pyridoxine [Darin et al 2016]. To date, a total of 23 affected individuals have been reported [Johnstone et al 2019].

Initially seven individuals with PDE-PLPBP were reported (3 from 1 kindred). Six of the seven affected individuals experienced clinical seizures on the first day of life, whereas the other affected individual's first seizure occurred at age one month. Three of the affected individuals were reported to have abnormal intrauterine movements; four showed signs of fetal distress, including metabolic acidosis with increased blood lactate levels within the first few days of life. While all seven demonstrated a clinical response to treatment with pyridoxine, five of the six surviving affected individuals also required the use of anti-seizure medications. With the exception of the one person whose seizures developed at age one month, all affected individuals have acquired microcephaly. All of the six surviving affected individuals have some degree of speech, motor, and learning developmental delays.

Pyridoxine-dependent epilepsy – PNPO (PDE-PNPO) (OMIM 610090), also referred to as pyridoxal phosphate-responsive pyridoxine phosphate oxidase deficiency epilepsy, is caused by biallelic pathogenic variants in PNPO, which encodes an enzyme that interconverts the phosphorylated forms of pyridoxine and pyridoxamine to biologically active pyridoxal 5'-phosphate (PLP). To date a total of 87 individuals with PDE-PNPO have been reported [Alghamdi et al 2021].

The initial reports of PDE-PNPO described infants with pharmacoresistant epileptic encephalopathy in whom the seizures responded to PLP but not to pyridoxine, suggesting that this disorder was clinically distinct from PDE-ALDH7A1 [Mills et al 2005]. However, it was subsequently demonstrated that seizures in some individuals with PNPO deficiency actually responded to pyridoxine rather than to PLP [Mills et al 2014, Plecko et al 2014]. Therefore, PNPO molecular genetic testing should be considered in persons with an epileptic encephalopathy responsive to pyridoxine who do not have pathogenic variants in either ALDH7A1 or PLPBP.

Neonatal and Childhood Epilepsy Conditions

Other causes of intractable neonatal seizures include the following:

  • A variety of single-gene disorders that result in neonatal/infantile seizures; the products of these genes may underlie the function of ion channels, signaling pathways, and transcription factors, among others [Mastrangelo & Leuzzi 2012]. In particular, a positive effect of vitamin B6 on seizures was described in a few individuals with KCNQ2-related neonatal epileptic encephalopathy (see KCNQ2-Related Disorders) [Reid et al 2016]; however, further studies are needed to confirm the anti-seizure effect of pyridoxine in the absence of an inherited disorder of vitamin B6 metabolism.
  • Epileptic encephalopathies associated with copy number variants resulting in chromosome deletions or duplications [Mefford et al 2011]
  • 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)

Other causes of neonatal seizures in which elevated levels of α-AASA may be present 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 seizure medications are withdrawn and pyridoxine is continued, individuals who have not had molecular confirmation of one of the three pyridoxine-dependent epilepsies should be diagnosed 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 [OMIM 236800], and cystathioninuria [OMIM 219500]), these conditions are not genetically related to pyridoxine-dependent epilepsy.

Management

Clinical practice guidelines for pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) have been published [Coughlin et al 2021].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PDE-ALDH7A1, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

  • Developmental assessment to include motor, adaptive, cognitive, & speech/language evaluation
  • Evaluation for early intervention programs / special education
  • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of PDE-ALDH7A1 in order to facilitate medical and personal decision making

Treatment of Manifestations

In the majority of individuals with PDE-ALDH7A1, once seizures come under control with the addition of daily supplements of pyridoxine (see Prevention of Primary Manifestations), all anti-seizure medications can be withdrawn, and seizure control will continue with daily pyridoxine monotherapy in pharmacologic doses.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • Individualized education plan (IEP) services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction. For individuals with delays in gross motor function, physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses or feeding refusal that is not otherwise explained.

Communication issues. As expressive language difficulties are common in PDE-ALDH7A1, consider evaluation by a speech-language pathologist. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of speech therapy. This may include alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.

Social/Behavioral Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Prevention of Primary Manifestations

Because individuals with PDE-ALDH7A1 are metabolically dependent on pyridoxine (rather than pyridoxine deficient), they require lifelong pharmacologic supplements of pyridoxine. Compliance with pyridoxine supplementation is critical, as status epilepticus may develop within days of discontinuation of pyridoxine.

The recommended daily allowance (RDA) for pyridoxine is 0.5 mg for infants and 2 mg for adults. Earlier studies revealed that 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 [Basura et al 2009, Stockler et al 2011]. Presently, the International PDE Consortium recommends that newborns receive 100 mg/day of pyridoxine (vitamin B6); infants 30 mg/kg/day with a maximum dose of 300 mg/day; and children, adolescents, and adults 30 mg/kg/day with a maximum dose of 500 mg/day [Coughlin et al 2021].

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.

Dietary modifications.ALDH7A1 encodes the enzyme α-aminoadipic semialdehyde dehydrogenase (antiquitin), which is involved in cerebral lysine catabolism. For this reason, dietary modifications targeted at reducing lysine intake have been recommended.

Lysine-restricted medicaldiet. It has been proposed that persons with pyridoxine-dependent epilepsy may benefit from a lysine-restricted diet. Improvements in development and behavior along with decreased biomarker levels have been described in affected individuals on such diets [Stockler et al 2011, van Karnebeek et al 2012].

L-arginine supplementation. L-arginine competitively inhibits lysine transport and can therefore reduce lysine levels. Some individuals with pyridoxine-dependent epilepsy have difficulty tolerating a lysine-restricted medical diet; in such individuals L-arginine supplementation has been offered as an alternative method of lowering lysine levels [Mercimek-Mahmutoglu et al 2014].

"Triple therapy." The effectiveness of treating pyridoxine-dependent epilepsy with "triple therapy" (a combination of pyridoxine supplementation, lysine restriction, and L-arginine supplementation) has also been studied [Coughlin et al 2015, Mahajnah et al 2016], with promising results in a small number of treated individuals.

Prevention of Secondary Complications

The dosage of pyridoxine should not exceed 500 mg/day [Stockler et al 2011], 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].

Surveillance

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, Coughlin et al 2021];
  • Assessed for developmental progress and educational needs at each visit.

Agents/Circumstances to Avoid

Overuse of pyridoxine (see Prevention of Secondary Complications) is to be avoided.

Evaluation of Relatives at Risk

Prenatal testing of a fetus at risk. Molecular genetic prenatal testing of fetuses at risk may be performed via amniocentesis or chorionic villus sampling to inform maternal pyridoxine supplementation (see Pregnancy Management) and facilitate institution of treatment at birth.

Newborn sib. If prenatal testing has not been performed on a pregnancy at risk, empiric pyridoxine supplementation of an at-risk newborn sib should be offered until molecular genetic testing for the family-specific ALDH7A1 variants has been completed.

Note: It would be unlikely for the proband's older sibs who have not experienced seizures to be pyridoxine dependent. However, if an older sib has neurodevelopmental disabilities, biomarker screening for α-AASA in urine or plasma should be considered.

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/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 [Stockler et al 2011]. 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].

Prenatal testing for the family-specific ALDH7A1 pathogenic variants can be performed; if both pathogenic variants are present, supplemental pyridoxine should be continued during pregnancy and postnatally. If one or none of the family-specific ALDH7A1 pathogenic variants are detected, supplemental pyridoxine can be discontinued.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one ALDH7A1 pathogenic variant based on family history).
  • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an ALDH7A1 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, the following possibilities should be considered:
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for an ALDH7A1 pathogenic variant, each sib of an affected individual has at conception 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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
  • Note: Once a molecular diagnosis has been established in the proband, testing to determine the genetic status of asymptomatic sibs of the proband should be considered, as late-onset seizures developing during adolescence have been reported. For those who have inherited both ALDH7A1 pathogenic variants, treatment should be initiated (see Evaluation of Relatives at Risk).

Offspring of a proband

  • Unless an individual with PDE-ALDH7A1 has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in ALDH7A1.
  • Note: Adults diagnosed with PDE-ALDH7A1 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 PDE-ALDH7A1.

Other family members. 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 relatives requires prior identification of the ALDH7A1 pathogenic variants 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

  • As the recurrence risk for couples who have a child with PDE-ALDH7A1 is 25%, the mother of a child with PDE-ALDH7A1 should receive counseling regarding empiric pyridoxine supplementation in subsequent pregnancies (see Pregnancy Management).
  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the ALDH7A1 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for PDE-ALDH7A1 are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

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
    3540 Crain Highway
    Suite 675
    Bowie MD 20716
    Phone: 800-332-1000 (toll-free)
    Email: ContactUs@efa.org
  • International Pyridoxine-Dependent Epilepsy Registry
    PDE Consortium

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 - ALDH7A1: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
ALDH7A1 5q23​.2 Alpha-aminoadipic semialdehyde dehydrogenase ALDH7A1 database ALDH7A1 ALDH7A1

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

Table B.

OMIM Entries for Pyridoxine-Dependent Epilepsy - ALDH7A1 (View All in OMIM)

107323 ALDEHYDE DEHYDROGENASE 7 FAMILY, MEMBER A1; ALDH7A1
266100 EPILEPSY, PYRIDOXINE-DEPENDENT; EPD

Molecular Pathogenesis

ALDH7A1 encodes the protein α-aminoadipic semialdehyde dehydrogenase (also referred to as antiquitin), an aldehyde dehydrogenase that functions as a Δ1-piperideine-6-carboxylate (P6C)-α-AASA dehydrogenase within the saccharopine pathway of L-lysine metabolism (Figure 2). 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 pyridoxal-5'-phosphate (PLP) by condensing with the cofactor, likely resulting in abnormal metabolism of neurotransmitters [Mills et al 2006].

Figure 2.

Figure 2.

Outline of the metabolism of L-lysine via the saccharopine and pipecolic acid pathways and biochemical pathophysiology of PDE-ALDH7A1 The two pathways converge where L-Δ1-piperideine 6-carboxylate (P6C), produced via the pipecolic acid pathway, (more...)

Additional novel metabolites, 6-oxo-pipecolate (6-oxo-PIP) and two diastereomers of 2-oxopropylpiperidine-2-carobylic acid (2-OPP) have been detected [Wempe et al 2019, Engelke et al 2021]. Importantly, these two metabolites are more stable than AASA at room temperature and can be detected via newborn screening techniques. AASA, P6C, 6-oxo-PIP, and 2-OPP have been detected in brain specimens of individuals with PDE-ALDH7A1, and Aldh7a1 knockout mice. Of note, 2-OPP may contribute to progressive neurotoxicity in PDE-ALDH7A1, as this substance has been shown to induce epilepsy-like behavior in a zebrafish model [Engelke et al 2021].

Antiquitin has been shown to localize to radial glia, astrocytes, and ependymal cells but not to neurons. Deficiency of antiquitin in pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) is associated with neuronal migration abnormalities and other forms of brain dysgenesis, such as thinning of the corpus callosum [Friedman et al 2014, Jansen et al 2014, Marguet et al 2016, Oesch et al 2018]. These neurodevelopmental aspects of antiquitin deficiency are not reversible with pyridoxine treatment, lysine restriction, or L-arginine supplementation.

Mechanism of disease causation. Loss of function

ALDH7A1-specific laboratory technical considerations. Deep intronic variants may be missed by sequence analysis that only includes exons and flanking regions. ALDH7A1 variant c.696-502G>C results in introduction of a cryptic acceptor splice site, activation of a cryptic donor splice site, and introduction of a pseudoexon between exons 7 and 8 [Milh et al 2012].

Intragenic deletions in ALDH7A1 will also be missed by sequence analysis but can be detected by investigations of copy number [Mefford et al 2015].

Table 2.

Notable ALDH7A1 Pathogenic Variants

Reference
Sequences
DNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_001182​.5
NP_001173​.2
c.696-502G>CIntroduction of pseudoexon between exons 7 & 8 Milh et al [2012]
c.1279G>Cp.Glu427GlnThe most common pathogenic variant, accounting for 33% of pathogenic variants [Coughlin et al 2019]
c.834G>AGenerates cryptic splice siteThe 2nd most common pathogenic variant, accounting for 5.4% of pathogenic variants [Salomons et al 2007, Coughlin et al 2019]

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Author Notes

Pyridoxine-Dependent Epilepsy Patient Registry

For diagnosed patients, operated by the PDE Consortium. Information about the registry may be obtained through the author or Dr Clara van Karnebeek at ln.cmuduobdar@keebenraKnav.aralC.

Acknowledgments

The author wishes to acknowledge research support from the Division of Neurology, Seattle Children's Hospital, Seattle, WA and the Department of Neurology, University of Washington, Seattle, WA, together with research collaborations with Drs Seth Friedman, Curtis Coughlin, Laura Tseng, and Clara van Karnebeek.

Revision History

  • 29 July 2021 (bp) Comprehensive update posted live
  • 13 April 2017 (ma) Comprehensive update posted live
  • 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 live
  • 18 December 2003 (me) Comprehensive update posted live
  • 7 December 2001 (me) Review posted live
  • 17 September 2001 (sg) Original submission

References

Literature Cited

  • Alghamdi M, Bashiri FA, Abdelhakim M, Adly N, Jamjoom DZ, Sumaily KM, Alghanem B, Arold ST. Phenotypic and molecular spectrum of pyridoxamine-5'-phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine-5'-phosphate oxidase deficiency. Clin Genet. 2021;99:99–110. [PMC free article: PMC7820968] [PubMed: 32888189]
  • Basura GJ, Hagland SP, Wiltse AM, Gospe SM Jr. Clinical features and the management of pyridoxine-dependent and pyridoxine-responsive seizures: review of 63 North American cases submitted to a patient registry. Eur J Pediatr. 2009;168:697–704. [PubMed: 18762976]
  • Baxter P. Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK. Arch Dis Child. 1999;81:431–3. [PMC free article: PMC1718118] [PubMed: 10519720]
  • Baxter P. Pyridoxine-dependent and pyridoxine-responsive seizures. Dev Med Child Neurol. 2001;43:416–20. [PubMed: 11409832]
  • Baxter P, Griffiths P, Kelly T, Gardner-Medwin D. Pyridoxine-dependent seizures: demographic, clinical, MRI and psychometric features, and effect of dose on intelligence quotient. Dev Med Child Neurol. 1996;38:998–1006. [PubMed: 8913181]
  • Baynes K, Farias ST, Gospe SM Jr. Pyridoxine-dependent seizures and cognition in adulthood. Dev Med Child Neurol. 2003;45:782–5. [PubMed: 14580135]
  • Bennett CL, Chen Y, Hahn S, Glass IA, Gospe SM Jr. Prevalence of ALDH7A1 mutations in 18 North American pyridoxine-dependent seizure (PDS) patients. Epilepsia. 2009;50:1167–75. [PubMed: 19128417]
  • Bok LA, Halbertsma FJ, Houterman S, Wevers RA, Vreeswijk C, Jakobs C, Struys E, Van Der Hoeven JH, Sival DA, Willemsen MA. Long-term outcome in pyridoxine dependent epilepsy. Dev Med Child Neurol. 2012;54:849–54. [PubMed: 22804844]
  • Bok LA, Maurits NM, Willemsen MA, Jakobs C, Teune LK, Poll-The BT, de Coo IF, Toet MC, Hagebeuk EE, Brouwer OF, van der Hoeven JH, Sival DA. The EEG response to pyridoxine-IV neither identifies nor excludes pyridoxine-dependent epilepsy. Epilepsia. 2010;51:2406–11. [PubMed: 20887371]
  • Costain G, Cordeiro D, Matviychuk D, Mercimek-Andrews S. Clinical application of targeted next-generation sequencing panels and whole exome sequencing in childhood epilepsy. Neuroscience. 2019;418:291–310. [PubMed: 31487502]
  • Coughlin CR 2nd, van Karnebeek CD, Al-Hertani W, Shuen AY, Jaggumantri S, Jack RM, Gaughan S, Burns C, Mirsky DM, Gallagher RC, Van Hove JL. Triple therapy with pyridoxine, arginine supplementation and dietary lysine restriction in pyridoxine-dependent epilepsy: neurodevelopmental outcome. Mol Genet Metab. 2015;116:35–43. [PubMed: 26026794]
  • Coughlin CR 2nd, Swanson MA, Spector E, Meeks NJL, Kronquist KE, Aslamy M, Wempe MF, van Karnebeek CDM, Gospe SM Jr, Aziz VG, Tsai BP, Gao H, Nagy PL, Hyland K, van Dooren SJM, Salomons GS, Van Hove JLK. The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: a common epileptic encephalopathy. J Inherit Metab Dis. 2019;42:353–61. [PMC free article: PMC6345606] [PubMed: 30043187]
  • Coughlin CR 2nd, Tseng LA, Abdenur JE, Ashmore C, Boemer F, Bok LA, Boyer M, Buhas D, Clayton PT, Das A, Dekker H, Evangeliou A, Feillet F, Footitt EJ, Gospe SM Jr, Hartmann H, Kara M, Kristensen E, Lee J, Lilje R, Longo N, Lunsing RJ, Mills P, Papadopoulou MT, Pearl PL, Piazzon F, Plecko B, Saini AG, Santra S, Sjarif DR, Stockler-Ipsiroglu S, Striano P, Van Hove JLK, Verhoeven-Duif NM, Wijburg FA, Zuberi SM, van Karnebeek CDM. Consensus guidelines for the diagnosis and management of pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency. J Inherit Metab Dis. 2021;44:178–92. [PubMed: 33200442]
  • Darin N, Reid E, Prunetti L, Samuelsson L, Husain RA, Wilson M, El Yacoubi B, Footitt E, Chong WK, Wilson LC, Prunty H, Pope S, Heales S, Lascelles K, Champion M, Wassmer E, Veggiotti P, de Crécy-Lagard V, Mills PB, Clayton PT. Mutations in PROSC disrupt cellular pyridoxal phosphate homeostasis and cause vitamin-B6-dependent epilepsy. Am J Hum Genet. 2016;99:1325–37. [PMC free article: PMC5142116] [PubMed: 27912044]
  • de Rooy RLP, Halbertsma FJ, Struijs EA, van Spronsen FJ, Lunsing RJ, Schippers HM, van Hasselt PM, Plecko B, Wohlrab G, Whalen S, Benoist JF, Valence S, Mills PB, Bok LA. Pyridoxine dependent epilepsy: Is late onset a predictor for favorable outcome? Eur J Paediatr Neurol. 2018;22:662–6. [PubMed: 29661537]
  • Engelke UF, van Outersterp RE, Merx J, van Geenen FA, van Rooij A, Berden G, Huigen MC, Kluijtmans LA, Peters TM, Al-Shekaili HH, Leavitt BR, de Vrieze E, Broekman S, van Wijk E, Tseng LA, Kulkarni P, Rutjes FP, Mecinovic J, Struys EA, Jansen LA, Gospe SM Jr, Mercimek-Andrews S, Hyland K, Willemsen MA, Bok LA, Van Karnebeek CD, Wevers RA, Boltje TJ, Oomens J, Martens J, Coene KL. Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy. J Clin Invest. 2021 Epub ahead of print. [PMC free article: PMC8321577] [PubMed: 34138754]
  • Friedman SD, Ishak GE, Poliachik S, Poliakov A, Otto RK, Shaw DWW, Willemsen MA, Bok LA, Gospe SM. Callosal alterations in pyridoxine-dependent epilepsy. Dev Med Child Neurol. 2014;56:1106–10. [PubMed: 24942048]
  • Gallagher RC, Van Hove JL, Scharer G, Hyland K, Plecko B, Waters PJ, Mercimek-Mahmutoglu S, Stockler-Ipsiroglu S, Salomons GS, Rosenberg EH, Struys EA, Jakobs C. Folinic acid-responsive seizures are identical to pyridoxine-dependent epilepsy. Ann Neurol. 2009;65:550–6. [PubMed: 19142996]
  • Hunt AD Jr, Stokes J Jr, McCrory WW, Stroud HH. Pyridoxine dependency: report of a case of intractable convulsions in an infant controlled by pyridoxine. Pediatrics. 1954;13:140–5. [PubMed: 13133562]
  • Jansen LA, Hevner RF, Roden WH, Hahn SH, Jung S, Gospe SM Jr. Glial localization of antiquitin: Implications for pyridoxine-dependent epilepsy. Ann Neurol. 2014;75:22–32. [PMC free article: PMC3945410] [PubMed: 24122892]
  • Johnstone DL, Al-Shekaili HH, Tarailo-Graovac M, Wolf NI, Ivy AS, Demarest S, Roussel Y, Ciapaite J, van Roermund CWT, Kernohan KD, Kosuta C, Ban K, Ito Y, McBride S, Al-Thihli K, Abdelrahim RA, Koul R, Al Futaisi A, Haaxma CA, Olson H, Sigurdardottir LY, Arnold GL, Gerkes EH, Boon M, Heiner-Fokkema MR, Noble S, Bosma M, Jans J, Koolen DA, Kamsteeg EJ, Drögemöller B, Ross CJ, Majewski J, Cho MT, Begtrup A, Wasserman WW, Bui T, Brimble E, Violante S, Houten SM, Wevers RA, van Faassen M, Kema IP, Lepage N, Lines MA, Dyment DA, Wanders RJA, Verhoeven-Duif N, Ekker M, Boycott KM, Friedman JM, Pena IA, van Karnebeek CDM, et al. PLPHP deficiency: clinical, genetic, biochemical, and mechanistic insights. Brain. 2019;142:542–59. [PMC free article: PMC6391652] [PubMed: 30668673]
  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
  • Mahajnah M, Corderio D, Austin V, Herd S, Mutch C, Carter M, Struys E, Mercimek-Mahmutoglu S. A prospective case study of the safety and efficacy of lysine-restricted diet and arginine supplementation therapy in a patient with pyridoxine-dependent epilepsy caused by mutations in ALDH7A1. Pediatr Neurol. 2016;60:60–5. [PubMed: 27212567]
  • Marguet F, Barakizou H, Tebani A, Abily-Donval L, Torre S, Bayoudh F, Jebnoun S, Brasseur-Daudruy M, Marret S, Laquerriere A, Bekri S. Pyridoxine-dependent epilepsy: report on three families with neuropathology. Metab Brain Dis. 2016;31:1435–43. [PubMed: 27438048]
  • Mastrangelo M, Leuzzi V. Genes of early-onset epileptic encephalopathies: from genotype to phenotype. Pediatr Neurol. 2012;46:24–31. [PubMed: 22196487]
  • McLachlan RS, Brown WF. Pyridoxine dependent epilepsy with iatrogenic sensory neuronopathy. Can J Neurol Sci. 1995;22:50–1. [PubMed: 7750075]
  • Mefford HC, Yendle SC, Hsu C, Cook J, Geraghty E, McMahon JM, Eeg-Olofsson O, Sadleir LG, Gill D, Ben-Zeev B, Lerman-Sagie T, Mackay M, Freeman JL, Andermann E, Pelakanos JT, Andrews I, Wallace G, Eichler EE, Berkovic SF, Scheffer IE. Rare copy number variants are an important cause of epileptic encephalopathies. Ann Neurol. 2011;70:974–85. [PMC free article: PMC3245646] [PubMed: 22190369]
  • Mefford HC, Zemel M, Geraghty E, Cook J, Clayton PT, Paul K, Plecko B, Mills PB, Nordli DR Jr, Gospe SM Jr. Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination. Neurology. 2015;85:756–62. [PMC free article: PMC4553021] [PubMed: 26224730]
  • Mercimek-Mahmutoglu S, Cordeiro D, Cruz V, Hyland K, Struys EA, Kyriakopoulou L, Mamak E. Novel therapy for pyridoxine dependent epilepsy due to ALDH7A1 genetic defect: L-arginine supplementation alternative to lysine-restricted diet. Eur J Paediatr Neurol. 2014;18:741–6. [PubMed: 25127453]
  • Milh M, Pop A, Kanhai W, Villeneuve N, Cano A, Struys EA, Salomons GS, Chabrol B, Jakobs C. Atypical pyridoxine-dependent epilepsy due to a pseudoexon in ALDH7A1. Mol Genet Metab. 2012;105:684–6. [PubMed: 22305855]
  • Mills PB, Camuzeaux SS, Footitt EJ, Mills KA, Gissen P, Fisher L, Das KB, Varadkar SM, Zuberi S, McWilliam R, Stödberg T, Plecko B, Baumgartner MR, Maier O, Calvert S, Riney K, Wolf NI, Livingston JH, Bala P, Morel CF, Feillet F, Raimondi F, Del Giudice E, Chong WK, Pitt M, Clayton PT. Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome. Brain. 2014;137:1350–60. [PMC free article: PMC3999720] [PubMed: 24645144]
  • Mills PB, Footitt EJ, Ceyhan S, Waters PJ, Jakobs C, Clayton PT, Struys EA. Urinary AASA excretion is elevated in patients with molybdenum cofactor deficiency and isolated sulphite oxidase deficiency. J Inherit Metab Dis. 2012;35:1031–6. [PubMed: 22403017]
  • Mills PB, Struys E, Jakobs C, Plecko B, Baxter P, Baumgartner M, Willemsen MA, Omran H, Tacke U, Uhlenberg B, Weschke B, Clayton PT. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med. 2006;12:307–9. [PubMed: 16491085]
  • Mills PB, Surtees RA, Champion MP, Beesley CE, Dalton N, Scambler PJ, Heales SJ, Briddon A, Scheimberg I, Hoffmann GF, Zschocke J, Clayton PT. Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5'-phosphate oxidase. Hum Mol Genet. 2005;14:1077–86. [PubMed: 15772097]
  • Mills PB, Footitt EJ, Mills KA, Tuschl K, Aylett S, Varadkar S, Hemingway C, Marlow N, Rennie J, Baxter P, Dulac O, Nabbout R, Craigen WJ, Schmitt B, Feillet F, Christensen E, De Lonlay P, Pike MG, Hughes MI, Struys EA, Jakobs C, Zuberi SM, Clayton PT. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain. 2010;133:2148–59. [PMC free article: PMC2892945] [PubMed: 20554659]
  • Oesch G, Maga AM, Friedman SD, Poliachik SL, Budech CB, Wright JN, Bok LA, Gospe SM Jr. Geometric morphometrics reveal altered corpus callosum shape in pyridoxine-dependent epilepsy. Neurology. 2018;91:e78–e86. [PubMed: 29875223]
  • Plecko B, Hikel C, Korenke GC, Schmitt B, Baumgartner M, Baumeister F, Jakobs C, Struys E, Erwa W, Stockler-Ipsiroglu S. Pipecolic acid as a diagnostic marker of pyridoxine-dependent epilepsy. Neuropediatrics. 2005;36:200–5. [PubMed: 15944906]
  • Plecko B, Paul K, Mills P, Clayton P, Paschke E, Maier O, Hasselmann O, Schmiedel G, Kanz S, Connolly M, Wolf N, Struys E, Stockler S, Abela L, Hover D. Pyridoxine responsiveness in novel mutations of the PNPO gene. Neurology. 2014;82:1425–33. [PMC free article: PMC4001193] [PubMed: 24658933]
  • Rankin PM, Harrison S, Chong WK, Boyd S, Aylett SE. Pyridoxine-dependent seizures: a family phenotype that leads to severe cognitive deficits, regardless of treatment regime. Dev Med Child Neurol. 2007;49:300–5. [PubMed: 17376142]
  • Reid ES, Williams H, Stabej Ple Q, James C, Ocaka L, Bacchelli C, Footitt EJ, Boyd S, Cleary MA, Mills PB, Clayton PT. Seizures due to a KCNQ2 mutation: treatment with vitamin B6. JIMD Rep. 2016;27:79–84. [PMC free article: PMC5580730] [PubMed: 26446091]
  • Salomons GS, Bok LA, Struys EA, Pope LL, Darmin PS, Mills PB, Clayton PT, Willemsen MA, Jakobs C. An intriguing "silent" mutation and a founder effect in antiquitin (ALDH7A1). Ann Neurol. 2007;62:414–8. [PubMed: 17721876]
  • Scharer G, Brocker C, Vasiliou V, Creadon-Swindell G, Gallagher RC, Spector E, Van Hove JL. The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1. J Inherit Metab Dis. 2010;33:571–81. [PMC free article: PMC3112356] [PubMed: 20814824]
  • Schmitt B, Baumgartner M, Mills PB, Clayton PT, Jakobs C, Keller E, Wohlrab G. Seizures and paroxysmal events: symptoms pointing to the diagnosis of pyridoxine-dependent epilepsy and pyridoxine phosphate oxidase deficiency. Dev Med Child Neurol. 2010;52:e133–42. [PubMed: 20370816]
  • Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–77. [PMC free article: PMC5429360] [PubMed: 28349240]
  • Stockler S, Plecko B, Gospe SM Jr, Coulter-Mackie M, Connolly M, van Karnebeek C, Mercimek-Mahmutoglu S, Hartmann H, Scharer G, Struijs E, Tein I, Jakobs C, Clayton P, Van Hove JL. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab. 2011;104:48–60. [PubMed: 21704546]
  • Struys EA, Nota B, Bakkali A, Al Shahwan S, Salomons GS, Tabarki B. Pyridoxine-dependent epilepsy with elevated urinary α-amino adipic semialdehyde in molybdenum cofactor deficiency. Pediatrics. 2012;130:e1716–9. [PubMed: 23147983]
  • van Karnebeek CD, Hartmann H, Jaggumantri S, Bok LA, Cheng B, Connolly M, Coughlin CR 2nd, Das AM, Gospe SM Jr, Jakobs C, van der Lee JH, Mercimek-Mahmutoglu S, Meyer U, Struys E, Sinclair G, Van Hove J, Collet JP, Plecko BR, Stockler S. Lysine restricted diet for pyridoxine-dependent epilepsy: first evidence and future trials. Mol Genet Metab. 2012;107:335–44. [PubMed: 23022070]
  • van Karnebeek CD, Tiebout SA, Niermeijer J, Poll-The BT, Ghani A, Coughlin CR 2nd, Van Hove JL, Richter JW, Christen HJ, Gallagher R, Hartmann H, Stockler-Ipsiroglu S. Pyridoxine-dependent epilepsy: an expanding clinical spectrum. Pediatr Neurol. 2016;59:6–12. [PubMed: 26995068]
  • Wempe MF, Kumar A, Kumar V, Choi YJ, Swanson MA, Friederich MW, Hyland K, Yue WW, Van Hove JLK, Coughlin CR 2nd. Identification of a novel biomarker for pyridoxine-dependent epilepsy: Implications for newborn screening. J Inherit Metab Dis. 2019;42:565–74. [PubMed: 30663059]
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