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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.

Author Information and Affiliations

Initial Posting: ; Last Update: September 22, 2022.

Estimated reading time: 31 minutes

Summary

Clinical characteristics.

Pyridoxine-dependent epilepsy – ALDH7A1 (PDE-ALDH7A1) is characterized by seizures not well controlled with anti-seizure medication 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 medication 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 alpha-aminoadipic semialdehyde (α-AASA) in urine and/or plasma. The diagnosis is established in a proband with suggestive clinical findings and biallelic pathogenic (or likely pathogenic) variants in ALDH7A1 identified by molecular genetic testing.

Management.

Treatment of manifestations: There is no cure for PDE-ALDH7A1. Targeted therapy requires lifelong pharmacologic supplements of pyridoxine; the rarity of the disorder has precluded controlled studies to evaluate the optimal dose. The International PDE Consortium published clinical practice guidelines recommending pyridoxine doses by age (newborns: 100 mg/day; infants: 30 mg/kg/day with a maximum of 300 mg/day; children, adolescents, and adults: 30 mg/kg/day with a maximum of 500 mg/day) and dietary modifications targeted at reducing lysine intake. To prevent exacerbation of clinical seizures and/or encephalopathy during an acute illness, the daily dose of pyridoxine may be doubled for several days. Supportive care for developmental delay and/or intellectual disability follows standard practice.

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

Surveillance: Recommendations to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations include regular assessments by the treating neurologist for control of epilepsy via targeted therapy with pyridoxine, need for concomitant use of anti-seizure medications, and signs of sensory neuropathy, as well as 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, the neonate should receive therapeutic doses of pyridoxine 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, response to intravenous (IV) or oral (PO) administration of pyridoxine, laboratory findings, and family history.

Suggestive 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
  • In neonates, 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
  • In infants and children, 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
  • A history of transient or unclear response of seizures to pyridoxine
  • In infants and children, a history of seizures responsive to folinic acid

Positive response to IV or PO administration of pyridoxine

  • IV. In an acute setting, for individuals experiencing prolonged clinical seizures (i.e., status epilepticus), administer 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 the administration of 100 mg of pyridoxine, making close systemic monitoring essential.
  • PO. For individuals experiencing frequent medication-resistant seizures but not status epilepticus, administer 30 mg/kg/day of pyridoxine orally. Clinical seizures should cease within three to five days [Baxter 2001, Stockler et al 2011].

Note: Treatment with pharmacologic doses of pyridoxine should begin immediately or be continued when concern for PDE-ALDH7A1 has been raised while additional testing is performed to establish the diagnosis.

Supportive laboratory findings

  • Elevated plasma and urinary levels of alpha-aminoadipic semialdehyde (α-AASA)
    Note that α-AASA is a nonspecific biomarker, as it can also be elevated in individuals with molybdenum cofactor deficiency and isolated sulfate oxidase deficiency (see Differential Diagnosis).
  • 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 high-performance liquid chromatography, 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 is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Note: Sibs with seizures, epileptic encephalopathy, and/or epilepsy attributed to birth trauma or prematurity should be reevaluated when subsequent sibs have a similar presentation.

Establishing the Diagnosis

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

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic ALDH7A1 variants of uncertain significance (or of one known ALDH7A1 pathogenic variant and one ALDH7A1 variant of uncertain significance) does not itself establish or rule out a diagnosis.

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).

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

  • 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.
  • Comprehensive genomic 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 2020]

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 a range of techniques such as 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 medication (ASM) but 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. 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 ASMs 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 seizures 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), sometimes presenting after age one year and as late as adolescence
  • Seizures that initially respond to ASM 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
  • In a small number of infants, intractable seizures that are either unresponsive or only partially responsive to pyridoxine but responsive to folinic acid [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 that is 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].

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

Figure 1.

Figure 1.

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

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

The common c.1279G>C; 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 those in whom seizures recur after ASMs 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 [Baxter 1999, Basura et al 2009].

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 (i.e., mutation of PLPBP and of 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) must be distinguished from PNPO deficiency and PLPBP deficiency (also referred to as PLPHP deficiency), as well as other disorders associated with pyridoxine (PN)- and pyridoxal 5'-phosphate (PLP)-responsive seizures (see Table 2).

Table 2.

Selected Disorders of Interest in the Differential Diagnosis of Pyridoxine-Dependent Epilepsy – ALDH7A1

GeneDisorderLaboratory FeaturesResponse to PN/PLPClinical Features
Pyridoxine (vitamin B6)-dependent epilepsy 1
PLPBP PLPBP (PLPHP) deficiency 2 (OMIM 617290)Secondary biochemical abnormalities suggesting abnormal vitamin B6 metabolism may be present, as may lactic acidosis.Szs in affected children respond to supraphysiologic doses of PN (or PLP).Majority have sz onset w/in 1st wk of life; some children present as late as 6 mos. 3 Acquired microcephaly, structural brain abnormalities, & DD/ID are variable.
PNPO PNPO deficiency 2Low CSF & plasma levels of PLP when measured prior to administration of PN or PLP. Biochemical changes in CSF, plasma, & urine prior to treatment w/PN or PLP indicative of ↓ activity of PLP-dependent enzymes (e.g., aromatic acid decarboxylase or glycine cleavage enzyme).Szs in affected children respond to supraphysiologic doses of PLP (60% of affected persons) or PN (40% of affected persons).~90% have sz onset in neonatal period (often age <2 wks); some children present as late as age 3 yrs. ≥60% have DD/ID.
Pyridoxine (vitamin B6)-responsive seizures 1
ALDH4A1 Hyperprolinemia type II 2 (OMIM 239510)Markedly ↑ plasma proline levels as well as ↑ P5C in urineSzs may respond to ASM & PN.Szs usually manifest beyond neonatal period, may occur w/febrile infections, & may respond to common ASM. Persons may have ID or normal intelligence.
ALPL Infantile hypophosphatasia 4Suspected in presence of ↓ serum ALP enzyme activity (based on appropriate pediatric normative reference values)Vitamin B6-responsive seizures may occur.Clinical signs resembling rickets may be recognized between birth & age 6 mos. Prior to availability of ERT, ~50% died of respiratory failure caused by undermineralization of ribs. Intractable szs may precede biochemical or radiographic manifestations of rickets.
CACNA1A Developmental & epileptic encephalopathy 42 5 (OMIM 617106)No assoc biochemical abnormalitiesA female w/CACNA1A-related absence epilepsy & ataxia responded dramatically to PN. 6
KCNQ2 KCNQ2-related disorders 5No assoc biochemical abnormalitiesSome w/neonatal epilepsy are vitamin B6 responsive. 7May present w/benign familial neonatal epilepsy or severe neonatal epileptic encephalopathy. Szs are tonic & often asymmetric.
MOCS2 MOSC2-related molybdenum cofactor deficiency 2When present, ↑ α-AASA is secondary to ALDH7A1 inhibition by accumulated S-sulfocysteine.A clear but transient response of szs to PN observed in 2 affected sibs 8
PGAP3 Hyperphosphatasia w/ID syndrome 4 2 (OMIM 615716)↑ serum ALPSzs may respond to PN.DD/ID, structural brain anomalies, dysmorphic facies, & szs
PIGA Multiple congenital anomalies-hypotonia-seizures syndrome 2 9 (OMIM 300868)↑ serum ALP in some personsHeterogeneous effect of PN on szsDysmorphic features, hypotonia, early-onset myoclonic seizures, & variable congenital anomalies
PIGL CHIME syndrome 2 (OMIM 280000)↑ serum ALPSzs may respond to PN (but much more slowly than in PDE-ALDH7A1).Coloboma, congenital heart disease, ichthyosiform dermatosis, ID, & ear anomalies
PIGO Hyperphosphatasia w/ID syndrome 2 2 (OMIM 614749)↑ serum ALPSzs w/variable response to PNModerate-to-severe DD/ID; facial dysmorphism & brachytelephalangy ± szs
PIGS Developmental & epileptic encephalopathy 95 2 (OMIM 618143)Normal serum ALP (except mildly ↑ in 1 person)Szs may be PN responsive.Severe DD/ID, ataxia, hypotonia, coarse facies, & intractable szs
PIGV Hyperphosphatasia w/ID syndrome 1 2 (OMIM 239300)↑ serum ALPVariable neurologic features incl szs that may respond to PNDistinct facial phenotype, DD, & brachytelephalangy ± anorectal malformations

α-AASA = alpha-aminoadipic semialdehyde; ALP = alkaline phosphatase; ASM = anti-seizure medication; CSF = cerebrospinal fluid; DD = developmental delay; ERT = enzyme replacement therapy; ID = intellectual disability; P5C = pyrroline-5-carboxylate; PLP = pyridoxal 5'-phosphate; PN = pyridoxine; sz = seizure

1.

The epilepsies in this table may respond to treatment with vitamin B6 either long term or transiently. In this context vitamin B6 dependency indicates a need for lifelong supplementation of supraphysiologic doses of a respective vitamin, while vitamin B6 responsiveness may be a transient effect and may not be directly linked to vitamin B6 metabolism.

2.

Autosomal recessive mode of inheritance

3.
4.

Perinatal and most infantile cases of hypophosphatasia are inherited in an autosomal recessive manner.

5.

Autosomal dominant mode of inheritance

6.
7.
8.
9.

Note: In the Far East, PLP has been used as an anticonvulsant when anti-seizure medications have failed, and to control seizures in children with infantile spasms and generalized and focal epilepsy in cohorts that had not undergone molecular genetic testing [Ohtahara et al 1993, Nakagawa et al 1997, Ito et al 2000, Wang et al 2005, Ohtahara et al 2011]. Specifically, PLP responsiveness was reported in 20.2% of 119 individuals with West syndrome of unknown etiology and 10.7% of individuals with West syndrome of known etiology, such as birth asphyxia or brain malformation [Ohtahara et al 2011], and PLP or PN responsiveness was reported in 11.7% of 94 children with idiopathic intractable epilepsy, including West syndrome [Wang et al 2005]. (International guidelines do not generally recommend a standardized trial of PN or PLP in infants with infantile spasms; recently, however, consideration of a therapeutic trial with PN or PLP has been proposed in children with West syndrome when infantile spasms are associated with other seizure types or have started before age two months [Gibaud et al 2021].)

Other Considerations in the Differential Diagnosis of PDE-ALDH7A1

Inborn pyridoxine dependency states. While other inborn pyridoxine dependency states have been described – for example, pyridoxine-dependent anemia and pyridoxine-dependent forms of homocystinuria (see Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency), xanthurenic aciduria (OMIM 236800), and cystathioninuria (OMIM 219500) – these conditions are not genetically related to pyridoxine-dependent epilepsy and are phenotypically distinct disorders.

Mitochondrial disorders. PDE-ALDH7A1 may present with lactic acidosis. Lactate acid elevation can be an important (albeit nonspecific) marker of mitochondrial disease and mislead clinicians toward other less treatable inborn errors of metabolism.

Hypoxic ischemic encephalopathy (HIE). About 15% of individuals with PDE-ALDH7A1 have fetal distress followed by poor adaptation and low Apgar scores. This presentation can mislead clinicians toward symptomatic seizures as a sign of HIE. Resistance to common anticonvulsants, a history of prematurity, and severely pathologic or persistent EEG changes should lead to reevaluation for genetic causes of neonatal seizures.

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 or any of the other disorders listed in Table 2 should be diagnosed with "pyridoxine-responsive seizures" [Baxter 1999, Basura et al 2009].

Other causes of neonatal seizures in which elevated levels of alpha-aminoadipic semialdehyde may be present include the following:

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:

  • Neurologic examination to evaluate cranial nerve function, muscle strength, tone (for hypotonia or rigidity), and symmetry, and to describe seizure semiology
  • EEG including sleep and wake cycles
  • As congenital brain developmental abnormalities may occur in PDE-ALDH7A1, brain MRI when clinically indicated (e.g., macrocephaly, incomplete control of seizures to pyridoxine)
  • Developmental assessment including motor, adaptive, cognitive, and 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 – Targeted Therapy with Pyridoxine

There is no cure for PDE-ALDH7A1.

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

Dosage

The International PDE Consortium [Coughlin et al 2021] presently recommend the following:

  • Newborns: 100 mg/day of pyridoxine (vitamin B6)
  • Infants: 30 mg/kg/day of pyridoxine (maximum dose 300 mg/day)
  • Children, adolescents, and adults: 30 mg/kg/day of pyridoxine (maximum dose 500 mg/day)

Because affected individuals may have exacerbations of clinical seizures and/or encephalopathy during an acute illness (such as gastroenteritis or a febrile respiratory infection), the daily dose of pyridoxine may be doubled for several days until the acute illness resolves.

Once seizures come under control with the addition of daily pyridoxine monotherapy in pharmacologic doses, all anti-seizure medication (ASM) can be withdrawn in the majority of individuals.

Side Effects

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].

Treatment – Dietary Modifications

ALDH7A1 encodes the enzyme alpha-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 medical diet. 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 been demonstrated [Coughlin et al 2015, Mahajnah et al 2016].

The combination of pyridoxine and lysine-reduction therapies improves the developmental profile of individuals with PDE-ALDH7A1. This was particularly noticeable in families with multiple affected sibs when the younger sib began treatment at an earlier age [Tseng et al 2022a]. A clinically significant improvement in developmental test scores has been shown when these therapies are started within the first six months of life [Coughlin et al 2022].

Treatment – Supportive Care

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:

  • 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, when necessary.

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

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended:

  • Regular assessment by treating neurologist for:
    • Control of epilepsy via targeted therapy with pyridoxine, and need for concomitant use of ASM
    • 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]
  • Assessment for developmental progress and educational needs at each visit
  • If lysine reduction therapies are used, regular follow up by a biochemical geneticist and/or medical dietician

Agents/Circumstances to Avoid

Avoid overuse of pyridoxine (see Treatment – Targeted Therapy with Pyridoxine, Side Effects).

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.

When prenatal testing has not been performed on a pregnancy at risk, prompt evaluation of the newborn is essential to determine if treatment with pyridoxine is necessary. While pending results of molecular genetic testing, two options for management of an at-risk newborn are:

  • Prophylactic treatment with pyridoxine until molecular genetic testing clarifies whether the newborn is affected
    Note: At least one newborn at risk for PDE-ALDH7A1 developed status epilepticus after being given high-dose pyridoxine treatment before molecular genetic testing determined that the child was not affected [Hartmann et al 2011].
  • Clinical and EEG monitoring with initiation of treatment with pyridoxine at the first sign of seizures or encephalopathy

Note: It would be unlikely for the proband's older sibs who have not experienced seizures to be pyridoxine dependent; however, testing to determine the genetic status of asymptomatic sibs should be considered, as late-onset seizures (developing in adolescence) have been reported. If an older sib has neurodevelopmental disabilities, biomarker screening for alpha-aminoadipic semialdehyde in urine or plasma and/or molecular genetic testing 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 PDE-ALDH7A1 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 presumed to be heterozygous for an ALDH7A1 pathogenic variant.
  • 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 and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • 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 affected individual's reproductive partner also has PDE-ALDH7A1 or is a carrier, 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 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.

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)

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

Molecular Pathogenesis

ALDH7A1 encodes the protein alpha-aminoadipic semialdehyde (α-AASA) 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). Decreased activity of antiquitin 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 α-AASA at room temperature and can be detected via newborn screening techniques. Of note, 2-OPP may contribute to progressive neurotoxicity in PDE-ALDH7A1, as 2-OPP induces epilepsy-like behavior in a zebra fish model [Engelke et al 2021]. α-AASA, P6C, 6-oxo-PIP, and 2-OPP can be detected via next-generation metabolic screening [Tseng et al 2022b].

Antiquitin localizes 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].

Table 3.

Notable ALDH7A1 Pathogenic Variants

Reference
Sequences
DNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_001182​.5 c.696-502G>C 1-- Milh et al [2012]

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.

1.

Results in introduction of pseudoexon between exons 7 & 8

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 (email: c.d.vankarnebeek@amsterdamumc.nl).

Acknowledgments

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

Revision History

  • 22 September 2022 (bp) Comprehensive update posted live
  • 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

  • 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]
  • 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, 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]
  • Coughlin CR 2nd, Tseng LA, Bok LA, Hartmann H, Footitt E, Striano P, Tabarki BM, Lunsing RJ, Stockler-Ipsiroglu S, Gordon S, Van Hove JLK, Abdenur JE, Boyer M, Longo N, Andrews A, Janssen MC, van Wegberg A, Prasad C, Prasad AN, Lamb MM, Wijburg FA, Gospe SM Jr, van Karnebeek C, et al. Association between lysine reduction therapies and cognitive outcomes in patients with pyridoxine-dependent epilepsy. Neurology. 2022. Epub ahead of print. [PMC free article: PMC9754645] [PubMed: 36008148]
  • 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]
  • 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]
  • Du X, Chen Y, Zhao Y, Luo W, Cen Z, Hao W. Dramatic response to pyridoxine in a girl with absence epilepsy with ataxia caused by a de novo CACNA1A mutation. Seizure. 2017;45:189–91. [PubMed: 28088730]
  • 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;131:3148272. [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]
  • Gibaud M, Barth M, Lefranc J, Mention K, Villeneuve N, Schiff M, Maurey H, Barthez MA, Caubel I, Chouchane M, Doummar D, Kossorotoff M, Lamblin MD, Roubertie A, Nabbout R, Van Bogaert P. West syndrome is an exceptional presentation of pyridoxine- and pyridoxal phosphate-dependent epilepsy: data from a French cohort and review of the literature. Front Pediatr. 2021;9:621200. [PMC free article: PMC7973036] [PubMed: 33748042]
  • Hartmann H, Fingerhut M, Jakobs C, Plecko B. Status epilepticus in a neonate treated with pyridoxine because of a familial recurrence risk for antiquitin deficiency: pyridoxine toxicity? Dev Med Child Neurol. 2011;53:1150–3. [PubMed: 21707605]
  • 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]
  • Ito M, Seki T, Takuma Y. Current therapy for West syndrome in Japan. J Child Neurol. 2000;15:424–8. [PubMed: 10868790]
  • 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]
  • Jiao X, Gong P, Niu Y, Zhang Y, Yang Z. A rare presentation characterized by epileptic spasms in ALDH7A1, pyridox(am)ine-5'-phosphate oxidase, and PLPBP deficiency. Front Genet. 2022;13:804461. [PMC free article: PMC9039010] [PubMed: 35495162]
  • 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]
  • McLachlan RS, Brown WF. Pyridoxine dependent epilepsy with iatrogenic sensory neuronopathy. Can J Neurol Sci. 1995;22:50–1. [PubMed: 7750075]
  • 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, 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, 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]
  • 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]
  • Nakagawa E, Tanaka T, Ohno M, Yamano T, Shimada M. Efficacy of pyridoxal phosphate in treating an adult with intractable status epilepticus. Neurology. 1997;48:1468–9. [PubMed: 9153499]
  • 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]
  • Ohtahara S, Ohtsuka Y, Yamatogi Y, Oka E, Yoshinaga H, Sato M. Prenatal etiologies of West syndrome. Epilepsia. 1993;34:716–22. [PubMed: 8330583]
  • Ohtahara S, Yamatogi Y, Ohtsuka Y. Vitamin B(6) treatment of intractable seizures. Brain Dev. 2011;33:783–9. [PubMed: 21345627]
  • 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]
  • 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]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • 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, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
  • 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]
  • Tseng LA, Abdenur JE, Andrews A, Aziz VG, Bok LA, Boyer M, Buhas D, Hartmann H, Footitt EJ, Grønborg S, Janssen MCH, Longo N, Lunsing RJ, MacKenzie AE, Wijburg FA, Gospe SM Jr, Coughlin CR 2nd, van Karnebeek CDM. Timing of therapy and neurodevelopmental outcomes in 18 families with pyridoxine-dependent epilepsy. Mol Genet Metab. 2022a;135:350–6. [PubMed: 35279367]
  • Tseng LA, Engelke UFH, Huigen MCDG, Kluijtmans LAJ, Haaxma CA, Koolen DA, Bok LA, Wright JN, Gospe SM Jr, van Karnebeek CDM, Coene KLM. Targeting the diagnosis in an adolescent with epilepsy and intellectual disability through untargeted metabolomics/next generation metabolic screening. Clin Chem. 2022b;68:732–5. [PubMed: 36189752]
  • 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]
  • Wang H-S, Kuo M-F, Chou M-L, Hung P-C, Lin K-L, Hsieh M-Y, Chang M-Y. Pyridoxal phosphate is better than pyridoxine for controlling idiopathic intractable epilepsy. Arch Dis Child. 2005;90:512–15. [PMC free article: PMC1720393] [PubMed: 15851435]
  • 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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