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.

In 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.

In 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.

Targeted therapies: 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: 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.

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 variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview 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 the 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.

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 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.

Midsagittal 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)

• Universal thinning of the corpus callosum (greatest in the isthmus) [Friedman et al 2014, Oesch et al 2018]
• Mega cisterna magna, hydrocephalus, ventriculomegaly, and cortical dysplasia, reported in several individuals [Mills et al 2010, Friedman et al 2014, Oesch et al 2018]

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].

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:

• Molybdenum cofactor deficiency. This heterogeneous group of conditions can be distinguished from pyridoxine-responsive epilepsy by the presence of increased urinary xanthine, hypoxanthine, and S-sulfocysteine [Mills et al 2012, Struys et al 2012]. Molybdenum cofactor deficiency is caused by biallelic pathogenic variants in GPHN, MOCS1, MOCS2, or MOCS3 and inherited in an autosomal recessive manner.
• Isolated sulfite oxidase deficiency. This condition can be distinguished from pyridoxine-responsive epilepsy by increased urinary sulfite and decreased urinary sulfate [Mills et al 2012]. Isolated sulfite oxidase deficiency is caused by biallelic pathogenic variants in SUOX and inherited in an autosomal recessive manner.

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 of Manifestations

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 Targeted Therapies, 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.

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:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• 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 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.

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.

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].

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

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