TOPICAL REVIEW

Open Access

Pyridoxine-dependent epilepsy: Current perspectives and questions for future research

Curtis R. Coughlin II

orcid.org/0000-0002-3545-7903

Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

Contribution: Writing - original draft, Writing - review & editing

Search for more papers by this author

Sidney M. Gospe Jr.,

Corresponding Author

Sidney M. Gospe Jr.

[email protected]

orcid.org/0000-0002-0099-109X

Departments of Neurology and Pediatrics, University of Washington, Seattle, Washington, USA

Department of Pediatrics, Duke University, Durham, North Carolina, USA

Correspondence Sidney M. Gospe, Jr., Departments of Neurology and Pediatrics, University of Washington, Seattle, WA, USA.

Email: [email protected]

Contribution: Conceptualization, Project administration, Writing - original draft, Writing - review & editing

Search for more papers by this author

Curtis R. Coughlin II,

Curtis R. Coughlin II

orcid.org/0000-0002-3545-7903

Section of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

Contribution: Writing - original draft, Writing - review & editing

Search for more papers by this author

Sidney M. Gospe Jr.,

Corresponding Author

Sidney M. Gospe Jr.

[email protected]

orcid.org/0000-0002-0099-109X

Departments of Neurology and Pediatrics, University of Washington, Seattle, Washington, USA

Department of Pediatrics, Duke University, Durham, North Carolina, USA

Correspondence Sidney M. Gospe, Jr., Departments of Neurology and Pediatrics, University of Washington, Seattle, WA, USA.

Email: [email protected]

Contribution: Conceptualization, Project administration, Writing - original draft, Writing - review & editing

Search for more papers by this author

First published: 07 March 2023

https://doi.org/10.1002/cns3.20016

Citations: 2

Share a link

Email
Wechat
Bluesky

Abstract

Pyridoxine-dependent epilepsy (PDE) was historically defined by a dramatic clinical response to a trial of pyridoxine and the re-emergence of seizures after withdrawal of pyridoxine. Research conducted over the last seven decades has revealed that the phenotype of PDE results from multiple genetic disorders, and the most common disorder, PDE-ALDH7A1, is caused by a deficiency of an enzyme involved in lysine metabolism. PDE-ALDH7A1 is characterized by more than epilepsy, as many patients have abnormalities of brain development, and most patients have intellectual and developmental disability. Treatment aimed at the underlying metabolic defect, in addition to pyridoxine supplementation, has improved clinical outcomes. Recently discovered biomarkers and genetic testing allow for the diagnosis of PDE-ALDH7A1 without the need of a pyridoxine trial and hold the promise for newborn screening. Despite these many advances, PDE-ALDH7A1 remains a clinical and biochemical conundrum. The increasing use of model systems and an international collaboration of clinician-scientists are among the reasons to be optimistic that these questions will be answered in the near future and that the clinical outcomes and quality of life will continue to improve for patients with PDE-ALDH7A1.

Pyridoxine-Dependent Epilepsy (PDE): Essential Clinical Features and Historical Aspects

First reported by Hunt and colleagues in 1954,¹ PDE is frequently described as the prototypical metabolic epileptic encephalopathy that is unresponsive to antiseizure drugs, but which is generally successfully treated with a vitamin or another cofactor. These patients commonly present with medication-resistant neonatal seizures that may lead to status epilepticus and that come under control only with the addition of pharmacologic doses of pyridoxine (vitamin B₆) to their treatment regimen.^2-4 Concomitant improvement in the electroencephalogram (EEG) may occur as well, particularly if the patient is experiencing ongoing clinical seizures and EEG monitoring is conducted at the time of pyridoxine administration (Figure 1).⁶ The long-term treatment of these patients requires daily supplementation of large (i.e., pharmacologic, not physiologic) doses of pyridoxine.^2-4 Hence, these individuals are dependent on the vitamin; they are not deficient. Indeed, clinical pyridoxine deficiency is rare, with an incidence of 0.23 cases/100 000 person-year in US military personal;⁷ significant deficiency is associated with irritability, abdominal pain, insomnia, weakness, and difficulty with ambulation.⁸ In childhood, the most often cited example was iatrogenic pyridoxine deficiency secondary to an error in the manufacturing of infant formula, which led to an epileptic encephalopathy quite similar to the neonatal presentation of PDE.^{9, 10} Importantly, a pyridoxine deficiency may be induced by treatment with isoniazid, and pyridoxine is the antidote for isoniazid overdose.¹¹

Details are in the caption following the image — **Figure 1**
Open in figure viewer PowerPoint

Continuous monitoring with an ambulatory electroencephalographic recorder was performed in a three-month-old girl undergoing evaluation for pyridoxine-dependent epilepsy. (A) Clinical seizure, consisting of eye deviation to the right and asymmetric clonic movements of the extremities, was associated with widely distributed high-voltage electrographic seizure activity. (B) Five minutes after patient received 100 mg pyridoxine by intravenous infusion, electrographic seizure activity was markedly reduced. All clinical and electrographic seizure activity resolved within 7 min of administration of pyridoxine. (C) At 10 min after the administration of pyridoxine, electrographic activity was markedly depressed without evidence of epileptiform activity. The electroencephalogram remained depressed throughout the next 12 h, at which point the monitoring was discontinued. Compound heterozygous pathogenic variants in *ALDH7A1* were subsequently demonstrated. Horizontal calibration = 1 s; vertical calibration = 200 mv. Reproduced with permission of the publisher from Gospe.⁵

Prior to the discovery of the genetic etiologies of the now three established forms of PDE, the disorder could only be clinically proven by withdrawing the vitamin from a patient who had been successfully treated, in order to demonstrate that clinical seizures would reemerge, generally within a few days, and then be controlled once again by reintroducing the vitamin supplement.^2-4 Now, as clinicians have become more familiar with PDE, many patients are treated proactively with pyridoxine, and the diagnosis of the disorder is demonstrated either through the detection of biomarkers and/or by genetic testing.³ In addition, with the availability of targeted genetic screening for epileptic encephalopathies, some patients with PDE are diagnosed prior to institution of pyridoxine treatment. An important distinction to mention is that some patients whose seizures were controlled after the addition of pyridoxine do not have a reappearance of clinical seizures after the withdrawal of the vitamin supplementation. These patients are deemed to be pyridoxine responsive,¹² and it has therefore been suggested that the vitamin may have some intrinsic antiseizure effects. For example, the clinical efficacy of pyridoxine in treating seizures in patients with epilepsy due to mutations in KCNQ2 and in some patients with infantile spasms has been reported.^{13, 14}

The Three Established Forms of PDE

Since the initial description of PDE in 1954, additional clinical reports of patients with PDE have appeared, together with a rapidly increasing number of publications describing the natural history, imaging characteristics, neurophysiological features, phenotypic variations, genetic and biochemical features, and treatment recommendations. In a review of the Medline database, between 1954 and 2022, 333 papers concerning PDE have been published, with 72% of the papers appearing since 2005. It is now established that there are at least three forms of PDE (Table 1). The first type of PDE to be molecularly characterized, in 2005, is associated with biallelic pathogenic variants in the PNPO gene, which encodes pyridox(am)ine 5′-phosphate oxidase (OMIM 610090).¹⁵ This condition is designated as PDE-PNPO, or PNPO deficiency, and an important feature of this disorder is that approximately 60% of affected patients require treatment with pyridoxal-5′-phosphate (PLP), the biologically active form of pyridoxine, rather than pyridoxine.¹⁶ A second form of PDE, due to biallelic pathogenic variants in PLPBP, which encodes PLP homeostasis protein (PLPHP), was discovered in 2016 (OMIM 617290).¹⁷ PLP binds to PLPHP, but little is known about the function of this protein.¹⁸ Sandwiched between the discovery of these two disorders was the 2006 demonstration of the biochemical and genetic etiology of the most thoroughly described and studied form of PDE. This pyridoxine-dependent metabolic epileptic encephalopathy is due to biallelic pathogenic variants in ALDH7A1, the gene that encodes the enzyme α-aminoadipic acid semialdehyde (α-AASA) dehydrogenase (OMIM 266100).¹⁹ This condition is now designated as PDE-ALDH7A1.³ It should be stressed that while PDE-ALDH7A1 is the best studied form of PDE, the specific form of PDE that affected the first PDE patient described by Hunt and colleagues in 1954, along with many additional patients reported through the latter half of the 20th century, is not established. PDE-ALDH7A1 will be the topic of this review, which will focus on clinical, biochemical, and genetic features of the disease, with a particular emphasis on recent developments and ongoing research questions.

Table 1. Genetic causes of pyridoxine-dependent epilepsy.

Disorder	Gene	Chromosomal location (hg38)	Function
Pyridoxine-dependent epilepsy	ALDH7A1	Location: 5q23.2 (chr5: 126 541 841–126 595 219)	Lysine degradation
Pyridoxamine-5′-phophate oxidase deficiency	PNPO	Location: 17q21.32 (chr17: 47 941 571–47 949 308)	Catalyzes the synthesis of PLP
Pyridoxal phosphate homeostasis protein	PLPBP	Location: 8p11.23 (chr8: 37 762 645–37 779 768)	Homeostatic regulation of PLP

Abbreviation: PLP, pyridoxal-5′-phosphate.

Clinical, Genetic, and Biochemical Aspects of PDE-ALDH7A1

Natural history

PDE-ALDH7A1 is inherited in an autosomal recessive manner and is a rare cause of epileptic encephalopathy. Over 200 affected individuals have been reported either in the literature or through rare disease patient registries,^{2, 4, 20-25} and the estimated birth incidence is 1:64,352.²³ The classic neonatal presentation has been well-described in textbooks for several decades. These infants develop medication-resistant seizures within the first several days of life, with some mothers having reported unusual rhythmic fetal movements concerning for intrauterine fetal seizures. In some instances, affected newborns have signs suggestive of birth asphyxia, which can lead to a missed or delayed diagnosis.^{4, 21, 26-28} A variety of clinical seizure types have been described, including partial, generalized, atonic, myoclonic events, and epileptic spasms. In many instances, patients develop status epilepticus, which may be clinically obscured by the administration of multiple antiseizure medications, but seizures persist electrographically.^{2, 4, 21} Patients not yet treated with pyridoxine may have waxing and waning encephalopathy, and periods of recurrent seizure activity may be preceded or accompanied by unusual eye movements or facial grimacing.²⁹ A variety of atypical presentations have been described, including onset outside of the neonatal period (up to three years of age and rarely presenting in adolescence or later^{20, 21, 30-32}); seizures that initially respond to antiseizure medications but become intractable; seizures that initially do not respond to the initial administration of pyridoxine but are subsequently controlled with pyridoxine treatment; and patients who have a prolonged seizure-free interval (up to five months) after a trial of pyridoxine discontinuation.^{2, 4, 21}

The natural history of patients with PDE-ALDH7A1 is variable, both with respect to control of seizures and intellectual development. While the sine qua non of PDE is that the affected patient's seizures only come under (often dramatic) control once pyridoxine is added, there are patients who, over time, may require one or more anti-seizure medications.^{2, 4} This may occur in patients with either the classic neonatal presentation or atypical manifestations. Approximately 75% of patients have some degree of neurodevelopmental disability, ranging from mild to severe intellectual disability, autistic features, and other behavioral problems.^2-4 Verbal skills, particularly expressive language, tend to be more impaired. Patients with later-onset of seizures and those with a prompt early diagnosis and treatment tend to have a better prognosis, but this is not always the case.^{2, 4, 30, 33} This variable natural history may also be due, in part, to associated brain dysgenesis, unknown genotype–phenotype correlations, and levels of one or more toxic metabolites.

Associated developmental features

Patients with PDE-ALDH7A1 may have congenital and/or progressive abnormalities of brain development. Thinning of the posterior corpus callosum, primarily the isthmus (Figure 2), is universal and can be quantitatively demonstrated via magnetic resonance imaging (MRI) geometric morphometry.^{34, 35} In addition, mega cisterna magna and other posterior fossa abnormalities have been noted in approximately 20% of patients (Figure 2).³⁴ Uncommonly, heterotopia and other forms of cortical dysplasia have been demonstrated with imaging and neuropathological studies.^36-38 Obstructive hydrocephalus and progressive ventriculomegaly (hydrocephalus ex vacuo, presumably due to late diagnosis and/or poor seizure control) have been described.³⁹ Other developmental abnormalities include congenital cataracts⁴⁰ as well as variable pattern of facial dysmorphism that includes hypertelorism, depressed nasal bridge, epicanthal folds,⁴¹ high hairline, pointed chin, full eyebrows, and broad nasal root (Gospe, unpublished observations).

Biochemical pathophysiology and genetics

PDE-ALDH7A1 is a metabolic encephalopathy due to an inborn error of lysine catabolism. Biallelic pathogenic variants in ALDH7A1 result in absence or dysfunction of α-AASA dehydrogenase (also known as antiquitin), the enzyme that oxidizes α-AASA to α-aminoadipic acid.¹⁹ The underlying pathophysiology of PDE-ALDH7A1 is due to an accumulation of several intermediate metabolites in both the pipecolic acid and saccharopine branches of the lysine catabolic pathway, including pipecolic acid, α-AASA, and Δ¹-piperideine-6-carboxylate (Δ¹-P6C) (Figure 3). Through a Knoevenagel condensation reaction, Δ¹-P6C binds and effectively deactivates PLP, the cofactor that is required for the function of more than 160 enzymatic activities in human cells.⁴² Dysfunction of one or several PLP-dependent enzymes likely contributes to the epileptic encephalopathy experienced by these patients. In particular, dysfunction of glutamic acid decarboxylase, which converts excitatory glutamic acid to inhibitory gamma-aminobutyric acid (GABA), was first suggested in 1960 by Scriver,⁴³ and reduced GABA synthesis has been demonstrated in cultured fibroblasts from a PDE-ALDH7A1 patient.⁴⁴ Reduced activity of this enzyme would result in an excitatory/inhibitory imbalance that could underly the epileptic encephalopathy. It is a stark coincidence that while these patients are not pyridoxine deficient, they have a secondary PLP deficiency, thereby requiring large daily supplements of pyridoxine.

Biomarkers

The diagnosis of PDE-ALDH7A1 is now facilitated through the detection of biomarkers in biological fluids and the confirmation of pathogenic variants through testing of the ALDH7A1 gene. Assays for α-AASA⁴⁵ and pipecolic acid⁴⁶ can be conducted on urine or blood, and if elevated in a patient with an epileptic encephalopathy would suggest a diagnosis of PDE-ALDH7A1.³ It must be stressed that these metabolites are not specific, as α-AASA can also be elevated in patients with molybdenum cofactor deficiency and isolated sulfite oxidase deficiency,⁴⁷ and pipecolic acid can be elevated in patients with peroxisomal disorders.⁴⁸ In addition, in older patients with PDE-ALDH7A1 treated with pyridoxine, pipecolic acid levels may normalize.^{49, 50} Therefore, specific confirmation of PDE-ALDH7A1 requires an evaluation of the ALDH7A1 gene, generally via both sequence analysis, which will detect >95% of pathogenic variants, and deletion/duplication analysis that will detect <5% of pathogenic variants.²³ Evaluation of ALDH7A1 can be done through specific gene testing, multigene panels, and comprehensive genomic testing. The common c.1279G>C (p.Glu427Gln) variant in exon 14 accounts for approximately 33% of the pathogenic variants. Importantly, homozygous c.1279G>C variants have been reported in both patients with classic neonatal-onset PDE-ALDH7A1 and late-onset disease.^20-23

The identification of these biomarkers and the availability of genetic testing was critical to the understanding of PDE-ALDH7A1. As we have already discussed, there are multiple genetic causes of PDE that may present with a similar seizure phenotype, and each genetic cause has unique implications for treatment.⁵¹ Most notably, establishing PDE-ALDH7A1 as a disorder of lysine catabolism had distinct treatment implications that will be discussed later. Despite the diagnostic implication of elevated pipecolic acid and α-AASA/Δ¹-P6C, these biomarkers also had some limitations. Importantly, α-AASA/Δ¹-P6C is relatively unstable at room temperature, which requires samples to be frozen prior to shipment to diagnostic laboratories.^52-54 This may limit the availability of biochemical testing, and makes the possibility of extending these biomarkers to newborn screening impractical.

In 2019, the metabolite 6-oxo-pipecolate (6-oxo-2-piperidinecarboxylic acid) was identified in children and adolescents with PDE-ALDH7A1.⁵⁵ Previous studies in Penicillium chrysogenum demonstrated that 6-oxo-pipecolate was a product of the lysine biosynthetic pathway.^{56, 57} The main benefit of 6-oxo-pipecolate over existing biomarkers was the relative stability at room temperature.⁵⁵ Shortly thereafter, a second novel biomarker was identified: 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP).⁵⁸ Although the role of 2-OPP in lysine degradation is less clear, infrared ion spectroscopy suggests 2-OPP may result from the reaction between Δ¹-P6C and acetoacetate.⁵⁹ Similar to 6-oxo-pipecolate, 2-OPP is relatively stable at room temperature and may have implications for the underlying pathophysiology of disease⁵⁸ (Figure 3).

Potential for newborn screening

As discussed above, new biomarkers were initially investigated to pursue metabolite-based newborn screening. Although rare, it appears as though newborns with PDE-ALDH7A1 have had fatal status epilepticus before treatment with pyridoxine could be initiated.^{21, 37, 38} Additionally, treatment with both pyridoxine and lysine reduction therapies in the first six months of life has been associated with significant developmental improvements (see below).²⁴ Therefore, the delay in diagnosis and treatment may be the most significant contributor to mortality and morbidity in this treatable disorder, and suggests that PDE-ALDH7A1 may be an ideal candidate for newborn screening.⁶⁰ Indeed, it was recently selected as a top priority for newborn screening by members of the US Pediatric Epilepsy Research Consortium.⁶¹

The first study focused on newborn screening measured α-AASA and Δ¹-P6C in residual dried blood spots, although neither metabolite was detected in unrefrigerated samples.⁶² Pipecolic acid has also been proposed as a primary biomarker for newborn screening of PDE-ALDH7A1.⁶³ The lack of stability (α-AASA/Δ¹-P6C) and concerns about sensitivity and specificity (pipecolic acid) make these biomarkers less than ideal. Both 6-oxo-pipecolate and 2-OPP are promising biomarkers for newborn screening and have been elevated in dried blood spots from affected patients.^{55, 58} These pilot studies are encouraging, including one study documenting elevated 6-oxo-pipecolate in a 33-year-old residual dried blood spot (Woontner et al. in review), although larger studies are still needed before newborn screening of PDE-ALDH7A1 will be widely adopted.

Treatment of PDE-ALDH7A1

Initial recommendations for the diagnosis, treatment, and follow-up of patients with PDE-ALDH7A1 were published in 2011,⁶⁴ and treatment recommendations were updated after the first study using a lysine-restricted diet.⁶⁵ In 2021 the first consensus guidelines for the diagnosis and management of PDE-ALDH7A1 were published by the International PDE Consortium (www.pdeonline.org).³ Recommendations were based on several individual factors such as the age of the patient and the severity of the phenotype. The authors were transparent about the relatively low level of available evidence, and many of the recommendations relied on expert consensus.

Pyridoxine supplementation

PDE is historically defined based on the resolution of seizures following treatment with pharmacologic doses of pyridoxine,¹ and treatment with pyridoxine remains central to the treatment of the epilepsy that has defined this disorder. The importance of vitamin B₆ supplementation is highlighted by the recurrence of seizures following pyridoxine withdrawal^66-70 and case reports that describe patients who died before pyridoxine was administered.^{21, 37, 38} As noted above, patients with PDE-ALDH7A1 have a secondary deficiency of PLP most likely due to a Knoevenagel reaction between the accumulating Δ¹-P6C and PLP.¹⁹ Treatment with pyridoxine, as opposed to PLP, is recommended for several reasons. There is an association between PLP supplementation and cirrhosis, including at doses usually required for successful treatment of seizures.^{71, 72} It is also worth considering that commercial pyridoxine preparations are relatively easy to obtain and stable, whereas PLP degrades quickly when exposed to light.⁷³ The International PDE Consortium consensus guideline for pyridoxine supplementation by age is listed in Table 2. Note that these pharmacologic doses are substantially higher than the recommended dietary allowance (physiologic doses), which ranges from 0.1 mg for infants to 2 mg for lactating females.⁷⁴ While there is a risk of peripheral neuropathy when the dose of pyridoxine exceeds 500 mg/day,^{33, 75} the vast majority of patients with PDE-ALDH7A1 do not require such large doses for seizure control. Some patients may require one or more anti-seizure medications, in addition to the maximum recommended dose of pyridoxine, to achieve control of their seizures.

Table 2. Consensus guideline for pyridoxine supplementation for patients with PDE-ALDH7A1.

Age of patient	Pyridoxine dose range	Maximum daily dose (mg)
Newborns	100 mg/day	100
Infants	30 mg/kg/day	300
Children and adolescents	20 mg/kg/day Range 5–30 mg/kg/day	500
Adults	200–500 mg/day	500

Adapted from 2021 PDE Consortium consensus guidelines.³

There have been many reports of presumed intrauterine fetal seizures in newborns subsequently diagnosed with PDE-ALDH7A1. As there is a 25% recurrence risk for a couple having another affected child, maternal pyridoxine supplementation during gestation has been proposed for these at-risk pregnancies, specifically to help control intrauterine seizures and improve developmental outcome.⁷⁶ Ideally, plans should be made for the fetus to be delivered at an institution that is equipped to care for a newborn at risk of developing an epileptic encephalopathy, and the baby should receive pyridoxine supplementation until the results of confirmatory biochemical studies and/or gene testing have been obtained.

Lysine-reduction therapies

From the early description of the disorder, patients with PDE were described as having intellectual or developmental disability (IDD).^{1, 77} More recent studies noted that there was no association between the time of seizure onset or severity and IDD, suggesting the poor developmental outcomes may be due to a separate disease mechanism.^{2, 25, 78} The discovery that PDE-ALDH7A1 was, in fact, an organic aciduria led to the current hypothesis that accumulating α-AASA (or related) metabolites are neurotoxic and contribute to the IDD phenotype.⁶⁴ Current adjunct (to pyridoxine) therapies attempt to reduce the nutritional intake of lysine or reduce the transport of lysine and are collectively referred to as lysine-reduction therapies (LRTs).

In a cross-sectional study of seven subjects, van Karnebeek et al. treated patients with PDE-ALDH7A1 with pyridoxine and a lysine-free medical formula and demonstrated a decrease in pipecolic acid, α-AASA, and Δ¹-P6C.⁷⁹ Shortly thereafter, a single patient was treated with pyridoxine and arginine, as the dibasic amino acids lysine, arginine, and ornithine are transported by the same cationic transporter in the intestine, the kidney, and the blood-brain barrier.^80-82 Following daily arginine supplementation, the patient had a decrease in urine and cerebrospinal fluid (CSF) α-AASA and improved neuropsychiatric testing.⁸³ In a pre–post design, patients who were initially treated with pyridoxine and lysine-restricted diet had arginine supplementation added to their treatment regimen (also referred to as triple therapy). These patients demonstrated a significant decrease in plasma α-AASA and Δ¹-P6C.⁸⁴

Although not the primary outcome measure in these studies, all of the reports noted improved development in those patients treated with a form of LRTs. A recent cohort study evaluated the association between treatment with LRTs and cognitive outcomes. Cohort assignment was based on treatment at the time of developmental testing, and treatment with pyridoxine and LRT was associated with a nonsignificant increase on developmental testing compared to treatment with pyridoxine alone.²⁴ Notably, treatment with pyridoxine and LRTs in the first six months of life was associated with a significant increase on developmental testing scores,²⁴ which emphasizes both the efficacy of LRTs and the importance of early, if not newborn, diagnosis and treatment.

Proposed Future Research Questions

It has been almost 70 years since the initial description of a newborn in whom seizures ceased following a dose of pyridoxine.¹ In 2003, three years before the discovery of the genetic basis of PDE-ALDH7A1, Peter Baxter published a review paper on PDE titled “Pyridoxine-dependent seizures: a clinical and biochemical conundrum” in which he discussed both some contradictory biochemical observations and, importantly, some initial biochemical clues that eventually help lead investigators to the discovery of altered function of α-AASA dehydrogenase in affected patients.⁸⁵ While our understanding of the molecular mechanisms associated with PDE-ALDH7A1 has advanced significantly over the past two decades, several questions regarding underlying biochemistry, pathology, and phenotypic variability of the disorder remain, all of which are ripe for investigation.

Is there a biochemical signature for PDE-ALDH7A1?

Shortly after the initial description of PDE, it was suggested that the glutamic acid-GABA system was involved in the underlying pathophysiology of the disorder.⁴³ It was known that glutamic acid decarboxylase was a vitamin B₆-dependent enzyme,⁸⁶ although prior to the identification of ALDH7A1 it was clear that glutamic acid decarboxylase was not the genetic etiology of PDE.⁸⁷ Although it remains unclear, elevated CSF glutamate in patients with PDE-ALDH7A1 further suggests the role of the GABA synthetic pathway in this disorder.⁸⁸ As noted above, PLP is a cofactor for many critical enzymes, and the impact of PDE-ALDH7A1 on these enzymes remains opaque. Of note, patients with PDE-ALDH7A1 have been initially misdiagnosed as having nonketotic hyperglycinemia, as the glycine cleavage enzyme is also PLP dependent.^{89, 90} These examples further emphasize the impact of the secondary vitamin B₆ deficiency in PDE-ALDH7A1 and highlight the importance of evaluating the role of these secondary enzyme deficiencies in the early course of the disease.

What is the biochemical pathophysiology of PDE-ALDH7A1?

The hypothesis that α-AASA is a neurotoxic organic acid was based on relatively circumstantial evidence.⁶⁴ Of course α-AASA is the primary substrate of the enzyme α-AASA dehydrogenase and, therefore, is the most proximal metabolite to the underlying defect. Although α-AASA is fairly reactive and may quickly be converted to its dehydration product Δ¹-P6C,⁵⁵ the role of Δ¹-P6C and PLP deficiency has been better defined, although the chemical condensation product has only been identified in a single study.¹⁹ In a study of brain tissue extract from a patient with PDE-ALDH7A1, the metabolites 6-oxo-pipecolate (29 nmol/g), α-AASA (13.02 nmol/g), Δ¹-P6C (8.14 nmol/g), and 2-OPP (5 nmol/g) were present,⁵⁸ although the presence and relative quantification of these metabolites in brain tissue does support direct causality. It is conceivable that the improvement of metabolomics platforms will continue to identify metabolic derangements in PDE,^{59, 91-93} and future studies need to address whether these metabolites are directly associated with disease pathophysiology or are simply diagnostic biomarkers. It remains possible that other mechanisms are involved in the natural history of this disease, such as mitochondrial impairment⁸⁸ or oxidative stress.⁹⁴

It is important to note that lysine is metabolized through two pathways (Figure 3) that were originally thought to have distinct roles, with the saccharopine pathway being predominant in the liver and the pipecolic acid pathway in the brain. The compartmentalized role of each enzyme was supported by high levels of saccharopine dehydrogenase in the liver, relative absence of saccharopine dehydrogenase in the brain, and low levels of l-pipecolic acid oxidase in the liver and predominance in the brain.^95-97 Recent studies using wild-type mice and cultured human astrocytes suggest the saccharopine pathway may have a role in brain lysine metabolism and may even be the predominant lysine oxidation pathway in the brain,^{98, 99} and a number of therapeutic strategies exclusively target the saccharopine pathway. Although these recent studies are compelling, the role of each pathway in critical cells is still unclear.

Is there a genotype–phenotype correlation for PDE-ALDH7A1?

As noted above, PDE-ALDH7A1 is caused by biallelic mutations in ALDH7A1.¹⁹ This discovery provided insight into the mechanism of disease and made genetic testing to diagnose the condition widely available.³ The genotypic spectrum has been well defined,^{22, 23, 100, 101} and these studies have confirmed the presence of a relatively common mutation (p.Glu427Gln) and allowed for the estimation of disease frequency. Thus far, no genotype–phenotype correlation has been identified. It is possible that this is due to the difficulty in generating longitudinal phenotypic data in rare diseases. An alternative hypothesis is that the phenotype is driven by chronic accumulation of α-AASA or related metabolite. If this hypothesis is correct, the rate of α-AASA accumulation and subsequent rate of developmental regression would have a genotype–phenotype correlation. This may be overlooked due to a clinical bias where most patients are diagnosed or evaluated after the accumulation of α-AASA has reached a clinical threshold.

Why do some patients with PDE-ALDH7A1 require treatment with antiseizure medications?

Despite the often dramatic clinical and electrographic response to pyridoxine, many patients require the use of one or several antiseizure medications to control their epilepsy, and in some circumstances complete control is not achieved.² There are several explanations for why epileptic seizures may not completely respond to pyridoxine and LRTs. For patients who went undiagnosed and untreated for months to years, brain injury from multiple episodes of status epilepticus together with ongoing metabolic neurotoxicity likely result in brain injury that can result in epileptogenic foci. Neuropathological studies of PDE-ALDH7A1 patients have demonstrated areas of cortical necrosis, gliosis, hippocampal sclerosis, and status marmoratus,^{36, 37} and similar features have been noted on imaging studies.^{35, 101} In addition, developmental brain dysgenesis, including cortical dysplasia and heterotopia, have also been demonstrated via neuropathological studies^{36, 37} and magnetic resonance imaging.^{35, 101} Treatment of epilepsy emanating from these developmental lesions would likely require the use of one or multiple antiseizure medications.

How does α-AASA dehydrogenase dysfunction result in structural anomalies?

It is perplexing that reduced or absent activity of an enzyme that functions within the lysine catabolism pathway also leads to abnormal development of the central nervous system (partial agenesis of the corpus callosum, mega cisterna magma, cortical dysplasia, heterotopia), as well as less common phenotypic features such as congenital cataracts⁴⁰ and facial dysmorphism.⁴¹ Prior to the discovery of the role of antiquitin in lysine catabolism, it was known that the enzyme functioned as an aldehyde dehydrogenase, and that plant antiquitins played a role in osmoregulation.¹⁰² Hyperosmotic stress can be cataractogenic, and it has been suggested that this may explain the development of cataracts in some individuals with PDE-ALDH7A1.⁴⁰ As far as the development of heterotopia and other forms of cortical dysgenesis are concerned, antiquitin has been localized to radial glia and other nonneuronal cells,³⁶ and dysfunction of this protein is likely responsible for these neurodevelopmental lesions. It is conceivable that antiquitin plays biological roles other than just serving as an aldehyde dehydrogenase. Indeed, it has been noted that specific single nucleotide polymorphisms in ALDH7A1 can modify the prognosis of certain oral cancers,¹⁰³ while a genome-wide association study noted that ALDH7A1 was a susceptibility gene for osteoporosis.¹⁰⁴ The concepts of moonlighting (where a site remote from the active site of the enzyme is recruited to serve a secondary function) and catalytic promiscuity (where the active site catalyzes an adventitious secondary reaction)^{105, 106} should be explored as potential explanations for why these structural anomalies are components of the PDE-ALDH7A1 phenotype.

Are there characteristic structural features of PDE-ALDH7A1?

Thinning of the posterior corpus callosum and abnormal development of the posterior fossa (Figure 2) are well described in PDE-ALDH7A1, and patients have been noted with dysmorphic facial features. Should these various structural changes be considered as characteristic components of the phenotype? Shape analysis of imaging studies in cohorts of PDE-ALDH7A1 patients have quantified the abnormal structure of the corpus callosum, demonstrating that the finding is present across the age spectrum and independent of the time of diagnosis and initiation of treatment.³⁵ These changes may not always be obvious via a routine review of an MRI scan. As far as posterior fossa abnormalities are concerned, mega cisterna magna, when present, is an imaging finding that is quite evident to a clinician. But are there more subtle posterior fossa structural features that may only be detected via geometric morphometry? What about the facial dysmorphic features that have been described? These should not be out-of-hand discounted as part of the clinical phenotype, as various forms of facial dysmorphism are well known in other inborn errors of metabolism such as Zellweger spectrum disorder,¹⁰⁷ hyperosmotic stress,¹⁰⁸ and congenital disorder of glycosylation type Ia.¹⁰⁹ Documentation of the facial features of PDE-ALDH7A1 patients via 3D photography will help determine if certain dysmorphic features are common.

What components of the PDE-ALDH7A1 phenotype will newborn screening followed by early lysine-reduction therapy improve?

As noted above, advocates for newborn screening emphasize the risk of fatal status epilepticus prior to treatment with pyridoxine and the poor developmental outcome for late pyridoxine-treated patients as well as those treated with LRTs after 6 months of age.⁶⁰ While some patients have had normal development despite delays in treatment with pyridoxine and without the addition of LRTs,^{24, 110, 111} there is an association between the onset of initial seizures and developmental outcomes,^{24, 30} although this association must be due to more than seizures alone. Affected patients who receive antenatal or immediate neonatal pyridoxine treatment often have no clinical evidence of seizures and may still have quite poor developmental outcomes.^{25, 33, 78} It is possible that other modifiers affect the cognitive phenotype of the disorder. Thus far, studies evaluating the impact of pyridoxine and LRT have focused on either surrogate biomarkers or developmental testing such as IQ. It is unlikely that the addition of LRT would modify the anatomical features noted on MRI such as thinning of the corpus callosum, mega cisterna magna, or cortical dysplasia.^34-36 Conversely, further studies should also focus on the impact (both positive and negative) of adjunct therapies on behavioral difficulties²⁵ and general quality of life for patients with PDE-ALDH7A1 and their families.¹¹²

How will model systems help resolve some of these questions?

Several cellular and animal models have been used to answer these and other questions. Crowther and colleagues used a combination of human fibroblasts and astrocytes derived from human cortex to study the role of pipecolate and saccharopine pathways in lysine degradation.⁹⁹ Using l-[α¹⁵N]-lysine and l-[ε¹⁵N]-lysine, the cellular models suggested the saccharopine pathway is the predominant pathway for human lysine degradation to amino adipic acid. A similar isotope tracer method was used to demonstrate saccharopine is the primary pathway for lysine metabolism in mouse liver, kidney, cerebral cortex, and cerebellum.⁹⁸ Both zebrafish and mouse knockout models have been developed to further understand both disease pathophysiology and response to treatment. In zebrafish, the aldh7a1^−/− fish demonstrate spontaneous seizures leading to death, a phenotype which can be rescued with pyridoxine.^{113, 114} Of note, exposure to lysine exasperates this phenotype. A morpholino knockdown aldh7a1 zebrafish model resulted in both uveal coloboma and skeletal abnormalities, implicating ALDH7A1 in the development of structures other than the central nervous system.¹¹⁵ Conversely, the Aldh7a1^−/− mouse does not have an epilepsy phenotype unless exposed to high dietary lysine.¹¹⁶ These models demonstrate that high dietary lysine is associated with both increased metabolic disturbances and worsening of the epilepsy phenotype. On their own, these results do not support the benefit of LRTs, although these cellular and animal models may be critical for the evaluation of current and future therapies.

Conclusion

It has been close to 70 years since the first description of pyridoxine dependency in an infant with antiseizure medication–resistant epilepsy. In the subsequent years, several genetic causes of PDE have been described where first-line treatment with pharmacologic doses of pyridoxine or PLP typically provide dramatic improvement in the epileptic encephalopathy. PDE-ALDH7A1, the most reported and studied of these disorders, is primarily a disorder of lysine metabolism, and current therapeutic strategies are similar to those developed for other organic acidurias. Patients who are diagnosed in early infancy and promptly treated with the combination of pyridoxine and LRT have significantly improved clinical outcomes. Despite these advances, many questions remain about disease pathophysiology, phenotypic heterogeneity, and response to treatment. Current cellular and animal models hold promise to help further unravel many of these questions. Collaborative efforts, such as the International PDE Consortium (www.pdeonline.org), have aided our understanding of the natural history of the disease and the efficacy of various treatment regimens. Taken together, there is reason to be optimistic that the next few years will include more effective treatments leading to improved outcomes and quality of life for patients with PDE.

Author Contributions

Curtis R. Coughlin II: Writing—original draft; writing—review and editing. Sidney M. Gospe Jr.: Conceptualization; project administration; writing—original draft; writing—review and editing.

Acknowledgments

The authors wish to thank Ann Madhavan and Lynly Beard of the University of Washington Health Sciences Library for their assistance with bibliometric research. This publication was supported, in part, by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number R21HD104952. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflicts of Interest

The authors declare no conflict of interest.

References

1Hunt AD, Stokes J, McCrory WW, Stroud HH. Pyridoxine dependency: report of a case of intractable convulsions in an infant controlled by pyridoxine. Pediatrics. 1954; 13(2): 140-145.
10.1542/peds.13.2.140
CAS PubMed Web of Science® Google Scholar
2Basura GJ, Hagland SP, Wiltse AM, Gospe Jr. SM. 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(6): 697-704.
10.1007/s00431-008-0823-x
PubMed Web of Science® Google Scholar
3Coughlin II CR, Tseng LA, Abdenur JE, et al. Consensus guidelines for the diagnosis and management of pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency. J Inherit Metab Dis. 2021; 44(1): 178-192.
10.1002/jimd.12332
CAS PubMed Web of Science® Google Scholar
4van Karnebeek CDM, Tiebout SA, Niermeijer J, et al. Pyridoxine-dependent epilepsy: an expanding clinical spectrum. Pediatr Neurol. 2016; 59: 6-12.
10.1016/j.pediatrneurol.2015.12.013
PubMed Web of Science® Google Scholar
5Gospe Jr. SM. Current perspectives on pyridoxine-dependent seizures. J Pediatr. 1998; 132(6): 919-923.
10.1016/S0022-3476(98)70384-1
PubMed Web of Science® Google Scholar
6Bok LA, Maurits NM, Willemsen MA, et al. The EEG response to pyridoxine-IV neither identifies nor excludes pyridoxine-dependent epilepsy. Epilepsia. 2010; 51(12): 2406-2411.
10.1111/j.1528-1167.2010.02747.x
PubMed Web of Science® Google Scholar
7Knapik JJ, Farina EK, Fulgoni VL, Lieberman HR. Clinically-diagnosed vitamin deficiencies and disorders in the entire United States military population, 1997-2015. Nutr J. 2021; 20(1): 55.
10.1186/s12937-021-00708-2
CAS PubMed Web of Science® Google Scholar
8Aring CD, Spies TD. A critical review: vitamin B deficiency and nervous disease. J Neurol Neurosurg Psychiatry. 1939; 2(4): 335-360.
10.1136/jnnp.2.4.335
CAS Google Scholar
9Coursin DB. Convulsive seizures in infants with pyridoxine-deficient diet. JAMA. 1954; 154(5): 406-408.
10.1001/jama.1954.02940390030009
CAS PubMed Web of Science® Google Scholar
10Molony CJ. Convulsions in young infants as a result of pyridoxine (vitamin B6) deficiency. JAMA. 1954; 154(5): 405-406.
10.1001/jama.1954.02940390029008
CAS PubMed Web of Science® Google Scholar
11Dart RC, Goldfrank LR, Erstad BL, et al. Expert consensus guidelines for stocking of antidotes in hospitals that provide emergency care. Ann Emerg Med. 2018; 71(3): 314-325.
10.1016/j.annemergmed.2017.05.021
PubMed Web of Science® Google Scholar
12Baxter P. Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK. Arch Dis Child. 1999; 81(5): 431-433.
10.1136/adc.81.5.431
CAS PubMed Web of Science® Google Scholar
13Reid ES, Williams H, Stabej PLQ, et al. Seizures due to a KCNQ2 mutation: treatment with vitamin B6. JIMD Rep. 2016; 27: 79-84.
10.1007/8904_2015_460
PubMed Google Scholar
14Riikonen R, Mankinen K, Gaily E. Long-term outcome in pyridoxine-responsive infantile epilepsy. Eur J Paediatr Neurol. 2015; 19(6): 647-651.
10.1016/j.ejpn.2015.08.001
CAS PubMed Web of Science® Google Scholar
15Mills PB, Surtees RAH, Champion MP, et al. Neonatal epileptic encephalopathy caused by mutations in the PNPO gene encoding pyridox(am)ine 5′-phosphate oxidase. Hum Mol Gen. 2005; 14(8): 1077-1086.
10.1093/hmg/ddi120
CAS PubMed Web of Science® Google Scholar
16Alghamdi M, Bashiri FA, Abdelhakim M, et al. Phenotypic and molecular spectrum of pyridoxamine-5′-phosphate oxidase deficiency: a scoping review of 87 cases of pyridoxamine-5′-phosphate oxidase deficiency. Clin Genet. 2021; 99(1): 99-110.
10.1111/cge.13843
CAS PubMed Web of Science® Google Scholar
17Darin N, Reid E, Prunetti L, et al. Mutations in PROSC disrupt cellular pyridoxal phosphate homeostasis and cause vitamin-B6-dependent epilepsy. Am J Hum Genet. 2016; 99(6): 1325-1337.
10.1016/j.ajhg.2016.10.011
CAS PubMed Web of Science® Google Scholar
18Johnstone DL, Al-Shekaili HH, Tarailo-Graovac M, et al. PLPHP deficiency: clinical, genetic, biochemical, and mechanistic insights. Brain. 2019; 142(3): 542-559.
10.1093/brain/awy346
PubMed Web of Science® Google Scholar
19Mills PB, Struys E, Jakobs C, et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med. 2006; 12(3): 307-309.
10.1038/nm1366
CAS PubMed Web of Science® Google Scholar
20Bennett CL, Chen Y, Hahn S, Glass IA, Gospe Jr. SM. Prevalence of ALDH7A1 mutations in 18 North American pyridoxine-dependent seizure (PDS) patients. Epilepsia. 2009; 50(5): 1167-1175.
10.1111/j.1528-1167.2008.01816.x
CAS PubMed Web of Science® Google Scholar
21Mills PB, Footitt EJ, Mills KA, et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain. 2010; 133(Pt 7): 2148-2159.
10.1093/brain/awq143
PubMed Web of Science® Google Scholar
22Scharer G, Brocker C, Vasiliou V, et al. The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1. J Inherit Metab Dis. 2010; 33(5): 571-581.
10.1007/s10545-010-9187-2
CAS PubMed Web of Science® Google Scholar
23Coughlin II CR, Swanson MA, Spector E, et al. The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: a common epileptic encephalopathy. J Inherit Metab Dis. 2019; 42(2): 353-361.
10.1002/jimd.12045
CAS PubMed Web of Science® Google Scholar
24Coughlin II CR, Tseng LA, Bok LA, et al. Association between lysine reduction therapies and cognitive outcomes in patients with pyridoxine-dependent epilepsy. Neurology. 2022; 99(23): e2627-e2636.
10.1212/WNL.0000000000201222
PubMed Google Scholar
25Tseng LA, Abdenur JE, Andrews A, et al. Timing of therapy and neurodevelopmental outcomes in 18 families with pyridoxine-dependent epilepsy. Mol Gen Metab. 2022; 135(4): 350-356.
10.1016/j.ymgme.2022.02.005
CAS PubMed Web of Science® Google Scholar
26Mercimek-Mahmutoglu S, Horvath GA, Coulter-Mackie M, et al. Profound neonatal hypoglycemia and lactic acidosis caused by pyridoxine-dependent epilepsy. Pediatrics. 2012; 129(5): e1368-e1372.
10.1542/peds.2011-0123
PubMed Web of Science® Google Scholar
27Dowa Y, Shiihara T, Akiyama T, et al. A case of pyridoxine-dependent epilepsy with novel ALDH7A1 mutations. Oxf Med Case Reports. 2020; 2020(3): omaa008.
10.1093/omcr/omaa008
PubMed Web of Science® Google Scholar
28Aquilano G, Linnér A, Ygberg S, Stödberg T, Henckel E. Case report: fatal outcome of pyridoxine-dependent epilepsy presenting as respiratory distress followed by a circulatory collapse. Front Pediatr. 2022; 10:940103.
10.3389/fped.2022.940103
PubMed Web of Science® Google Scholar
29Schmitt B, Baumgartner M, Mills PB, et al. Seizures and paroxysmal events: symptoms pointing to the diagnosis of pyridoxine-dependent epilepsy and pyridoxine phosphate oxidase deficiency. Dev Med Child Neurol. 2010; 52(7): e133-e142.
10.1111/j.1469-8749.2010.03660.x
CAS PubMed Web of Science® Google Scholar
30de Rooy RLP, Halbertsma FJ, Struijs EA, et al. Pyridoxine dependent epilepsy: is late onset a predictor for favorable outcome? Eur J Paediatr Neurol. 2018; 22(4): 662-666.
10.1016/j.ejpn.2018.03.009
PubMed Web of Science® Google Scholar
31Osman C, Foulds N, Hunt D, Jade Edwards C, Prevett M. Diagnosis of pyridoxine-dependent epilepsy in an adult presenting with recurrent status epilepticus. Epilepsia. 2020; 61(1): e1-e6.
10.1111/epi.16408
PubMed Web of Science® Google Scholar
32Srinivasaraghavan R, Parameswaran N, Mathis D, Bürer C, Plecko B. Antiquitin deficiency with adolescent onset epilepsy: molecular diagnosis in a mother of affected offsprings. Neuropediatrics. 2018; 49(2): 154-157.
10.1055/s-0037-1621721
CAS PubMed Web of Science® Google Scholar
33Rankin 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(4): 300-305.
10.1111/j.1469-8749.2007.00300.x
PubMed Web of Science® Google Scholar
34Friedman SD, Ishak GE, Poliachik SL, et al. Callosal alterations in pyridoxine-dependent epilepsy. Dev Med Child Neurol. 2014; 56(11): 1106-1110.
10.1111/dmcn.12511
PubMed Web of Science® Google Scholar
35Oesch G, Maga AM, Friedman SD, et al. Geometric morphometrics reveal altered corpus callosum shape in pyridoxine-dependent epilepsy. Neurology. 2018; 91(1): e78-e86.
10.1212/WNL.0000000000005748
PubMed Web of Science® Google Scholar
36Jansen LA, Hevner RF, Roden WH, et al. Disruption of antiquitin (ALDH7A1) function in astrocytes is associated with neuronal migration defects in pyridoxine-dependent epilepsy. Ann Neurol. 2012; 72: S218-S219.
Web of Science® Google Scholar
37Marguet F, Barakizou H, Tebani A, et al. Pyridoxine-dependent epilepsy: report on three families with neuropathology. Metab Brain Dis. 2016; 31(6): 1435-1443.
10.1007/s11011-016-9869-z
CAS PubMed Web of Science® Google Scholar
38Toldo I, Bonardi CM, Bettella E, et al. Brain malformations associated to Aldh7a1 gene mutations: report of a novel homozygous mutation and literature review. Eur J Paediatr Neurol. 2018; 22(6): 1042-1053.
10.1016/j.ejpn.2018.06.010
PubMed Web of Science® Google Scholar
39Navarro-Abia V, Soriano-Ramos M, Núñez-Enamorado N, et al. Hydrocephalus in pyridoxine-dependent epilepsy: new case and literature review. Brain Dev. 2018; 40(4): 348-352.
10.1016/j.braindev.2017.12.005
PubMed Web of Science® Google Scholar
40Yusuf IH, Sandford V, Hildebrand GD. Congenital cataract in a child with pyridoxine-dependent epilepsy. J Am Assoc Pediatr Ophthalmol Strabismus. 2013; 17(3): 315-317.
10.1016/j.jaapos.2013.01.006
Web of Science® Google Scholar
41Haidar Z, Jalkh N, Corbani S, Fawaz A, Chouery E, Mégarbané A. Atypical pyridoxine dependent epilepsy resulting from a new homozygous missense mutation, in ALDH7A1. Seizure. 2018; 57: 32-33.
10.1016/j.seizure.2018.03.010
PubMed Web of Science® Google Scholar
42Cellini B, Montioli R, Oppici E, Astegno A, Borri Voltattorni C. The chaperone role of the pyridoxal 5′-phosphate and its implications for rare diseases involving B6-dependent enzymes. Clin Biochem. 2014; 47(3): 158-165.
10.1016/j.clinbiochem.2013.11.021
CAS PubMed Web of Science® Google Scholar
43Scriver CR. Vitamin B6-dependency and infantile convulsions. Pediatrics. 1960; 26: 62-74.
10.1542/peds.26.1.62
CAS PubMed Web of Science® Google Scholar
44Gospe Jr. SM, Olin KL, Keen CL. Reduced GABA synthesis in pyridoxine-dependent seizures. The Lancet. 1994; 343(8906): 1133-1134.
10.1016/S0140-6736(94)90236-4
PubMed Web of Science® Google Scholar
45Bok LA, Struys E, Willemsen MAAP, Been JV, Jakobs C. Pyridoxine-dependent seizures in Dutch patients: diagnosis by elevated urinary alpha-aminoadipic semialdehyde levels. Arch Dis Child. 2007; 92(8): 687-689.
10.1136/adc.2006.103192
PubMed Web of Science® Google Scholar
46Plecko B, Stöckler-Ipsiroglu S, Paschke E, Erwa W, Struys EA, Jakobs C. Pipecolic acid elevation in plasma and cerebrospinal fluid of two patients with pyridoxine-dependent epilepsy. Ann Neurol. 2000; 48(1): 121-125.
10.1002/1531-8249(200007)48:1<121::AID-ANA20>3.0.CO;2-V
CAS PubMed Web of Science® Google Scholar
47Mills PB, Footitt EJ, Ceyhan S, et al. Urinary AASA excretion is elevated in patients with molybdenum cofactor deficiency and isolated sulphite oxidase deficiency. J Inherit Metab Dis. 2012; 35(6): 1031-1036.
10.1007/s10545-012-9466-1
CAS PubMed Web of Science® Google Scholar
48Peduto A, Baumgartner MR, Verhoeven NM, et al. Hyperpipecolic acidaemia: a diagnostic tool for peroxisomal disorders. Mol Gen Metab. 2004; 82(3): 224-230.
10.1016/j.ymgme.2004.04.010
CAS PubMed Web of Science® Google Scholar
49Plecko B, Hikel C, Korenke G-C, et al. Pipecolic acid as a diagnostic marker of pyridoxine-dependent epilepsy. Neuropediatrics. 2005; 36(3): 200-205.
10.1055/s-2005-865727
CAS PubMed Web of Science® Google Scholar
50Mercimek-Mahmutoglu S, Donner EJ, Siriwardena K. Normal plasma pipecolic acid level in pyridoxine dependent epilepsy due to ALDH7A1 mutations. Mol Gen Metab. 2013; 110(1-2): 197.
10.1016/j.ymgme.2013.04.018
CAS PubMed Web of Science® Google Scholar
51Wilson MP, Plecko B, Mills PB, Clayton PT. Disorders affecting vitamin B6 metabolism. J Inherit Metab Dis. 2019; 42(4): 629-646.
10.1002/jimd.12060
CAS PubMed Web of Science® Google Scholar
52Struys EA, Jakobs C. α-Aminoadipic semialdehyde is the biomarker for pyridoxine-dependent epilepsy caused by α-aminoadipic semialdehyde dehydrogenase deficiency. Mol Gen Metab. 2007; 91(4): 405.
10.1016/j.ymgme.2007.04.016
CAS PubMed Web of Science® Google Scholar
53Struys EA, Bok LA, Emal D, Houterman S, Willemsen MA, Jakobs C. The measurement of urinary Δ¹-piperideine-6-carboxylate, the alter ego of α-aminoadipic semialdehyde, in Antiquitin deficiency. J Inherit Metab Dis. 2012; 35(5): 909-916.
10.1007/s10545-011-9443-0
CAS PubMed Web of Science® Google Scholar
54Sadilkova K, Gospe Jr. SM, Hahn SH. Simultaneous determination of alpha-aminoadipic semialdehyde, piperideine-6-carboxylate and pipecolic acid by LC-MS/MS for pyridoxine-dependent seizures and folinic acid-responsive seizures. J Neurosci Methods. 2009; 184(1): 136-141.
10.1016/j.jneumeth.2009.07.019
CAS PubMed Web of Science® Google Scholar
55Wempe MF, Kumar A, Kumar V, et al. Identification of a novel biomarker for pyridoxine-dependent epilepsy: implications for newborn screening. J Inherit Metab Dis. 2019; 42(3): 565-574.
10.1002/jimd.12059
CAS PubMed Web of Science® Google Scholar
56Brundidge SP, Gaeta FCA, Hook DJ, Sapino Jr. C, Elander RP, Morin RB. Association of 6-oxo-piperidine-2-carboxylic acid with penicillin V production in Penicillium chrysogenum fermentations. J Antibiot. 1980; 33(11): 1348-1351.
10.7164/antibiotics.33.1348
CAS PubMed Web of Science® Google Scholar
57Henriksen CM, Nielsen J, Villadsen J. Cyclization of alpha-aminoadipic acid into the delta-lactam 6-oxo-piperidine-2-carboxylic acid by Penicillium chrysogenum. J Antibiot. 1998; 51(2): 99-106.
10.7164/antibiotics.51.99
CAS PubMed Web of Science® Google Scholar
58Engelke UFH, van Outersterp RE, Merx J, et al. Untargeted metabolomics and infrared ion spectroscopy identify biomarkers for pyridoxine-dependent epilepsy. J Clin Invest. 2021; 131(15):148272.
10.1172/JCI148272
CAS PubMed Web of Science® Google Scholar
59van Outersterp RE, Engelke UFH, Merx J, et al. Metabolite identification using infrared ion spectroscopy─novel biomarkers for pyridoxine-dependent epilepsy. Anal Chem. 2021; 93(46): 15340-15348.
10.1021/acs.analchem.1c02896
PubMed Web of Science® Google Scholar
60Coughlin II CR, Tseng LA, van Karnebeek CD. A case for newborn screening for pyridoxine-dependent epilepsy. Mol Case Stud. 2022; 8(2):mcs.a006197.
10.1101/mcs.a006197
Google Scholar
61Hess-Homeier DL, Cunniff C, Grinspan ZM. Priorities for newborn screening of genetic epilepsy. Pediatr Neurol. 2019; 101: 83-85.
10.1016/j.pediatrneurol.2019.07.009
PubMed Web of Science® Google Scholar
62Jung S, Tran N-TB, Gospe Jr. SM, Hahn SH. Preliminary investigation of the use of newborn dried blood spots for screening pyridoxine-dependent epilepsy by LC-MS/MS. Mol Gen Metab. 2013; 110(3): 237-240.
10.1016/j.ymgme.2013.07.017
CAS PubMed Web of Science® Google Scholar
63Mathew EM, Moorkoth S, Lewis L, Rao P. Biomarker profiling for pyridoxine dependent epilepsy in dried blood spots by HILIC-ESI-MS. Int J Anal Chem. 2018; 2018: 1-8.
10.1155/2018/2583215
Web of Science® Google Scholar
64Stockler S, Plecko B, Gospe Jr. SM, et al. Pyridoxine dependent epilepsy and antiquitin deficiency. Mol Gen Metab. 2011; 104(1-2): 48-60.
10.1016/j.ymgme.2011.05.014
CAS PubMed Web of Science® Google Scholar
65van Karnebeek CDM, Stockler-Ipsiroglu S, Jaggumantri S, et al. Lysine-restricted diet as adjunct therapy for pyridoxine-dependent epilepsy: the PDE consortium consensus recommendations. JIMD Rep. 2014; 15: 1-11.
10.1007/8904_2014_296
PubMed Google Scholar
66Gül-Mert G, İncecik F, Hergüner MÖ, Ceylaner S, Altunbaşak Ş. Pyridoxine-dependent epilepsy in two Turkish patients in Turkey and review of the literature. Turk J Pediatr. 2015; 57(4): 394-397.
PubMed Web of Science® Google Scholar
67Nam SH, Kwon M-J, Lee J, et al. Clinical and genetic analysis of three Korean children with pyridoxine-dependent epilepsy. Ann Clin Lab Sci. 2012; 42(1): 65-72.
PubMed Web of Science® Google Scholar
68Russell KE, Mulligan SR, Mallory LA. Diagnosis of pyridoxine-dependent seizures in a nineteen-year-old patient. Pediatr Neurol. 2012; 47(2): 141-143.
10.1016/j.pediatrneurol.2012.04.018
PubMed Web of Science® Google Scholar
69Yang Z, Yang X, Wu Y, et al. Clinical diagnosis, treatment, and ALDH7A1 mutations in pyridoxine-dependent epilepsy in three Chinese infants. PLoS One. 2014; 9(3):e92803.
10.1371/journal.pone.0092803
PubMed Web of Science® Google Scholar
70Ben Younes T, Kraoua I, Benrhouma H, et al. Pyridoxine-dependent epilepsy: a novel mutation in a Tunisian child. Archives de Pédiatrie. 2017; 24(3): 241-243.
10.1016/j.arcped.2016.11.019
CAS PubMed Web of Science® Google Scholar
71Sudarsanam A, Singh H, Wilcken B, et al. Cirrhosis associated with pyridoxal 5′-phosphate treatment of pyridoxamine 5′-phosphate oxidase deficiency. JIMD Rep. 2014; 17: 67-70.
10.1007/8904_2014_338
PubMed Web of Science® Google Scholar
72Raimondi F, Mills P, Clayton PT, Del Giudice E. A preterm neonate with seizures unresponsive to conventional treatment. Case Reports. 2015; 2015:bcr2015209743.
Google Scholar
73Mohamed-Ahmed AHA, Wilson MP, Albuera M, et al. Quality and stability of extemporaneous pyridoxal phosphate preparations used in the treatment of paediatric epilepsy. J Pharm Pharmacol. 2017; 69(4): 480-488.
10.1111/jphp.12701
CAS PubMed Web of Science® Google Scholar
74 Institute of Medicine (US). Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline [Internet]. Washington (DC): National Academies Press (US); 1998. Accessed February 8, 2023.
Google Scholar
75McLachlan RS, Brown WF. Pyridoxine-dependent epilepsy with iatrogenic sensory neuronopathy. Can J Neurol Sci/J Can des Sci Neurol. 1995; 22(1): 50-51.
10.1017/S0317167100040506
CAS PubMed Web of Science® Google Scholar
76Bok LA, Been JV, Struys EA, Jakobs C, Rijper EAM, Willemsen MA. Antenatal treatment in two Dutch families with pyridoxine-dependent seizures. Eur J Pediatr. 2010; 169(3): 297-303.
10.1007/s00431-009-1020-2
PubMed Web of Science® Google Scholar
77Baxter 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(11): 998-1006.
10.1111/j.1469-8749.1996.tb15060.x
CAS PubMed Web of Science® Google Scholar
78Bok LA, Halbertsma FJ, Houterman S, et al. Long-term outcome in pyridoxine-dependent epilepsy. Dev Med Child Neurol. 2012; 54(9): 849-854.
10.1111/j.1469-8749.2012.04347.x
PubMed Web of Science® Google Scholar
79van Karnebeek CDM, Hartmann H, Jaggumantri S, et al. Lysine restricted diet for pyridoxine-dependent epilepsy: first evidence and future trials. Mol Gen Metab. 2012; 107(3): 335-344.
10.1016/j.ymgme.2012.09.006
PubMed Web of Science® Google Scholar
80Stoll J, Wadhwani KC, Smith QR. Identification of the cationic amino acid transporter (System y+) of the rat blood-brain barrier. J Neurochem. 1993; 60(5): 1956-1959.
10.1111/j.1471-4159.1993.tb13428.x
CAS PubMed Web of Science® Google Scholar
81Hawkins RA, O'Kane RL, Simpson IA, Viña JR. Structure of the blood-brain barrier and its role in the transport of amino acids. J Nutr. 2006; 136(1 suppl): S218-S226.
10.1093/jn/136.1.218S
CAS PubMed Web of Science® Google Scholar
82O'Kane RL, Viña JR, Simpson I, Zaragozá R, Mokashi A, Hawkins RA. Cationic amino acid transport across the blood-brain barrier is mediated exclusively by system y+. Am J Physiol-Endocrinol Metab. 2006; 291(2): E412-E419.
10.1152/ajpendo.00007.2006
PubMed Web of Science® Google Scholar
83Mercimek-Mahmutoglu S, Cordeiro D, Cruz V, et al. 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(6): 741-746.
10.1016/j.ejpn.2014.07.001
PubMed Web of Science® Google Scholar
84Coughlin II CR, van Karnebeek CDM, Al-Hertani W, et al. Triple therapy with pyridoxine, arginine supplementation and dietary lysine restriction in pyridoxine-dependent epilepsy: neurodevelopmental outcome. Mol Gen Metab. 2015; 116(1–2): 35-43.
10.1016/j.ymgme.2015.05.011
CAS PubMed Web of Science® Google Scholar
85Baxter P. Pyridoxine-dependent seizures: a clinical and biochemical conundrum. Biochim Biophys Acta (BBA). 2003; 1647(1–2): 36-41.
10.1016/S1570-9639(03)00045-1
CAS PubMed Web of Science® Google Scholar
86Roberts E, Rothstein M, Baxter CF. Some metabolic studies of gamma-aminobutyric acid. Proc Soc Exp Biol Med. 1958; 97(4): 796-802.
10.3181/00379727-97-23883
CAS PubMed Web of Science® Google Scholar
87Battaglioli G, Rosen DR, Gospe Jr. SM, Martin DL. Glutamate decarboxylase is not genetically linked to pyridoxine-dependent seizures. Neurology. 2000; 55(2): 309-311.
10.1212/WNL.55.2.309
CAS PubMed Web of Science® Google Scholar
88Minenkova A, Jansen EEW, Cameron J, et al. Is impaired energy production a novel insight into the pathogenesis of pyridoxine-dependent epilepsy due to biallelic variants in ALDH7A1? PLoS One. 2021; 16(9):e0257073.
10.1371/journal.pone.0257073
CAS PubMed Web of Science® Google Scholar
89Wang PJ, Lee WT, Hwu WL, Young C, Yau KIT, Shen YZ. The controversy regarding diagnostic criteria for early myoclonic encephalopathy. Brain Dev. 1998; 20(7): 530-535.
10.1016/S0387-7604(98)00042-4
CAS PubMed Web of Science® Google Scholar
90Gazeteci-Tekin H, Demir M, Aktan G, Tekgül H, Gökben S. The case of pyridoxine dependent epilepsy misdiagnosed as non-ketotic hyperglycinemia. Turk J Pediatr. 2019; 61(4): 599-603.
10.24953/turkjped.2019.04.019
PubMed Web of Science® Google Scholar
91Coene KLM, Kluijtmans LAJ, van der Heeft E, et al. Next-generation metabolic screening: targeted and untargeted metabolomics for the diagnosis of inborn errors of metabolism in individual patients. J Inherit Metab Dis. 2018; 41(3): 337-353.
10.1007/s10545-017-0131-6
CAS PubMed Web of Science® Google Scholar
92Böhm H-O, Yazdani M, Sandås EM, et al. Global metabolomics discovers two novel biomarkers in pyridoxine-dependent epilepsy caused by ALDH7A1 deficiency. Int J Mol Sci. 2022; 23(24):16061.
10.3390/ijms232416061
CAS PubMed Web of Science® Google Scholar
93Crowther LM, Poms M, Zandl-Lang M, et al. Metabolomics analysis of antiquitin deficiency in cultured human cells and plasma: relevance to pyridoxine-dependent epilepsy. J Inherit Metab Dis. 2023; 46(1): 129-142.
10.1002/jimd.12569
CAS PubMed Web of Science® Google Scholar
94Yazdani M, Elgstøen KBP. Is oxidative stress an overlooked player in pyridoxine-dependent epilepsy? A focused review. Seizure. 2021; 91: 369-373.
10.1016/j.seizure.2021.07.014
PubMed Web of Science® Google Scholar
95Chang YF. Lysine metabolism in the rat brain: the pipecolic acid-forming pathway. J Neurochem. 1978; 30(2): 347-354.
10.1111/j.1471-4159.1978.tb06536.x
CAS PubMed Web of Science® Google Scholar
96Chang YF. Pipecolic acid pathway: the major lysine metabolic route in the rat brain. Biochem Biophys Res Commun. 1976; 69(1): 174-180.
10.1016/S0006-291X(76)80288-4
CAS PubMed Web of Science® Google Scholar
97Mihalik SJ, Rhead WJ. Species variation in organellar location and activity of L-pipecolic acid oxidation in mammals. J Comp Physiol B. 1991; 160(6): 671-675.
10.1007/BF00571266
CAS PubMed Web of Science® Google Scholar
98Pena IA, Marques LA, Laranjeira ÂBA, et al. Mouse lysine catabolism to aminoadipate occurs primarily through the saccharopine pathway; implications for pyridoxine dependent epilepsy (PDE). Biochim Biophys Acta. 2017; 1863(1): 121-128.
10.1016/j.bbadis.2016.09.006
CAS Web of Science® Google Scholar
99Crowther LM, Mathis D, Poms M, Plecko B. New insights into human lysine degradation pathways with relevance to pyridoxine-dependent epilepsy due to antiquitin deficiency. J Inherit Metab Dis. 2019; 42(4): 620-628.
10.1002/jimd.12076
CAS PubMed Web of Science® Google Scholar
100Plecko B, Paul K, Paschke E, et al. Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene. Hum Mutat. 2007; 28(1): 19-26.
10.1002/humu.20433
CAS PubMed Web of Science® Google Scholar
101Mills PB, Footitt EJ, Mills KA, et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency). Brain. 2010; 133(Pt 7): 2148-2159.
10.1093/brain/awq143
PubMed Web of Science® Google Scholar
102Fong W-P, Cheng CHK, Tang W-K. Antiquitin, a relatively unexplored member in the superfamily of aldehyde dehydrogenases with diversified physiological functions. Cell Mol Life Sci. 2006; 63(24): 2881-2885.
10.1007/s00018-006-6089-4
CAS PubMed Web of Science® Google Scholar
103Lu H-J, Chuang C-Y, Chen M-K, et al. The impact of ALDH7A1 variants in oral cancer development and prognosis. Aging. 2022; 14(10): 4556-4571.
10.18632/aging.204099
CAS PubMed Google Scholar
104Guo Y, Tan L-J, Lei S-F, et al. Genome-wide association study identifies ALDH7A1 as a novel susceptibility gene for osteoporosis. PLoS Genet. 2010; 6(1):e1000806.
10.1371/journal.pgen.1000806
CAS PubMed Web of Science® Google Scholar
105Copley S. Enzymes with extra talents: moonlighting functions and catalytic promiscuity. Curr Opin Chem Biol. 2003; 7(2): 265-272.
10.1016/S1367-5931(03)00032-2
CAS PubMed Web of Science® Google Scholar
106Tawfik OKDS. Enzyme promiscuity: a mechanistic and evolutionary perspective. Annu Rev Biochem. 2010; 79: 471-505.
10.1146/annurev-biochem-030409-143718
CAS PubMed Web of Science® Google Scholar
107Klouwer FCC, Berendse K, Ferdinandusse S, Wanders RJA, Engelen M, Poll-The BT. Zellweger spectrum disorders: clinical overview and management approach. Orphanet J Rare Dis. 2015; 10: 151.
10.1186/s13023-015-0368-9
PubMed Web of Science® Google Scholar
108Arican P, Gencpinar P, Kirbiyik O, et al. The clinical and molecular characteristics of molybdenum cofactor deficiency due to MOCS2 mutations. Pediatr Neurol. 2019; 99: 55-59.
10.1016/j.pediatrneurol.2019.04.021
PubMed Web of Science® Google Scholar
109Grünewald S. The clinical spectrum of phosphomannomutase 2 deficiency (CDG-Ia). Biochim Biophys Acta. 2009; 1792(9): 827-834.
10.1016/j.bbadis.2009.01.003
CAS PubMed Web of Science® Google Scholar
110Nasr E, Mamak E, Feigenbaum A, Donner EJ, Mercimek-Mahmutoglu S. Long-term treatment outcome of two patients with pyridoxine-dependent epilepsy caused by ALDH7A1 mutations: normal neurocognitive outcome. J Child Neurol. 2015; 30(5): 648-653.
10.1177/0883073814531331
PubMed Web of Science® Google Scholar
111Strijker M, Tseng LA, van Avezaath LK, et al. Cognitive and neurological outcome of patients in the Dutch pyridoxine-dependent epilepsy (PDE-ALDH7A1) cohort, a cross-sectional study. Eur J Paediatr Neurol. 2021; 33: 112-120.
10.1016/j.ejpn.2021.06.001
CAS PubMed Web of Science® Google Scholar
112Tseng LA, Teela L, Janssen MC, et al. Pyridoxine-dependent epilepsy (PDE-ALDH7A1) in adulthood: a Dutch pilot study exploring clinical and patient-reported outcomes. Mol Genet Metab Rep. 2022; 31:100853.
10.1016/j.ymgmr.2022.100853
CAS PubMed Web of Science® Google Scholar
113Pena IA, Roussel Y, Daniel K, et al. Pyridoxine-dependent epilepsy in zebrafish caused by Aldh7a1 deficiency. Genetics. 2017; 207(4): 1501-1518.
10.1534/genetics.117.300137
CAS PubMed Web of Science® Google Scholar
114Zabinyakov N, Bullivant G, Cao F, et al. Characterization of the first knock-out aldh7a1 zebrafish model for pyridoxine-dependent epilepsy using CRISPR-Cas9 technology. PLoS One. 2017; 12(10):e0186645.
10.1371/journal.pone.0186645
PubMed Web of Science® Google Scholar
115Babcock HE, Dutta S, Alur RP, et al. aldh7a1 regulates eye and limb development in zebrafish. PLoS One. 2014; 9(7):e101782.
10.1371/journal.pone.0101782
PubMed Web of Science® Google Scholar
116Al-Shekaili HH, Petkau TL, Pena I, et al. A novel mouse model for pyridoxine-dependent epilepsy due to antiquitin deficiency. Hum Mol Gen. 2020; 29(19): 3266-3284.
10.1093/hmg/ddaa202
CAS PubMed Web of Science® Google Scholar

Citing Literature

Volume1, Issue1

March 2023

Pages 24-37

Pyridoxine-dependent epilepsy: Current perspectives and questions for future research

Abstract

Pyridoxine-Dependent Epilepsy (PDE): Essential Clinical Features and Historical Aspects

The Three Established Forms of PDE