Pyridoxine dependent epilepsy and antiquitin deficiency: Clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up

doi:10.1016/j.ymgme.2011.05.014

Molecular Genetics and Metabolism

Volume 104, Issues 1–2, September–October 2011, Pages 48-60

https://doi.org/10.1016/j.ymgme.2011.05.014 Get rights and content

Abstract

Antiquitin (ATQ) deficiency is the main cause of pyridoxine dependent epilepsy characterized by early onset epileptic encephalopathy responsive to large dosages of pyridoxine. Despite seizure control most patients have intellectual disability. Folinic acid responsive seizures (FARS) are genetically identical to ATQ deficiency. ATQ functions as an aldehyde dehydrogenase (ALDH7A1) in the lysine degradation pathway. Its deficiency results in accumulation of α-aminoadipic semialdehyde (AASA), piperideine-6-carboxylate (P6C) and pipecolic acid, which serve as diagnostic markers in urine, plasma, and CSF.

To interrupt seizures a dose of 100 mg of pyridoxine-HCl is given intravenously, or orally/enterally with 30 mg/kg/day. First administration may result in respiratory arrest in responders, and thus treatment should be performed with support of respiratory management.

To make sure that late and masked response is not missed, treatment with oral/enteral pyridoxine should be continued until ATQ deficiency is excluded by negative biochemical or genetic testing. Long-term treatment dosages vary between 15 and 30 mg/kg/day in infants or up to 200 mg/day in neonates, and 500 mg/day in adults. Oral or enteral pyridoxal phosphate (PLP), up to 30 mg/kg/day can be given alternatively. Prenatal treatment with maternal pyridoxine supplementation possibly improves outcome.

PDE is an organic aciduria caused by a deficiency in the catabolic breakdown of lysine. A lysine restricted diet might address the potential toxicity of accumulating αAASA, P6C and pipecolic acid. A multicenter study on long term outcomes is needed to document potential benefits of this additional treatment.

The differential diagnosis of pyridoxine or PLP responsive seizure disorders includes PLP-responsive epileptic encephalopathy due to PNPO deficiency, neonatal/infantile hypophosphatasia (TNSALP deficiency), familial hyperphosphatasia (PIGV deficiency), as well as yet unidentified conditions and nutritional vitamin B6 deficiency.

Commencing treatment with PLP will not delay treatment in patients with pyridox(am)ine phosphate oxidase (PNPO) deficiency who are responsive to PLP only.

Introduction

Pyridoxine dependent epilepsy (PDE) (MIM#266100) is an autosomal recessive epileptic encephalopathy characterized by a therapeutic response to pharmacological dosages of vitamin B₆ and resistance to conventional antiepileptic treatment. PDE was first described in 1954 in an infant with therapy-resistant seizures who showed prompt cessation of seizures after the administration of a multivitamin cocktail containing vitamin B6 [1]. Since then, over 200 patients have been described in the literature. The underlying genetic defect remained unknown for a long time and diagnosis was limited to the demonstration of seizure remission and relapse after a controlled trial of pyridoxine administration and withdrawal [2]. Due to the lack of a biological diagnostic marker, diagnosis may have been missed in many cases. The variation in diagnostic hits is reflected in the considerable heterogeneity of published prevalence data, ranging from 1:20.000 in a German center with a pyridoxine trial routinely performed in all patients with epileptic encephalopathy, [3] to 1:400.000 in a survey focusing on diagnosed cases in Dutch neuropediatric clinics, [4] and 1:600.000 in the UK [5]. In a hospital based study 7.4% (6 out of 81) children with intractable seizures below 3 years of age, showed a clear response to pyridoxine [6].

Notably, despite the clear response of seizures to high dosages of vitamin B₆, patients with PDE do not have biochemical evidence of vitamin B₆ deficiency [7], [8]. For a long time deficiency of glutamic acid decarboxylase (GAD), catalyzing the conversion of glutamate to GABA and requiring vitamin B₆ (pyridoxal-phosphate) as cofactor, was considered the underlying cause of PDE [9]. However, conflicting results of glutamate and GABA studies in CSF [8], [10], [11] and negative linkage studies to the two GAD isoforms in the brain (Gad1 and Gad2) [12], [13] made clear that GAD deficiency is not the primary cause of PDE.

Following the description of pipecolic acid as a first diagnostic marker of PDE [14] mutations in the gene for α-aminoadipic-semialdehyde dehydrogenase and resultant enzyme deficiency were identified as the major underlying genetic cause of PDE [15]. Since then this association has been confirmed in numerous cases ascertained clinically with PDE [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27].

α-Aminoadipic-semialdehyde dehydrogenase (also known as ALDH7A1 or antiquitin, ATQ) is encoded by the ALDH7A1 or ATQ gene, and its function lies in the catabolism of lysine. The direct link to amino acid metabolism provides new insights into the pathophysiology of PDE and clues for improved diagnostic and therapeutic options for this condition.

We reviewed the current state and new developments in diagnosis and treatment of PDE and ATQ deficiency. This article provides an overview of the current knowledge of clinical, biochemical, and molecular genetic characteristics of ATQ deficiency and summarizes recommendations for diagnosis and management.

Section snippets

Clinical presentation of antiquitin deficiency

The clinical phenotype of ATQ deficiency is that of pyridoxine dependent epilepsy, characterized by intractable seizures that are not controlled with conventional anticonvulsants but that respond clinically and electroencephalographically to pharmacologic doses of pyridoxine [28].

Folinic acid responsive seizures (FARS) are genetically identical to ATQ deficiency

Recently FARS were shown to be genetically identical to ATQ deficiency [16]. FARS were first described in 1995, in patients with intractable seizures and encephalopathy who had two characteristic, but yet unidentified peaks (peak X) in the HPLC chromatogram for CSF monoamine neurotransmitter analysis. Patients showed an improvement of seizures upon administration of folinic acid (3–5 mg/kg/day), but the genetic basis of this condition remained elusive [56]. Two patients, whose CSF showed the

Metabolic function of antiquitin

ATQ (ALDH7A1) takes part in lysine catabolism in the brain and in the liver (Fig. 1). In humans there are two biochemical pathways for lysine catabolism: the saccharopine pathway, which is dominant in the liver and many other tissues [60]; and the pipecolic acid pathway, which is dominant in brain (reviewed in [61]). There seems to be separation of both pathways in different cell compartments. While the saccharopine pathway is mitochondrial, the pipecolic acid pathway has been located mostly in

Molecular properties of antiquitin

ATQ is classified as a member of the aldehyde dehydrogenase family 7 (ALDH7) of which there are three subfamilies: ALDH7A for humans and animals, ALDH7B for plants, and ALDH7C for Drosophila[71]. ATQ from seabream has been the prototype for most biochemical and structural work [69], [72], [73]. The name “Antiquitin” derives from the apparent ancient origin of the protein [74]. The human and rat cDNAs for ATQ were identified through their remarkable similarity to a plant turgor protein [74]. The

Mutational spectrum of antiquitin deficiency

To date more than 60 different mutations within the 18 exons of the ATQ gene have been published [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [80]. Of these, 50–60% are missense mutations, resulting in an altered amino acid in the protein sequence. Missense mutations cluster around exons 14, 15, and 16 [21]. The missense mutation p.Glu399Gln in exon 14 occurs in various populations and accounts for about 30% of published alleles [17], [22]. The “silent mutation”

Pathophysiology

The pathophysiology of ATQ deficiency is determined by three different components. First, the accumulation of αAASA and its heterocyclic form, l-Δ¹-piperideine-6-carboxylate (P6C) as the primary consequence ATQ deficiency; second, PLP deficiency as a consequence of αAASA and P6C accumulation; third, the accumulation of pipecolic acid as a secondary consequence of ATQ deficiency (Fig. 1).

The accumulation of P6C leads to a spontaneous, type Knoevenagel, chemical reaction with PLP resulting in the

Diagnostic markers

Both αAASA [15], [17], [22], [92], [93] and pipecolic acid [14], [32], [94] serve as diagnostic markers of ATQ deficiency.

Patients at risk

The availability of diagnostic markers in urine and plasma makes low threshold screening possible. Typically, patients with unexplained early onset epilepsy poorly responsive to pharmacological treatment should be screened. As already recommended by Goutières and Aicardi [52], pyridoxine dependency should be considered as the cause of intractable seizures in the following situations:

•
Seizures of unknown etiology in a previously normal infant without an abnormal gestational or perinatal history
•

Pyridoxine

The standard treatment of ATQ deficiency includes lifelong supplementation of pyridoxine in pharmacological doses.

In the acutely seizing infant, an initial dosage of pyridoxine should be given without delay. For patients in the ICU setting pyridoxine can be administered intravenously, under EEG monitoring and with adequate support for respiratory management in case apnea occurs as an immediate treatment response. If EEG monitoring is not instantly available, the trial is done without EEG

Other vitamin B₆ responsive conditions

In addition to ATQ deficiency, three other autosomal recessive conditions with seizures responsive to pyridoxine or its vitamers are known [111], [114]: Pyridoxal phosphate responsive epileptic encephalopathy (MIM#610090), caused by deficiency of Pyridoxamine 5′-phosphate oxidase deficiency (PNPO) (MIM603287), tissue non-specific alkaline phosphatase (TNSALP) deficiency (MIM#171760), and hyperprolinemia type II (MIM#239510). Mabry Syndrome (familial hyperphosphatasia with mental retardation,

Future perspectives

Due to limited awareness by clinicians of PDE and especially ATQ deficiency as a potentially treatable, albeit rare, cause of epilepsy, it may still be under-diagnosed. Given the efficacy of treatment with pyridoxine, one may even consider it a candidate condition for newborn screening once the analytical issues in identification have been resolved. Inherent to their rarity, patients are scattered throughout the world hampering systematic studies. Therefore, knowledge dissemination and

Summary points

-
Antiquitin deficiency is the main cause of pyridoxine dependent epilepsy. The prevalence of PDE is unknown with estimates varying from 1:20.000 infants with epileptic encephalopathy to 1:600.000 in patients in the UK.
-
PDE caused by ATQ deficiency is characterized by intractable or difficult to treat seizures that are poorly controlled with pharmacologic anticonvulsants but that respond clinically and electroencephalographically to large dosages of pyridoxine. Seizures recur upon pyridoxine

Acknowledgments

The need and the lead authors for this review were identified at the Canadian Metabolic Epilepsy Meeting in Vancouver, May 2009. This meeting was supported by a CIHR Meeting Planning and Dissemination Grant (193596). Apart from authors of this review (S.S., M.C, M.C.C.; S.M.G., S.M.; B.P.; I.T.; J.L.K.V H.), the contributions of the following participants are acknowledged: J Dooley, Dalhousie University; C Hahn, Hospital of Sick Kids/Toronto; G Horvath, BC Children's Hospital/Vancouver; A Khan,

References (130)

R. Ramachandran Nair et al.
Prevalence of pyridoxine dependent seizures in south Indian children with early onset intractable epilepsy: a hospital based prospective study
Eur. J. Paediatr. Neurol.
(2005)
T. Goto et al.
CSF glutamate/GABA concentrations in pyridoxine-dependent seizures: etiology of pyridoxine-dependent seizures and the mechanisms of pyridoxine action in seizure control
Brain Dev.
(2001)
V. Cormier-Daire et al.
A gene for pyridoxine-dependent epilepsy maps to chromosome 5q31
Am. J. Hum. Genet.
(2000)
J. Kanno et al.
Allelic and non-allelic heterogeneities in pyridoxine dependent seizures revealed by ALDH7A1 mutational analysis
Mol. Genet. Metab.
(2007)
S. Parikh et al.
Vitamins, not surgery: spinal fluid testing in hemispheric epilepsy
Pediatr. Neurol.
(2009)
A. Millet et al.
Novel mutations in pyridoxine-dependent epilepsy
Eur. J. Paediatr. Neurol.
(2011)
S.M. Gospe
Pyridoxine-dependent seizures: findings from recent studies pose new questions
Pediatr. Neurol.
(2002)
M.A. Mikati et al.
Pyridoxine-dependent epilepsy: EEG investigations and long-term follow-up
Electroencephalogr. Clin. Neurophysiol.
(1991)
P. Baxter et al.
Neonatal seizures after pyridoxine use
Lancet
(1999)
J. Nicolai et al.
Folinic acid-responsive seizures initially responsive to pyridoxine
Pediatr. Neurol.
(2006)

E.H. Rosenberg et al.

Mutation detection in DNA isolated from cerebrospinal fluid and urine: clinical utility and pitfalls of multiple displacement amplification

Mol. Genet. Metab.

(2009)

V.V. Rao et al.

L-pipecolic acid oxidation in rat: subcellular localization and developmental study

Biochim. Biophys. Acta

(1993)

V.V. Rao et al.

Developmental changes of l-lysine-ketoglutarate reductase in rat brain and liver

Comp. Biochem. Physiol. B

(1992)

F. Papes et al.

The essential amino acid lysine acts as precursor of glutamate in the mammalian central nervous system

FEBS Lett.

(2001)

C. Brocker et al.

Aldehyde dehydrogenase 7A1 (ALDH7A1) is a novel enzyme involved in cellular defense against hyperosmotic stress

J. Biol. Chem.

(2010)

W.K. Tang et al.

Seabream antiquitin: molecular cloning, tissue distribution, subcellular localization and functional expression

FEBS Lett.

(2005)

W.K. Tang et al.

First purification of the antiquitin protein and demonstration of its enzymatic activity

FEBS Lett.

(2002)

W.K. Tang et al.

The crystal structure of seabream antiquitin reveals the structural basis of its substrate specificity

FEBS Lett.

(2008)

P. Lee et al.

Homology between a human protein and a protein of the green garden pea

Genomics

(1994 May)

Y.F. Chang et al.

L-pipecolic acid metabolism in human liver: l-alpha-aminoadipate delta-semialdehyde oxidoreductase

Biochim. Biophys. Acta

(1990)

Y.S. Shin et al.

Pyridoxal 5′-phosphate concentration as marker for vitamin-B6-dependent seizures in the newborn

Lancet

(1984)

R.D. Farrant et al.

Pyridoxal phosphate de-activation by pyrroline-5-carboxylic acid

J. Biol. Chem.

(2001)

K. Hanada

Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism

Biochim. Biophys. Acta

(2003)

M. Ikeda et al.

Sphingosine-1-phosphate lyase SPL is an endoplasmic reticulum-resident, integral membrane protein with the pyridoxal 5′-phosphate binding domain exposed to the cytosol

Biochem. Biophys. Res. Commun.

(2004)

E.A. Struys et al.

Metabolism of lysine in alpha-aminoadipic semialdehyde dehydrogenase-deficient fibroblasts: evidence for an alternative pathway of pipecolic acid formation

FEBS Lett.

(2010)

E.A. Struys et al.

Alpha-aminoadipic semialdehyde is the biomarker for pyridoxine dependent epilepsy caused by alpha-aminoadipic semialdehyde dehydrogenase deficiency

Mol. Genet. Metab.

(2007)

K. Sadilkova et al.

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)

A. Peduto et al.

Hyperpipecolic acidaemia: a diagnostic tool for peroxisomal disorders

Mol. Genet. Metab.

(2004)

R.M. Kok et al.

Stable isotope dilution analysis of pipecolic acid in cerebrospinal fluid, plasma, urine and amniotic fluid using electron capture negative ion mass fragmentography

Clin. Chim. Acta

(1987)

A.D. Hunt et al.

Pyridoxine dependency: report of a case of intractable convulsions in an infant controlled by pyridoxine

Pediatrics

(1954)

P. Baxter

Pyridoxine-dependent and pyridoxine-responsive seizures

Dev. Med. Child Neurol.

(2001)

M. Ebinger et al.

Demographics and diagnosis of pyridoxine-dependent seizures

J. Pediatr.

(1999)

J.V. Been et al.

Epidemiology of pyridoxine dependent seizures in the Netherlands

Arch. Dis. Child.

(2005)

P. Baxter

Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK

Arch. Dis. Child.

(1999)

C.R. Scriver et al.

Urinary vitamin B6 and 4-Pyridoxic acid in health and in vitamin B6 dependency

Pediatrics

(1965)

S.M. Gospe et al.

Reduced GABA synthesis in pyridoxine-dependent seizures

Lancet

(1994)

G. Kurlemann et al.

Disturbance of GABA metabolism in pyridoxine-dependent seizures

Neuropediatrics

(1992)

F.A. Baumeister et al.

Glutamate in pyridoxine-dependent epilepsy: neurotoxic glutamate concentration in the cerebrospinal fluid and its normalization by pyridoxine

Pediatrics

(1994)

G. Battaglioli et al.

Glutamate decarboxylase is not genetically linked to pyridoxine-dependent seizures

Neurology

(2000)

B. Plecko et al.

Pipecolic acid elevation in plasma and cerebrospinal fluid of two patients with pyridoxine-dependent epilepsy

Ann. Neurol.

(2000)

P.B. Mills et al.

Mutations in antiquitin in individuals with pyridoxine-dependent seizures

Nat. Med.

(2006)

R.C. Gallagher et al.

Folinic acid-responsive seizures are identical to pyridoxine-dependent epilepsy

Ann. Neurol.

(2009)

B. Plecko et al.

Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene

Hum. Mutat.

(2007)

G.S. Salomons et al.

An intriguing “silent” mutation and a founder effect in antiquitin (ALDH7A1)

Ann. Neurol.

(2007)

C.L. Bennett et al.

Prevalence of ALDH7A1 mutations in 18 North American pyridoxine-dependent seizure (PDS) patients

Epilepsia

(2009)

G. Scharer et al.

The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1

J. Inherit. Metab. Dis.

(2010)

P.B. Mills et al.

Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)

Brain

(2010)

P.M. Rankin et al.

Pyridoxine-dependent seizures: a family phenotype that leads to severe cognitive deficits, regardless of treatment regime

Dev. Med. Child Neurol.

(2007)

G. Kluger et al.

Pyridoxine-dependent epilepsy: normal outcome in a patient with late diagnosis after prolonged status epilepticus causing cortical blindness

Neuropediatrics

(2008)

M. Kaczorowska et al.

Pyridoxine-dependent seizures caused by alpha amino adipic semialdehyde dehydrogenase deficiency: the first polish case with confirmed biochemical and molecular pathology

J. Child Neurol.

(2008)

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MinireviewPyridoxine dependent epilepsy and antiquitin deficiency: Clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up

Abstract

Introduction

Section snippets

Clinical presentation of antiquitin deficiency

Folinic acid responsive seizures (FARS) are genetically identical to ATQ deficiency

Metabolic function of antiquitin

Molecular properties of antiquitin

Mutational spectrum of antiquitin deficiency

Pathophysiology

Diagnostic markers

Patients at risk

Pyridoxine

Other vitamin B6 responsive conditions

Future perspectives

Summary points

Acknowledgments

Eur. J. Paediatr. Neurol.

Brain Dev.

Am. J. Hum. Genet.

Mol. Genet. Metab.

Pediatr. Neurol.

Eur. J. Paediatr. Neurol.

Pediatr. Neurol.

Electroencephalogr. Clin. Neurophysiol.

Lancet

Pediatr. Neurol.

Mol. Genet. Metab.

Biochim. Biophys. Acta

Comp. Biochem. Physiol. B

FEBS Lett.

J. Biol. Chem.

FEBS Lett.

FEBS Lett.

FEBS Lett.

Genomics

Biochim. Biophys. Acta

Lancet

J. Biol. Chem.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

FEBS Lett.

Mol. Genet. Metab.

J. Neurosci. Methods

Mol. Genet. Metab.

Clin. Chim. Acta

Pyridoxine dependency: report of a case of intractable convulsions in an infant controlled by pyridoxine

Pediatrics

Pyridoxine-dependent and pyridoxine-responsive seizures

Dev. Med. Child Neurol.

Demographics and diagnosis of pyridoxine-dependent seizures

J. Pediatr.

Epidemiology of pyridoxine dependent seizures in the Netherlands

Arch. Dis. Child.

Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK

Arch. Dis. Child.

Urinary vitamin B6 and 4-Pyridoxic acid in health and in vitamin B6 dependency

Pediatrics

Reduced GABA synthesis in pyridoxine-dependent seizures

Lancet

Disturbance of GABA metabolism in pyridoxine-dependent seizures

Neuropediatrics

Glutamate in pyridoxine-dependent epilepsy: neurotoxic glutamate concentration in the cerebrospinal fluid and its normalization by pyridoxine

Pediatrics

Glutamate decarboxylase is not genetically linked to pyridoxine-dependent seizures

Neurology

Pipecolic acid elevation in plasma and cerebrospinal fluid of two patients with pyridoxine-dependent epilepsy

Ann. Neurol.

Mutations in antiquitin in individuals with pyridoxine-dependent seizures

Nat. Med.

Folinic acid-responsive seizures are identical to pyridoxine-dependent epilepsy

Ann. Neurol.

Biochemical and molecular characterization of 18 patients with pyridoxine-dependent epilepsy and mutations of the antiquitin (ALDH7A1) gene

Hum. Mutat.

An intriguing “silent” mutation and a founder effect in antiquitin (ALDH7A1)

Ann. Neurol.

Prevalence of ALDH7A1 mutations in 18 North American pyridoxine-dependent seizure (PDS) patients

Epilepsia

The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1

J. Inherit. Metab. Dis.

Minireview
Pyridoxine dependent epilepsy and antiquitin deficiency: Clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up

Other vitamin B₆ responsive conditions