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Antiquitin deficiency

Florent Marguet, Hager Barakizou, Abdellah Tebani, Lenaig Abily-Donval, Stéphanie Torre, Fethi Bayoudh, Sami Jebnoun, Marie Brasseur-Daudruy, Stéphane Marret, Annie Laquerriere, Soumeya Bekri
Pyridoxine-dependent epilepsy (PDE) is a pharmacoresistant epileptogenic encephalopathy controlled by pyridoxine supplementation at pharmacological doses. Despite supplementation, the long-term outcome is often poor possibly because of recurrent seizures and developmental structural brain abnormalities. We report on five patients with PDE from three unrelated families. The diagnosis was confirmed by ALDH7A1 sequencing, which allowed for the characterization of two homozygous variations [NM_001182.3:c.1279G > C - p...
July 20, 2016: Metabolic Brain Disease
Déborah Mathis, Lucia Abela, Monique Albersen, Céline Bürer, Lisa Crowther, Karin Beese, Hans Hartmann, Levinus A Bok, Eduard Struys, Sorina M Papuc, Anita Rauch, Martin Hersberger, Nanda M Verhoeven-Duif, Barbara Plecko
BACKGROUND: Recent decades have unravelled the molecular background of a number of inborn errors of metabolism (IEM) causing vitamin B6-dependent epilepsy. As these defects interfere with vitamin B6 metabolism by different mechanisms, the plasma vitamin B6 profile can give important clues for further molecular work-up. This has so far been investigated in only a small number of patients. METHODS: We evaluated the vitamin B6 vitamers pyridoxal 5'-phosphate (PLP), pyridoxal (PL), pyridoxamine (PM), pyridoxine (PN) and the catabolite pyridoxic acid (PA) in the so far largest patient cohort: reference (n = 50); pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency (n = 6); antiquitin (ATQ) deficiency (n = 21); tissue non-specific alkaline phosphatase (TNSALP) deficiency (n = 2) and epileptic encephalopathy (EE) of unknown etiology tested negative for ATQ and PNPO deficiency (n = 64)...
September 2016: Journal of Inherited Metabolic Disease
B Jaeger, N G Abeling, G S Salomons, E A Struys, M Simas-Mendes, V G Geukers, B T Poll-The
We report a patient with anti-epileptic treatment refractory neonatal seizures responsive to pyridoxine. Biochemical analysis revealed normal markers for antiquitin deficiency and also mutation analysis of the ALDH7A1 (Antiquitin) gene was negative. Mutation analysis of the PNPO gene revealed a novel, homozygous, presumed pathogenic mutation (c.481C > T; p.(Arg161Cys)). Measurements of B6 vitamers in a CSF sample after pyridoxine administration revealed elevated pyridoxamine as the only metabolic marker for PNPO deficiency...
March 2016: Molecular Genetics and Metabolism Reports
Clara D M van Karnebeek, Sylvia A Tiebout, Jikkemien Niermeijer, Bwee Tien Poll-The, Aisha Ghani, Curtis R Coughlin, Johan L K Van Hove, Jost Wigand Richter, Hans Juergen Christen, Renata Gallagher, Hans Hartmann, Sylvia Stockler-Ipsiroglu
BACKGROUND: Pyridoxine-dependent epilepsy is a rare autosomal recessive epileptic encephalopathy caused by antiquitin (ALDH7A1) deficiency. In spite of adequate seizure control, 75% of patients suffer intellectual developmental disability. Antiquitin deficiency affects lysine catabolism resulting in accumulation of α-aminoadipic semialdehyde/pyrroline 6' carboxylate and pipecolic acid. Beside neonatal refractory epileptic encephalopathy, numerous neurological manifestations and metabolic/biochemical findings have been reported...
June 2016: Pediatric Neurology
Clara D M van Karnebeek, Sylvia Stockler-Ipsiroglu, Sravan Jaggumantri, Birgit Assmann, Peter Baxter, Daniela Buhas, Levinus A Bok, Barbara Cheng, Curtis R Coughlin, Anibh M Das, Alette Giezen, Wahla Al-Hertani, Gloria Ho, Uta Meyer, Philippa Mills, Barbara Plecko, Eduard Struys, Keiko Ueda, Monique Albersen, Nanda Verhoeven, Sidney M Gospe, Renata C Gallagher, Johan K L Van Hove, Hans Hartmann
BACKGROUND: Seventy-five percent of patients with pyridoxine-dependent epilepsy (PDE) due to Antiquitin (ATQ) deficiency suffer from developmental delay and/or intellectual disability (IQ < 70) despite seizure control. An observational study showed that adjunct treatment with a lysine-restricted diet is safe, results in partial normalization of lysine intermediates in body fluids, and may have beneficial effects on seizure control and psychomotor development. METHODS: In analogy to the NICE guideline process, the international PDE Consortium, an open platform uniting scientists and clinicians working in the field of this metabolic epilepsy, during four workshops (2010-2013) developed a recommendation for a lysine-restricted diet in PDE, with the aim of standardizing its implementation and monitoring of patients...
2014: JIMD Reports
Barbara Plecko, Karl Paul, Philippa Mills, Peter Clayton, Eduard Paschke, Oliver Maier, Oswald Hasselmann, Gudrun Schmiedel, Simone Kanz, Mary Connolly, Nicole Wolf, Eduard Struys, Sylvia Stockler, Lucia Abela, Doris Hofer
OBJECTIVE: To determine whether patients with pyridoxine-responsive seizures but normal biomarkers for antiquitin deficiency and normal sequencing of the ALDH7A1 gene may have PNPO mutations. METHODS: We sequenced the PNPO gene in 31 patients who fulfilled the above-mentioned criteria. RESULTS: We were able to identify 11 patients carrying 3 novel mutations of the PNPO gene. In 6 families, a homozygous missense mutation p.Arg225His in exon 7 was identified, while 1 family was compound heterozygous for a novel missense mutation p...
April 22, 2014: Neurology
Eduard A Struys, Erwin E W Jansen, Gajja S Salomons
We have conducted biochemical studies with commercial available pyrroline-5-carboxylate (P5C) reductase (PYCR1) to investigate whether this enzyme plays a role in L-lysine degradation. Our recent studies with antiquitin/ALDH7A1 deficient fibroblasts revealed an alternative genesis of L-pipecolic acid, and we then hypothesized that PYCR1 was responsible for the conversion of Δ(1)-piperideine-6-carboxylate (P6C) into pipecolic acid. We here present evidence that PYCR1 is indeed able to produce L-pipecolic acid from P6C preparations, and the observed K m for this conversion is of the same magnitude as the K m described for the conversion of P5C to L-proline by PYCR1...
May 2014: Journal of Inherited Metabolic Disease
Winnie W Y Tso, Anna K Y Kwong, Cheuk Wing Fung, Virginia C N Wong
BACKGROUND: Ohtahara syndrome is a severe condition with early onset of recurrent unprovoked seizures associated with abnormal electroencephalography and global developmental delay. Folinic acid-responsive seizures are treatable causes of Ohtahara syndrome, which is thought to be due to recessive mutations in the ALDH7A1 gene, resulting in deficiency of antiquitin. METHOD: Here we report a girl with Ohtahara syndrome who exhibited transient folinic acid responsiveness but without evidence of antiquitin dysfunction...
February 2014: Pediatric Neurology
Renata Oliveira, Cristina Pereira, Fidjy Rodrigues, Claudia Alfaite, Paula Garcia, Conceição Robalo, Isabel Fineza, Olavo Gonçalves, Eduard Struys, Gajja Salomons, Cornelis Jakobs, Luísa Diogo
We report 4 pyridoxine-dependent epilepsy patients in which good outcome was determined in three. The 4 patients were male and aged from 7 to 24 years old (from three unrelated Caucasian families). A clinical diagnosis of neonatal pyridoxine-dependent epilepsy was confirmed by biochemical and genetic studies. Clinical evaluation was performed and medical records were reviewed for therapy implementation and management, neurodevelopment outcome, magnetic resonance imaging, and electroencephalography. All were taking pyridoxine treatment and were seizure-free...
December 2013: Epileptic Disorders: International Epilepsy Journal with Videotape
Sujatha Jagadeesh, Beena Suresh, V Murugan, S Suresh, G S Salomans, E A Struys, C Jacobs
Pyridoxine-dependent epilepsy (PDE) is an inborn error of metabolism resulting from antiquitin deficiency. There is marked elevation of α-amino adipic semi-aldehyde (αAASA), piperidine-6-carboxylate (P6C) and pipecolic acid. The diagnosis can be confirmed by identifying the mutation in the ALDH7A1 gene in chromosome 5q3l. An 8-year-old Indian girl presented with severe developmental delay and seizures and was found to have pyridoxine-dependent epilepsy owing to an antiquitin mutation. Genetic evaluation of the parents allowed antenatal diagnosis to be made during the next pregnancy...
May 2013: Paediatrics and International Child Health
Barbara Plecko
To date we know of four inborn errors of autosomal recessive inheritance that lead to vitamin B6-dependent seizures. Among these, pyridoxine-dependent seizures due to antiquitin deficiency is by far the most common, although exact incidence data are lacking. In PNPO deficiency, samples have to be collected prior to treatment, while PDE, hyperprolinemia type II and congenital HPP can be diagnosed while on vitamin B6 supplementation. A vitamin B6 withdrawal for diagnostic purposes is nowadays only indicated in patients with a clear vitamin B6 response but normal biochemical work-up...
2013: Handbook of Clinical Neurology
Imran H Yusuf, Victoria Sandford, Göran Darius Hildebrand
Pyridoxine-dependent epilepsy (PDE) is a cause of neonatal epileptic encephalopathy not previously known to cause ophthalmic disease. We describe the novel observation of a 5-year-old girl with pyridoxine-dependent epilepsy and bilateral cataracts. PDE is the result of mutations in the ALDH7A1 gene encoding antiquitin, an enzyme protective against cellular dehydration and osmotic stress. Accumulating metabolic precursors in PDE have been shown to be cataractogenic in vitro, and experimental pyridoxine deficiency has been associated with lenticular opacities in vivo...
June 2013: Journal of AAPOS: the Official Publication of the American Association for Pediatric Ophthalmology and Strabismus
Malcolm Proudfoot, Philip Jardine, Agne Straukiene, Rupert Noad, Andrew Parrish, Sian Ellard, Stuart Weatherby
Autosomal recessive disorders affecting pyridoxine (vitamin B6) metabolism are a rare but well-recognized cause of neonatal seizures. Antiquitin deficiency, caused by mutations in ALDH7A1, is a disorder of the lysine degradation pathway causing accumulation of an intermediate that complexes with pyridoxal phosphate. Reports of long-term follow-up of neonatal pyridoxine-dependent seizures (PDS) remain scarce and prognostic information is varied. We report a case of PDS in a 47-year-old lady who originally presented shortly after birth in 1964...
2013: JIMD Reports
Belén Pérez, Luis González Gutiérrez-Solana, Alfonso Verdú, Begoña Merinero, Patricia Yuste-Checa, Pedro Ruiz-Sala, Rocio Calvo, Anil Jalan, Laura López Marín, Oscar Campos, Maria Ángeles Ruiz, Marta San Miguel, Maria Vázquez, Margarita Castro, Isaac Ferrer, Rosa Navarrete, Lourdes Ruiz Desviat, Pablo Lapunzina, Magdalena Ugarte, Celia Pérez-Cerdá
PURPOSE: Pyridoxine-dependent epilepsy seizure (PDE; OMIM 266100) is a disorder associated with severe seizures that can be controlled pharmacologically with pyridoxine. In the majority of patients with PDE, the disorder is caused by the deficient activity of the enzyme α-aminoadipic semialdehyde dehydrogenase (antiquitin protein), which is encoded by the ALDH7A1 gene. The aim of this work was the clinical, biochemical, and genetic analysis of 12 unrelated patients, mostly from Spain, in an attempt to provide further valuable data regarding the wide clinical, biochemical, and genetic spectrum of the disease...
February 2013: Epilepsia
Heather C Mefford, Joseph Cook, Sidney M Gospe
A cause of antiepileptic medication resistant seizures presenting in neonates and young infants is pyridoxine-dependent epilepsy (PDE), an organic aciduria, which is due to recessive mutations in the ALDH7A1 gene, resulting in deficiency of antiquitin. Since the discovery of molecular basis of this disorder, a few patients have been reported with a similar clinical phenotype but without evidence of antiqutin dysfunction. We report on a patient who had carried a clinical diagnosis of PDE for 7 years, but who was than shown to have normal ALDH7A1 sequencing and the absence of biomarkers characteristic of this familial epilepsy...
December 2012: American Journal of Medical Genetics. Part A
Eduard Alexander Struys, Benjamin Nota, Abdellatif Bakkali, Saad Al Shahwan, Gajja Sophi Salomons, Brahim Tabarki
α-Amino adipic semialdehyde (α-AASA) accumulates in body fluids from patients with pyridoxine-dependent epilepsy because of mutations in antiquitin (ALDH7A1) and serves as the biomarker for this condition. We have recently found that the urinary excretion of α-AASA was also increased in molybdenum cofactor and sulfite oxidase deficiencies. The seizures in pyridoxine-dependent epilepsy are caused by lowered cerebral levels of pyridoxal-5-phosphate (PLP), the bioactive form of pyridoxine (vitamin B(6)), which can be corrected by the supplementation of pyridoxine...
December 2012: Pediatrics
Clara D M van Karnebeek, Hans Hartmann, Sravan Jaggumantri, Levinus A Bok, Barb Cheng, Mary Connolly, Curtis R Coughlin, Anibh M Das, Sidney M Gospe, Cornelis Jakobs, Johanna H van der Lee, Saadet Mercimek-Mahmutoglu, Uta Meyer, Eduard Struys, Graham Sinclair, Johan Van Hove, Jean-Paul Collet, Barbara R Plecko, Sylvia Stockler
OBJECTIVE: To evaluate the efficacy and safety of dietary lysine restriction as an adjunct to pyridoxine therapy on biochemical parameters, seizure control, and developmental/cognitive outcomes in children with pyridoxine-dependent epilepsy (PDE) caused by antiquitin (ATQ) deficiency. METHODS: In this observational study, seven children with confirmed ATQ deficiency were started on dietary lysine restriction with regular nutritional monitoring. Biochemical outcomes were evaluated using pipecolic acid and α-aminoadipic semialdehyde (AASA) levels in body fluids; developmental/cognitive outcomes were evaluated using age-appropriate tests and parental observations...
November 2012: Molecular Genetics and Metabolism
Majid Alfadhel, Sandra Sirrs, Paula J Waters, András Szeitz, Eduard Struys, Marion Coulter-Mackie, Sylvia Stockler-Ipsiroglu
BACKGROUND: Pyridoxine dependent epilepsy (PDE) is characterized by neonatal epileptic encepahalopathy responsive to pharmacological doses of vitamin B6. Recently an autosomal recessive deficiency in Antiquitin (ALDH7A1), a gene involved in the catabolism of lysine has been identified as the underlying cause. CASE REPORT: In 21 and 23 year-old sisters, who had presented with neonatal / early infantile onset seizures, PDE was confirmed by elevated urinary alpha aminoadipic- 6- semialdehyde (α-AASA) excretion and compound heterozygosity for two known ALDH7A1 missense mutations...
July 2012: Canadian Journal of Neurological Sciences. le Journal Canadien des Sciences Neurologiques
Philippa B Mills, Emma J Footitt, Serkan Ceyhan, Paula J Waters, Cornelis Jakobs, Peter T Clayton, Eduard A Struys
Analysis of α-aminoadipic semialdehyde is an important tool in the diagnosis of antiquitin deficiency (pyridoxine-dependent epilepsy). However continuing use of this test has revealed that elevated urinary excretion of α-aminoadipic semialdehyde is not only found in patients with pyridoxine-dependent epilepsy but is also seen in patients with molybdenum cofactor deficiency and isolated sulphite oxidase deficiency. This should be taken into account when interpreting the laboratory data. Sulphite was shown to inhibit α-aminoadipic semialdehyde dehydrogenase in vitro...
November 2012: Journal of Inherited Metabolic Disease
Eduard A Struys, Levinus A Bok, Dina Emal, Saskia Houterman, Michel A Willemsen, Cornelis Jakobs
The assessment of urinary α-aminoadipic semialdehyde (α-AASA) has become the diagnostic laboratory test for pyridoxine dependent seizures (PDS). α-AASA is in spontaneous equilibrium with its cyclic form Δ(1)-piperideine-6-carboxylate (P6C); a molecule with a heterocyclic ring structure. Ongoing diagnostic screening and monitoring revealed that in some individuals with milder ALDH7A1 variants, and patients co-treated with a lysine restricted diet, α-AASA was only modestly increased. This prompted us to investigate the diagnostic power and added value of the assessment of urinary P6C compared to α-AASA...
September 2012: Journal of Inherited Metabolic Disease
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