Long-term follow-up in two siblings with pyridoxine-dependent seizures associated with a novel ALDH7A1 mutation

Yeghiazaryan, Nune S.; Striano, Pasquale; Spaccini, Luigina; Pezzella, Marianna; Cassandrini, Denise; Zara, Federico; Mastrangelo, Massimo

doi:10.1016/j.ejpn.2011.05.011

Cited by 18 publications

(9 citation statements)

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“…In case P10, mental retardation is severe. In a recent report of two sibs, which include long‐term observation, both patients showed moderate to severe mental retardation despite an adequate and early pyridoxine administration and seizure control (Yeghiazaryan et al., ). Another recent publication has described the long‐term neurodevelopment outcome in a cohort of 14 patients with PDE (Bok et al., ).…”

Section: Discussionmentioning

confidence: 99%

Clinical, biochemical, and molecular studies in pyridoxine‐dependent epilepsy. Antisense therapy as possible new therapeutic option

et al. 2013

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Summary 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. Methods The disease was confirmed based on the presence of α‐aminoadipic semialdehyde (α‐AASA) in urine measured by liquid chromatography tandem mass spectrometry (LC‐MS/MS) and pipecolic acid (PA) in plasma and/or cerebrospinal fluid (CSF) measured by high performance liquid chromatography (HPLC)/MS/MS and by sequencing analysis of messenger RNA (mRNA) and genomic DNA of ALDH7A1. Key Findings Most of the patients had seizures in the neonatal period, but they responded to vitamin B6 administration. Three patients developed late‐onset seizures, and most patients showed mild‐to‐moderate postnatal developmental delay. All patients had elevated PA and α‐AASA levels, even those who had undergone pyridoxine treatment for several years. The clinical spectrum of our patients is not limited to seizures but many of them show associated neurologic dysfunctions such as muscle tone alterations, irritability, and psychomotor retardation. The mutational spectrum of the present patients included 12 mutations, five already reported (c.500A>G, c.919C>T, c.1429G>C c.1217_1218delAT, and c.1482‐1G>T) and seven novel sequence changes (c.75C>T, c.319G>T, c.554_555delAA, c.757C>T, c.787 + 1G>T, c.1474T>C, c.1093‐?_1620+?). Only one mutation, p.G477R (c.1429G>C), was recurrent; this was detected in four different alleles. Transcriptional profile analysis of one patient's lymphoblasts and ex vivo splicing analysis showed the silent nucleotide change c.75C>T to be a novel splicing mutation creating a new donor splice site inside exon 1. Antisense therapy of the aberrant mRNA splicing in a lymphoblast cell line harboring mutation c.75C>T was successful. Significance The present results broaden our knowledge of PDE, provide information regarding the genetic background of PDE in Spain, afford data of use when making molecular‐based prenatal diagnosis, and provide a cellular proof‐of concept for antisense therapy application.

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Section: Discussionmentioning

confidence: 99%

Clinical, biochemical, and molecular studies in pyridoxine‐dependent epilepsy. Antisense therapy as possible new therapeutic option

et al. 2013

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“…EEG results were reported in 56% of the patients. Burst suppression pattern was present in %26 of the patients [11,25,28,37,38,40,53,56]. In this group in addition to burst suppression pattern, one patient had irregular discontinuous background activity and high-voltage spikes [37], two patients had multifocal sharp waves [25,40] and one patient had diffuse slowing [38].…”

Section: Initial Eeg Prior To Pyridoxine Therapymentioning

confidence: 81%

“…Three patients had no seizures as they were treated prenatally and immediately after delivery in the neonatal period [15]. Intrauterine seizures were reported only in few patients [28,38,42]. Seventy-four percent of the patients presented with seizures within the first week of life, almost two third of those within the first day of life [1, 11, 15, 18, 21, 25-30, 32-34, 37, 38, 40, 42-45, 47-56].…”

Section: Onset Of Seizuresmentioning

confidence: 99%

“…EEG response to the first dose of pyridoxine therapy was reported in 26 patients only. Seventy-seven percent of these patients had normalization of EEG findings from immediate to 1 mo of initiation of pyridoxine therapy [18,25,28,36,38,42,44,47,48,52,53,55,60]. In 23% of the patients, EEG features showed some improvements, but did not normalize including burst suppression pattern [26,40], decreased slow wave activity [1] and decreased sharp waves [57,58].…”

Section: Eeg Response To Pyridoxine Therapymentioning

confidence: 99%

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Pyridoxine dependent epilepsy: Seizure onset, seizure types and EEG features

2015

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Pyridoxine dependent epilepsy (PDE) is an autosomal recessively inherited disorder. It is caused by mutations in the ALDH7A1 gene (PDE-ALDH7A1) encoding the alpha-aminoadipic semialdehyde dehydrogenase enzyme in the lysine catabolic pathway. The alpha-aminoadipic semialdehyde dehydrogenase enzyme deficiency leads to accumulation of alpha-aminoadipic semialdehyde and piperidine 6-carboxylic acid, the latter inactivates pyridoxal-5-phosphate. The majority of the patients present with neonatal onset intractable seizures with a dramatic response to pyridoxine therapy. Later seizure onset up to 3 yr of age has been reported too. Generalized tonic-clonic seizures are the most common seizure type. The treatment of PDE consists of high dose pyridoxine supplementation therapy. Since the underlying genetic defect was identified in the lysine catabolic pathway, few patients were treated with lysine-restricted diet to decrease, likely neurotoxic, alpha-aminoadipic semialdehyde and piperidine 6-carboxylic acid accumulation in the central nervous system.

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“…Long-term follow-up studies are rare owing to the wide temporal and spatial dispersion of cases. Most reported cases readily responded to pyridoxine and had a good prognosis ( 4 ). Only few Chinese cases of PDE have been reported, all of which had a classical presentation of PDE ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

Clinical and genetic characteristics of pyridoxine-dependent epilepsy: Case series report of three Chinese patients with phenotypic variability

Wang

Sun

et al. 2017

Experimental and Therapeutic Medicine

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Pyridoxine-dependent epilepsy (PDE) is a rare disorder caused by aldehyde dehydrogenase 7 family member A1 (ALDH7A1) deficiency. The present study reported on three Chinese cases of PDE with phenotypic variability for providing further insight into this disease. All three patients presented with recurrent seizures and readily responded to treatment with pyridoxine, in line with the typical symptomology of PDE. The three cases varied in their clinical manifestations with regard to the time of onset, seizure type, EEG findings and mental development. Four ALDH7A1 mutations were identified in Case 1 (c.1008+1G>A and c.871+5G>A) and Case 2 (c.977A>G and c.1463A>G). To the best of our knowledge, the present study was the first to report on the mutations c.871+5G>A and c.1463A>G. Early definitive diagnosis and timely treatment with pyridoxine was the cornerstone of management of PDE. Timely treatment was associated with excellent prognosis. A high index of suspicion in cases and early genetic testing may facilitate early diagnosis of this rare disease.

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Long-term follow-up in two siblings with pyridoxine-dependent seizures associated with a novel ALDH7A1 mutation

Cited by 18 publications

References 10 publications

Clinical, biochemical, and molecular studies in pyridoxine‐dependent epilepsy. Antisense therapy as possible new therapeutic option

Clinical, biochemical, and molecular studies in pyridoxine‐dependent epilepsy. Antisense therapy as possible new therapeutic option

Pyridoxine dependent epilepsy: Seizure onset, seizure types and EEG features

Clinical and genetic characteristics of pyridoxine-dependent epilepsy: Case series report of three Chinese patients with phenotypic variability

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