Pyridoxine-Dependent Epilepsy in Zebrafish Caused by Aldh7a1 Deficiency

Pena, Izabella A.; Roussel, Yann; Daniel, Kate; Mongeon, Kevin; Johnstone, Devon L.; Mendes, Hellen Weinschutz; Bosma, Marjolein; Saxena, Vishal; Lepage, Nathalie; Chakraborty, Pranesh; Dyment, David A.; Karnebeek, Clara van; Verhoeven‐Duif, Nanda M.; Bui, Tuan V.; Boycott, Kym M.; Ekker, Marc; MacKenzie, Alex

doi:10.1534/genetics.117.300137

Cited by 81 publications

(102 citation statements)

References 71 publications

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“…These include PNPO (Mendelian Inheritance in Man [MIM]: 603287), 48 ALDH7A1 (MIM: 266100), 49,50 and PROSC deficiency 51,52 where the lack of PLP in the brain leads to early onset, vitamin B 6 -dependent epilepsy refractory to anticonvulsants. We have shown previously that several inherited disorders affecting B 6 vitamer metabolism, or resulting in inactivation of PLP, are implicated in neurological conditions.…”

Section: Discussionmentioning

confidence: 99%

PDXK mutations cause polyneuropathy responsive to pyridoxal 5′‐phosphate supplementation

Chelban

Wilson

Warman‐Chardon

et al. 2019

Annals of Neurology

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Objective To identify disease‐causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods We performed genome‐wide sequencing, homozygosity mapping, and segregation analysis for novel disease‐causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient‐derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. Results We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair‐bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP‐binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5′‐phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. Interpretation We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225–240

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Section: Discussionmentioning

confidence: 99%

PDXK mutations cause polyneuropathy responsive to pyridoxal 5′‐phosphate supplementation

Chelban

Wilson

Warman‐Chardon

et al. 2019

Annals of Neurology

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“…When utilizing knockdown approaches, protein function must be considered. For example, Pena et al (2017) used morpholinos and CRISPR/Cas9 to knock down or knock out, respectively, aldh7a1. This gene encodes α-aminoadipic-semialdehyde dehydrogenase (antiquitin), an enzyme important in the pathology of pyridoxinedependent epilepsy (PDE).…”

Section: Proteins With High Affinity or Efficiencymentioning

confidence: 99%

Loss-of-function approaches in comparative physiology: is there a future for knockdown experiments in the era of genome editing?

Zimmer

Pan

Chandrapalan

et al. 2019

Journal of Experimental Biology

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Loss-of-function technologies, such as morpholino-and RNAimediated gene knockdown, and TALEN-and CRISPR/Cas9mediated gene knockout, are widely used to investigate gene function and its physiological significance. Here, we provide a general overview of the various knockdown and knockout technologies commonly used in comparative physiology and discuss the merits and drawbacks of these technologies with a particular focus on research conducted in zebrafish. Despite their widespread use, there is an ongoing debate surrounding the use of knockdown versus knockout approaches and their potential off-target effects. This debate is primarily fueled by the observations that, in some studies, knockout mutants exhibit phenotypes different from those observed in response to knockdown using morpholinos or RNAi. We discuss the current debate and focus on the discrepancies between knockdown and knockout phenotypes, providing literature and primary data to show that the different phenotypes are not necessarily a direct result of the off-target effects of the knockdown agents used. Nevertheless, given the recent evidence of some knockdown phenotypes being recapitulated in knockout mutants lacking the morpholino or RNAi target, we stress that results of knockdown experiments need to be interpreted with caution. We ultimately argue that knockdown experiments should not be discontinued if proper control experiments are performed, and that with careful interpretation, knockdown approaches remain useful to complement the limitations of knockout studies (e.g. lethality of knockout and compensatory responses).

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“…Strachan et al have recently described a zebrafish model for XALD, which, better than the previously reported mouse models, recapitulates key features of XALD including disrupted CNS development, hypomyelination of the spinal cord, abnormal patterning and decreased numbers of oligodendrocytes, and increased cell death . Another example of the power of zebrafish is work done by Pena et al who described a zebrafish model for pyridoxine‐dependent epilepsy (PDE) due to mutations in the gene ALDH7A1 which codes for an enzyme in the lysine degradation route . Epileptiform electrographic activity was observed in the mutants as a series of population bursts which is reminiscent of human PDE.…”

Section: Model Organismsmentioning

confidence: 99%

“…48 Another example of the power of zebrafish is work done by Pena et al who described a zebrafish model for pyridoxine-dependent epilepsy (PDE) due to mutations in the gene ALDH7A1 which codes for an enzyme in the lysine degradation route. 49 Epileptiform electrographic activity was observed in the mutants as a series of population bursts which is reminiscent of human PDE. Recapitulating the human phenotype the seizures showed an almost immediate response to addition of pyridoxine and pyridoxal 5 0 -phosphate and there was an extension of life span.…”

Section: Model Organismsmentioning

confidence: 99%

Translational Metabolism: A multidisciplinary approach towards precision diagnosis of inborn errors of metabolism in the omics era

Wanders

Vaz

Ferdinandusse

et al. 2019

J of Inher Metab Disea

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The laboratory diagnosis of inborn errors of metabolism has been revolutionized in recent years, thanks to the amazing developments in the field of DNA sequencing including whole exome and whole genome sequencing (WES and WGS). Interpretation of the results coming from WES and/or WGS analysis is definitely not trivial especially since the biological relevance of many of the variants identified by WES and/or WGS, have not been tested experimentally and prediction programs like POLYPHEN‐2 and SIFT are far from perfect. Correct interpretation of WES and/or WGS results can only be achieved by performing functional studies at multiple levels (different metabolomics platforms, enzymology, in vitro and in vivo flux analysis), often requires studies in model organisms like zebra fish, Caenorhabditis elegans, Saccharomyces cerevisiae, mutant mice and others, and also requires the input of many different disciplines to make this Translational Metabolism approach effective.

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Pyridoxine-Dependent Epilepsy in Zebrafish Caused by Aldh7a1 Deficiency

Abstract: Pyridoxine-dependent epilepsy (PDE) is a severe neonatal seizure disorder and is here modeled in aldh7a1 -/- zebrafish. Mutant larvae display spontaneous..

Cited by 81 publications

References 71 publications

PDXK mutations cause polyneuropathy responsive to pyridoxal 5′‐phosphate supplementation

PDXK mutations cause polyneuropathy responsive to pyridoxal 5′‐phosphate supplementation

Loss-of-function approaches in comparative physiology: is there a future for knockdown experiments in the era of genome editing?

Translational Metabolism: A multidisciplinary approach towards precision diagnosis of inborn errors of metabolism in the omics era

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