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Personalized medicine approach confirms a milder case of ABAT deficiency

Overview of attention for article published in Molecular Brain, December 2016
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Title
Personalized medicine approach confirms a milder case of ABAT deficiency
Published in
Molecular Brain, December 2016
DOI 10.1186/s13041-016-0273-8
Pubmed ID
Authors

A. Besse, A. K. Petersen, J. V. Hunter, V. Appadurai, S. R. Lalani, P. E. Bonnen

Abstract

ABAT deficiency (OMIM 613163) is a rare inborn error of metabolism caused by recessive variants in the gene 4-aminobutyric acid transaminase (ABAT), which is responsible for both the catalysis of GABA and maintenance of nucleoside pools in the mitochondria. To date, only a few patients have been reported worldwide. Their clinical presentation has been remarkably consistent with primary features of severe psychomotor retardation, encephalopathy, hypotonia, and infantile-onset refractory epilepsy. We report a new case of ABAT deficiency that marks an important departure from previous clinical findings. The patient presented at age 6 months with global developmental delay, hypotonia, hypersomnolence and mild choreiform movements. At age 18 months, the subject's clinical presentation was still milder than all previously reported patients and, most notably, did not include seizures. Clinical whole exome sequencing revealed two heterozygous ABAT missense variants that are rare and predicted damaging, but never before reported in a patient and were reported as variants of unknown significance. To test the potential pathogenicity of the variants identified in this patient we developed a cell-based system to test both functions of the ABAT protein via GABA transaminase enzyme activity and mtDNA copy number assays. This systematic approach was validated using vigabatrin, the irreversible inhibitor of ABAT, and leveraged to test the functionality of all ABAT variants in previously reported patients plus the variants in this new case. This work confirmed the novel variants compromised ABAT function to similar levels as variants in previously characterized cases with more severe clinical presentation, thereby confirming the molecular diagnosis of this patient. Additionally, functional studies conducted in cells from both mild and severe patient fibroblasts showed similar levels of compromise in mitochondrial membrane potential, respiratory capacity, ATP production and mtDNA depletion. These results illustrate how cell-based functional studies can aid in the diagnosis of a rare, neurological disorder. Importantly, this patient marks an expansion in the clinical phenotype for ABAT deficiency to a milder presentation that is more commonly seen in pediatric genetics and neurology clinics.

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Mendeley readers

The data shown below were compiled from readership statistics for 21 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 21 100%

Demographic breakdown

Readers by professional status Count As %
Student > Bachelor 5 24%
Student > Doctoral Student 2 10%
Researcher 2 10%
Student > Postgraduate 2 10%
Student > Master 2 10%
Other 4 19%
Unknown 4 19%
Readers by discipline Count As %
Pharmacology, Toxicology and Pharmaceutical Science 4 19%
Medicine and Dentistry 3 14%
Biochemistry, Genetics and Molecular Biology 2 10%
Psychology 2 10%
Agricultural and Biological Sciences 1 5%
Other 5 24%
Unknown 4 19%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 01 December 2016.
All research outputs
#6,635,262
of 8,711,471 outputs
Outputs from Molecular Brain
#364
of 462 outputs
Outputs of similar age
#206,748
of 299,472 outputs
Outputs of similar age from Molecular Brain
#10
of 14 outputs
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