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Updated: May 11, 2025
Simultaneous Video-EEG-ECG Monitoring to Identify Neurocardiac Dysfunction in Mouse Models of Epilepsy
Published on: January 29, 2018
Epileptic encephalopathy in a young Bengal cat caused by CAD deficiency
Adriana Kaczmarska1, Matthias Christen2, Francisco Del Caño-Ochoa3
1School of Biodiversity, One Health and Veterinary Medicine, University of Glasgow, Glasgow, G61 1QH, UK.
Insights
A novel variant in the CAD gene causes a severe neurometabolic disorder in Bengal cats, similar to human developmental and epileptic encephalopathy type 50. Genetic testing and uridine supplementation show potential for diagnosis and treatment in affected felines.
Area of Science:
- Genetics
- Neuroscience
- Biochemistry
Background:
- Developmental and epileptic encephalopathy type 50 (DEE50) is a severe human neurometabolic disorder.
- It stems from loss-of-function variants in the CAD gene, crucial for pyrimidine nucleotide synthesis.
- Uridine supplementation is a known treatment for DEE50 by bypassing the CAD-dependent pathway.
Purpose of the Study:
- To identify the genetic cause of severe neurological symptoms in a Bengal kitten.
- To investigate a novel CAD gene variant and its functional impact.
- To explore the potential of feline models for human DEE50 research.
Main Methods:
- Whole exome sequencing and variant analysis in an affected kitten.
- Functional studies using a CAD-knockout human cell line.
- Genotyping of Bengal cat population to determine carrier frequency.
Main Results:
- A novel pathogenic variant (p.Ser2015Asn) in the feline CAD gene was identified in a Bengal kitten with seizures.
- The variant disrupts the aspartate transcarbamylase (ATCase) domain function, impairing pyrimidine synthesis.
- The variant was found in 4 out of 110 healthy Bengal cats, indicating carrier status within the breed.
Conclusions:
- The identified CAD variant is pathogenic and causes a DEE50-like disorder in cats.
- Genetic testing can identify carriers, and uridine supplementation may be a viable treatment.
- CAD-deficient Bengal cats represent a valuable large animal model for studying DEE50.
Abstract:
Developmental and epileptic encephalopathy type 50 (DEE50) in humans is a severe early-onset neurometabolic disorder caused by biallelic loss-of-function variants in the CAD gene encoding a key multi-enzymatic protein for de novo pyrimidine nucleotide synthesis. Untreated, the condition is often fatal, but patients respond to uridine supplementation, which fuels nucleotide synthesis through CAD-independent salvage pathways. Here, we report a novel variant in the feline CAD gene in a 4-month-old Bengal kitten with intractable seizures and abnormal behavior. The variant, XP_011279586.1:p.(Ser2015Asn), was predicted to affect the oligomerization of the C-terminal aspartate transcarbamylase (ATCase) domain of CAD. Genotyping of 110 unaffected Bengal cats revealed four additional carriers of the mutant allele, confirming its presence in the breed. In a CAD-knockout human cell line dependent on uridine, the recombinant expression of human wildtype CAD, but not of the Asn2015 mutant, restored cell growth without uridine, demonstrating that the p.Ser2015Asn variant disrupts CAD function and is pathogenic. This study facilitates genetic testing of carriers and affected cats and suggests that uridine supplementation could be a potential treatment. Furthermore, CAD-deficient Bengal cats might serve as a valuable spontaneous large animal model to further investigate the pathogenic mechanisms of this rare epileptic encephalopathy in humans.
