Epileptic encephalopathy in a young Bengal cat caused by CAD deficiency
Por:
A. KACZMARSKA, M. CHRISTEN, F. DEL CANO-OCHOA, S. RAMON-MAIQUES, A. MIRO, A. RUPP, V. JAGANNATHAN, T. LEEB and R. GUTIERREZ-QUINTANA
Publicada:
18 abr 2025
Resumen:
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.
Filiaciones:
A. KACZMARSKA:
Univ Glasgow, Sch Biodivers One Hlth & Vet Med, Glasgow City G61 1QH, Scotland
M. CHRISTEN:
Univ Bern, Inst Genet, Vetsuisse Fac, Bremgartenstr 109A, CH-3001 Bern, Switzerland
F. DEL CANO-OCHOA:
Inst Biomed Valencia IBV CSIC, Valencia, Spain
:
Inst Biomed Valencia IBV CSIC, Valencia, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras CIBERER, Grp CB06 07 0077, Valencia, Spain
Valencia Biomed Res Fdn, Ctr Invest Principe Felipe, CIPF Associated Unit Inst Biomed Valencia IBV, Valencia, Spain
A. MIRO:
Univ Glasgow, Sch Biodivers One Hlth & Vet Med, Glasgow City G61 1QH, Scotland
A. RUPP:
Univ Glasgow, Sch Biodivers One Hlth & Vet Med, Glasgow City G61 1QH, Scotland
V. JAGANNATHAN:
Univ Bern, Inst Genet, Vetsuisse Fac, Bremgartenstr 109A, CH-3001 Bern, Switzerland
T. LEEB:
Univ Bern, Inst Genet, Vetsuisse Fac, Bremgartenstr 109A, CH-3001 Bern, Switzerland
R. GUTIERREZ-QUINTANA:
Univ Glasgow, Sch Biodivers One Hlth & Vet Med, Glasgow City G61 1QH, Scotland
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