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Abstract Details

Uridine Supplementation for Treatment of Epileptic Encephalopathy from Carbamoyl-Phosphate Synthetase 2, Aspartate Transcarbamylase and Dihydroorotase (CAD) Gene Mutation
Child Neurology and Developmental Neurology
P14 - Poster Session 14 (8:00 AM-9:00 AM)
5-006
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An 8 year old female with developmental delay, autism and intractable epilepsy was admitted to Rady Children’s Hospital San Diego with seizures.  Seizures started with a febrile illness when the patient was one year old however over time, she had febrile and afebrile seizures that were increasingly difficult to control.  She had focal and generalized seizures and frequent episodes of status epilepticus. The patient was found to harbor a homozygous variant (c.98T>G. p.Met33Arg) in the Carbamoyl-Phosphate Synthetase 2, Aspartate Transcarbamylase and Dihydroorotase (CAD) gene.  This gene encodes a trifunctional enzyme complex important in the initial steps necessary for de novo pyrimidine nucleotide synthesis.  Pathologic variants in the CAD gene have been reported in five individuals; four of whom were described to have epileptic encephalopathy, developmental delay and intractable epilepsy.  In its untreated form, this disorder is progressive and fatal however there are reports of two patients with clinical improvement after uridine supplementation when monitored for six months.
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Our patient had seizures refractory to combinations of several standard anti-seizure medications, encephalopathy and regression of functional skills. Triacetyluridine (TAU) was initiated at the recommended dose of 100 mg/kg/day divided QID.  The patient had decreasing amounts of daily seizures following initiation of uridine supplementation and cessation of seizures after four days of treatment. The patient also had improvement in her mental status and functionality. When last assessed after three months, the patient had not had any further seizures.
Our patient is the third child reported with intractable epilepsy and neurodegeneration secondary to CAD gene mutation who has clinically responded to treatment with uridine using the prodrug TAU. Exogenous uridine is thought to bypass the loss of CAD function thereby improving pyrimidine synthesis and downstream pathways. 
Authors/Disclosures
Aliya Frederick, MD, PhD (RADY CHILDRENS HOSPITAL/UCSD)
PRESENTER 		No disclosure on file
No disclosure on file
Linda Nguyen, MD, PhD (UT Southwestern Medical Center) Dr. Nguyen has nothing to disclose.
Michelle Sahagian, MD (UCSD) No disclosure on file
Richard H. Haas, MD Dr. Haas has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for SPARC. Dr. Haas has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB Pharma. Dr. Haas has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Various Law Firms. Dr. Haas has stock in Various Companies Stock Trading. The institution of Dr. Haas has received research support from NIH North American Mitochondrial Disease Consortium. The institution of Dr. Haas has received research support from Reneo Pharma. The institution of Dr. Haas has received research support from Astellas Pharma. The institution of Dr. Haas has received research support from Acadia Pharma. The institution of Dr. Haas has received research support from Taysha Gene Therapies. The institution of Dr. Haas has received research support from Tisento Pharma.