Abstracts

Rationale:  We report the case of a 4 years old Puerto Rican girl who presented with multiple seizure types, infantile spasms and severe global developmental delay. Her examination was significant for profound hypotonia, myopathic face and areflexia. Her genetic workup revealed a homozygous likely pathogenic c.376C>T (p.R126X) mutation in the TBCK gene. A second homozygous, likely pathogenic c.908G>T (p.G303V) mutation in the HADH gene, responsible for medium/short chain 3-hydroxyacyl-CoA dehydrogenase deficiency (MCHAD/SCHAD), was also found. Several seizure medications were tried in Puerto Rico without success. ACTH was considered but not tried due to concern for side effects. Methods: Electronic medical records were reviewed.Magnetic resonance imaging brain, long term video electroencephalogram monitoring and genetic tests were analyzed. Results: A single nucleotide polymorphism microarray demonstrated a 1q21 chromosome duplication, which was also present in the mother, and a large region of homozygosity (ROH) involving 10.3 Mb on 4q24- q25, suggesting the possibility of an autosomal recessive disorder.Whole exome sequencing identified a pathogenic homozygous nonsense mutation c.376C>T (p.R126X) in the TBCKgene. A second homozygous likely pathogenic mutation c.908G>T (p.G303V) in the HADH gene (which causes MCHAD/SCHAD) was also found. Both parents were heterozygous for each variant. Both of these genes were located in the ROH on chromosome 4 that was previously detected on SNP microarray.The neuroimaging was significant for generalized brain atrophy, abnormal periventricular white matter T2 signal. A cerebellar cyst was also noticed. EEG was abnormal for hypsarrhythmia and epileptic spasms.Monthly IV infusion of solumedrol, resulted in resolution of infantile spasms and marked reduction of seizure burden with improved quality of life. Conclusions: Our case is unique due to coexistence of a TBCK gene mutation along with homozygous pathogenic variant in the 3-hydroxyacyl -CoA dehydrogenase (HADH) gene. Homozygous mutations found in two separate genes, located within the ROH inherited from unrelated parents of the same ancestry suggest the possibility the variants are part of a haplotype segregating together.It is important to diagnose MCHAD/SCHAD and start dietary treatment early for patients with Puerto Rican ancestry who are homozygous for the p.R126X variant in TBCK.Possible therapeutic role of steroids in patients with TBCK epileptic encephalopathy should be considered..  Funding: None