P3D323: Open Your Eyes to a New Variation of Ethylmalonic Encephalopathy

Introduction: Ethylmalonic encephalopathy (EE) is a rare autosomal recessive metabolic disorder that causes a buildup of toxic metabolites in the body resulting in progressive multi-organ injury, including neurologic deterioration and microvascular destruction. Previously described phenotypic findings include developmental delays, tonic-clonic seizures, petechiae, and purpura. A definitive diagnosis is typically made in affected children by identifying biallelic pathogenic variants in ETHE1 with supportive biochemical findings including elevated urinary ethylmalonic acid and elevated plasma C4 and C5 acylcarnitine esters.

Case Description: An eight-month-old male arrived at Walter Reed National Military Medical Center to undergo evaluation for global developmental delay. At two months old, parents reported inconsolable irritability and severe photophobia (Image 1), and concerns arose for developmental delay. His physical exam was notable for hypotonia and stertor by five months of life. At eight months old, the patient’s echocardiogram, electroencephalogram, and abdominal ultrasound were all normal for age. However, a brain MRI showed nonspecific diffuse parenchymal atrophy with mild delayed white matter myelination. A sedated eye exam showed myopia and microspherophakia. Laboratory evaluation for metabolic disease revealed elevated urine ethylmalonic acid and elevated plasma C4 acylcarnitine ester, raising concerns for EE. Exome sequencing (Table 1) showed compound heterozygosity, in the trans configuration, of a likely pathogenic variant in ETHE1, c.596-2A>G, and a previously unreported ETHE1 variant of uncertain significance, c.702_703delTC, p.Gln235Alafs*32. Given his clinical phenotype and biochemical testing results, we presumed that the novel ETHE1 c.702_703delTC, p.Gln235Alafs*32 variant is likely pathogenic, and a diagnosis of EE was assigned.

Discussion: Cases of EE are exceedingly rare, with a majority geographically clustered around the Mediterranean Basin, and being the products of consanguinity. The case we presented, however, displayed many unique features. While born in Bahrain, our patient was the offspring of two white, American parents. Our patient was found to have some characteristic features of EE, including developmental delay, brain abnormalities, hypotonia, and petechial rash, but he was also found to have photophobia and microspherophakia – both findings that have not yet been described in documented cases of EE. Additionally, this case highlights a unique, compound heterozygous genotype featuring a previously unreported variant in ETHE1 c.702_703delTC, p.Gln235Alafs*3, which we presumed is pathogenic due to its existence in trans configuration with a known pathogenic variant for EE, ETHE1 c.596-2A>G.

Conclusion: Our findings suggest that, when suspicion for metabolic disease is high, providers should initiate early and broad biochemical and genetic testing, even when clinical findings do not completely match the previously reported phenotypes of a given disease. Continued efforts towards early identification of genetic/metabolic disorders will become increasingly important as new, effective therapies are developed for these diseases.