2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Atypically Mild Ethylmalonic Encephalopathy Expands Phenotypic Spectrum

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This document presents a case study of a 19-month-old male patient with developmental delays and mild hyperammonemia. The patient had a non-contributory pregnancy and birth history and a normal newborn screen. He had feeding difficulties requiring thickened feeds during infancy. The patient's family history revealed consanguinity.<br /><br />On physical examination, the patient appeared non-dysmorphic and had a slightly wide-based gait with occasional out-toeing. At 3 years and 8 months of age, the patient had articulation difficulties and <50% speech intelligibility. Neurologic examination showed paresis of lateral tongue movements and right arm flexion and right leg out-swinging when asked to run.<br /><br />Initial biochemical evaluation showed normal plasma amino acids, isolated elevated C4 acylcarnitine on the acylcarnitine profile, normal urine organic acids, and normal lactate. Exome sequencing identified a homozygous pathogenic variant in the ETHE1 gene, diagnostic for ETHE1-related ethylmalonic encephalopathy. Additional biochemical evaluation confirmed the diagnosis, showing elevated ethylmalonic acid levels in urine.<br /><br />The report discusses the genetic and phenotypic spectrum of ethylmalonic encephalopathy. The identified ETHE1 variant has been associated with severe cases presenting with pyramidal signs, acrocyanosis, and marked hypotonia. However, the spectrum of the disease is broader, with some patients presenting with chronic diarrhea and global developmental delay without acrocyanosis or hypotonia. Genotype-phenotype correlation in ethylmalonic encephalopathy remains poor.<br /><br />The study concludes that, although the current patient is mildly affected, they may still be at risk of acute decompensation. The patient does not exhibit symptoms like recurrent petechiae, chronic diarrhea, regression, progressive encephalopathy, stroke-like episodes, or orthostatic acrocyanosis, which are common in ethylmalonic encephalopathy. However, these symptoms may manifest in the future.<br /><br />Overall, this case highlights the clinical and genetic variability of ethylmalonic encephalopathy, emphasizing the need for comprehensive evaluation and monitoring of patients with this condition.

Asset Subtitle

Presenting Author - Christina Sloan-Heggen, MD, PhD; Co-Author - Daniel Kashima, MD, PhD; Co-Author - Rachel Gottlieb-Smith, MD; Co-Author - Amanda Barone Pritchard, MD;

Meta Tag

Biochemical genetics

Cognitive Disorders

Genetic Diversity

Genetic Testing

Genotype-Phenotype Correlations

Metabolic Disorder

Phenotype

Co-Author Daniel Kashima, MD, PhD

Co-Author Rachel Gottlieb-Smith, MD

Co-Author Amanda Barone Pritchard, MD

Presenting Author Christina Sloan-Heggen, MD, PhD

Keywords

case study

19-month-old male

developmental delays

hyperammonemia

feeding difficulties

consanguinity

ethylmalonic encephalopathy

genetic variability

comprehensive evaluation

monitoring