Novel Compound Heterozygous Variants of ETHE1 Causing Ethylmalonic Encephalopathy in a Chinese Patient: A Case Report

Abstract

Ethylmalonic encephalopathy (EE) is a very rare autosomal recessive metabolic disorder that primarily affects children. Less than one hundred EE patients have been diagnosed worldwide. The clinical manifestations include chronic diarrhea, petechiae, orthostatic acrocyanosis, psychomotor delay and regression, seizures, and hypotonia. The ETHE1 gene has been shown to be associated with EE, and genetic sequencing provides concrete evidence for diagnosis. To date, only 37 variants of ETHE1 have been reported as disease-causing in EE patients. We identified two novel ETHE1 variants, i.e., c.595+1G>T at the canonical splice site and the missense variant c.586G>C (p. D196H), in a 3-year-old Chinese boy with EE. The patient had mild symptoms with only chronic diarrhea. The typical symptoms, including spontaneous petechiae, acrocyanosis, and hypotonia, were all absent. Herein, we report on the clinical, biochemical, and genetic findings of our patient and review the phenotypes and genotypes of all patients with EE caused by ETHE1 variants with available information. This study supports the early assessment and diagnosis of EE.

Ethylmalonic encephalopathy: Clinical course and therapy response in an uncommon mild case with a severe ETHE1 mutation

“…Ethylmalonic encephalopathy (EE) (MIM #602473) is an autosomal recessive severe metabolic disorder of infancy affecting the brain, gastrointestinal tract, and peripheral vessels. The disorder is characterized by neurodevelopmental delay and regression, prominent pyramidal and extrapyramidal signs, seizures, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhoea [ 1 ]. Brain magnetic resonance imaging (MRI) shows widespread necrotic lesions in deep grey matter structures [ 2 ].…”

An atypically mild case of ethylmalonic encephalopathy with pathogenic ETHE1 variant

“…This patient had normal brain MRI and spectroscopy and an elevation of urine ethylmalonic acid of 46 mmol/mol creatinine [ref <8.8] (Ersoy et al, 2020). A third patient was compound heterozygous for ETHE1 c.595+1G>T and c.586G>C who had chronic diarrhea, global developmental delay, and consistently elevated urine ethylmalonic acid 28.96–71.84 μM/L [ref <4.70] but was without acrocyanosis, hypotonia, or pyramidal signs (Chen et al, 2020). MRI brain for the third patient showed evidence of demyelination and during follow‐up, developmental delay was restricted to language delay.…”

Red Flags in Primary Mitochondrial Diseases: What Should We Recognize?

“…ETHE1 encodes for a mitochondrial protein that plays a key role in hydrogen sulfide detoxification as a sulfur dioxygenase. ETHE1 mutations lead to the toxic accumulation of H 2 S and metabolites in tissues and body fluids, causing a severe fatal metabolic disorder known as ethylmalonic encephalopathy, a complex disorder characterized by, in addition to liver dysfunction, chronic diarrhea, petechial rush, and neurological manifestations [132,133]. Liver transplantation could increase the survival of patients with DGUOK and ETHE1 mutations [134,135].…”