Encephalopathy, Ethylmalonic

A number sign (#) is used with this entry because ethylmalonic encephalopathy (EE) is caused by homozygous or compound heterozygous mutation in the ETHE1 gene (608451), which encodes a mitochondrial matrix protein, on chromosome 19q13.

Description

Ethylmalonic encephalopathy 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, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea. Brain MRI shows necrotic lesions in deep gray matter structures. Death usually occurs in the first decade of life (summary by Drousiotou et al., 2011).

Clinical Features

Burlina et al. (1991) first described ethylmalonic encephalopathy as a syndrome characterized by developmental delay, acrocyanosis, petechiae, and chronic diarrhea. Laboratory studies showed ethylmalonic and methylsuccinic aciduria and lactic acidemia. However, in vitro activities of short chain acyl-CoA dehydrogenase (SCAD; 606885) and 2-methyl-branched chain acyl-CoA dehydrogenase, 2 enzymes whose deficiencies could theoretically produce the biochemical findings observed in ethylmalonic encephalopathy, were found to be normal (Burlina et al., 1994).

Nowaczyk et al. (1998) reported the cases of 2 sibs with ethylmalonic encephalopathy and central nervous system malformations. The girl had primary tethered cord. Her younger brother, who was evaluated at the age of 4 years because of a similar phenotype (episodic ataxia, chronic diarrhea, and acrocyanosis), had cerebellar tonsillar ectopia (Chiari I malformation).

Tiranti et al. (2004) stated that since the initial report no more than 30 cases of ethylmalonic encephalopathy had been described worldwide, leading to the assumption that the disorder is very rare. However, the actual incidence of the condition may be significantly underestimated because the biochemical phenotype may be incorrectly attributed to other metabolic disorders.

Drousiotou et al. (2011) reported 3 patients from 2 unrelated families of Greek Cypriot origin with ethylmalonic encephalopathy. The first patient presented at age 2.5 months with feeding difficulties, failure to thrive, petechiae, and ecchymosis. She was floppy with severe head lag and microcephaly, and showed poor responses to auditory and visual stimuli. Deep tendon reflexes were exaggerated, and there was sustained clonus and bilateral Babinski sign. She subsequently developed chronic diarrhea and seizures. Brain MRI revealed multiple bilateral loci of high intensity in the basal ganglia on T2-weighted images. She showed neurologic regression and was 5.5 years old at the time of the report. Her older brother died at age 6 months of a presumably similar disorder. Ultrasound of the brain showed hyperechogenicity of gyri and sulci. No tissues were available for confirmation of diagnosis. A girl from a second family was born prematurely at 36 weeks' gestation and presented at age 6 months with feeding difficulties, hypotonia, and global developmental delay. She later developed diarrhea, petechiae, ecchymosis, and seizures, and brain MRI showed abnormal signals in the basal ganglia and thinning of the corpus callosum. She died at age 8 months from cardiopulmonary arrest. Laboratory studies of all 3 patients showed increased serum lactate and butyrylcarnitine, and increased urinary ethylmalonic acid, methylsuccinate, and thiosulfate. Western blot analysis from 2 patients showed complete absence of the ETHE1 protein.

Clinical Management

Viscomi et al. (2010) treated a 29-month-old Italian boy with ethylmalonic encephalopathy with metronidazole and N-acetylcysteine, a precursor of sulfide-buffering glutathione. The therapy was designed to act against accumulation of toxic hydrogen sulfide. Over the next 8 months, the patient showed increased body weight, a decrease and then disappearance of diarrhea, petechiae, and acrocyanosis, and marked neurologic improvement, with decreased seizures, less severe hypotonia, reversion of brain atrophy, and a reduction in leukodystrophy, although lesions in the neostriatum become more evident. Biochemical abnormalities also lessened. Treatment of 4 additional patients showed similar clinical, biochemical, and MRI improvements. The clinical treatment was performed after Viscomi et al. (2010) obtained favorable results in an Ethe -/- mouse model.

Molecular Genetics

By a combination of homozygosity mapping, integration of physical and functional genomic datasets, and mutational screening, Tiranti et al. (2004) identified the ETHE1 gene (608451) as the site of mutations causing EE. They demonstrated that the ETHE1 protein is targeted to mitochondria and internalized into the matrix after energy-dependent cleavage of a short leader peptide. The severe consequences of its malfunctioning indicate an important role of the ETHE1 gene product in mitochondrial homeostasis and energy metabolism.

In 14 patients with ethylmalonic encephalopathy, Mineri et al. (2008) identified homozygosity for mutations in the ETHE1 gene (see, e.g., 608451.0006 and 608451.0007). At the time of the report, 11 patients were deceased; age of death ranged from 18 months to 3 years. Three patients were alive at 6 months, 7 years, and 13 years, respectively.

In 2 patients from 2 unrelated families of Greek Cypriot origin with ethylmalonic encephalopathy, Drousiotou et al. (2011) identified 2 different mutations in the ETHE1 gene (608451.0007 and 608451.0008). One was compound heterozygous for the mutations, whereas the other was homozygous for 1 of the mutations.

Population Genetics

With few exceptions, the patients with ethylmalonic encephalopathy have been of Mediterranean (Garcia-Silva et al., 1997; Grosso et al., 2002) or Arabic (Ozand et al., 1994) extraction.

Animal Model

Tiranti et al. (2009) found that Ethe1-null mice developed the cardinal features of ethylmalonic encephalopathy, including poor growth, reduced motor activity, early death, low cytochrome c oxidase (COX) in muscle and brain, and increased urinary excretion of ethylmalonic acid. Both mutant mice and humans with the disorder excreted massive amounts of thiosulfate in the urine, and there was an accumulation of thiosulfate and hydrogen sulfide (H2S) in mutant mouse tissue. Hydrogen sulfide is powerful inhibitor of COX and short-chain fatty acid oxidation, and has vasoactive and vasotoxic effects. The findings suggested that ethylmalonic encephalopathy is a disease associated with impaired catabolism of inorganic sulfur leading to accumulation of hydrogen sulfide in key tissues. The toxic effects of this accumulation can account for several features, including ethylmalonic aciduria, COX deficiency, microangiopathy, acrocyanosis, and chronic diarrhea. Sulfide is detoxified by a mitochondrial pathway that includes a sulfur dioxygenase. Sulfur dioxygenase activity was absent in Ethe1-null mice, but it was markedly increased by ETHE1 overexpression in HeLa cells and E. coli. These findings indicated that ETHE1 is a mitochondrial sulfur dioxygenase involved in catabolism of sulfide that accumulates to toxic levels in ethylmalonic encephalopathy.