Ethylmalonic encephalopathy

Ethylmalonic encephalopathy
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Field	Medical genetics
Symptoms
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Ethylmalonic encephalopathy (EE) is a rare autosomal recessive inborn error of metabolism. Patients affected with EE are typically identified shortly after birth, with symptoms including diarrhea, petechiae and seizures.<ref name="eeo">,

 Ethylmalonic encephalopathy: clinical and biochemical observations, 
 Neuropediatrics, 
 2007,
 Vol. 38(Issue: 2),
 pp. 78–82,
 DOI: 10.1055/s-2007-984447,
 PMID: 17712735,</ref><ref>, 
 Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy, 
 Nature Medicine, 
 2009,
 Vol. 15(Issue: 2),
 pp. 200–205,
 DOI: 10.1038/nm.1907,
 PMID: 19136963,</ref>  The genetic defect in EE is thought to involve an impairment in the degradation of sulfide intermediates in the body.  Hydrogen sulfide then builds up to toxic levels.<ref name=omim>

Encephalopathy, Ethylmalonic(link). {{{website}}}. Johns Hopkins University.

</ref> EE was initially described in 1994.<ref name=initial>,

 A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts, 
 The Journal of Pediatrics, 
 1994,
 Vol. 124(Issue: 1),
 pp. 79–86,
 DOI: 10.1016/S0022-3476(94)70257-8,
 PMID: 8283379,</ref>  Most cases of EE have been described in individuals of Mediterranean or Arabic origin.<ref name=omim />

Cause

Ethylmalonic encephalopathy results from mutations in the ETHE1 gene. This gene provides instructions for making an enzyme that is active in mitochondria, which are the energy-producing centers in cells. The ETHE1 enzyme is part of a pathway that breaks down sulfide (H2S), a molecule that is critical at very low levels for normal cell functioning but is toxic at high levels. Excess sulfide interferes with numerous cell activities, including mitochondrial energy production.

Mutations in the ETHE1 gene lead to the production of a nonfunctional version of the enzyme or prevent any enzyme from being made. A shortage of functional ETHE1 enzyme prevents sulfide from being broken down, allowing this molecule to accumulate in cells. The buildup of sulfide interferes with the ability of mitochondria to produce energy and damages tissues and organs throughout the body. Researchers believe that the effects of excess sulfide in the brain, muscles, blood vessels, and lining of the intestines underlie most of the major features of ethylmalonic encephalopathy.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Neurologic signs and symptoms include progressively delayed development, weak muscle tone (hypotonia), seizures, and abnormal movements. The body's network of blood vessels is also affected. Children with this disorder may experience rashes of tiny red spots (petechiae) caused by bleeding under the skin and blue discoloration in the hands and feet due to reduced oxygen in the blood (acrocyanosis). Chronic diarrhea is another common feature of ethylmalonic encephalopathy.<ref name=omim /> EE is often identified by urine organic acid analysis, the excretion of ethylmalonic acid, methylsuccinic acid, isobutyrylglycine and isovalerylglucine. Patients will also often have elevated thiosulphate concentration in their urine.<ref name=biochem>,

 Ethylmalonic encephalopathy: Application of improved biochemical and molecular diagnostic approaches, 
 Clinical Genetics, 
 2011,
 Vol. 79(Issue: 4),
 pp. 385–390,
 DOI: 10.1111/j.1399-0004.2010.01457.x,
 PMID: 20528888,</ref>

The signs and symptoms of ethylmalonic encephalopathy are apparent at birth or begin in the first few months of life. Problems with the nervous system typically worsen over time, and most affected individuals survive only into early childhood. A few children with a milder, chronic form of this disorder have been reported, and there can be considerable phenotypic variation, even within families.<ref name=variability>,

 Clinical Heterogeneity in Ethylmalonic Encephalopathy, 
 Journal of Child Neurology, 
 2009,
 Vol. 24(Issue: 8),
 pp. 991–996,
 DOI: 10.1177/0883073808331359,
 PMID: 19289697,</ref>  The life expectancy of individuals with EE is less than ten years.<ref name=omim />

Pathophysiology

Mutations in the ETHE1 gene cause ethylmalonic encephalopathy.<ref name=eear>,

 Identification of new mutations in the ETHE1 gene in a cohort of 14 patients presenting with ethylmalonic encephalopathy, 
 Journal of Medical Genetics, 
 
 Vol. 45(Issue: 7),
 pp. 473–8,
 DOI: 10.1136/jmg.2008.058271,
 PMID: 18593870,</ref> The ETHE1 gene makes an enzyme that plays an important role in energy production. It is active in mitochondria, which are the energy-producing centers within cells. Little is known about its exact function, however.

Mutations in the ETHE1 gene lead to the production of a defective version of the enzyme or prevents the enzyme from being made. A lack of the ETHE1 enzyme impairs the ability to make energy in mitochondria. Additionally, a loss of this enzyme allows potentially toxic compounds, including ethylmalonic acid and lactic acid, to build up in the body. Excess amounts of these compounds can be detected in urine. It remains unclear how a loss of the ETHE1 enzyme leads to progressive brain dysfunction and the other features of ethylmalonic encephalopathy.

Ethylmalonic encephalopathy is an autosomal recessive disorder, which means the defective gene is located on an autosome, and both parents must carry one copy of the defective gene in order to have a child born with the disorder. The parents of a child with an autosomal recessive disorder are usually not affected by the disorder.

Diagnosis

The diagnosis of EE is suggested by clinical findings and the laboratory findings of increased blood lactate levels, C4- and C5-acylcarnitine esters, plasma thiosulphate, and urinary ethylmalonic acid. The diagnosis is established by identification of biallelic pathogenic variants in ETHE1 on molecular genetic testing.

Treatment

Multi-specialty care that includes child neurology, pediatrics, clinical genetics, nutrition, gastroenterology, pain management, and physical therapy can help with timely detection and treatment of the multiorgan dysfunction that characterizes EE. Treatment is primarily supportive including antispastic medications, muscle relaxants, and antiepileptic drugs (AEDs). Physical therapy early in the disease course can help prevent contractures. For severe diarrhea, it is important to maintain hydration and caloric intake. Tube feeding is often necessary.

External links

• Ethylmalonic encephalopathy at NLM Genetics Home Reference