Ethylmalonic encephalopathy (EE) is a rare

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...

recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

inborn error of metabolism Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrat ...

. Patients affected with EE are typically identified shortly after birth, with symptoms including

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...

petechiae A petechia () is a small red or purple spot (≤4 mm in diameter) that can appear on the skin, conjunctiva, retina, and mucous membranes which is caused by haemorrhage of capillaries. The word is derived from Italian , 'freckle,' of obscure origin ...

and

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...

s. The genetic defect in EE is thought to involve an impairment in the degradation of sulfide intermediates in the body.

Hydrogen sulfide Hydrogen sulfide is a chemical compound with the formula . It is a colorless chalcogen-hydride gas, and is poisonous, corrosive, and flammable, with trace amounts in ambient atmosphere having a characteristic foul odor of rotten eggs. The unde ...

then builds up to toxic levels. EE was initially described in 1994. Most cases of EE have been described in individuals of Mediterranean or Arabic origin.

Signs and symptoms

Neurologic signs and symptoms include progressively delayed development, weak muscle tone (

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases a ...

), 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 (

) caused by bleeding under the skin and blue discoloration in the hands and feet due to reduced oxygen in the blood (

acrocyanosis Acrocyanosis is persistent blue or cyanotic discoloration of the extremities, most commonly occurring in the hands, although it also occurs in the feet and distal parts of face.Kurklinsky AK, Miller VM, Rooke TW. "Acrocyanosis: The Flying Dutchma ...

). Chronic diarrhea is another common feature of ethylmalonic encephalopathy. 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 Thiosulfate ( IUPAC-recommended spelling; sometimes thiosulphate in British English) is an oxyanion of sulfur with the chemical formula . Thiosulfate also refers to the compounds containing this anion, which are the salts of thiosulfuric acid, e ...

concentration in their urine. 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 In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

variation, even within families. The life expectancy of individuals with EE is less than ten years.

Pathophysiology

Mutations in the ''

ETHE1 Protein ETHE1, mitochondrial, also known as "ethylmalonic encephalopathy 1 protein" and "per sulfide dioxygenase", is a protein that in humans is encoded by the ''ETHE1'' gene located on chromosome 19. Structure The human ETHE1 gene consists o ...

'' gene cause ethylmalonic encephalopathy. The ''ETHE1'' gene makes an enzyme that plays an important role in energy production. It is active in

mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

, 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 An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...

, 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

Treatment

References

External links

* {{Amino acid metabolic pathology Autosomal recessive disorders Brain disorders