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| {{Infobox medical condition (new) | | {{Short description|A rare genetic disorder affecting metabolism}} |
| | name = Ethylmalonic encephalopathy | |
| | image = autorecessive.svg
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| | caption = Ethylmalonic encephalopathy has an autosomal recessive pattern of [[inheritance]].
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| | field = [[Medical genetics]]
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| '''Ethylmalonic encephalopathy''' ('''EE''') is a rare [[autosome|autosomal]] [[dominance (genetics)|recessive]] [[inborn error of metabolism]]. Patients affected with EE are typically identified shortly after birth, with symptoms including [[diarrhea]], [[petechiae]] and [[seizure]]s.<ref name="eeo">{{cite journal |vauthors=Zafeiriou DI, Augoustide-Savvopoulou P, Haas D, Smet J, Triantafyllou P, Vargiami E, Tamiolaki M, Gombakis N, van Coster R, Seweil AC, Vianey-Saban C, Gregersen N |title=Ethylmalonic encephalopathy: clinical and biochemical observations |journal=Neuropediatrics |volume=38 |issue=2 |pages=78–82 |year=2007 |pmid=17712735 |doi=10.1055/s-2007-984447 }}</ref><ref>{{Cite journal | last1 = Tiranti | first1 = V. | last2 = Viscomi | first2 = C. | last3 = Hildebrandt | first3 = T. | last4 = Di Meo | first4 = I. | last5 = Mineri | first5 = R. | last6 = Tiveron | first6 = C. | last7 = Levitt | first7 = M. | last8 = Prelle | first8 = A. | last9 = Fagiolari | first9 = G. | last10 = Rimoldi | doi = 10.1038/nm.1907 | first10 = M. | last11 = Zeviani | first11 = M. | title = Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy | journal = Nature Medicine | volume = 15 | issue = 2 | pages = 200–205 | year = 2009 | 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>{{cite web|title=Encephalopathy, Ethylmalonic|url=http://www.omim.org/entry/602473|publisher=[[Johns Hopkins University]]|accessdate=2012-05-12}}</ref> EE was initially described in 1994.<ref name=initial>{{Cite journal | doi = 10.1016/S0022-3476(94)70257-8 | last1 = Burlina | first1 = A. B. | last2 = Dionisi-Vici | first2 = C. | last3 = Bennett | first3 = M. J. | last4 = Gibson | first4 = K. M. | last5 = Servidei | first5 = S. | last6 = Bertini | first6 = E. | last7 = Hale | first7 = D. E. | last8 = Schmidt-Sommerfeld | first8 = E. | last9 = Sabetta | first9 = G. | last10 = Zacchello | first10 = F. | last11 = Rinaldo | first11 = P. | title = A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts | journal = The Journal of Pediatrics | volume = 124 | issue = 1 | pages = 79–86 | year = 1994 | pmid = 8283379}}</ref> Most cases of EE have been described in individuals of Mediterranean or Arabic origin.<ref name=omim /> | | '''Ethylmalonic encephalopathy''' is a rare [[genetic disorder]] that primarily affects the [[nervous system]], [[gastrointestinal tract]], and [[blood vessels]]. It is characterized by a combination of neurological symptoms, chronic diarrhea, and vascular lesions. The condition is caused by mutations in the ETHE1 gene, which plays a crucial role in the metabolism of sulfur-containing compounds. |
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| == '''Cause''' == | | ==Signs and symptoms== |
| 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.'''
| | Individuals with ethylmalonic encephalopathy typically present with symptoms in infancy or early childhood. Common signs and symptoms include: |
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| 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.
| | * '''Neurological symptoms''': These may include [[developmental delay]], [[hypotonia]] (reduced muscle tone), [[seizures]], and [[ataxia]] (lack of voluntary coordination of muscle movements). |
| | * '''Gastrointestinal symptoms''': Chronic diarrhea is a hallmark of the condition, often leading to dehydration and malnutrition. |
| | * '''Vascular lesions''': Patients may develop petechiae (small red or purple spots on the skin) and other vascular abnormalities due to small blood vessel damage. |
| | * '''Metabolic abnormalities''': Elevated levels of ethylmalonic acid and other metabolites can be detected in the urine. |
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| == '''Inheritance''' == | | ==Genetics== |
| [[File:Autorecessive.svg|thumb|right|Autosomal recessive inheritance, a 25% chance]]
| | Ethylmalonic encephalopathy is inherited in an [[autosomal recessive]] pattern, meaning that both copies of the ETHE1 gene in each cell have mutations. The ETHE1 gene provides instructions for making an enzyme that is involved in the breakdown of sulfur-containing compounds. Mutations in this gene lead to the accumulation of toxic substances that damage cells and tissues, particularly in the brain and blood vessels. |
| 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.
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| ==Signs and symptoms== | | ==Diagnosis== |
| 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>{{Cite journal | last1 = Drousiotou | first1 = A. | last2 = Dimeo | first2 = I. | last3 = Mineri | first3 = R. | last4 = Georgiou | first4 = T. | last5 = Stylianidou | first5 = G. | last6 = Tiranti | first6 = V. | doi = 10.1111/j.1399-0004.2010.01457.x | title = Ethylmalonic encephalopathy: Application of improved biochemical and molecular diagnostic approaches | journal = Clinical Genetics | volume = 79 | issue = 4 | pages = 385–390 | year = 2011 | pmid = 20528888 | pmc = }}</ref>
| | Diagnosis of ethylmalonic encephalopathy is based on clinical evaluation, laboratory tests, and genetic testing. Key diagnostic indicators include: |
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| 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 [[phenotype|phenotypic]] variation, even within families.<ref name=variability>{{Cite journal | last1 = Pigeon | first1 = N. | last2 = Campeau | first2 = P. M. | last3 = Cyr | first3 = D. | last4 = Lemieux | first4 = B. | last5 = Clarke | first5 = J. T. R. | title = Clinical Heterogeneity in Ethylmalonic Encephalopathy | doi = 10.1177/0883073808331359 | journal = Journal of Child Neurology | volume = 24 | issue = 8 | pages = 991–996 | year = 2009 | pmid = 19289697 | pmc = }}</ref> The life expectancy of individuals with EE is less than ten years.<ref name=omim />
| | * '''Biochemical testing''': Elevated levels of ethylmalonic acid in the urine are a significant marker. |
| | * '''Genetic testing''': Identification of mutations in the ETHE1 gene confirms the diagnosis. |
| | * '''Imaging studies''': [[Magnetic resonance imaging]] (MRI) of the brain may reveal characteristic changes associated with the disorder. |
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| ==Pathophysiology== | | ==Treatment== |
| Mutations in the ''[[ETHE1]]'' gene cause ethylmalonic encephalopathy.<ref name=eear>{{cite journal |pmid=18593870 |date=Jul 2008 |vauthors=Mineri R, Rimoldi M, Burlina AB, Koskull S, Perletti C, Heese B, Von Döbeln U, Mereghetti P, Di Meo I, Invernizzi F, Zeviani M, Uziel G, Tiranti V |title=Identification of new mutations in the ETHE1 gene in a cohort of 14 patients presenting with ethylmalonic encephalopathy |volume=45 |issue=7 |pages=473–8 |doi=10.1136/jmg.2008.058271 |journal=Journal of Medical Genetics}}</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.
| | There is currently no cure for ethylmalonic encephalopathy, and treatment is primarily supportive and symptomatic. Management strategies may include: |
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| 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.
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| 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.
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| ==Diagnosis==
| | * '''Nutritional support''': Addressing malnutrition and dehydration due to chronic diarrhea. |
| 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.
| | * '''Seizure management''': Use of [[anticonvulsant]] medications to control seizures. |
| The diagnosis is established by identification of biallelic pathogenic variants in ETHE1 on molecular [[genetic testing]].
| | * '''Physical therapy''': To improve muscle tone and coordination. |
| | * '''Experimental therapies''': Research is ongoing to explore potential treatments that target the underlying metabolic defect. |
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| ==Treatment== | | ==Prognosis== |
| 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 drug|antiepileptic drugs]] (AEDs). [[Physical therapy]] early in the disease course can help prevent [[Contracture|contractures]]. For severe [[diarrhea]], it is important to maintain hydration and caloric intake. Tube feeding is often necessary.
| | The prognosis for individuals with ethylmalonic encephalopathy varies. The condition is progressive, and the severity of symptoms can differ among affected individuals. Early diagnosis and intervention may improve quality of life and outcomes. |
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| ==References== | | ==Related pages== |
| {{reflist}}
| | * [[Genetic disorder]] |
| == External links ==
| | * [[Metabolic disorder]] |
| {{Medical resources
| | * [[Neurological disorder]] |
| | ICD10 =
| | * [[Autosomal recessive inheritance]] |
| | ICD9 =
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| | ICDO =
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| | OMIM = 602473
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| | MedlinePlus =
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| | eMedicineTopic =
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| | MeshID =
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| | SNOMED CT = 723307008
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| | Orphanet = 51188
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| }}
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| * {{NLM|ethylmalonicencephalopathy}} | |
| {{Amino acid metabolic pathology}}
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| [[Category:Autosomal recessive disorders]] | | [[Category:Genetic disorders]] |
| [[Category:Brain disorders]] | | [[Category:Metabolic disorders]] |
| | [[Category:Neurological disorders]] |
A rare genetic disorder affecting metabolism
Ethylmalonic encephalopathy is a rare genetic disorder that primarily affects the nervous system, gastrointestinal tract, and blood vessels. It is characterized by a combination of neurological symptoms, chronic diarrhea, and vascular lesions. The condition is caused by mutations in the ETHE1 gene, which plays a crucial role in the metabolism of sulfur-containing compounds.
Signs and symptoms
Individuals with ethylmalonic encephalopathy typically present with symptoms in infancy or early childhood. Common signs and symptoms include:
- Neurological symptoms: These may include developmental delay, hypotonia (reduced muscle tone), seizures, and ataxia (lack of voluntary coordination of muscle movements).
- Gastrointestinal symptoms: Chronic diarrhea is a hallmark of the condition, often leading to dehydration and malnutrition.
- Vascular lesions: Patients may develop petechiae (small red or purple spots on the skin) and other vascular abnormalities due to small blood vessel damage.
- Metabolic abnormalities: Elevated levels of ethylmalonic acid and other metabolites can be detected in the urine.
Genetics
Ethylmalonic encephalopathy is inherited in an autosomal recessive pattern, meaning that both copies of the ETHE1 gene in each cell have mutations. The ETHE1 gene provides instructions for making an enzyme that is involved in the breakdown of sulfur-containing compounds. Mutations in this gene lead to the accumulation of toxic substances that damage cells and tissues, particularly in the brain and blood vessels.
Diagnosis
Diagnosis of ethylmalonic encephalopathy is based on clinical evaluation, laboratory tests, and genetic testing. Key diagnostic indicators include:
- Biochemical testing: Elevated levels of ethylmalonic acid in the urine are a significant marker.
- Genetic testing: Identification of mutations in the ETHE1 gene confirms the diagnosis.
- Imaging studies: Magnetic resonance imaging (MRI) of the brain may reveal characteristic changes associated with the disorder.
Treatment
There is currently no cure for ethylmalonic encephalopathy, and treatment is primarily supportive and symptomatic. Management strategies may include:
- Nutritional support: Addressing malnutrition and dehydration due to chronic diarrhea.
- Seizure management: Use of anticonvulsant medications to control seizures.
- Physical therapy: To improve muscle tone and coordination.
- Experimental therapies: Research is ongoing to explore potential treatments that target the underlying metabolic defect.
Prognosis
The prognosis for individuals with ethylmalonic encephalopathy varies. The condition is progressive, and the severity of symptoms can differ among affected individuals. Early diagnosis and intervention may improve quality of life and outcomes.
Related pages
