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Ethylmalonic encephalopathy(EE)

MedGen UID:
355966
Concept ID:
C1865349
Disease or Syndrome
Synonyms: EE; Encephalopathy, petechiae, and ethylmalonic aciduria; EPEMA syndrome; Syndrome of encephalopathy, petechiae, and ethylmalonic aciduria
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: HPO
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
SNOMED CT: Ethylmalonic encephalopathy (811000124106)
 
Gene (location): ETHE1 (19q13.31)
OMIM®: 602473
Orphanet: ORPHA51188

Definition

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). [from OMIM]

Additional description

From GHR
Ethylmalonic encephalopathy is an inherited disorder that affects several body systems, particularly the nervous system. Neurologic signs and symptoms include progressively delayed development, weak muscle tone (hypotonia), seizures, and abnormal movements. The body's network of blood vessels (the vascular system) 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.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.  http://ghr.nlm.nih.gov/condition/ethylmalonic-encephalopathy

Clinical features

Petechiae
MedGen UID:
10680
Concept ID:
C0031256
Disease or Syndrome
A group of small reddish or purplish spots in skin or mucous membrane as a result of localized hemorrhage.
Abnormality of the retinal vasculature
MedGen UID:
870311
Concept ID:
C4024753
Anatomical Abnormality
An arterial or venous retinal vascular anomaly.
Abnormality of the retinal vasculature
MedGen UID:
870311
Concept ID:
C4024753
Anatomical Abnormality
An arterial or venous retinal vascular anomaly.
Petechiae
MedGen UID:
10680
Concept ID:
C0031256
Disease or Syndrome
A group of small reddish or purplish spots in skin or mucous membrane as a result of localized hemorrhage.
Ethylmalonic aciduria
MedGen UID:
355967
Concept ID:
C1865353
Finding
An increased concentration of ethylmalonic acid in the urine.
Failure to thrive
MedGen UID:
115900
Concept ID:
C0231246
Finding
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Sign or Symptom
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Seizure Disorders
MedGen UID:
4506
Concept ID:
C0014544
Disease or Syndrome
Epilepsy is a brain disorder that causes people to have recurring seizures. The seizures happen when clusters of nerve cells, or neurons, in the brain send out the wrong signals. People may have strange sensations and emotions or behave strangely. They may have violent muscle spasms or lose consciousness. Epilepsy has many possible causes, including illness, brain injury, and abnormal brain development. In many cases, the cause is unknown. Doctors use brain scans and other tests to diagnose epilepsy. It is important to start treatment right away. There is no cure for epilepsy, but medicines can control seizures for most people. When medicines are not working well, surgery or implanted devices such as vagus nerve stimulators may help. Special diets can help some children with epilepsy. NIH: National Institute of Neurological Disorders and Stroke.
Extrapyramidal disease
MedGen UID:
41927
Concept ID:
C0015371
Disease or Syndrome
A neurological condition related to lesions of the basal ganglia leading to typical abnormalities including akinesia (inability to initiate changes in activity and perform volitional movements rapidly and easily), muscular rigidity (continuous contraction of muscles with constant resistance to passive movement), chorea (widespread arrhythmic movements of a forcible, rapid, jerky, and restless nature), athetosis (inability to sustain the muscles of the fingers, toes, or other group of muscles in a fixed position), and akathisia (inability to remain motionless).
Intellectual functioning disability
MedGen UID:
7544
Concept ID:
C0025362
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
Unspecified encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Developmental regression
MedGen UID:
373115
Concept ID:
C1836550
Finding
Loss of developmental skills, as manifested by loss of developmental milestones.
Focal T2 hyperintense basal ganglia lesion
MedGen UID:
400746
Concept ID:
C1865351
Finding
A lighter than expected T2 signal on magnetic resonance imaging (MRI) of the basal ganglia. This term refers to a localized hyperintensity affecting a particular region of the basal ganglia.
Chronic diarrhea
MedGen UID:
96036
Concept ID:
C0401151
Finding
The presence of chronic diarrhea, which is usually taken to mean diarrhea that has persisted for over 4 weeks.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A diminution of the skeletal muscle tone marked by a diminished resistance to passive stretching.
Decreased activity of cytochrome C oxidase in muscle tissue
MedGen UID:
867360
Concept ID:
C4021724
Finding
An abnormally reduced activity of the enzyme cytochrome C oxidase in muscle tissue.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
Acidosis caused by accumulation of lactic acid more rapidly than it can be metabolized. It may occur spontaneously or in association with diseases such as DIABETES MELLITUS; LEUKEMIA; or LIVER FAILURE.
Ethylmalonic aciduria
MedGen UID:
355967
Concept ID:
C1865353
Finding
An increased concentration of ethylmalonic acid in the urine.
Petechiae
MedGen UID:
10680
Concept ID:
C0031256
Disease or Syndrome
A group of small reddish or purplish spots in skin or mucous membrane as a result of localized hemorrhage.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVEthylmalonic encephalopathy
Follow this link to review classifications for Ethylmalonic encephalopathy in Orphanet.

Recent clinical studies

Etiology

Di Meo I, Lamperti C, Tiranti V
EMBO Mol Med 2015 Jul 20;7(10):1257-66. doi: 10.15252/emmm.201505040. PMID: 26194912Free PMC Article
Wajner M, Goodman SI
J Bioenerg Biomembr 2011 Feb;43(1):31-8. doi: 10.1007/s10863-011-9324-0. PMID: 21249436
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
J Med Genet 2008 Jul;45(7):473-8. doi: 10.1136/jmg.2008.058271. PMID: 18593870
McGowan KA, Nyhan WL, Barshop BA, Naviaux RK, Yu A, Haas RH, Townsend JJ
Arch Neurol 2004 Apr;61(4):570-4. doi: 10.1001/archneur.61.4.570. PMID: 15096407
Nowaczyk MJ, Lehotay DC, Platt BA, Fisher L, Tan R, Phillips H, Clarke JT
Metabolism 1998 Jul;47(7):836-9. PMID: 9667231

Diagnosis

Pavlou E, Augoustides-Savvopoulou P, Gregersen N, Haas D, Gkampeta A, Athanassiadou-Piperopoulou F
J Child Neurol 2013 May;28(5):668-71. Epub 2012 Jul 17 doi: 10.1177/0883073812449070. [Epub ahead of print] PMID: 22805253
Giordano C, Viscomi C, Orlandi M, Papoff P, Spalice A, Burlina A, Di Meo I, Tiranti V, Leuzzi V, d'Amati G, Zeviani M
J Inherit Metab Dis 2012 May;35(3):451-8. Epub 2011 Oct 22 doi: 10.1007/s10545-011-9408-3. [Epub ahead of print] PMID: 22020834
Drousiotou A, DiMeo I, Mineri R, Georgiou T, Stylianidou G, Tiranti V
Clin Genet 2011 Apr;79(4):385-90. doi: 10.1111/j.1399-0004.2010.01457.x. PMID: 20528888
Barth M, Ottolenghi C, Hubert L, Chrétien D, Serre V, Gobin S, Romano S, Vassault A, Sefiani A, Ricquier D, Boddaert N, Brivet M, de Keyzer Y, Munnich A, Duran M, Rabier D, Valayannopoulos V, de Lonlay P
J Inherit Metab Dis 2010 Dec;33 Suppl 3:S443-53. Epub 2010 Oct 27 doi: 10.1007/s10545-010-9227-y. [Epub ahead of print] PMID: 20978941
Pigeon N, Campeau PM, Cyr D, Lemieux B, Clarke JT
J Child Neurol 2009 Aug;24(8):991-6. Epub 2009 Mar 16 doi: 10.1177/0883073808331359. [Epub ahead of print] PMID: 19289697

Therapy

Tiranti V, Zeviani M
Cold Spring Harb Perspect Biol 2013 Jan 1;5(1):a011437. doi: 10.1101/cshperspect.a011437. PMID: 23284046Free PMC Article
Di Meo I, Auricchio A, Lamperti C, Burlina A, Viscomi C, Zeviani M
EMBO Mol Med 2012 Sep;4(9):1008-14. Epub 2012 Aug 20 doi: 10.1002/emmm.201201433. [Epub ahead of print] PMID: 22903887Free PMC Article
Barth M, Ottolenghi C, Hubert L, Chrétien D, Serre V, Gobin S, Romano S, Vassault A, Sefiani A, Ricquier D, Boddaert N, Brivet M, de Keyzer Y, Munnich A, Duran M, Rabier D, Valayannopoulos V, de Lonlay P
J Inherit Metab Dis 2010 Dec;33 Suppl 3:S443-53. Epub 2010 Oct 27 doi: 10.1007/s10545-010-9227-y. [Epub ahead of print] PMID: 20978941
Viscomi C, Burlina AB, Dweikat I, Savoiardo M, Lamperti C, Hildebrandt T, Tiranti V, Zeviani M
Nat Med 2010 Aug;16(8):869-71. Epub 2010 Jul 25 doi: 10.1038/nm.2188. [Epub ahead of print] PMID: 20657580
Yoon HR, Hahn SH, Ahn YM, Jang SH, Shin YJ, Lee EH, Ryu KH, Eun BL, Rinaldo P, Yamaguchi S
J Inherit Metab Dis 2001 Dec;24(8):870-3. PMID: 11916321

Prognosis

Pavlou E, Augoustides-Savvopoulou P, Gregersen N, Haas D, Gkampeta A, Athanassiadou-Piperopoulou F
J Child Neurol 2013 May;28(5):668-71. Epub 2012 Jul 17 doi: 10.1177/0883073812449070. [Epub ahead of print] PMID: 22805253
Dweikat I, Naser E, Damsah N, Libdeh BA, Bakri I
Metab Brain Dis 2012 Dec;27(4):613-6. Epub 2012 May 15 doi: 10.1007/s11011-012-9313-y. [Epub ahead of print] PMID: 22584649
Pigeon N, Campeau PM, Cyr D, Lemieux B, Clarke JT
J Child Neurol 2009 Aug;24(8):991-6. Epub 2009 Mar 16 doi: 10.1177/0883073808331359. [Epub ahead of print] PMID: 19289697
Zafeiriou DI, Augoustides-Savvopoulou P, Haas D, Smet J, Triantafyllou P, Vargiami E, Tamiolaki M, Gombakis N, van Coster R, Sewell AC, Vianey-Saban C, Gregersen N
Neuropediatrics 2007 Apr;38(2):78-82. doi: 10.1055/s-2007-984447. PMID: 17712735
Grosso S, Mostardini R, Farnetani MA, Molinelli M, Berardi R, Dionisi-Vici C, Rizzo C, Morgese G, Balestri P
J Neurol 2002 Oct;249(10):1446-50. doi: 10.1007/s00415-002-0880-4. PMID: 12382164

Clinical prediction guides

Pettinati I, Brem J, McDonough MA, Schofield CJ
Hum Mol Genet 2015 May 1;24(9):2458-69. Epub 2015 Jan 16 doi: 10.1093/hmg/ddv007. [Epub ahead of print] PMID: 25596185Free PMC Article
Palmfeldt J, Vang S, Stenbroen V, Pavlou E, Baycheva M, Buchal G, Monavari AA, Augoustides-Savvopoulou P, Mandel H, Gregersen N
J Proteome Res 2011 May 6;10(5):2389-96. Epub 2011 Mar 28 doi: 10.1021/pr101218d. [Epub ahead of print] PMID: 21410200
Zafeiriou DI, Augoustides-Savvopoulou P, Haas D, Smet J, Triantafyllou P, Vargiami E, Tamiolaki M, Gombakis N, van Coster R, Sewell AC, Vianey-Saban C, Gregersen N
Neuropediatrics 2007 Apr;38(2):78-82. doi: 10.1055/s-2007-984447. PMID: 17712735
Grosso S, Mostardini R, Farnetani MA, Molinelli M, Berardi R, Dionisi-Vici C, Rizzo C, Morgese G, Balestri P
J Neurol 2002 Oct;249(10):1446-50. doi: 10.1007/s00415-002-0880-4. PMID: 12382164
Yoon HR, Hahn SH, Ahn YM, Jang SH, Shin YJ, Lee EH, Ryu KH, Eun BL, Rinaldo P, Yamaguchi S
J Inherit Metab Dis 2001 Dec;24(8):870-3. PMID: 11916321

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