Multiple sources of metabolic disturbance in ETHE1-related ethylmalonic encephalopathy.
Ethylmalonic encephalopathy (EE) is a rare metabolic disorder caused by dysfunction of ETHE1, a mitochondrial dioxygenase involved in hydrogen sulfide (H2S) detoxification. Patients present in infancy with psychomotor retardation, chronic diarrhea, orthostatic acrocyanosis and relapsing petechiae. High levels of lactic acid, ethymalonic acid (EMA) and methylsuccinic acid (MSA) are detected in body fluids. Several pathways may contribute to the pathophysiology, including isoleucine, methionine and fatty acid metabolism. We report on a 15-month-old male presenting with typical EE associated with a homozygous ETHE1 mutation. We investigated oral isoleucine (150 mg/kg), methionine (100 mg/kg), fatty acid loading tests and isoleucine-restricted diet (200 mg/day) for any effects on several metabolic parameters. Before loading tests or specific dietary interventions, EMA, C4-C5 acylcarnitines and most acylglycines were elevated, indicating functional deficiency of short chain acyl-CoA (SCAD) as well as all branched acyl-CoA dehydrogenases. Excretion of EMA and n-butyrylglycine increased following each of the loads, and isoleucine led to increased levels of derivative metabolites. An isoleucine-restricted diet for 8 days corrected some of the abnormalities but led to no obvious clinical improvement and only partial effects on EMA. A principal component analysis supports the inference that these dietary conditions have consistent effects on the global metabolic profile. Our results suggest that multiple pathways modulate EMA levels in EE. They might all interact with H2S toxicity. Prolonged dietary interventions involving the restriction for branched aminoacids, fatty acids and methionine could be discussed as auxiliary therapeutical strategies in EE.
Barth
Magalie
M
Centre de Référence des Maladies Métaboliques, Hôpital Necker - Enfants Malades, Paris, France.
Ottolenghi
Chris
C
Hubert
Laurence
L
Chrétien
Dominique
D
Serre
Valérie
V
Gobin
Stéphanie
S
Romano
Stéphane
S
Vassault
Anne
A
Sefiani
Aziz
A
Ricquier
Daniel
D
Boddaert
Nathalie
N
Brivet
Michèle
M
de Keyzer
Yves
Y
Munnich
Arnold
A
Duran
Marinus
M
Rabier
Daniel
D
Valayannopoulos
Vassili
V
de Lonlay
Pascale
P
D000596:Amino Acids / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood / Q000652:urine; D020739:Brain Diseases, Metabolic, Inborn / Q000175:diagnosis / Q000178:diet therapy / Q000201:enzymology* / Q000235:genetics; D018753:Diet, Protein-Restricted; D019587:Dietary Supplements; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D008314:Malonates / Q000097:blood / Q000652:urine; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D025341:Principal Component Analysis; D011693:Purpura / Q000175:diagnosis / Q000178:diet therapy / Q000201:enzymology* / Q000235:genetics; D016896:Treatment Outcome
D000596:Amino Acids; D015415:Biomarkers; C483228:ETHE1 protein, human; D008314:Malonates; D024101:Mitochondrial Proteins; D029543:Nucleocytoplasmic Transport Proteins; C038080:ethylmalonic acid