PP03.1 - 3059: Mutations in ECHS1: A defect in a multifunctional enzyme causing a mitochondrial disorder

详细信息    查看全文

• 作者：P. Freisinger ; T.B. Haack ; S. Kö ; lker ; M. Schü ; lke-Gerstenfeld ; J. Mayr ; T. Klopstock ; R. Rodenburg ; R. Trollmann ; J.M. Nuoffer ; W. Sperl ; R. Taylpr ; I. Krä ; geloh-Mann ; T. Meitinger ; H. Prokisch
• 刊名：European Journal of Paediatric Neurology
• 出版年：2015
• 出版时间：May 2015
• 年：2015
• 卷：19
• 期：supp_S1
• 页码：S36
• 全文大小：90 K

文摘

ECHS1 encodes the short chain enoyl coenzyme A (CoA) hydratase an enzyme located in the inner mitochondrial Matrix, which catalyzes the second step of fatty acid oxidation and is involved in the metabolism of valine and isoleucine. Recently two siblings with mutations in ECHS1 have been described presenting a clinical picture with symmetrical basal ganglia alterations and encephalopathy suggesting a mitochondrial disease. This disorder can be diagnosed by increased excretion of S-(2-carboxypropyl) cysteine and methacrylyl-CoA and acryloyl-CoA in urine (Peters et al. Brain 2014 Nov;137:2903–8).

Method

We report 12 patients from 8 families with mutations in ECHS1 and demonstrate the large phenotypic spectrum of this defect.

Results

In all patients severe dystonia, mental retardation and deafness were the leading symptoms. In 7/12 epilepsy was described; in 4/12 there was cardiomyopathy. No other inner organs were involved. The beginning of symptoms varies from birth to 3 years of age. The oldest patient is 32 years old. 4/12 died between 4 months and 8 years of age. In 7/12 patients brain MRI revealed symmetrical changes of the basal ganglia and in 3/11 white matter disease. Elevated lactate in blood/CSF was found in 7/12 patients. Only 2/8 patients showed abnormal results in the activity of pyruvate dehydrogenase complex (PDHc) and respiratory chain complexes (RCC)in muscle.

Conclusion

a40">ECHS1-deficiency is a newly recognized metabolic disorder with a “mitochondrial” phenotype but frequently normal activity of PDHc and RCC. This combination should prompt to investigate S-(2-carboxypropyl)cysteine, methacrylyl-CoA and acryloyl-CoA for early diagnosis. This will be particularly important, if a treatment is available: a diet reduced in valine and isoleucine, the precursors of the potentially toxic metabolites might be a promising approach.