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Cells lacking energy

A gene defect triggers severe brain disease in children

Munich, 06/22/2009

A particularly severe form of infantile leukoencephalopathy is caused by a genetic defect in the mitochondria. This was revealed by a research group working with Professor Massimo Zeviani of the Istituto Nazionale Neurologico in Milan, which also included doctors and scientists from LMU Munich and Helmholtz Zentrum München. As reported in the June issue of “Nature Genetics”, this variant of mitochondrial leukoencephalopathy is triggered by a defect in a gene containing the blueprint for a newly discovered protein. This protein is responsible for the assembly and function of the various subunits of the enzyme succinate dehydrogenase, or SDH for short. SDH itself is instrumental in the generation of energy inside the cells of higher organisms. (Nature Genetics, June issue)

Mitochondria are components inside the cells of higher organisms. They convert energy from food into the molecule ATP, the most important energy carrier in the body. Disruption of this essential function can result in diseases with severe symptoms. An Italian-German research group cooperating with medical practitioners and scientists from the Friedrich Baur Institute at the Neurological Clinic of LMU Munich and from the Institute of Human Genetics at Helmholtz Zentrum München has shown that a severe form of infantile leukoencephalopathy is one of these diseases. Infants afflicted with this rare disease typically suffer from severe physical and mental impairment in the first years of their life. Most never learn to walk and talk.

Medical diagnostic imaging techniques reveal significant changes within the white matter of the patients’ brains. “It has been known for some years that succinate accumulates abnormally in the brains of these patients,” reports Professor Thomas Klopstock, one of the LMU scientists involved. “This is caused by reduced activity of the enzyme succinate dehydrogenase – SDH for short – which can be observed in various tissues of the patients.”

Yet, searches for genetic defects in the four subunits of SDH have so far been futile, and there were no other genes known that could potentially cause an SDH defect. A breakthrough was achieved, however, when a linkage analysis was made of a German family of Turkish origin and an Italian family, many members of which are affected. “The gene locus was identified first, and then the actual gene responsible for the disease,” says Klopstock. “This hitherto unknown gene encodes an SDH assembly factor, which means it mediates the correct assembly of the SDH subunits and the enzyme’s function.”

It had long been suspected that such an assembly factor exists. Yet, it had never been detected in any organism until now. “This result also demonstrates how molecular analysis of rare diseases can help get to the bottom of fundamental biological problems,” Klopstock continues. “Our results will not directly affect patients at the time being, since a gene defect cannot be corrected just like that. But deciphering the cause of a disease is always the first step towards a potential therapy.”

Professor Thomas Klopstock of the Friedrich Baur Institute at the Neurological Clinic of LMU Munich and Dr. Holger Prokisch of the Institute of Human Genetics at Helmholtz Zentrum München, two of the German scientists involved in the study, emphasize that this work is also a result of the national and international cooperation that has become so strong in the field of mitochondrial diseases in recent years. In particular, the German Federal Ministry for Education and Research (BMBF) has been sponsoring the German network for mitochondrial diseases mitoNET since the beginning of 2009, which aims at improving research and therapy in this field (www.mitoNET.org). (suwe)

 

Publication:
“SDHAF1, encoding a LYR complex-II specific assembly factor, is mutated in SDH-defective infantile leukoencephalopathy”,
Daniele Ghezzi, Paola Goffrini, Graziell Uziel, Rita Horvath, Thomas Klopstock, Hanns Lochmüller, Pio D’Adamo, Paolo Gasparini, Tim M. Strom, Holger Prokisch, Federica Invernizzi, Ileana Ferrero & Massimo Zeviani,
Nature Genetics, June 2009

Contact:
Professor Dr. med. Thomas Klopstock
Friedrich Baur Institute, Department of Neurology, Ludwig-Maximilians-Universität (LMU) München
Phone: +49 (0) 89 / 5160-7474
E-Mail: thomas.klopstock@med.uni-muenchen.de
Web: www.baur-institut.de

 

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