MUTATION OF THE FUMARASE GENE IN 2 SIBLINGS WITH PROGRESSIVE ENCEPHALOPATHY AND FUMARASE DEFICIENCY

We report an inborn error of the tricarboxylic acid cycle, fumarase de ficiency, in two siblings born to first cousin parents. They presented with progressive encephalopathy, dystonia, leucopenia, and neutropeni a. Elevation of lactate in the cerebrospinal fluid and high fumarate e xcretion in the urine led us to investigate the activities of the resp iratory chain and of the Krebs cycle, and to finally identify fumarase deficiency in these two children. The deficiency was profound and pre sent in all tissues investigated, affecting the cytosolic and the mito chondrial fumarase isoenzymes to the same degree. Analysis of fumarase cDNA demonstrated that both patients were homozygous for a missense m utation, a G-955 --> C transversion, predicting a Glu-319 --> Gln subs titution. This substitution occurred in a highly conserved region of t he fumarase cDNA. Both parents exhibited half the expected fumarase ac tivity in their lymphocytes and were found to be heterozygous for this substitution. The present study is to our knowledge the first molecul ar characterization of tricarboxylic acid deficiency, a rare inherited inborn error of metabolism in childhood.