Molecular and biochemical investigations in fumarase deficiency.

Fumarase (FH) deficiency is a rare autosomal recessive disease of the Krebs cycle causing severe neurological impairment in early childhood, characterized by encephalopathy with seizures and muscular hypotonia. Only a handful of patients with various recessive mutations in the FH gene have been described so far. Interestingly, autosomal dominant mutations in the same gene are associated with hereditary leiomyomatosis and renal cell cancer (HLRCC). We investigated a boy with developmental and growth delay, microcephaly, and muscular hypotonia recognized at the age of 3 months. No leiomyomatosis or renal cancer is known in the parents. Investigation of the patient's urine revealed massive fumarate excretion. FH activity was severely reduced in muscle and fibroblasts. Respirometric investigation of fibroblasts showed only modest changes indicating that fumarate mediated inhibition of enzymatic pathways other than oxidative phosphorylation might be more relevant in pathophysiology of FH deficiency. Molecular analysis revealed a known 435insK mutation on the paternal allele and a novel H275L mutation due to an A to T transversion of nucleotide 824 on the maternal allele. This mutation affects the same codon as a C to T transition of nucleotide 823, resulting in a H275Y mutation that was found in two families with HLRCC.