Molecular and biochemical investigations in fumarase deficiency

Molecular Genetics and Metabolism
M DeschauerF N Gellerich

Abstract

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...Continue Reading

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Citations

Jan 11, 2014·Journal of Inherited Metabolic Disease·Betty Su, Robert O Ryan
Jun 16, 2010·Journal of Inherited Metabolic Disease·Gabriella AllegriMaria L Costa de Oliveira
Mar 30, 2011·Journal of Inherited Metabolic Disease·Sarah PicaudUdo Oppermann
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Oct 27, 2018·Frontiers in Molecular Neuroscience·Tina HarmuthJeannette Hübener-Schmid
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Oct 15, 2020·Journal of Child Neurology·Marieke PeetsoldCacha Peeters
Aug 24, 2021·Gastroenterology·Valerio AzzimatoMyriam Aouadi

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