Fumaric aciduria: Clinical and imaging features

Abstract

Fumaric aciduria (fumaric acidemia, fumarase deficiency) is a rare inborn error of metabolism caused by deficient activity of fumarate hydratase, one of the constituent enzymes of the Krebs tricarboxylic acid cycle. We describe the clinical and imaging features of this disease arising from a consanguineous pedigree in 8 patients in the southwestern United States. Thirteen patients have been previously described in the medical literature. Our patients presented with an early infantile encephalopathy with profound developmental retardation and hypotonia, and most experienced seizures. Previously unreported characteristics described here include structural brain malformations, dysmorphic facial features, and neonatal polycythemia. Magnetic resonance imaging showed multiple abnormalities, including diffuse polymicrogyria, decreased cerebral white matter, large ventricles, and open opercula. Fumaric aciduria should be included in the differential diagnosis of inborn errors of metabolism that cause cerebral malformations and dysmorphic features. The possibility that inborn errors of energy metabolism may cause structural malformations deserves increased recognition. Ann Neurol 2000;47:583–588

Fumaric aciduria: an overview and the first Brazilian case report

“…It must be observed that in disorders with abnormalities in cell energy production, dysmorphic features may occur. However, the underlying mechanism in fumaric aciduria is unknown (Kerrigan et al 2000;Peters and Kahler 2003).…”

“…In general, the main fetal anomalies associated with polyhydramnios are a consequence of disorders that affect gastrointestinal, musculoskeletal and the central nervous system (CNS) (Kyle et al 1997). Angulation of the frontal horns and optic nerve hypoplasia/pallor were described in a consanguineous family that had eight affected members; these features are unique in study group (Kerrigan et al 2000). By the time of their respective reports, ten patients had died early (28%), seven of them being younger than 1 year, such as the case here reported.…”

“…However, a higher frequency can be observed at the border of northern Arizona and southern Utah, USA. This is probably due to a founder effect in closed, religious polygamist communities living in these regions, among which marriage between relatives seems to be frequent (Kerrigan et al 2000, Szep 2007). Fumaric aciduria is classified into the group of disorders that involve metabolic energy.…”

Cloning, expression, purification, crystallization and preliminary X-ray diffraction analysis of recombinant human fumarase

“…Mutations in fumarase have been implicated in a variety of human diseases, including progressive encephalopathy, fumaric aciduria, hereditary leiomyomatosis and renal cell cancer (Kerrigan et al, 2000;Yang et al, 2013;Whelan et al, 1983). Despite its remarkable importance, the only structural study presently available regarding the clinical relevance of human fumarase (HsFH) was performed on the Escherichia coli FumC homologue, which shares 60% identity with the human enzyme (Esté vez et al, 2002).…”

Fumaric aciduria: Mild phenotype in a 8‐year‐old girl with novel mutations

“…We report a patient with mild phenotype and two novel mutations, at least one being related to familial tumors. (Kerrigan JF et al 2000). Twelve autosomal recessive mutations in the FH gene associated with FH deficiency have been reported so far.…”