Clinical and biochemical heterogeneity associated with fumarase deficiency

Area of Science:

• Biochemistry
• Genetics
• Metabolic Disorders

Background:

• Fumarase deficiency (FD) is a rare metabolic disorder caused by biallelic mutations in the Fumarase Hydratase (FH) gene, impacting the Krebs cycle.
• FD is associated with severe neurological impairment and fumaric aciduria, with fewer than 30 cases documented.
• Heterozygous FH mutations are linked to hereditary leiomyomatosis and renal cell cancer (HLRCC).

Purpose of the Study:

• To report three new patients with distinct clinical presentations of fumarase deficiency.
• To identify novel mutations in the FH gene associated with these presentations.
• To broaden the understanding of the clinical and biochemical variability in FD.

Main Methods:

• Clinical case reporting of three patients with FD.
• Genetic analysis to identify mutations in the FH gene.
• Enzyme activity assays and biochemical analysis of urinary fumarate levels.
• In silico analysis of predicted protein structural changes.

Main Results:

• Three patients exhibited diverse clinical phenotypes, ranging from severe neonatal encephalopathy to mild mental retardation.
• Novel missense mutations in the FH gene were identified in all three patients.
• Enzyme activity varied from <1% to 61%, with corresponding increases in urinary fumarate levels.
• In silico analysis suggested minor but significant structural alterations in the encoded fumarase proteins.

Conclusions:

• The clinical and biochemical spectrum of fumarase deficiency is broader than previously recognized.
• Patients with moderate increases in urinary fumarate should be evaluated for FD.
• The identified FH mutations and associated tumoral risk necessitate appropriate screening protocols for patients and relatives.