A Diagnostic Conundrum in Fumarase Deficiency: Expanding the Clinical and Genetic Spectrum in a Cohort of Pediatric and Adult Patients

Fumarase deficiency (FMRD) is a rare autosomal recessive disorder caused by fumarate hydratase (FH) deficiency, with variable presentation from severe early-onset encephalopathy to mild cognitive impairment. Heterozygous carriers of some variants are predisposed to hereditary leiomyomatosis and renal cell carcinoma (HLRCC). We retrospectively reviewed clinical, biochemical, and molecular data from patients with confirmed or suspected FMRD across three metabolic centers in Northern England. Ten patients (seven females, three males) from seven families were identified, with a median diagnostic age of 5 years (range: 1 day-16 years). All had developmental delay and learning difficulties of varying severity. Elevated urinary fumarate was found in 7/10 patients but was inconsistent on repeat analysis. Five patients had neutropenia, and four had abnormal neuroimaging findings. Biallelic FH variants were identified in nine patients, comprising five variants: four missense and one in-frame duplication. The c. 410C>T variant accounted for 44% of mutant alleles, and three patients were homozygous for c. 1431₁433dupAAA p. (Lys477dup). Renal lesions were detected in two heterozygous fathers. Elevated urinary fumarate was not a consistent feature in some patients. The c. 1431₁433dupAAA variant was identified in the homozygous state in patients with mild intellectual disability and features overlapping with FMRD. Our findings suggest that all variants identified in FMRD patients require independent clinical evaluation for HLRCC association.