FH – Fumaric Aciduria

Fumaric aciduria (fumarase deficiency) is a rare autosomal recessive metabolic encephalopathy caused by biallelic pathogenic variants in the FH gene. Affected infants present with early-onset seizures, profound psychomotor deterioration, hypotonia, and lactic acidosis, often leading to death in infancy. Biochemically, patients exhibit marked deficiency of both mitochondrial and cytosolic fumarase activities in multiple tissues, with parents showing ~30–50% residual activity in fibroblasts (PMID:2314594).

Genetic evidence supports a definitive gene–disease relationship. More than 30 unrelated probands from over 10 consanguineous and non-consanguineous families harbor biallelic FH variants, including missense, frameshift, splice, and whole-gene deletions, with segregation of homozygous or compound heterozygous changes in affected sibships (PMID:8200987). The recurrent variant c.955G>C (p.Asp319His) exemplifies a highly conserved active-site residue whose alteration abolishes enzyme function.

Phenotypic spectrum extends beyond the central nervous system to include microcephaly, ventriculomegaly, agenesis of the corpus callosum, cardiomyopathy, leukopenia, neutropenia, and failure to thrive. Neuroimaging often reveals cerebral atrophy, polymicrogyria, and periventricular cysts. Survivors of infancy may demonstrate heterogeneous severity, ranging from profound global developmental delay to milder cognitive impairment.

The variant spectrum in FH is broad: missense substitutions predominate in catalytic or oligomerization domains, but loss-of-function alleles (nonsense, frameshift, splicing) and a novel whole-gene deletion have been described. No clear genotype–phenotype correlation has been established, although active-site and oligomerization-interface mutations tend to cause severe neonatal presentations.

Functional studies corroborate pathogenicity via multiple approaches. Patient tissue assays demonstrate negligible fumarase activity and antifumarase cross-reacting material in homozygotes, while carriers show half-normal activity. Recombinant expression and blue-native PAGE reveal defective tetramerization for interface mutants, and fibroblast respirometry indicates impaired TCA cycle flux, confirming loss of enzyme function.

No conflicting reports dispute FH as the causal gene for fumaric aciduria. The accumulated genetic and biochemical data meet ClinGen criteria for a definitive clinical validity classification.

Key take-home: FH testing is essential in infants with unexplained early-onset encephalopathy, seizures, and lactic acidosis, as molecular confirmation enables accurate recurrence risk counseling and supports targeted metabolic management.

References

• Neurology • 1990 • Fumarase deficiency is an autosomal recessive encephalopathy affecting both the mitochondrial and the cytosolic enzymes. PMID:2314594
• The Journal of clinical investigation • 1994 • Mutation of the fumarase gene in two siblings with progressive encephalopathy and fumarase deficiency. PMID:8200987

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