FTCD – Formiminoglutamic Aciduria

Formiminoglutamic aciduria is an autosomal recessive disorder caused by loss of function in the bifunctional enzyme glutamate formiminotransferase-cyclodeaminase encoded by FTCD. Affected individuals present with elevated urinary formiminoglutamate (FIGLU) levels and variable clinical features ranging from severe megaloblastic anemia and intellectual disability to mild developmental delay without hematological abnormalities ([PMID:12815595]).

Initial molecular studies in three patients (two siblings and one unrelated individual) identified compound heterozygous missense variants and a frameshift allele in FTCD: c.403C>T (p.Arg135Cys) in two sibs and a hemizygous c.1033insG with deletion of the second allele ([PMID:12815595]). Subsequent screening of 20 individuals revealed 12 additional FTCD variants, including 5 missense substitutions, 4 nonsense changes, 2 frameshift insertions/deletions, and 1 in-frame deletion, all in biallelic configuration ([PMID:29178637]).

The allelic spectrum comprises missense variants affecting conserved residues (e.g., p.Arg135Cys, p.Gly172Trp), predicted loss-of-function alleles (nonsense and frameshift), and an in-frame deletion (p.Val458del). These diverse variant classes underline the importance of comprehensive sequencing of FTCD in suspected cases. Carrier frequency and population prevalence remain to be determined.

Segregation data include one additional affected relative (the sib pair) with concordant genotype–phenotype correlation. No conflicting evidence has been reported, and all identified variants co-segregate with FIGLU-uria in families.

Functional assays using porcine FTCD mutants expressed in Escherichia coli demonstrated that p.Arg135Cys and p.Arg299Pro reduce formiminotransferase activity to 61% and 57% of wild-type, respectively, confirming a loss-of-function mechanism ([PMID:12815595]). Rescue experiments or animal models have not yet been reported.

Collectively, these data support a Strong clinical validity classification for FTCD in formiminoglutamic aciduria, with both robust genetic evidence from 23 probands and concordant enzymatic studies. Key Take-home: Biallelic FTCD variants causing partial or complete loss of enzyme activity underlie formiminoglutamic aciduria, informing molecular diagnosis and genetic counseling.

References

• Human Mutation • 2003 • The molecular basis of glutamate formiminotransferase deficiency. PMID:12815595
• Molecular Genetics & Genomic Medicine • 2017 • Allelic spectrum of formiminotransferase-cyclodeaminase gene variants in individuals with formiminoglutamic aciduria. PMID:29178637

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