RESUMO
BACKGROUND: Glutamate formiminotransferase deficiency (FTCD deficiency) or formiminoglutamic aciduria is the second most common of the known inherited disorders of folate metabolism. Initial case reports suggested that patients may have severe intellectual disability and megaloblastic anemia. However, these cases were obtained from screening cohorts of patients with developmental delay. Subsequently, patients with milder clinical phenotypes have been reported. The full phenotypic spectrum of this disorder remains unknown. METHODS: In many states, FTCD deficiency can be incidentally detected on tandem mass spectrometry-based newborn screening of dried blood spots. In this work, we report the outcomes of infants identified to have FTCD deficiency through newborn screening. RESULTS: During the study period, 18 patients were identified to have FTCD deficiency and were referred and evaluated at one of the two participating metabolic centers. The overall rate of FTCD deficiency detected through the New Jersey screening program over the study time period was 1:58,982. At a mean age of 56 months at last follow-up: 3/18 (16%) had developmental delays requiring individualized education plans, no patients had profound intellectual disability; 4/16 (25%) had mild self-limited anemia, no patients had profound anemia. CONCLUSIONS: These data suggest that the majority of individuals with FTCD deficiency detected by newborn screening are asymptomatic.
RESUMO
BACKGROUND: Elevated plasma and urine formiminoglutamic acid (FIGLU) levels are commonly indicative of formiminoglutamic aciduria (OMIM #229100), a poorly understood autosomal recessive disorder of histidine and folate metabolism, resulting from formiminotransferase-cyclodeaminase (FTCD) deficiency, a bifunctional enzyme encoded by FTCD. METHODS: In order to further understanding about the molecular alterations that contribute to FIGLU-uria, we sequenced FTCD in 20 individuals with putative FTCD deficiency and varying laboratory findings, including increased FIGLU excretion. RESULTS: Individuals tested had biallelic loss-of-function variants in protein-coding regions of FTCD. The FTCD allelic spectrum comprised of 12 distinct variants including 5 missense alterations that replace conserved amino acid residues (c.223A>C, c.266A>G, c.319T>C, c.430G>A, c.514G>T), an in-frame deletion (c.1373_1375delTGG), with the remaining alterations predicted to affect mRNA processing/stability. These included two frameshift variants (c.990dup, c.1366dup) and four nonsense variants (c.337C>T, c.451A>T, c.763C>T, c.1607T>A). CONCLUSION: We observed additional FTCD alleles leading to urinary FIGLU elevations, and thus, providing molecular evidence of FTCD deficiency in cases identified by newborn screening or clinical biochemical genetic laboratory testing.
