We report a seven-week-old male infant, born to consanguineous (double cousin) parents, incidentally through routine newborn screening, following an abnormal acylcarnitine profile caused by elevated formiminoglutamate (FIGLU), with subsequent biochemical confirmation of glutamate formiminotransferase cyclodeaminase (FTCD) deficiency. The infant was born at 37 weeks' gestation via spontaneous vaginal delivery, was vigorous at birth, and required no resuscitation. He remained clinically asymptomatic at the time of metabolic and genetic evaluation. Plasma acylcarnitine analysis demonstrated elevated formiminoglutamate (FIGLU) at a mass-to-charge ratio (m/z) of 287. Urine organic acid analysis revealed increased hydantoin-5-propionic acid, consistent with FTCD deficiency. Whole-genome sequencing identified a homozygous in-frame deletion in the FTCD gene, c.754_756del (p.Glu252del), inherited from both parents. This variant affects a conserved region of the bifunctional FTCD enzyme, which plays a critical role in histidine degradation and folate-dependent one-carbon metabolism. FTCD deficiency is an autosomal recessive disorder historically associated with megaloblastic anemia and mild neurodevelopmental delay. However, data from newborn screening programs increasingly demonstrate a spectrum of presentations, including individuals with isolated biochemical abnormalities and normal growth and neurodevelopment. In this case, the infant exhibited no clinical evidence of anemia, neurologic impairment, or failure to thrive. Complete blood count, folate, and vitamin B12 levels were within normal limits. Family history was notable for anemia of unknown etiology in a maternal aunt and grandmother, and breast cancer in a paternal aunt. This was the first child of the couple, with no prior affected siblings. This case reinforces that FTCD deficiency, while biochemically detectable, often follows a benign clinical course when identified presymptomatically. It highlights the expanding phenotypic spectrum of FTCD deficiency and underscores the importance of thoughtful biochemical follow-up, genotype-phenotype correlation, and tailored genetic counseling in the era of expanded newborn screening.

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. 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. 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. These data suggest that the majority of individuals with FTCD deficiency detected by newborn screening are asymptomatic.

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. 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. 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). 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.