Incidental Detection of Glutamate Formiminotransferase Deficiency Through Newborn Screening in a Clinically Asymptomatic Infant: Molecular Findings and Counseling Considerations

TL;DR

A newborn was found to have a rare enzyme deficiency through routine screening, but showed no symptoms, highlighting the importance of genetic counseling.

Contribution

This case expands the known phenotypic spectrum of FTCD deficiency by demonstrating a clinically asymptomatic presentation.

Findings

The infant had elevated formiminoglutamate (FIGLU) and hydantoin-5-propionic acid, confirming FTCD deficiency.

Whole-genome sequencing identified a homozygous in-frame deletion in the FTCD gene.

The infant remained asymptomatic with normal blood counts and development.

Abstract

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.

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