Affected infants present within a few months after birth with failure to thrive and severe folate deficiency manifested as macrocytic anemia and developmental delays.

[2][3][4] Untreated, or with inadequate treatment, there are progressive systemic and neurological signs with a spectrum of manifestations including seizures that are often intractable.

[citation needed] PCFT is located on chromosome 17q11.2 and consists of 459 amino acids, with five exons, and a MW of approximately 50kDa.

[9] The secondary structure has been established and consists of twelve transmembrane domains with the N- and C- termini directed into the cytoplasm.

Under these conditions transport of a folate molecule across the cell membrane is accompanied by a sufficient number of protons to result a positive charge and current mediated by the ternary carrier complex.

[9][19] It is the pH gradient present across the apical brush-border membrane of the proximal jejunum,[20] where PCFT is highly expressed, that drives intestinal folate absorption.

[22] As indicated above, PCFT is also expressed at the basolateral membrane of ependymal cells of the choroid plexus where it presumably plays a role in transport of folates into the CSF.

The basis for the delay in the appearance of clinical manifestations due to loss of FRα function is not clear; the normal blood folate levels may be protective, although for a limited time.

It binds tightly to, and may impede, FRα-mediated endocytosis which plays an important role in the transport of folates across the choroid plexus into the CSF (see above).

However, a number of families of Puerto Rican ancestry have been reported with a common pathogenic variant at a splice receptor site resulting in the deletion of exon 3 and the absence of transport function.

[2][5][9][32] A subsequent population-based study of newborn infants in Puerto Rico identified the presence of the same variant on the island.