Extensive clinical studies established that HFM is due to (i) impaired intestinal absorption of folates and (ii) impaired transport of folates across the blood-choroid plexus-cerebrospinal fluid (CSF) barrier. Hence, patients with HFM have very low or undetectable folate blood levels. When a modest dose of a folate is given by mouth, there is impaired intestinal folate absorption without other signs of<unk> . Molecular pathogenesis The molecular basis for HFM was established in 2006 with the identification of the proton-coupled folate transporter (PCFT) as the mechanism of intestinal absorption of folates and the detection of loss-of-function mutations in this transporter in subjects with a clinical diagnosis of HFM. Hence, beyond the characteristic clinical features, genotyping is now available to establish the diagnosis of HFM. PCFT PCFT is located on chromosome 17q11.2 and consists of 459 amino acids, with five exons, and a MW of approximately 50kDa. The secondary structure has been established and consists of twelve transmembrane domains with the N- and C- termini directed into the cytoplasm. The properties of this transporter and its physiological and pharmacological roles were recently reviewed. Elements of PCFT regulation have been described and include the minimal promoter, Vitamin D and NRF1 response elements. PCFT operates most efficiently when there is a strong transmembrane pH gradient. 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. It is the pH gradient present across the apical brush-border membrane of the proximal jejunum, where PCFT is highly expressed, that drives intestinal folate absorption. PCFT is expressed to a lesser extent elsewhere in the small and large intestine along with the canalicular membrane of the hepatic sinusoid and in the apical brush-border membrane of the proximal tubule of the kidney. However, its function at these latter sites is unclear. 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.
Hereditary folate malabsorption
Cerebral folate deficiency
Folate deficiency
Iron metabolism disorder
Iron deficiency
Zinc deficiency
Vitamin E deficiency
Familial isolated vitamin E deficiency