Hereditary folate malabsorption - Family report and review of the literature

Rare disorders such as hereditary folate malabsorption (HFM) provide insights as to how human physiology reacts to a particular deficiency in its purest form, in this case, folate deficiency. The particular defect in central nervous system transport evident in HFM provides us with a clinical model of the human brain deprived of folate during childhood at which time growth and development are critical for adequate neurologic outcome. The clinical syndrome of HFM, as described, highlights the gastrointestinal, hematologic, immunologic, and neurologic clinical consequences of folate deficiency present from the newborn period onward. From children with HFM we have also learned that folate is not absorbed through the gastrointestinal tract into the blood stream passively, that peripheral neuropathy and intracranial calcifications can result from isolated folate deficiency, and that folate deficiency can lead to a clinically significant immunodeficiency. The diagnosis of HFM rests on demonstrating impaired transport of folate across the gastrointestinal tract and across the blood brain barrier in the proper clinical setting. Metabolic profiling (plasma amino acid analysis) may be helpful in detecting folate deficiency, and in following response to treatment. Understanding the molecular basis underlying folate deficiency and, particularly, HFM, is critical for improving diagnostic and treatment modalities for patients with suspected HFM. Evolution has provided for multiple uptake mechanisms to transport folate into cells and across barrier systems. These different systems may predominate at different sites of the human body, and perhaps at the same site of the body at different stages of development and age. Recent research, largely derived from oncology laboratories interested in the transport, uptake, and mutations of folate and folate analog transporters, has provided us with an abundant amount of knowledge in this regard. The discovery of the reduced folate carrier may indeed lead to the final resolution of the genetic defects underlying HFM, and such tests are being pursued to test this hypothesis. Critical to treating individuals with HFM successfully is early diagnosis and maintenance of adequate CSF folate concentrations. Normal neurologic outcome is possible in cases of HFM by treating aggressively with folate replacement therapy via frequent intramuscular injections of folinic acid. Moreover, oral folinic acid can also be used in some patients effectively, assuring that timely and appropriate developmental milestones occur.