Diagnosis of HFM is confirmed by impaired absorption of an oral folate load and low cerebrospinal fluid (CSF) folate concentration (even after correction of the serum folate concentration).　SLC46A1, a gene encoding the proton-coupled folate transporter (PCFT) protein, a member of the superfamily of facilitative carriers, is associated with HFM [5-7]. We report a child who had severe neurological involvement with relative sparing of immunological system, and extensive intracranial calcifications.

A 4-year-old child, product of 3rd degree consanguineous marriage, was admitted in our hospital with suspicion of a storage disorder in view of anemia, organomegaly and a neurodegenerative course. He was born at term after an uneventful pregnancy at term with no perinatal complications. At four months of age, he was hospitalized for pneumonia and concurrent anemia. Blood transfusion was given once. He received two more blood transfusions at ages of 18 months and 3 years. He had repeated generalized tonic-clonic seizures at 7 months of age when he was put on oral phenytoin. Phenytoin was changed to sodium valproate after a diagnosis of megaloblastic anemia was made at 18 months of age. However, seizure control was poor despite two anticonvulsants: sodium valproate and levetiracetam at maximum recommended doses. He also had painful oral lesions. Developmental delay was present in all domains of development. In last few months, he became progressively less communi-cative and showed less interest in play; regression was most prominent in motor milestones and was bedridden at the time of hospitalization.

Fig. 1 Non-contrast computed tomography of head demonstrating extensive intracranial calcifications.

Hereditary folate malabsorption is an autosomal recessive disorder characterized by signs and symptoms of folate deficiency that appear within a few months after birth [7]. Infants exhibit low blood and CSF folate levels. Treatment with folate supplementation results in resolution of the signs and symptoms. The disorder is caused by impaired intestinal folate absorption and impaired transport of folate into the central nervous system [5]. Folate deficiency results primarily in megaloblastic anemia but may affect all three hematopoietic lineages resulting in pancytopenia [2]. Neurological features include developmental delay, cognitive and motor impairment, behavioral abnormalities, ataxia and other movement disorders, peripheral neuropathy, and seizures [8-10]. Diagnosis is confirmed by very low baseline serum folate concentrations (often <1.0 ng/mL; normal: 5-15 ng/mL) and little or no increase after an oral loading dose of 5-formyl-tetrahydrofolate. In　unaffected　individuals, the serum folate concentration increases to at least 100 ng/mL [3,4,8,9]. CSF folate concentrations are also low and may remain low after normalization of serum folate levels.

Our patient was diagnosed when he presented with severe neurological involvement. He had developed neurological deterioration and was bedridden for last few months, likely due to neuropathy. Our patient also had extensive intracranial calcifications. Congenital infections, neurocutaneous disorders, tumors, traumatic or ischemic insults and endocrine diseases were ruled out in our patient. Though intracranial calcifications have been reported to occur in the cortex or basal ganglia in hereditary folate malabsorption [2,3,9], such extensive calcifications are unusual.

We conclude that hereditary folate malabsorption is a treatable cause of neurological deterioration in children, and should be suspected in any child having concomitant megaloblastic anemia.

Contributors: IA, WA: diagnosed and managed the case; IA, GM: reviewed literature; JI: Prepared the manuscript. All authors approved the final version of manuscript.

Funding: None; Competing interests: None stated.

1. Luhby AL, Cooperman JM, Pesci-Bourel A.　A new inborn error of metabolism: Folic acid responsive megaloblastic anemia, ataxia, mental retardation, and convulsions. 　J Pediatr. 1965;67:1052.

2. Jebnoun S, Kacem S, Mokrani C, Chabchoub A, Khrouf N, Zittoun J.　A family study of congenital malabsorption of folate.　J Inherit Metab Dis. 2001;24:749-50.　

3. Lanzkowsky P, Erlandson ME, Bezan AI.　Isolated defect of folic acid absorption associated with mental retardation and cerebral calcification.　Blood. 1969;34:452-65.

4. Lanzkowsky P.　Congenital malabsorption of folate.　Am J Med. 1970;48:580-3.

5. Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E, et al.　 Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption.　Cell. 2006;127:917-28.　

6. Zhao R, Min SH, Qiu A, Sakaris A, Goldberg GL, Sandoval C, et al.　The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption.　Blood. 2007; 110:1147-52.　

7. Shin DS, Mahadeo K, Min SH, Diop-Bove N, Clayton P, Zhao R, et al.　 Identification of novel mutations in the proton-coupled folate transporter (PCFT-SLC46A1) associated with hereditary folate malabsorption. Molec Genet Metab. 2011;103:33-7.　

8. Geller J, Kronn D, Jayabose S, Sandoval C.　Hereditary folate malabsorption: Family report and review of the literature.　Medicine. 2002;81:51-68.

9. Corbeel L, Van den Berghe G, Jaeken J, Van Tornout J, Eeckels R. Congenital folate malabsorption.　Eur J Pediatr. 1985;143:284-90.