Folate Malabsorption, Hereditary

A number sign (#) is used with this entry because hereditary folate malabsorption is caused by homozygous or compound heterozygous mutation in the SLC46A1 gene (611672) on chromosome 17q11.

Description

Hereditary folate malabsorption is an autosomal recessive disorder characterized by signs and symptoms of folate deficiency that appear within a few months after birth. Infants exhibit low blood and cerebrospinal fluid folate levels with megaloblastic anemia, diarrhea, immune deficiency, infections, and neurologic deficits. 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 (summary by Qiu et al., 2006).

Clinical Features

Luhby et al. (1965) observed affected sisters, and Lanzkowsky (1970) described a sporadic case in a 20-year-old. The patients had an isolated defect in intestinal absorption of folic acid and a defect in transport of folic acid across the blood-brain barrier. Recurrent megaloblastic anemia, mental retardation, convulsions, and movement disorder (ataxia in Luhby's cases, athetosis in Lanzkowsky's) were manifestations. Basal ganglion calcification was described in Lanzkowsky's cases. The seizures were said to be reduced by folic acid in Luhby's cases but aggravated by folic acid in Lanzkowsky's. Parenteral folic acid corrected the anemia.

Corbeel et al. (1985) reported a patient in whom oral folic acid cured the anemia, diarrhea, and susceptibility to infections, but failed to prevent convulsions and the development of mental retardation and cerebral calcifications. (Cases of dihydropteridine reductase deficiency (261630) in which treatment with folinic acid is not given also develop intracranial calcification (Woody et al., 1989).) Corbeel et al. (1985) were prompted to give methionine along with vitamin B12 and folic acid because of low plasma methionine; the convulsions were controlled.

In a male patient, Steinschneider et al. (1990) confirmed improvement in the peripheral neuropathy with intramuscular folinic acid therapy as had been reported by Su (1976).

Rosenblatt and Fenton (2001) stated that this disorder had been described in fewer than 20 patients, mostly females.

Jebnoun et al. (2001) reported a large family of 8 children (6 males and 2 females) affected by congenital folate malabsorption. The first 5 children (4 boys and 1 girl) died within the first few months of life with diarrhea, vomiting, drowsiness, pallor, and glossitis. The 3 surviving children (1 girl and 2 boys) developed the same symptoms within the first weeks of life. In the surviving girl, studied at 3 months of age, blood cell count showed severe pancytopenia with an aregenerative normocytic anemia, leukopenia, and thrombocytopenia. The peripheral blood smear revealed hypersegmented neutrophils. Bone marrow was hypercellular with an excess of megaloblastic erythroblasts. Folate deficiency was confirmed in serum, red cells, and cerebrospinal fluid (CSF). Methylfolate was undetectable. Congenital malabsorption of folate was confirmed by a folic acid loading test that showed a peak serum folate of 8 microg/liter 2 hours after oral administration of 40 microg/liter folic acid and body saturation 2 days before the test with an injection of 5 mg folinic acid. Intramuscular administration of folinic acid achieved detectable CSF folate levels in a dose-dependent manner. With intermittent folinic acid administration the child had normal growth and hematologic parameters but developed epilepsy at age 4 years and had a low IQ.

Geller et al. (2002) reported 2 Puerto Rican sibs with hereditary folate malabsorption. The female proband presented at 6.5 months of age with recurrent diarrhea, gastroesophageal reflux, frequent upper respiratory infections, bilateral pneumonia, urinary tract infection, eosinophilia, anemia, anorexia, poor weight gain, and oral ulcers. She continued to have infections and diarrhea and required blood and platelet transfusions for anemia and thrombocytopenia. Folate deficiency was diagnosed at age 8 months, and she responded well to folate therapy. Her younger sister was diagnosed with the disorder at age 2 months and responded well to proper treatment. Family history revealed that a deceased sister had also experienced recurrent diarrhea, pulmonary disease, eosinophilia, and seizures; she died from sepsis at age 4 months. Qiu et al. (2006) noted that the sisters reported by Geller et al. (2002) developed normally and remained completely well on folate supplements at ages 9 and 6 years, respectively.

Zhao et al. (2007) reported a male infant of Spanish/Brazilian/Mexican origin with hereditary folate malabsorption. He presented at age 4 months with severe macrocytic anemia and thrombocytopenia. He subsequently developed Pneumocystis carinii pneumonia. He had low serum folate and immunoglobulins. Treatment with folate replacement led to clinical improvement. An older sister had developed pancytopenia at age 3 months and died due to cytomegalovirus pneumonia. Molecular analysis identified compound heterozygosity for 2 mutations in the SLC46A1 gene (611672.0004 and 611672.0005).

Sofer et al. (2007) reported an Arab Israeli infant, born of consanguineous parents, with folate malabsorption. He presented at age 15 months with generalized and focal seizures and a decline in mental status. Laboratory tests revealed low folate levels in blood and CSF, accompanied by pancytopenia. Bone marrow aspiration confirmed the presence of megaloblastic anemia. Treatment with high-dose intravenous folinic acid led to normalization of CSF folate levels.

Shin et al. (2011) reported an English boy with hereditary folate malabsorption. The child developed Pneumocystis jiroveci pneumonia associated with anemia and undetectable plasma folate at age 2 months. He later showed delayed motor development, hyperreflexia, jerky movements, tremor, and proximal muscle wasting. Brain MRI at 3 years 9 months showed a slight delay in myelination. He improved neurologically with treatment, but had mild difficulty in fine motor skills and reading but good math skills. He developed occipital seizures at age 5 years. Shin et al. (2011) also reported an 8-year-old Tunisian boy, born of consanguineous parents, with hereditary folate malabsorption. The patient developed macrocytic anemia with low serum folate at age 2.5 months. He was treated with leucovorin, which corrected the anemia and axial hypertonia. EEG and head CT scan were normal. Two affected sibs had died.

Inheritance

Parental consanguinity was noted in the families reported by Lanzkowsky et al. (1969), Santiago-Borrero et al. (1973), and Urbach et al. (1987), supporting autosomal recessive inheritance.

Molecular Genetics

In 2 sisters with hereditary folate malabsorption (Geller et al., 2002), Qiu et al. (2006) identified a homozygous mutation in the SLC46A1 gene (611672.0001).

In 5 infants with hereditary folate malabsorption, Zhao et al. (2007) identified 6 different biallelic mutations in the SLC46A1 gene (see, e.g., 611672.0002-611672.0005). One of the patients had been reported by Corbeel et al. (1985) (R113S; 611672.0003).

In an affected patient reported by Sofer et al. (2007), Lasry et al. (2008) identified a homozygous mutation in the SLC46A1 gene (611672.0006).

In a Tunisian patient, born of consanguineous parents, with hereditary folate malabsorption, previously reported by Jebnoun et al., 2001, Shin et al. (2011) identified a homozygous mutation in the SLC46A1 gene (611672.0007). They also identified compound heterozygosity for 2 mutations in the SLC46A1 gene (611672.0008 and 611672.0009) in an English boy with the disorder and identified a homozygous mutation (611672.0010) in another unrelated Tunisian patient.