Hereditary folate malabsorption

Huddar, Akshata, MD, DM, Chiplunkar, Shwetha, et al. Child Neurology: Hereditary Folate Malabsorption. Neurology. 2021;97(1):40-43. doi:10.1212/WNL.0000000000012083. 

Hereditary folate malabsorption (HFM, congenital folate malabsorption; OMIM#229050) is a rare, potentially treatable autosomal recessive disorder with multisystem involvement.  It is caused by homozygous or compound heterozygous mutations in SLC46A1 resulting in loss of function of proton-coupled folate transporter (PCFT),2 required for intestinal absorption and transport of folate across choroid plexus. This leads to the deficiency of folate in serum and CSF, causing hematologic, immunologic, gastrointestinal, and neurologic manifestations. Neuroimaging shows intracranial calcification. Diagnosis is confirmed by impaired absorption of an oral folate load, low CSF folate concentration (even after correction of the serum folate concentration), or the identification of pathogenic variants in SLC46A1 on molecular genetic testing.  We describe the clinical, imaging, biochemical, and genetic findings of a patient with HFM... 

Seizures became refractory to multiple antiseizure drugs at optimal dosages (phenytoin, levetiracetam, carbamazepine, topiramate, and clobazam). By 11 months of age, the patient had generalized hyperpigmentation, tremors, and oral ulcers. Developmental delay was noted at 18 months of age, with episodes of further regression following infections. The diagnosis of infantile tremor syndrome, a nutritional deficiency syndrome typically associated with vitamin B12 deficiency, characterized by pallor, developmental delay/regression, tremors, skin pigmentation, and brown scanty scalp hair, was considered at this stage. The patient received B12 supplementation. At 32 months of age, she was able to sit and stand with support, transfer objects, and say 2-3 meaningful words. There was a history of similar illness in her older sister, with seizures, fever, vomiting, loose stools, and pancytopenia, who died at 3 months of age. 

Examination revealed microcephaly (head circumference 45 cm, <3rd percentile) and low weight (10.5 kg, <3rd percentile). The patient was alert, fixed, and followed light and sound. She had normal extraocular, facial, palatal, and tongue movements. She had generalized hypotonia, normal limb movements, and brisk deep tendon reflexes. She had choreoathetosis involving distal extremities. There was no organomegaly. Fundus showed normal retina and optic discs. 

Investigations revealed anemia (hemoglobin 10.4 g/dL, reference 13-17 g/dL) with mean corpuscular volume on higher end of normal (96.6 fL, reference 83-101 fL) and normal leukocyte and platelet count. Renal and hepatic function tests were normal. Serum folate (1.52 ng/mL, reference 3.1-19.9 ng/mL) and vitamin B12 (54 pg/mL, reference 180-914 pg/mL) were low, while homocysteine was high (27.8 [mu]mol/L, reference <8 [micro]mol/L). Metabolic investigations revealed normal lactate, mildly elevated ammonia, and normal plasma amino acids, acylcarnitine profile, and urinary organic acid profile. 

Cranial CT scan done at 12 months of age was normal. MRI brain done at 13 months showed mild cerebral atrophy and hypointensity involving the basal ganglia and left parieto-occipital region on T1-weighted images  with corresponding hyperintensity on T2-weighted sequences. Repeat neuroimaging at 32 months of age showed progressive changes, including calcification in bilateral basal ganglia and thalamus on CT scan. MRI brain done at 32 months showed diffuse cerebral and cerebellar atrophy, T2/fluid-attenuated inversion recovery hyperintensities of periventricular and deep white matter, and mixed intensity lesions in bilateral basal ganglia. EEG showed focal epileptiform activity across the left temporal region. 

Constellation of megaloblastic anemia, oral ulcers, recurrent infections, and neurologic features with positive family history and biochemical and imaging findings led to the suspicion of hereditary folate deficiency. CSF folate estimation was not done. Clinical exome sequencing showed a pathogenic homozygous single base pair duplication in exon 2 of the SLC46A1 (chr17:26732094_26732095dupC) c.620dupG variation resulting in a frameshift and premature truncation of the protein 25 amino acids downstream to codon 208 (p. Tyr208LeufsTer25; ENST00000440501), confirming the diagnosis of HFM. Both parents were heterozygous carriers. 

The patient received oral folic acid from 4 months of age prior to presentation to our facility. Hematologic measures and hyperpigmentation improved, but neurologic features worsened, and she continued to have recurrent infections. After the genetic diagnosis, she was treated with intramuscular injection of folinic acid (l20 mg/d), leading to the cessation of seizures. After 1 week, parenteral folinic acid was replaced by oral folinic acid (150 mg/d, 15 mg/kg/d) due to financial constraints and continued along with anticonvulsants. At 2 months follow-up, she was seizure-free, and development had stabilized. However, she was noncompliant with treatment and presented multiple times with recurrent seizures, anemia, and infections, which responded to parenteral folinic acid. On follow-up at 7 years, the patient was able to stand with support, speak 5-10 words, and feed herself. Although there was a reduction in seizure frequency, she continued to have daily seizures requiring multiple anticonvulsants.

The patient received oral folic acid from 4 months of age prior to presentation to our facility. Hematologic measures and hyperpigmentation improved, but neurologic features