Case report: cerebral atrophy-induced hygroma in a 3-month-old floppy infant: Unusual and severe manifestation of 5-methylentetrahydrofolate reductase (MTHFR) deficiency

Case Report: The patient is the first child of nonconsanguineous parents. After uneventful pregnancy and delivery muscular hypotonia and poor sucking were noticed from the neonatal period onwards. Failure to thrive with severely retarded psychomotor development became obvious. Seizures were first observed at 3 months of age.

Diagnostic Procedures: Electroencephalography revealed multifocal sharp waves with low voltage background activity and seizures. Biochemically reduced methionine levels were found, plasma homocysteine was 10-fold increased and 5-methylenetetrahydrofolate in cerebrospinal fluid was clearly reduced. In the absence of methylmalonic aciduria and macrocytic anemia, MTHFR deficiency is the only differential diagnosis compatible with this profile. The investigation of enzyme activity in lymphocytes is pending. Cranial MRI showed cerebral volume deficiency with massive bifrontal subdural hygroma and a retardation of myelination.

Therapy: Betaine and folinic acid. The aim is both, a reduction of homocysteine, which is a risk factor for thromboembolic complications and an increase of methionine availability for methylation reactions necessary for the biosynthesis of myelin and creatine. With levetiracetam, the child became seizure-free.

Discussion: MTHFR deficiency is an autosomal recessive disease with a heterogeneous phenotype. Such an early and fulminant brain atrophy with consecutive hygroma was not yet described. The enzyme defect results in reduced remethylation of homocysteine to methionine. Elevated homocysteine concentrations promote thromboembolic events and diminished methionine levels lead to disturbances in brain development because of impaired methylation reactions of several metabolic pathways. By early therapeutic intervention improvement of neurological symptoms and a reduced risk for thromboembolic complications (including stroke) can be achieved.

Summary: MTHFR deficiency is an important differential diagnosis in floppy infants, infantile epilepsy and also infantile brain atrophy with hygroma as illustrated in this case report.