GLUT-1 deficiency syndrome with ataxia, acquired microcephaly and leukoencephalopathy in monozygotic twins

Glucose transporter type 1 deficiency syndrome (Glut-1 DS; MIM #606777) is a metabolic disorder due to impaired glucose transport across the blood-brain barrier. Patients commonly present with infantile seizures refractory to anticonvulsants, deceleration of head growth, delay in mental and motor development, ataxia and dysarthria. Some patients show a carbohydrate-responsive phenotype with fasting intolerance. In most patients, treatment with a ketogenic diet is successful in controlling seizures.

Here, we report 3-year old monozygotic twin girls who presented with ataxia, fasting intolerance and acquired microcephaly, but without epilepsy. In both patients cranial MRI at age 25 months and 34 months revealed a striking pattern identical to that observed in L-2-hydroxyglutaric aciduria. The myelin signal of subcortical U-fibers was abnormal, whereas central white matter and cerebellum were spared. Screening for inborn errors of metabolism including L-2-hydroxyglutaric aciduria did not show any abnormalities. CSF glucose (26 and 27mg/dl) and lactate (0.6 and 0.9 mmol/l) levels were reduced, as was the ratio of CSF/blood glucose (0.36 and 0.39). Both girls had a significant reduction in glucose uptake by erythrocytes when compared with their parents. Mutation analyses of GLUT-1 gene revealed a heterozygous missense mutation R153L in the twin girls. Ketogenic diet was initiated in both girls and seems to have a beneficial effect on ataxia.

These twins are the second and third case of Glut-1 DS presenting with ataxia as the prominent clinical symptom, but without epilepsy. The described MRI pattern with isolated involvement of subcortical U-fibers is so far only known for L-2-hydroxyglutaric aciduria. These two cases extend the phenotypic spectrum of Glut1-DS.