Glut1 deficiency: inheritance pattern determined by haploinsufficiency

Abstract

Two families manifesting Glut1 deficiency syndrome (DS) as an autosomal recessive trait are described. In 1 family, a severely affected boy inherited a mutated allele from his asymptomatic heterozygous mother. A de novo mutation developed in the paternal allele, producing compound heterozygosity. In another family, 2 mildly affected sisters inherited mutations from their asymptomatic heterozygous consanguineous parents. Red blood cell glucose uptake residual activity, a surrogate of haploinsufficiency, correlated with the clinical severity. These cases demonstrate that Glut1 DS may present as an autosomal recessive trait. The clinical pattern of inheritance is determined by the relative pathogenicity of the mutation and the resulting degree of haploinsufficiency.

Figure 1

The proposed Glut1 protein transmembrane configuration with the locations of the R126L, K256V and R468W missense mutations.

Figure 2

Relative 3-OMG RBC glucose uptake values in homozygous affected patients, heterozygous (AD) and compound heterozygous affected patients, heterozygous unaffected patients and healthy controls RBC 3-O-methyl-D-glucose uptake was performed as described elsewhere (12). The data are expressed as the percent of uptake compared with an intra-assay control sample. Activities of the described two family members are shown individually. The individual assays were performed in triplicate and the results were averaged. The average uptake for 74 patients with an autosomal dominant (AD) pattern of inheritance is 52% ± 8.94. A total of 144 normal subjects were used as controls in the individual patient assays that have been performed over the past decade. The intra-assay uptake values were normalized to the respective control sample. The residual RBC glucose uptake (left vertical axis) is a surrogate marker for the degree of haploinsufficiency. The increasing severity of the clinical phenotypes correlating with the degree of presumed haploinsufficiency is listed on the right vertical axis.