Molecular characteristics

Homozygous missense variants in SLC45A1 gene (NM_001080397.1) were reported in five patients from three unrelated consanguineous families: c.526C>T [p.Arg176Trp], c.629C>T [p.Ala210Val] and c.167T>C [p.Ile56Thr].

SLC45A1 is a protein coding gene located on chromosome 1p36. It is predominantly expressed in the developing and adult brain, including the cortex and cerebellum. Several studies suggest that SLC45A1, also known as proton associated sugar transporter (PAST-A), functions as a glucose and galactose transporter. The uptake of glucose is PH dependent and increases significantly at low PH value. Its primary structure it typical of glucose transporters consisting of 12 putative transmembrane(TM)-spanning helices, a long cytoplasmic loop between TM6 and TM7, and several motifs associated with transport o the sugar.

The c.526C>T (p.Arg176Trp) and c.629C>T (p.Ala210Val), are located in exon 3 of SLC45A1.
p.Arg176 is located in the extracellular loop just after the third transmembrane domain, whereas p.Ala210 is positioned at the beginning of the intracellular loop just after the fourth transmembrane domain. In vitro functional analysis of transfected COS-7 cells revealed that the glucose transport activity of the p.Arg176Trp and p.Ala210Val variants was significantly decreased by approximately 50% and 30%, respectively, in comparison with that of intact SLC45A1. The Ile56Thr variant, located in the intracellular N-tail, had no significant effect on the glucose transport activity, either suggesting that this variant is not pathogenic or affects the function of the protein in a manner that is not measured in the assay. Note that the affected individuals from the 2 families bearing the p.Arg176Trp and p.Ala210Val substitutions had global developmental delay, intellectual disability, epilepsy and neuropsychiatric features, whereas the individual with Ile56Thr variant had global developmental delay, intellectual disability and Dandy-Walker malformation without epilepsy or psychiatric features.

Mode of inheritance: Autosomal Recessive

Genetic Counselling: Since the disease is inherited in autosomal recessive pattern and both parents are heterozygous for the pathogenic variant in SLC45A1 gene, the risk of having another proband’s affected sibling is 25%.