GLUT1 deficiency syndrome in a consanguineous Arab family carrying a novel homozygous missense mutation

GLUT1deficiency syndrome (GLUT1DS) results from impaired glucose transport into brain. To date only heterozygous mutations in the SLC2A1gene have been described – homozygous mutations are thought to be letal in utero.

We report two sisters of a consanguinous Arab family. Clinical features in the elder sibling suggestive of GLUT1DS were global developmental delay, epilepsy, secondary microcephaly, ataxia, and hypotonia. The fasting lumbar puncture confirmed hypoglycorrhachia with a CSF glucose of 36mg/dl and a CSF/blood glucose ratio of 0.44. CSF lactate was 1.09mmol/l. The younger sister was asymptomatic, CSF glucose was 36mg/dl, the ratio was 0.46, CSF lactate was 1.08mmol/l. Molecular analysis of the SLC2A1 gene identified a homozygous c1402C>T (p.Arg468Trp) mutation in exon 10 in the index patient and her younger sister. Both parents were clinically unaffected and heterozygous for the mutation. Additional healthy family members are currently investigated. A ketogenic diet was initiated in the two sisters carrying the homozygous mutation.

Conclusion: SLC2A1 mutations in GLUT1DS can be homozygous. Either the mutation is a neutral polymorphism or the mutation is relatively mild and only pathogenic in the homozygous state. Evidence that the mutation is indeed pathogenic are

i) the exchange of a basic, aliphatic amino acid for an aromatic amino acid at a highly conserved locus,

ii) the location in the GLUT1 carboxy-terminus previously shown to be essential for substrate recognition and transport, and

iii) previously published in-vitro analysis of amino residue Arg468.

The current understanding of GLUT1DS as a heterozygous autosomal dominant disease may need reevaluation.