Last modified: 2014-04-03
Abstract
A 3-year-old, male, the second child of a non-consanguineous couple, no pre or perinatal complications had his neuropsychomotor development delayed. He walked and spoke after two years. He had normal head circumference and moderate hypotonia with joint laxity but no motor deficits. Reflexes exalted in lower limbs without Babinski sign. He was investigated with brain MRI, EEG, BAEP, electromyography, complete blood count, transaminases, CPK, ammonia, lactate, molecular test for Fragile X, HPLC of amino acids, urine organic acids analysis, Acylcarnitine profile analysis, karyotype and CGH-Array. These tests were normal. The family refused to collect CSF.
He presented with 6 hour episodes in which he was lethargic, hypotonic and drowsy. These started when he was 1-year-old and happened on average every 3 months. Metabolic changes or epileptiform activity on EEG-video monitoring were never found during crises.
Whole exome sequencing: heterozygous mutation nonsense c.724 C>T (p.Gln242*) in SLC2A1 (Glut 1).
GLUT1 deficiency syndrome-1 is caused by heterozygous mutation in the gene (SLC2A1) and rarely by homozygous or compound heterozygous mutation. Presents with infantile-onset epileptic encephalopathy, delayed development, acquired microcephaly, motor incoordination and spasticity. Other paroxysmal findings include intermittent ataxia, confusion, lethargy, sleep disturbance, and headache. Hypoglycorrhachia and low CSF lactate are essentially diagnosis. The phenotype includes individuals with ataxia and mental retardation but without seizures, individuals with dystonia and choreoathetosis, and rarely individuals without seizures and movement disorder. The disorder (a defect in the GLUT1 glucose transporter) causes decreased glucose concentration in the brain. A ketogenic diet results in clinical improvement.
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References
Brockmann, K. The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev. 31: 545-552, 2009.
Brockmann, K., Wang, D., Korenke, C. G., von Moers, A., Ho, Y.-Y., Pascual, J. M., Kuang, K., Yang, H., Ma, L., Kranz-Eble, P., Fischbarg, J., Hanefeld, F., De Vivo, D. C. Autosomal dominant Glut-1 deficiency syndrome and familial epilepsy. Ann. Neurol. 50: 476-485, 2001.
De Vivo, D. C., Trifiletti, R. R., Jacobson, R. I., Ronen, G. M., Behmand, R. A., Harik, S. I. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. New Eng. J. Med. 325: 703-709, 1991.
Klepper, J., Florcken, A., Fischbarg, J., Voit, T. Effects of anticonvulsants on GLUT1-mediated glucose transport in GLUT1 deficiency syndrome in vitro. Europ. J. Pediat. 162: 84-89, 2003.
Klepper, J., Leiendecker, B. GLUT1 deficiency syndrome-2007 update. Dev. Med. Child Neurol. 49: 707-716, 2007.
Klepper, J., Leiendecker, B., Bredahl, R., Athanassopoulos, S., Heinen, F., Gertsen, E., Florcken, A., Metz, A., Voit, T. Introduction of a ketogenic diet in young infants. J. Inherit. Metab. Dis. 25: 449-460, 2002.
Klepper, J., Scheffer, H., Elsaid, M. F., Kamsteeg, E.-J., Leferink, M., Ben-Omran, T. Autosomal recessive inheritance of GLUT1 deficiency syndrome. Neuropediatrics 40: 207-210, 2009.
Klepper, J., Scheffer, H., Leiendecker, B., Gertsen, E., Binder, S., Leferink, M., Hertzberg, C., Nake, A., Voit, T., Willemsen, M. A. Seizure control and acceptance of the ketogenic diet in GLUT1 deficiency syndrome: a 2- to 5-year follow-up of 15 children enrolled prospectively. Neuropediatrics 36: 302-308, 2005.
Klepper, J., Voit, T. Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain--a review. Europ. J. Pediat. 161: 295-304, 2002.
Klepper, J., Willemsen, M., Verrips, A., Guertsen, E., Herrmann, R., Kutzick, C., Florcken, A., Voit, T. Autosomal dominant transmission of GLUT1 deficiency. Hum. Molec. Genet. 10: 63-68, 2001.
Mullen, S. A., Marini, C., Suls, A., Mei, D., Della Giustina, E., Buti, D., Arsov, T., Damiano, J., Lawrence, K., De Jonghe, P., Berkovic, S. F., Scheffer, I. E., Guerrini,
R. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Arch. Neurol. 68: 1152-1155, 2011.
Pascual, J. M., Wang, D., Hinton, V., Engelstad, K., Saxena, C. M., Van Heertum, R. L., De Vivo, D. C. Brain glucose supply and the syndrome of infantile neuroglycopenia. Arch. Neurol. 64: 507-513, 2007.
.
Pascual, J. M., Wang, D., Lecumberri, B., Yang, H., Mao, X., Yang, R., De Vivo, D. C. GLUT1 deficiency and other glucose transporter diseases. Europ. J. Endocr. 150: 627-633, 2004.
Rotstein, M., Engelstad, K., Yang, H., Wang, D., Levy, B., Chung, W. K., De Vivo, D. C. Glut1 deficiency: inheritance pattern determined by haploinsufficiency. Ann. Neurol. 68: 955-958, 2010.
Seidner, G., Alvarez, M. G., Yeh, J.-I., O'Driscoll, K. R., Klepper, J., Stump, T. S., Wang, D., Spinner, N. B., Birnbaum, M. J., De Vivo, D. C. GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain barrier hexose carrier. Nature Genet. 18: 188-191, 1998.
Suls, A., Mullen, S. A., Weber, Y. G., Verhaert, K., Ceulemans, B., Guerrini, R., Wuttke, T. V., Salvo-Vargas, A., Deprez, L., Claes, L. R. F., Jordanova, A., Berkovic, S. F., Lerche, H., De Jonghe, P., Scheffer, I. E. Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1. Ann. Neurol. 66: 415-419, 2009.
Wang, D., Kranz-Eble, P., De Vivo, D. C. Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome. Hum. Mutat. 16: 224-231, 2000. Note: Erratum: Hum. Mutat. 16: 527 only, 2000.