The Effects of Ketogenic Diet on Seizures, Cognitive Functions, and Other Neurological Disorders in Classical Phenotype of Glucose Transporter 1 Deficiency Syndrome

Abstract

Objectives The purpose of this study was to characterize patients who were diagnosed with glucose transporter protein 1 deficiency syndrome (Glut1D), and also to assess the efficacy of ketogenic diet (KD) therapy on seizure control, cognitive functions, and other neurological disorders.

Patients and Methods We studied six unrelated patients with the classical phenotype of Glut1D, focusing on clinical and laboratory features, the KD therapy and outcome over the 25-month follow-up period.

Results Five patients became seizure-free with the onset of ketosis, and anticonvulsants were discontinued. Other neurological features such as ataxia, spasticity, and dystonia showed a less striking improvement than seizure control. There was no significant change in the intelligence quotient (IQ) level or microcephaly. In all patients, alertness, concentration, motivation, and activity resulted in a moderate improvement of variable degree. The early-onset adverse effects of KD were observed in five patients. The KD regimen failed in one patient, therefore, his diet was changed with an alternative to KD.

Conclusions Treatment with KD resulted in a marked improvement in seizures and cognitive functions but its effect appeared to be less striking on the other neurological disorders of the patients. When the classic KD is not tolerated, an alternative to KD may be helpful.

Keywords

glucose transporter protein 1 deficiency syndrome - ketogenic diet - cognitive functions - seizures - children

Authors' Contributions

G.H. conceived the study. P.H., K.M., and K.S. reviewed the literature, K.F., C.M., Ç.A.O., and K.B.A. were involved in patient care, including the process of the procedure, and routine clinical follow-up. G.H and K.B.A performed literature review and wrote the article. K.B.A. also conducted the statistical analysis. H.P., K.M., and S.K. also made helpful suggestions to improve the article.

• References

• 1 Klepper J, Scheffer H, Elsaid MF, Kamsteeg EJ, Leferink M, Ben-Omran T. Autosomal recessive inheritance of GLUT1 deficiency syndrome. Neuropediatrics 2009; 40 (5) 207-210
• 2 Klepper J, Voit T. Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain— a review. Eur J Pediatr 2002; 161 (6) 295-304
• 3 De Vivo DC, Trifiletti RR, Jacobson RI, Ronen GM, Behmand RA, Harik SI. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 1991; 325 (10) 703-709
• 4 Tzadok M, Nissenkorn A, Porper K , et al. The many faces of Glut1 deficiency syndrome. J Child Neurol 2014; 29 (3) 349-359
• 5 Alter AS, Engelstad K, Hinton VJ , et al. Long-term clinical course of Glut1 deficiency syndrome. J Child Neurol 2015; 30 (2) 160-169
• 6 De Giorgis V, Veggiotti P. GLUT1 deficiency syndrome 2013: current state of the art. Seizure 2013; 22 (10) 803-811
• 7 Wang D, Pascual JM, De Vivo D. Glucose Transporter Type 1 Deficiency Syndrome. In: Pagon RA, Adam MP, Ardinger HH, , et al. eds. University of Washington, Seattle: GeneReviews [Internet]; 1993–2014. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1430/
• 8 Klepper J, Leiendecker B. GLUT1 deficiency syndrome—2007 update. Dev Med Child Neurol 2007; 49 (9) 707-716
• 9 Leen WG, Klepper J, Verbeek MM , et al. Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain 2010; 133 (Pt 3) 655-670
• 10 Schneider SA, Paisan-Ruiz C, Garcia-Gorostiaga I , et al. GLUT1 gene mutations cause sporadic paroxysmal exercise-induced dyskinesias. Mov Disord 2009; 24 (11) 1684-1688
• 11 Veggiotti P, Teutonico F, Alfei E , et al. Glucose transporter type 1 deficiency: ketogenic diet in three patients with atypical phenotype. Brain Dev 2010; 32 (5) 404-408
• 12 Ramm-Pettersen A, Nakken KO, Skogseid IM , et al. Good outcome in patients with early dietary treatment of GLUT-1 deficiency syndrome: results from a retrospective Norwegian study. Dev Med Child Neurol 2013; 55 (5) 440-447
• 13 Weber YG, Kamm C, Suls A , et al. Paroxysmal choreoathetosis/spasticity (DYT9) is caused by a GLUT1 defect. Neurology 2011; 77 (10) 959-964
• 14 Wang D, Kranz-Eble P, De Vivo DC. Mutational analysis of GLUT1 (SLC2A1) in Glut-1 deficiency syndrome. Hum Mutat 2000; 16 (3) 224-231
• 15 Mueckler M, Caruso C, Baldwin SA , et al. Sequence and structure of a human glucose transporter. Science 1985; 229 (4717) 941-945
• 16 Ito Y, Takahashi S, Kagitani-Shimono K , et al. Nationwide survey of glucose transporter-1 deficiency syndrome (GLUT-1DS) in Japan. Brain Dev 2014;
• 17 Ramm-Pettersen A, Stabell KE, Nakken KO, Selmer KK. Does ketogenic diet improve cognitive function in patients with GLUT1-DS? A 6- to 17-month follow-up study. Epilepsy Behav 2014; 39: 111-115
• 18 Wechsler D. Wechsler Intelligence Scale for Children. 4th ed. London, UK: Pearson Assessment; 2004
• 19 Thorndike RL, Hagen EP, Sattler JM. The Stanford-Binet Intelligence Scale. 4th ed. Technical Manual. New York, NY: Riverside Publishing; 1986
• 20 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. (DSM-IV) Washington, DC: American Psychiatric Association; 1994
• 21 Salvador-Carulla L, Reed GM, Vaez-Azizi LM , et al. Intellectual developmental disorders: towards a new name, definition and framework for “mental retardation/intellectual disability” in ICD-11. World Psychiatry 2011; 10 (3) 175-180
• 22 Leen WG, Wevers RA, Kamsteeg EJ, Scheffer H, Verbeek MM, Willemsen MA. Cerebrospinal fluid analysis in the workup of GLUT1 deficiency syndrome: a systematic review. JAMA Neurol 2013; 70 (11) 1440-1444
• 23 Pong AW, Geary BR, Engelstad KM, Natarajan A, Yang H, De Vivo DC. Glucose transporter type I deficiency syndrome: epilepsy phenotypes and outcomes. Epilepsia 2012; 53 (9) 1503-1510
• 24 Haberlandt E, Karall D, Jud V , et al. Glucose transporter type 1 deficiency syndrome effectively treated with modified Atkins diet. Neuropediatrics 2014; 45 (2) 117-119
• 25 Klepper J, Leiendecker B. Glut1 deficiency syndrome and novel ketogenic diets. J Child Neurol 2013; 28 (8) 1045-1048
• 26 Veggiotti P, De Giorgis V. Dietary Treatments and New Therapeutic Perspective in GLUT1 Deficiency Syndrome. Curr Treat Options Neurol 2014; 16 (5) 291
• 27 Ito Y, Oguni H, Ito S, Oguni M, Osawa M. A modified Atkins diet is promising as a treatment for glucose transporter type 1 deficiency syndrome. Dev Med Child Neurol 2011; 53 (7) 658-663
• 28 Rodríguez-Morató J, Xicota L, Fitó M, Farré M, Dierssen M, de la Torre R. Potential role of olive oil phenolic compounds in the prevention of neurodegenerative diseases. Molecules 2015; 20 (3) 4655-4680
• 29 Covas MI, de la Torre K, Farré-Albaladejo M , et al. Postprandial LDL phenolic content and LDL oxidation are modulated by olive oil phenolic compounds in humans. Free Radic Biol Med 2006; 40 (4) 608-616