Ketogenic dietary therapy for neurometabolic disease

Written by: Elizabeth Neal MSc PhD RD; Prof. Dr. Joerg Klepper
Ketogenic Research Dietitian; Pediatrician,
Neuropediatrician
UCL – Great Ormond Street Institute of Child Health; Aschaffenburg Childrens’ Hospital, Germany

Ketogenic Dietary Therapies are high fat, restricted carbohydrate regimes that can be delivered by the traditional classical or medium chain triglyceride (MCT) ketogenic diets (KD), or by modified and more liberal dietary protocols such as the modified Atkins diet (MAD) and low glycaemic index treatment (LGIT). KDTs are designed to induce a similar metabolic response to starvation, with the ketone bodies acetoacetate and b-hydroxybutyrate becoming the primary brain energy source in absence of adequate glucose supply. The KDT has been used as a successful treatment for epilepsy since the 1920s and is also treatment of choice in two rare neurometabolic diseases which affect energy metabolism of the brain, glucose transporter type 1 deficiency syndrome (GLUT1DS) and pyruvate dehydrogenase (PDH) deficiency.

GLUT1DS is caused by a defect in the transporter protein responsible for moving glucose across the blood-brain barrier into the brain. It usually presents with seizures early in life; brain growth may be impaired with developmental delay and other neurological problems including a complex movement disorder. It is characterized by a low glucose concentration in the cerebrospinal fluid in the absence of hypoglycaemia, in combination with a low to normal lactate in the cerebrospinal fluid (1). Ketogenic dietary therapies are the recommended first-line treatment as ketones can be used as an alternative brain energy source (2). The classical KD will significantly reduce seizure frequency in most patients and improvements in movement disorders, neurological function and cognition have also been reported (3-9) with no significant adverse effects on short term inflammatory and metabolic profiles (10) or longer-term body composition or bone mineralization (11). There have been case reports (12-16) and a retrospective study (17) on successful use of MAD in GLUT1DS. Experimentally LGIT combined with modified high amylopectin corn starch has also been tried, but is not an established treatment (18). Two GLUT1DS surveys have highlighted use of the different dietary protocols in GLUT1DS. Japanese physicians provided positive efficacy data on 34 GLUT1DS patients: 5 on classical KD, 9 on MCT KD, 18 on MAD, one LGIT (and one unspecified) (19). A survey of 90 parents of diet-treated GLUT1DS children attending a GLUT1DS Foundation meeting in USA found no significant seizure outcome differences between the different diet variants (59 classical KD, 29 MAD, 4 MCT KD and 2 LGIT) with many switching between the types of diet (20). However, international GLUT1DS consensus recommendations suggest the stricter classical KD may be preferable for young children as typically yields higher ketone levels, with MAD more feasible for quality of life and compliance in adolescents and adults, but LGIT is not recommended as it has no evidence of benefit in GLUT1DS and provides very low if any ketones (2).

PDH deficiency is a severe mitochondrial disorder caused by deficiency in one of the enzymes involved in glucose metabolism (21). It can present with lactic acidosis and variable degrees of neurological degeneration during infancy and childhood including seizures; prognosis is poor. First-line therapy are KDT which will bypass the metabolic block by providing ketones as an alternative fuel to glucose. Although it will not fully reverse clinical symptoms, the progressive loss of neurological function can be slowed, especially if the diet is initiated early in life (21, 22, 23). A classical KD is usually recommended as stricter carbohydrate restriction has been associated with greater improvement in clinical outcome (22) although one case report suggests a modified diet may also be helpful (24). A study of 19 diet-treated PDH children included 7 on classical KD and 12 on modified KD. Median diet duration was 2.9 years, during which time the ketogenic ratio was increased in most patients, with an effective ketosis important in maintaining the benefits of the diet on motor and neurocognitive development (25). Monitoring KDT efficacy is difficult as seizures are not frequent in this entity.

As advised by international consensus recommendations (2, 26), KDT should be used as first line therapy for these neurometabolic diseases, and in GLUT1DS will usually need to be continued well beyond childhood, with benefits thought to extend to adults (2). A long-term follow up study of 10 GLUT1DS patients did not identify any cardiovascular risk factors after 10 years on KDT (27), however on-going regular monitoring and support from a ketogenic team will be essential to ensure the most appropriate dietary prescription with minimal risk of side-effects.

Recent data suggests that a substantial number of GLUT1DS patients do not respond to KDT despite adequate ketosis for reasons yet unknown. In particular, motor abnormalities are the predominant feature in adults. Currently alternative treatments include medication, oral ketones, ketoesters, triheptoin and others are experimental and used on an individual basis only.

References

  1. Leen WG, Klepper J, Verbeek MM, et al (2010) Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain. 133(3):655-70.
  2. Klepper J, Akman C, Armeno M, et al (2020) Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group. Epilepsia Open. 5(3):354-65.
  3. Klepper J (2004) Impaired glucose transport into the brain: the expanding spectrum of glucose transporter type 1 deficiency syndrome. Curr Opin Neurol. 17(2):193-6.
  4. Klepper J, Diefenbach S, Kohlschütter A, Voit T (2004) Effects of the ketogenic diet in the glucose transporter 1 deficiency syndrome. Prostagland Leukot Essent Fatty Acids. 70(3):321-7.
  5. Klepper J, Scheffer H, Leiendecker B, et al (2005) 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(5):302-8.
  6. Brockmann K (2009) The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev. 31(7):545-52.
  7. Ramm-Pettersen A, Nakken KO, Skogseid IM, et al (2013) Good outcome in patients with early dietary treatment of GLUT-1 deficiency syndrome: results from a retrospective Norwegian study. Dev Med Child Neurol. 55(5):440-7.
  8. Ramm-Pettersen A, Stabell KE, Nakken KO, Selmer KK (2014) Does ketogenic diet improve cognitive function in patients with GLUT1-DS? A 6- to 17-month follow-up study. Epilepsy Behav. 39:111-5.
  9. Gumus H, Bayram AK, Kardas F, et al (2015) The effects of ketogenic diet on seizures, cognitive functions, and other neurological disorders in classical phenotype of Glucose Transporter 1 Deficiency Syndrome. Neuropediatrics 46(5):313-20.
  10. Bertoli S, Neri IG, Trentani C, et al (2015) Short-term effects of ketogenic diet on anthropometric parameters, body fat distribution, and inflammatory cytokine production in GLUT1 deficiency syndrome. Nutrition 31(7-8):981-7.
  11. Bertoli S, Trentani C, Ferraris C, et al (2014) Long-term effects of a ketogenic diet on body composition and bone mineralization in GLUT-1 deficiency syndrome: a case series. Nutrition 30(6):726-8.
  12. Ito S, Oguni H, Ito Y, et al (2008) Modified Atkins diet therapy for a case with glucose transporter type 1 deficiency syndrome. Brain Dev. 30(3):226-8.
  13. Slaughter L, Vartzelis G, Arthur T (2009) New GLUT-1 mutation in a child with treatment-resistant epilepsy. Epilepsy Res. 84(2-3):254-6.
  14. Leen WG, Mewasingh L, Verbeek MM, et al (2013) Movement disorders in GLUT1 deficiency syndrome respond to the modified Atkins diet. Mov Disord. 28(10):1439-42.
  15. Haberlandt E, Karall D, Jud V, et al (2014) Glucose transporter type 1 deficiency syndrome effectively treated with modified Atkins diet. Neuropediatrics 45(2):117-9.
  16. Sandu C, Burloiu CM, Barca DG, et al (2019) Ketogenic Diet in Patients with GLUT1 Deficiency Syndrome. Maedica (Bucur) 14(2):93-7.
  17. Amalou S, Gras D, Ilea A, et al (2016) Use of modified Atkins diet in glucose transporter type 1 deficiency syndrome. Dev Med Child Neurol. 58(11):1193-9.
  18. Almuqbil M, Go C, Nagy LL, et al (2015) New paradigm for the treatment of Glucose Transporter 1 Deficiency Syndrome: Low Glycemic Index Diet and modified high amylopectin cornstarch. Pediatr Neurol. 53(3):243-6.
  19. Oguni H, Ito Y, Otani Y, Nagata S (2018) Questionnaire survey on the current status of ketogenic diet therapy in patients with glucose transporter 1 deficiency syndrome (GLUT1DS) in Japan. Eur J Paediatr Neurol 22(3):482-7.
  20. Kass HR, Winesett SP, Bessone SK, et al (2016) Use of dietary therapies amongst patients with GLUT1 deficiency syndrome. Seizure 35:83-7.
  21. Prasad C, Rupar T, Prasad AN (2011) Pyruvate dehydrogenase deficiency and epilepsy. Brain Dev 33(10):856-65.
  22. Wexler ID, Hemalatha SG, McConnell J, et al (1997) Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. Neurology. 49(6):1655-61.
  23. Di Pisa V, Cecconi I, Gentile V, et al (2012) Case report of pyruvate dehydrogenase deficiency with unusual increase of fats during ketogenic diet treatment. J Child Neurol. 27(12):1593-6.
  24. El-Gharbawy AH, Boney A, Young SP, Kishnani PS (2011) Follow-up of a child with pyruvate dehydrogenase deficiency on a less restrictive ketogenic diet. Mol Genet Metab. 102(2):214-5.
  25. Sofou K, Dahlin M, Hallböök T, et al (2017) Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes. JIMD 40 (2) 237-45.
  26. Kossoff EH, Zupec-Kania BA, Amark PE, et al (2009) Optimal clinical management of children receiving the ketogenic diet: recommendations of the international ketogenic diet study group. Epilepsia 50: 304-17.
  27. Heussinger N, Della Marina A, Beyerlein A, et al (2018) 10 patients, 10 years – Long term follow-up of cardiovascular risk factors in Glut1 deficiency treated with ketogenic diet therapies: A prospective, multicenter case series. Clin Nutr. 37(6 Pt A):2246-51.
  1. Leen WG, Klepper J, Verbeek MM, et al (2010) Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. 133(3):655-70.
  2. Klepper J, Akman C, Armeno M, et al (2020) Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group. Epilepsia Open. 5(3):354-65.
  3. Klepper J (2004) Impaired glucose transport into the brain: the expanding spectrum of glucose transporter type 1 deficiency syndrome. Curr Opin Neurol. 17(2):193-6.
  4. Klepper J, Diefenbach S, Kohlschütter A, Voit T (2004) Effects of the ketogenic diet in the glucose transporter 1 deficiency syndrome. Prostagland Leukot Essent Fatty Acids. 70(3):321-7.
  5. Klepper J, Scheffer H, Leiendecker B, et al (2005) Seizure control and acceptance of the ketogenic diet in GLUT1 deficiency syndrome: a 2- to 5-year follow-up of 15 children enrolled prospectively. 36(5):302-8.
  6. Brockmann K (2009) The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev. 31(7):545-52.
  7. Ramm-Pettersen A, Nakken KO, Skogseid IM, et al (2013) Good outcome in patients with early dietary treatment of GLUT-1 deficiency syndrome: results from a retrospective Norwegian study. Dev Med Child Neurol. 55(5):440-7.
  8. Ramm-Pettersen A, Stabell KE, Nakken KO, Selmer KK (2014) Does ketogenic diet improve cognitive function in patients with GLUT1-DS? A 6- to 17-month follow-up study. Epilepsy Behav. 39:111-5.
  9. Gumus H, Bayram AK, Kardas F, et al (2015) The effects of ketogenic diet on seizures, cognitive functions, and other neurological disorders in classical phenotype of Glucose Transporter 1 Deficiency Syndrome. Neuropediatrics 46(5):313-20.
  10. Bertoli S, Neri IG, Trentani C, et al (2015) Short-term effects of ketogenic diet on anthropometric parameters, body fat distribution, and inflammatory cytokine production in GLUT1 deficiency syndrome. Nutrition 31(7-8):981-7.
  11. Bertoli S, Trentani C, Ferraris C, et al (2014) Long-term effects of a ketogenic diet on body composition and bone mineralization in GLUT-1 deficiency syndrome: a case series. Nutrition 30(6):726-8.
  12. Ito S, Oguni H, Ito Y, et al (2008) Modified Atkins diet therapy for a case with glucose transporter type 1 deficiency Brain Dev. 30(3):226-8.
  13. Slaughter L, Vartzelis G, Arthur T (2009) New GLUT-1 mutation in a child with treatment-resistant epilepsy. Epilepsy Res. 84(2-3):254-6.
  14. Leen WG, Mewasingh L, Verbeek MM, et al (2013) Movement disorders in GLUT1 deficiency syndrome respond to the modified Atkins diet. Mov Disord. 28(10):1439-42.
  15. Haberlandt E, Karall D, Jud V, et al (2014) Glucose transporter type 1 deficiency syndrome effectively treated with modified Atkins diet. Neuropediatrics 45(2):117-9.
  16. Sandu C, Burloiu CM, Barca DG, et al (2019) Ketogenic Diet in Patients with GLUT1 Deficiency Syndrome. Maedica (Bucur) 14(2):93-7.
  17. Amalou S, Gras D, Ilea A, et al (2016) Use of modified Atkins diet in glucose transporter type 1 deficiency syndrome. Dev Med Child Neurol. 58(11):1193-9.
  18. Almuqbil M, Go C, Nagy LL, et al (2015) New paradigm for the treatment of Glucose Transporter 1 Deficiency Syndrome: Low Glycemic Index Diet and modified high amylopectin cornstarch. Pediatr Neurol. 53(3):243-6.
  19. Oguni H, Ito Y, Otani Y, Nagata S (2018) Questionnaire survey on the current status of ketogenic diet therapy in patients with glucose transporter 1 deficiency syndrome (GLUT1DS) in Japan. Eur J Paediatr Neurol 22(3):482-7.
  20. Kass HR, Winesett SP, Bessone SK, et al (2016) Use of dietary therapies amongst patients with GLUT1 deficiency syndrome. Seizure 35:83-7.
  21. Prasad C, Rupar T, Prasad AN (2011) Pyruvate dehydrogenase deficiency and epilepsy. Brain Dev 33(10):856-65.
  22. Wexler ID, Hemalatha SG, McConnell J, et al (1997) Outcome of pyruvate dehydrogenase deficiency treated with ketogenic Studies in patients with identical mutations. Neurology. 49(6):1655-61.
  23. Di Pisa V, Cecconi I, Gentile V, et al (2012) Case report of pyruvate dehydrogenase deficiency with unusual increase of fats during ketogenic diet J Child Neurol. 27(12):1593-6.
  24. El-Gharbawy AH, Boney A, Young SP, Kishnani PS (2011) Follow-up of a child with pyruvate dehydrogenase deficiency on a less restrictive ketogenic diet. Mol Genet Metab. 102(2):214-5.
  25. Sofou K, Dahlin M, Hallböök T, et al (2017) Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes. JIMD 40 (2) 237-45.
  26. Kossoff EH, Zupec-Kania BA, Amark PE, et al (2009) Optimal clinical management of children receiving the ketogenic diet: recommendations of the international ketogenic diet study group. Epilepsia 50: 304-17.
  27. Heussinger N, Della Marina A, Beyerlein A, et al (2018) 10 patients, 10 years – Long term follow-up of cardiovascular risk factors in Glut1 deficiency treated with ketogenic diet therapies: A prospective, multicenter case series. Clin Nutr. 37(6 Pt A):2246-51.

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