Ketogenic Diet and Inborn Errors of Metabolism

1. Ketogenic Diet and Inborn Errors of Metabolism CW Fung Division of Child Neurology, Developmental Paediatrics, NeuroHabilitationDepartment of Paediatrics and Adolescent Medicine, The University of Hong Kong Queen Mary Hospital / Duchess of Kent Children’s Hospital

2. ‘ Fasting and prayer have been mentioned as treatments for seizures and epilepsy since biblical times and are mentioned again in the literature of the Middle Ages’ Kossoff et al 2011 In: Ketogenic Diets

3. ADB Can Med Assoc J 1931

4. Ketogenic Diet and Inborn Errors of Metabolism Leigh Syndrome Associated with a Deficiency of the Pyruvate Dehydrogenase Complex: Results of Treatment with a Ketogenic Diet Wilburg et al 1992: Neuropediatrics

5. Use of Ketogenic Diet in Inborn Errors of Metabolism • Related to underlying metabolic defects • Contraindications • Related to associated epilepsy

6. Use of Ketogenic Diet in Inborn Errors of Metabolism • Related to underlying metabolic defects • Contraindications • Related to associated epilepsy

9. Ketogenesis Krebs cycle McNally & Hartman 2012: J Neurochem

10. Pyruvate Dehydrogenase Ketolysis ATP McPherson & McEneny 2012: J Physiol Biochem

11. Ketogenic diet in treating underlying inborn errors of metabolism Ketogenesis Krebs cycle Glucose Glucose Glucose Transporter (Glut-1) Deficiency McNally & Hartman 2012: J Neurochem

12. Modified Atkins Diet for Glucose Transporter Deficiency

13. Wilhelmina et al • Classical phenotype (refractory epilepsy and developmental delay +/- movement disorders including ataxia, dystonia or chorea) • Seizure control: • Seizure free (24 / 37 = 62%) • Seizure reduction (9 / 37 = 24%) • Movement disorder: reduced (12 / 29 = 41%) • Subjective improvement in cognitive function: (19 / 37 = 51%) • Non-classical phenotype (mental retardation and movement disorder without epilepsy) • Movement disorder: reduced (5 / 7 = 71%) • Subjective improvement in cognitive function: (2 / 7 = 29%) • 4 patients stopped ketogenic diet due to incompliance (9%) Treated with classical ketogenic diet

14. 6 patients with classical phenotype • MAD for 1-42 months • Epileptic seizures and other paroxysmal events decreased markedly in all patients • Improvement in cognitive function in all • Non-paroxysmal ataxia, spasticity, dysarthria, dystonia moderately improved in 4 and slightly improved in 2 • Urine ketones +2 to +3 in all (blood ketones ≥ 2.5mmol/l) • No significant side effects (secondary carnitine deficiency in 1 and hyperuricaemia in 1) 2011

15. Patient 1: classical phenotype: seizure free post classical ketogenic diet, improvement in ataxia and speech • Patient 2: early onset seizure with late onset episodic weakness / ataxia: pending treatment

16. Ketogenic diet in treating underlying inborn errors of metabolism Pyruvate Dehydrogenase Ketolysis ATP Pyruvate Dehydrogenase Deficiency McPherson & McEneny 2012: J Physiol Biochem

17. Diagnosis confirmed by: • Enzymatic analysis • Mutational analysis

18. ♥ ♥ Narrow head, frontal bossing, prominent philtrum and wide nasal bridge

19. Treatment: NO prospective evaluation studies !!

20. Prasad et al 2011: Brain & Development

21. After diet: • Seizure free • Developmentally improving • No more metabolic crisis

22. Ketogenic diet in treating underlying inborn errors of metabolism Mitochondrial Complex I Deficiency Koene & Smeitink 2009 J Intern Med

23. Low carbohydrate diet in mitochondrial diseases Glucose →→→→ Pyruvate metabolism Krebs cycle Oxidative phosphorylation (OXPHOS) Smeitink et al 2003: In Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases Mitochondrial Diseases

24. Can affect any system at any age… Haas et al 2007 Pediatrics Brain • Stroke • Neurodegeneration • Developmental delay • Epilepsy • Movement disorder Eye • Optic neuropathy • Retinitis pigmentosa • Ptosis / oculomotor defect • Cataracts Hearing Endocrine 心臟問題，如心律不正、心肌病變 • Hypothyroidism • Diabetes • Hypoparathyroidism • Deaf Skin • Lipomatosis Heart Kidneys, liver • Arrhythmia • Cardiomyopathy • Renal tubular dysfunction • Nephrotic syndrome • Hepatic dysfunction / failure 四肢神經病變 Gastrointestinal • Dysmotility • Pancreatic dysfunction 生長遲緩 Muscle, nerve, growth Blood • Myopathy, exercise intolerance, neuropathy • Failure to thrive, short statue • Sideroblastic anaemia • Pancytopenia

25. Mitochondrial syndromes • Leigh syndrome • Leber Hereditary Optic Neuropathy (LHON) • Maternally Inherited Diabetes and Deafness (MIDD) • Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS) • Neurogenic weakness, Ataxia and Retinitis Pigmentosa (NARP) • Myoclonic Epilepsy and Ragged Red Fibres (MERRF) • Alpers-Huttenlocher syndrome • Ataxia Neuropathy spectrum • Chronic Progressive External Ophthalmoplegia (CPEO) • Pearson syndrome • Kearns-Sayre syndrome • Mitochondrial Neuro-Gastro-Intestinal Encephalopathy (MNGIE) • Sengers syndrome • MEGDEL syndrome Koene & Smeitink 2011 Mitochondrial Medicine: a clinical guideline

26. Mitochondrial diseases Syndromic Non-syndromic

27. High fat diet treatment in 7 patients (duration up to 4y4m): • MELAS with A3243G n=2 (stable +/- slight deterioration) • Complex I deficiency n=5 (n=1 died, n=4 most initially improved then stabilized) • Complex IV deficiency n=2 (initially improved then died) • With concomitant multivitamin treatment • Conclusion: Well tolerated diet and possibly effective in short-term but ineffective in long-term

28. ‘Hypercaloric diet and a low carbohydrate diet in respiratory chain disorders’ Munnich et al 2012 In: Inborn Metabolic Diseases: Diagnosis and Treatment

29. ` Debranching enzyme Myophosphorylase Myophosphorylase deficiency (Glycogen storage disease V) Carbohydrate-based stimulation of insulin suppressed to minimize glycogen synthesis Ketogenic diet in treating underlying inborn errors of metabolism Roe et al 2003: In Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases Fat

30. Clinical symptoms: • Exercise intolerance with premature fatigue • Exercise-induced muscle pain with working muscles (contractures) • Recurrent myoglobinuria • 55y: exercise intolerance with myalgia with 3 – 60 times increase in endurance level 1year post ketogenic diet Ann Neurol 2005

31. Debranching enzyme Myophosphorylase Debranching enzyme deficiency (Glycogen storage disease III) Carbohydrate-based stimulation of insulin suppressed to minimize glycogen synthesis + High protein diet Ketogenic diet in treating underlying inborn errors of metabolism Fat Roe et al 2003: In Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases Ketone bodies supplementation

32. 2 forms: • Hepatic form (hepatomegaly, hypoglycaemia, hypertriglyceridaemia): favourable outcome with dietary intervention • Muscular form (myopathy, cardiomyopathy): high morbidity and mortality • 2 months boy: • Asymptomatic hypertrophic cardiomyopathy, fasting hypoglycaemia, hypertriglyceridaemia, hepatomegaly • Use of ketogenic and high protein diet, ketone bodies supplementation • 2y therapy: improved cardiomyopathy, no hypoglycaemia, normal muscle power, stable hepatomegaly

33. Ketogenic diet in treating inborn errors of metabolism

34. Use of Ketogenic Diet in Inborn Errors of Metabolism • Related to underlying metabolic defects • Contraindications • Related to associated epilepsy

35. + Disorders of ketogenesis and ketolysis Kossoff et al 2009: Epilepsia

36. Ketogenesis Krebs cycle McNally & Hartman 2012: J Neurochem

37. Contraindication of Ketogenic diet in inborn errors of metabolism Medium / Short Chain Fatty acids Fatty acid oxidation and Ketone metabolism Defects Duran 2003: In Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases

38. Three presentations: Hepatic presentation: hypoketotic hypoglycaemia and Reye-like condition in neonates / infancy triggered by catabolic state Cardiac presentation: dilated / hypertrophic cardiomyopathy +/- arrhythmias in infants Muscular presentation: exercise-induced myopathy and rhabdomyolysis in adults + Peripheral neuropathy Houten & Wanders 2010: J Inherit Metab Dis

39. Ketogenesis defects Hypoketotic hypoglycaemia Encephalopathy Hepatomegaly +/- Cardiomyopathies Ketone body utilization defects Recurrent attacks of ketoacidosis +/- Cardiomyopathies

40. Pyruvate Carboxylase Marin-Valencia et al 2010: Mol Genet Metab

41. Pyruvate Carboxylase Deficiency Pyruvate Carboxylase Contraindication of Ketogenic diet in inborn errors of metabolism

42. Type A: Infantile N. American form Failure to thrive, delayed development Ataxia, spasticity, nystagmus, seizures Type C: • Benign infantile form (RARE) • Episodic metabolic acidosis with high lactate +/- ketones • Normal / mildly impaired development • +/- Dystonia, episodic ataxia, dysarthria, transitory hemiparesis, seizures Type B: • Neonatal French form • Severe hypotonia, tachypnoea, failure to thrive, delayed development • Hepatomegaly, spasticity, seizures, abnormal motor / eye movements Marin-Valencia et al 2010: Mol Genet Metab

43. Marin-Valencia et al 2010: Mol Genet Metab

44. Contraindication of Ketogenic diet in inborn errors of metabolism Krebs Cycle Puy et al 2010: Lancet Porphyrias

45. Puy et al 2010: Lancet

46. Contraindication of Ketogenic diet in inborn errors of metabolism • Fatty acid oxidation disorders • Ketogenesis and ketone bodies utilization disorders • Pyruvate carboxylase deficiency • Porphyrias

47. Red Flags for ketogenic diet contraindications Brain • Motor / movement disorders • Developmental delay • Epilepsy • Neuropsychiatric • + Lactic acidosis Eye • Ocular movement disorder with lactic acidosis Endocrine 心臟問題，如心律不正、心肌病變 • Hypoglycaemia Skin • Photodermatosis Heart • Arrhythmia • Cardiomyopathy Liver • Reye-like syndrome • Hepatomegaly Gastrointestinal 四肢神經病變 • Dysmotility • Abdominal pain 生長遲緩 Blood Muscle, nerve, growth • Haemolytic anaemia • Recurrent metabolic acidosis • Exercise-induced myopathy, recurrent rhabdomyolysis, exercise intolerance, neuropathy • Failure to thrive

48. Kossoff et al

49. Use of Ketogenic Diet in Inborn Errors of Metabolism • Related to underlying metabolic defects • Contraindications • Related to associated epilepsy

50. McNally & Hartman 2012: J Neurochem