1. Ketogenic Diet and Inborn Errors of Metabolism CW Fung Division of Child Neurology, Developmental Paediatrics, NeuroHabilitation Department 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. Leigh Syndrome Associated with a Deficiency of the Pyruvate Dehydrogenase Complex: Results of Treatment with a Ketogenic Diet Wilburg et al 1992: Neuropediatrics Ketogenic Diet and Inborn Errors of Metabolism

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. McNally & Hartman 2012: J Neurochem Krebs cycle Ketogenesis

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

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

12. Modified Atkins Diet for Glucose Transporter Deficiency

13. 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%) Wilhelmina et al 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. McPherson & McEneny 2012: J Physiol Biochem ATP Ketolysis Pyruvate Dehydrogenase Ketogenic diet in treating underlying inborn errors of metabolism Pyruvate Dehydrogenase Deficiency

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

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

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

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 Non-syndromicSyndromic

27. High fat diet treatment in 7 patients (duration up to 4y4m): –MELAS with A3243Gn=2 (stable +/- slight deterioration) –Complex I deficiencyn=5 (n=1 died, n=4 most initially improved then stabilized) –Complex IV deficiencyn=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. ` Myophosphorylase Debranching enzyme Roe et al 2003: In Physician’s Guide to the Laboratory Diagnosis of Metabolic Diseases Ketogenic diet in treating underlying inborn errors of metabolism Myophosphorylase deficiency (Glycogen storage disease V) Fat Carbohydrate-based stimulation of insulin suppressed to minimize glycogen synthesis

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

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 DiseaseEffectiveness Glucose transporter deficiencyPositive Pyruvate dehydrogenase deficiency Positive / None Mitochondrial diseasesTransient improvement / None (High CHO diet with exacerbation) Myophosphorylase deficiencyOne case report: deviate from usual practice Debranching enzyme deficiency One case report: deviate from usual practice

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

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

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

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

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 Houten & Wanders 2010: J Inherit Metab Dis + Peripheral neuropathy

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

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

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

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

44. Puy et al 2010: Lancet Krebs Cycle Contraindication of Ketogenic diet in inborn errors of metabolism 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. 生長遲緩 心臟問題，如 心律不正、心 肌病變 Red Flags for ketogenic diet contraindications 四肢神經病變 Brain Motor / movement disorders Developmental delay Epilepsy Neuropsychiatric + Lactic acidosis Eye Ocular movement disorder with lactic acidosis Liver Reye-like syndrome Hepatomegaly Muscle, nerve, growth Exercise-induced myopathy, recurrent rhabdomyolysis, exercise intolerance, neuropathy Failure to thrive Gastrointestinal Dysmotility Abdominal pain Endocrine Hypoglycaemia Blood Haemolytic anaemia Recurrent metabolic acidosis Heart Arrhythmia Cardiomyopathy Skin Photodermatosis

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

51. 14 children with mitochondrial diseases put on classical ketogenic diet Responses: –7Seizure-free –1>90% seizure reduction –250-90% seizure reduction –4No improvement / diet stopped due to complications (hypoglycaemia, persistent metabolic acidosis, aspiration pneumonia)

52. 3 neonatal onset non-ketotic hyperglycinaemia (NKH) patients On classical ketogenic diet All showed >50% reduction in seizure frequency in combination with standard treatment for NKH No serious side effects

53. Ketogenic Diet and other Dietary Treatments for epilepsy Cochrane Review 2012 Levy et al Several large prospective observational, randomized controlled studies on ketogenic and related diets: reported efficacy in significant proportion of patients with epilepsy Recognized side effects: –Short-term: 30% gastrointestinal-related –Long-term: cardiovascular to be addressed A long-term study showed only 10% patients remained on diet at 3 to 6 years due to lack of effectiveness or restrictive nature of diet Ketogenic diet remains a valid option for medically-intractable non- surgical epilepsy candidates Other more palatable but related diets eg Atkins diet, may have similar effect on seizure control but requires more investigations

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