Ketogenic Diet and Inborn Errors of Metabolism

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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 Childrens
  Hospital

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• 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
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ADB Can Med Assoc J 1931
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Leigh Syndrome Associated with a Deficiency of
the Pyruvate Dehydrogenase Complex Results of
Treatment with a Ketogenic Diet
Ketogenic Diet and Inborn Errors of Metabolism

• Wilburg et al 1992 Neuropediatrics

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Use of Ketogenic Diet in Inborn Errors of
Metabolism

• Related to underlying metabolic defects
• Contraindications
• Related to associated epilepsy

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Use of Ketogenic Diet in Inborn Errors of
Metabolism

• Related to underlying metabolic defects
• Contraindications
• Related to associated epilepsy

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Ketogenesis
Krebs cycle
McNally Hartman 2012 J Neurochem
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Pyruvate Dehydrogenase
Ketolysis
ATP
McPherson McEneny 2012 J Physiol Biochem
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Ketogenic diet in treating underlying inborn
errors of metabolism
Ketogenesis
Krebs cycle
Glucose
Glucose
Glucose Transporter (Glut-1) Deficiency
McNally Hartman 2012 J Neurochem
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Modified Atkins Diet for Glucose Transporter
Deficiency
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Wilhelmina et al
Treated with classical ketogenic diet

• 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)

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2011

• 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)

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• 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

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Ketogenic diet in treating underlying inborn
errors of metabolism
Pyruvate Dehydrogenase
Ketolysis
ATP
Pyruvate Dehydrogenase Deficiency
McPherson McEneny 2012 J Physiol Biochem
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• Diagnosis confirmed by
• Enzymatic analysis
• Mutational analysis

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?
? Narrow head, frontal bossing, prominent
philtrum and wide nasal bridge
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Treatment NO prospective evaluation studies !!
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Prasad et al 2011 Brain Development
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• After diet
• Seizure free
• Developmentally improving
• No more metabolic crisis

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Ketogenic diet in treating underlying inborn
errors of metabolism
Mitochondrial Complex I Deficiency
Koene Smeitink 2009 J Intern Med
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Low carbohydrate diet in mitochondrial diseases
Glucose ????
Pyruvate metabolism
Krebs cycle
Oxidative phosphorylation (OXPHOS)
Smeitink et al 2003 In Physicians Guide to the
Laboratory Diagnosis of Metabolic Diseases
Mitochondrial Diseases
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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
????,??????????

• Hypothyroidism
• Diabetes
• Hypoparathyroidism

• Deaf

Skin

• Lipomatosis

Heart
Kidneys, liver

• Arrhythmia
• Cardiomyopathy

• Renal tubular dysfunction
• Nephrotic syndrome
• Hepatic dysfunction / failure

??????
Gastrointestinal

• Dysmotility
• Pancreatic dysfunction

????
Muscle, nerve, growth
Blood

• Myopathy, exercise intolerance, neuropathy
• Failure to thrive, short statue

• Sideroblastic anaemia
• Pancytopenia

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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
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Mitochondrial diseases
Non-syndromic
Syndromic
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• High fat diet treatment in 7 patients (duration
  up to 4y4m)
• MELAS with A3243G n2 (stable /- slight
  deterioration)
• Complex I deficiency n5 (n1 died, n4 most
  initially improved then stabilized)
• Complex IV deficiency n2 (initially improved
  then died)
• With concomitant multivitamin treatment
• Conclusion Well tolerated diet and possibly
  effective in short-term but ineffective in
  long-term

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Hypercaloric diet and a low carbohydrate diet in
respiratory chain disorders

• Munnich et al 2012 In Inborn Metabolic Diseases
  Diagnosis and Treatment

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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 Physicians Guide to the
Laboratory Diagnosis of Metabolic Diseases
Fat
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Ann Neurol 2005

• 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

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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 Physicians Guide to the
Laboratory Diagnosis of Metabolic Diseases
Ketone bodies supplementation
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• 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

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Ketogenic diet in treating inborn errors of
metabolism
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Use of Ketogenic Diet in Inborn Errors of
Metabolism

• Related to underlying metabolic defects
• Contraindications
• Related to associated epilepsy

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Disorders of ketogenesis and ketolysis
Kossoff et al 2009 Epilepsia
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Ketogenesis
Krebs cycle
McNally Hartman 2012 J Neurochem
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Contraindication of Ketogenic diet in inborn
errors of metabolism
Medium / Short Chain Fatty acids
Fatty acid oxidation and Ketone metabolism Defects
Duran 2003 In Physicians Guide to the
Laboratory Diagnosis of Metabolic Diseases
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• 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
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• Ketone body utilization defects
• Recurrent attacks of ketoacidosis
• /- Cardiomyopathies

• Ketogenesis defects
• Hypoketotic hypoglycaemia
• Encephalopathy
• Hepatomegaly
• /- Cardiomyopathies

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Pyruvate Carboxylase
Marin-Valencia et al 2010 Mol Genet Metab
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Pyruvate Carboxylase Deficiency
Pyruvate Carboxylase
Contraindication of Ketogenic diet in inborn
errors of metabolism
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• 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
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Marin-Valencia et al 2010 Mol Genet Metab
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Contraindication of Ketogenic diet in inborn
errors of metabolism
Krebs Cycle
Puy et al 2010 Lancet
Porphyrias
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Puy et al 2010 Lancet
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Contraindication of Ketogenic diet in inborn
errors of metabolism

• Fatty acid oxidation disorders
• Ketogenesis and ketone bodies utilization
  disorders
• Pyruvate carboxylase deficiency
• Porphyrias

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Red Flags for ketogenic diet contraindications
Brain

• Motor / movement disorders
• Developmental delay
• Epilepsy
• Neuropsychiatric
• Lactic acidosis

Eye

• Ocular movement disorder with lactic acidosis

Endocrine
????,??????????

• Hypoglycaemia

Skin

• Photodermatosis

Heart

• Arrhythmia
• Cardiomyopathy

Liver

• Reye-like syndrome
• Hepatomegaly

Gastrointestinal
??????

• Dysmotility
• Abdominal pain

????
Blood
Muscle, nerve, growth

• Haemolytic anaemia
• Recurrent metabolic acidosis

• Exercise-induced myopathy, recurrent
  rhabdomyolysis, exercise intolerance, neuropathy
• Failure to thrive

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Kossoff et al
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Use of Ketogenic Diet in Inborn Errors of
Metabolism

• Related to underlying metabolic defects
• Contraindications
• Related to associated epilepsy

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McNally Hartman 2012 J Neurochem
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• 14 children with mitochondrial diseases put on
  classical ketogenic diet
• Responses
• 7 Seizure-free
• 1 gt90 seizure reduction
• 2 50-90 seizure reduction
• 4 No improvement / diet stopped due to
  complications (hypoglycaemia, persistent
  metabolic acidosis, aspiration pneumonia)

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• 3 neonatal onset non-ketotic hyperglycinaemia
  (NKH) patients
• On classical ketogenic diet
• All showed gt50 reduction in seizure frequency in
  combination with standard treatment for NKH
• No serious side effects

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Ketogenic Diet and other Dietary Treatments for
epilepsyCochrane 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

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Use of Ketogenic Diet in Inborn Errors of
Metabolism

• Related to underlying metabolic defects
• Contraindications
• Related to associated epilepsy