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Ketogenic Diet and Inborn Errors of Metabolism
CW FungDivision of Child Neurology, Developmental Paediatrics,
NeuroHabilitationDepartment of Paediatrics and Adolescent Medicine,
The University of Hong KongQueen Mary Hospital / Duchess of Kent Children’s 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
Wilburg et al 1992: Neuropediatrics
Ketogenic Diet and 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
![Page 6: Ketogenic Diet and Inborn Errors of Metabolism CW Fung Division of Child Neurology, Developmental Paediatrics, NeuroHabilitation Department of Paediatrics.](https://reader035.fdocuments.us/reader035/viewer/2022062423/56649cdb5503460f949a5908/html5/thumbnails/6.jpg)
Use of Ketogenic Diet in Inborn Errors of Metabolism
• Related to underlying metabolic defects
• Contraindications
• Related to associated epilepsy
![Page 7: Ketogenic Diet and Inborn Errors of Metabolism CW Fung Division of Child Neurology, Developmental Paediatrics, NeuroHabilitation Department of Paediatrics.](https://reader035.fdocuments.us/reader035/viewer/2022062423/56649cdb5503460f949a5908/html5/thumbnails/7.jpg)
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McNally & Hartman 2012: J Neurochem
Krebs cycle
Ketogenesis
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McPherson & McEneny 2012: J Physiol Biochem
ATP
Ketolysis
Pyruvate Dehydrogenase
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McNally & Hartman 2012: J Neurochem
Krebs cycle
Ketogenesis
Ketogenic diet in treating underlying inborn errors of metabolism
GlucoseGlucose GlucoseGlucose
Glucose Transporter (Glut-1) Deficiency
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Modified Atkins Diet for Glucose Transporter Deficiency
0
2
4
6
8
10
12
Pre 1m 3m 4m 6m 9m
Sec
on
ds
Single legstand
0
2
4
6
8
10
12
14
Pre 1m 3m 4m 6m 9m
SARA score
0
5
10
15
20
25
30
Pre 3m 6m 9m
Sco
re
BO Test
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• 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
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• 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
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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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McPherson & McEneny 2012: J Physiol Biochem
ATP
Ketolysis
Pyruvate Dehydrogenase
Ketogenic diet in treating underlying inborn errors of
metabolism
Pyruvate Dehydrogenase Deficiency
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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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Koene & Smeitink 2009 J Intern Med
Ketogenic diet in treating
underlying inborn errors of
metabolism
Mitochondrial Complex I Deficiency
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Glucose →→→→
Smeitink et al 2003: In Physician’s Guide to the Laboratory Diagnosis of
Metabolic Diseases
Pyruvate metabolismKrebs cycle
Oxidative phosphorylation
(OXPHOS)
Low carbohydrate diet in mitochondrial diseases
Mitochondrial Diseases
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生長遲緩生長遲緩
心臟問題,如心臟問題,如心律不正、心心律不正、心肌病變肌病變
Can affect any system at any age…
四肢神經病變四肢神經病變
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 / failureMuscle, 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
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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-syndromicSyndromic
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• 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
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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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`
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
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• 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
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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
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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
Disease Effectiveness
Glucose transporter deficiency Positive
Pyruvate dehydrogenase deficiency
Positive / None
Mitochondrial diseases Transient improvement / None
(High CHO diet with exacerbation)
Myophosphorylase deficiency One case report: deviate from usual practice
Debranching enzyme deficiency
One case report: deviate from usual practice
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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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Kossoff et al 2009: Epilepsia
+ Disorders of ketogenesis and ketolysis
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McNally & Hartman 2012: J Neurochem
Krebs cycle
Ketogenesis
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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
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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
Houten & Wanders 2010: J Inherit Metab Dis
+ Peripheral neuropathy
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Ketogenesis defects• Hypoketotic hypoglycaemia• Encephalopathy• Hepatomegaly• +/- Cardiomyopathies
Ketone body utilization defects• Recurrent attacks of
ketoacidosis• +/- Cardiomyopathies
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Marin-Valencia et al 2010: Mol Genet Metab
Pyruvate Carboxylase
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Contraindication of Ketogenic diet
in inborn errors of metabolism
Pyruvate Carboxylase Deficiency
Pyruvate Carboxylase
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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
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Marin-Valencia et al 2010: Mol Genet Metab
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Puy et al 2010: Lancet
Krebs Cycle
Contraindication of Ketogenic diet in inborn errors of metabolism
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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生長遲緩生長遲緩
心臟問題,如心臟問題,如心律不正、心心律不正、心肌病變肌病變
Red Flags for ketogenic diet contraindications
四肢神經病變四肢神經病變
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
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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 >90% 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 >50% 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 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
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Use of Ketogenic Diet in Inborn Errors of Metabolism
• Related to underlying metabolic defects
• Contraindications
• Related to associated epilepsy