ketogenic diet and inborn errors of metabolism cw fung division of child neurology, developmental...

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

‘ 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

ADB Can Med Assoc J 1931

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

Use of Ketogenic Diet in Inborn Errors of Metabolism

• Related to underlying metabolic defects

• Contraindications

• Related to associated epilepsy

McNally & Hartman 2012: J Neurochem

Krebs cycle

Ketogenesis

McPherson & McEneny 2012: J Physiol Biochem

ATP

Ketolysis

Pyruvate Dehydrogenase


Krebs cycle

Ketogenesis

Ketogenic diet in treating underlying inborn errors of metabolism

GlucoseGlucose GlucoseGlucose

Glucose Transporter (Glut-1) Deficiency

Modified Atkins Diet for Glucose Transporter Deficiency

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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

• 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

• 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

McPherson & McEneny 2012: J Physiol Biochem

ATP

Ketolysis

Pyruvate Dehydrogenase

Ketogenic diet in treating underlying inborn errors of

metabolism

Pyruvate Dehydrogenase Deficiency

Diagnosis confirmed by:• Enzymatic analysis• Mutational analysis

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

♥

Treatment: NO prospective evaluation studies !!

Prasad et al 2011: Brain & Development

After diet:

• Seizure free

• Developmentally improving

• No more metabolic crisis

Koene & Smeitink 2009 J Intern Med

Ketogenic diet in treating

underlying inborn errors of

metabolism

Mitochondrial Complex I Deficiency

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

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

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

Mitochondrial diseases

Non-syndromicSyndromic

• 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

‘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



metabolism

Myophosphorylase deficiency (Glycogen storage disease V)

Fat

Carbohydrate-based stimulation of insulin

suppressed to minimize glycogen synthesis

• 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

Myophosphorylase Debranching enzyme

Roe et al 2003: In Physician’s Guide to the Laboratory Diagnosis of

Metabolic Diseases



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

• 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

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

Kossoff et al 2009: Epilepsia

+ Disorders of ketogenesis and ketolysis


Krebs cycle

Ketogenesis

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

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

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

Ketone body utilization defects• Recurrent attacks of

ketoacidosis• +/- Cardiomyopathies

Marin-Valencia et al 2010: Mol Genet Metab

Pyruvate Carboxylase

Contraindication of Ketogenic diet

in inborn errors of metabolism

Pyruvate Carboxylase Deficiency

Pyruvate Carboxylase

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


Puy et al 2010: Lancet

Krebs Cycle


Porphyrias

Puy et al 2010: Lancet


• Fatty acid oxidation disorders• Ketogenesis and ketone bodies utilization

disorders• Pyruvate carboxylase deficiency• Porphyrias

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

Kossoff et al

• 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)

• 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

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

ketogenic diet and inborn errors of metabolism cw fung division of child neurology, developmental...

Documents

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neuropediatricsketogenic

inborn errors of metabolismuse

j intern medketogenic

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deficiencymodified atkins

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