A practical overview of fatty acid oxidation disorders

A practical overview of fatty acid oxidation disorders

SWIM meeting 29.11.2018

Helena Kemp Consultant Chemical Pathologist

North Bristol NHS Trust

Outline

Fatty acid oxidation & mitochondrial -oxidation pathway Disorders & clinical presentation Diagnosis Management Clinical cases

Mitochondrial FAO

Pivotal role in energy homeostasis

Heart, skeletal muscle & liver

Fasting/exercise/illness

Adrenaline/NorAdr/Glucagon/ACTH Activate hormone sensitive lipase Lipolysis induced Release of free fatty acids to feed FAO

Fatty acid oxidation

Energy production (ATP) ? `glucose sparing' Hepatic ketogenesis Supports gluconeogenesis via production of acetyl

CoA/NADH/ATP

FAO Disorders

1. Disorders of plasma membrane function

Carnitine transporter defect (OCTN2), Long chain fatty acid transport/binding defect

2. Disorders of the entry of long-chain fatty acids into the mitochondria

CPT1, CACT, CPT2

3. oxidation defects of long chain fatty acids - mitochondrial membrane bound enzymes

VLCAD, MTP/LCHAD

4. oxidation defects of medium & short chain fatty acids - matrix enzymes

MCAD, SCAD, SCHAD, Crotonase, MCKAT, T2

5. Disorders of impaired electron transfer to the respiratory chain from mitochondrial beta oxidation

MADD

FAO Disorders

20 inherited disorders identified

Autosomal recessive inheritance

Individually rare, collectively more common

1 in 10,000 ? 1 in 750,000 Incidence increasing with newborn screening

Clinical manifestations

Heart, liver & skeletal muscle Provoked/aggravated by energy requiring states (fasting, illness,

prolonged exercise)

Disease specific clinical features/phenotypes

Clinical presentation

Common clinical symptoms Hypoketotic hypoglycaemia

Hepatic encephalopathy, hepatomegaly, hyperammonaemia Cardiomyopathy

Arrythmias & conduction defects Skeletal myopathy & rhabdomyolysis

Atypical and specific symptoms Polyneuropathy Retinopathy Cholestatic jaundice Maternal HELLP/AFLP Congenital abnormalities Hyperinsulinaemic hypoglycaemia Respiratory chain defects/Leigh syndrome

Disorders

CPT1A, CACT, CPT2, OCTN2, VLCADD, MCAD, LCHADD, MTP CPT1A, CACT, CTD, CPT2, VLCADD, LCHADD, MTP, MCAD, MADD

CACT, CPT2, OCTN2, VLCADD, LCHADD, MTP CACT, CPT2, VLCADD, LCHADD, MTP CACT, CPT2, PCD, VLCADD, LCHADD, MTP, MAD

Disorders

LCHADD, MTP LCHADD, MTP LCHADD, MTP, CPT1A

MADD, CPT2

SCHAD ACAD9, Crotonase

Other features...

Heterogeneous clinical phenotypes

Neonatal/severe Infancy onset Later-onset myopathic

Genotype phenotype correlations

CPT2, VLCADD, MADD (severe vs mild presentation) Less good for other disorders Symptomatic carriers described - CPT2 Synergistic heterozygosity

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