Fatty Acid oxidation defects
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Fatty Acid oxidation defects
- 1. Fatty acid - Beta oxidation defects Dr. Fahad ( Pediatric Resident - R4)
- 2. What is a FFA?
- 3. Fatty acid • a fatty acid is a carboxylic acid with a carbon based chain Carbon Based chain Carboxyl group
- 4. Types of FFA: • Fatty acids differ by length, often categorized as short to very long. • Short-chain fatty acids (SCFA) are fatty acids with aliphatic tails of five or fewer carbons (e.g. butyric acid) • Medium-chain fatty acids MCFA) are fatty acids with aliphatic tails of 6 to 12 carbons which can form medium- chain triglycerides. • Long-chain fatty acids (LCFA) are fatty acids with aliphatic tails of 13 to 21 carbons • Very long chain fatty acids (VLCFA) are fatty acids with aliphatic tails of 22 or more carbons.
- 5. Beta oxidation Defects: • Definition • Cases • Pathophysiology • Differential Diagnosis • History and PE • Clinical features • Approach • Management • Critical sample
- 6. Definition: • Fatty acid oxidation disorders (FAODs) are inborn errors of metabolism resulting in failure of : • Carnitine transport defects • Beta oxidation defects • Electron transport chain defects • Ketogenesis defects
- 7. How does it present?
- 8. • A 5-year-old girl is brought in by the emergency medical services to the pediatric emergency room for sudden loss of consciousness in school. She was found to have blood glucose level of 66 and was started on a bolus of intravenous fluids on the way to the hospital. Her mom insisted that patient be given a bolus of D10 Her birth history was as follows: a 6 lbs 3 oz baby girl was born to a 32- year-old G1P0 mom at 39 weeks gestational age with APGAR scores of 8 and 8 after 16 h of labor via spontaneous vaginal delivery without further instrumentation after artificial rupture of membranes. Baby was placed on hypoglycemia protocol for initial low blood glucose levels by finger sticks, but recovered after being given formula feeds in the nursery. The baby's hypoglycemic episodes resolved by day 8 of life and baby was discharged home on breastfeeds after follow-up was advised with a hospital-based pediatrician. Since the age of 4 months, the patient had been hospitalized multiple times for episodes of hypoglycemia (MCAD)
- 9. • A 3-month-old infant with shortness of breath, poor feeding, and lethargy is brought to the emergency department. The mother states that he has had 2 prior episodes of low blood sugar, 1 in the newborn period and the other at 1 month of age. He is non-dysmorphic with low tone, hepatomegaly, poor peripheral perfusion, tachypnea, rales in both lung fields, grunting with retractions, and nasal flaring. There is no jaundice present. An echocardiogram shows dilated cardiomyopathy with pericardial effusions. • The parents had a prior child that died of cardiac failure in early infancy. (VLCAD)
- 10. • A 7-month-old girl was admitted with fever and fatigue of 2 days duration. She was born at 38 weeks gestation after an uneventful pregnancy and delivery. Birth weight was 3115 g; the perinatal period was unremarkable. The child's parents were second-degree cousins of Arabic descent. She had three healthy sisters. At age 5 months, she was referred to a physiotherapist because of mild truncal hypotonia. • On admission, the patient was hemodynamically stable. Body temperature was 36.6°C. Physical examination was unremarkable apart from rales over the right lung, mild hypotonia, muscle weakness (especially in the lower limbs), and head lag. Deep tendon reflexes were normal. • Laboratory tests revealed leukocytosis (white blood cell count, 23,000/μL) with neutrophilia (neutrophils, 14,900/μL), mild microcytic anemia (hemoglobin, 10.6 g/dL), and thrombocytosis (thrombocytes 690,000/μL). Serum glucose, sodium, potassium, and chloride and blood urea nitrogen and creatinine levels were normal. Serum muscle enzyme levels were extremely elevated: creatine kinase was 75,000 U/L (normal, 150 U/L or less), of which 95% was the MM isoenzyme fraction; lactate dehydrogenase was 6075 U/L (normal, 240-1100 U/L), and aspartate aminotransferase was 2317 U/L (normal, 10-40 U/L). • (LCAD)
- 11. • 16 years old enlisted into the military. He has muscle fatigue and exercise intolerance affecting only his lower limbs after intense exercise. • His upper and lower limbs, as well as his neck muscles were affected. He also experienced difficulty in swallowing. • Creatinine kinase levels were elevated 20 times. Muscle biopsy histopathology showed the presence of fat globules within vacuolated muscle fibres and increased oxidative enzyme activates, suggesting a ‘lipid storage disease’. • Exercise intolerance had deteriorated and he can only manage 100 m of walking each time by the time he consulted our centre. No other muscles were affected. There were no accompanying cardiac or respiratory symptoms such as chest pain or breathlessness (ETF defect)
- 12. What sources of energy does our body need?
- 13. Source of fuel • Brain. Glucose is virtually the sole fuel for the human brain, except during prolonged starvation. ketone bodies generated by the liver partly replace glucose as fuel for the brain. • Muscle. The major fuels for muscle are glucose, fatty acids, and ketone bodies • α-Ketoacids derived from the degradation of amino acids are the liver's own fuel. • Fatty acids are the heart's main source of fuel, although ketone bodies as well as lactate can serve as fuel for heart muscle. In fact, heart muscle consumes acetoacetate in preference to glucose.
- 15. In periods of Stress or starvation
- 17. What is beta oxidation?
- 20. Pathophysiology : • Carnitine shuttle • Beta oxidation • Ketogenesis • Ketolysis FREE FATTY ACID FATTY ACYL COA CARNITINE SHUTTLE FATTY ACYL COA S- COA beta oxidation 4 different enzymes 1. Acyl CoA Dehydrogenase 2. Hydratase 3. Hydroxy ACyl CoA Dehydrogenase 4. Thiolase Acetyl CoA Ketogenesis ketolysis C 16 – palmitoyl CoA C16 palmitoleic acid FADH2 NADH FREE CARNITINE CARNITINE ETC
- 21. Steps: • Carnitine shuttle • Beta oxidation • Ketogenesis • Ketolysis FREE FATTY ACID FATTY ACYL COA CARNITINE SHUTTLE FATTY ACYL COA S- COA beta oxidation 4 different enzymes 1. Acyl CoA Dehydrogenase 2. Hydratase 3. Hydroxy ACyl CoA Dehydrogenase 4. Thiolase Acetyl CoA Ketone bodies ketolysis C 16 – palmitoyl CoA C16 palmitoleic acid FADH2 NADH ETC
- 22. Pathogenesis
- 23. Organs Affected: • Brain: • frontal cortex, amygdala and hippocampus* • Heart: • Myocardial ischemia • Muscle: • Rhabdomyolysis *Mini-review: Impact of recurrent hypoglycemia on cognitive and brain function, PMID: 20096711
- 27. Approach
- 29. Clinical Presentation: VLCADD • Severe early-onset form. • Hepatic form • myopathic form LCADD • Neonatal form • Infancy • Adult MCADD • Hypoketotic hypoglycemia with acute liver disease SCADD • Elevated C4 on newborn blood spots
- 30. Management
- 32. Specific Screening tests: • Intermediary Metabolites • Urine organic acids • Acylcarnitine Profiles
- 33. Confirmatory tests: • 1. Analysis of fatty acid β-oxidation in cultured fibroblasts • 2. Measurement of enzyme activity • 3. Mutation analysis
- 34. Acyl CoA Dehydrogenase deficiency Enzyme Age Prevalence Gene Symptoms Plasma FFA ( stress) Plasma acyl carnitines Urine Dicarboxylic acids ( stress) Very Long chain bimodal 1 in 120,000 ACADVL G, L, C, M, R Elevated C14, C16 C 6-12 Long chain hydroxy bimodal 1 in 110,000 HADHA G, L, C, M, R Elevated C16-OH ,C18- OH C 6 -C 14 Medium chain 3-24 months 1 in 20,000 ACADM G, L Elevated C6- C10 C6-C10 Short chain neonate 1 in 35,000 ACADS Asymptomatic Elevated C4 C5
- 35. Treatment
- 36. Treatment: • Acute illnesses should be promptly treated with intravenous fluids containing 10% dextrose to treat or prevent hypoglycemia and to suppress lipolysis as rapidly as possible (see Chapter 92 ). Chronic therapy consists of avoiding fasting. This usually requires simply adjusting the diet to ensure that overnight fasting periods are limited to <10-12 hr. Restricting dietary fat or treatment with carnitine is controversial • In LCADD Some investigators have suggested that dietary supplements with medium-chain triglyceride oil to bypass the defect in long-chain fatty acid oxidation and docosahexaenoic acid (for protection against the retinal changes) may be useful
Notes de l'éditeur
- FREE FATTY ACID IS ACTIVATED TO acYL COA VIA enzyme acyl coa synthase then transferred across the mitochondrial membrane via carnitine shuttle which involve three enzymes . Fatty acyl Coa undergoes beta oxidation to form acetyl CoA. each beta oxidation cycle removes two carbon atoms from the fatty acyl coa and gives it to FADH and NAD, to form FADH2 and NADH and release 1 acetyl coa. For eg 16 carbon atoms palmitoleic acid under goes 7 cycle of beta oxidation forming 8 acetyl Coa The longer the chain the more the acetyl coa . More the acetyl coa , more the ATP the sequential removal of 2-carbon segments in the form of acetyl-CoA
- FREE FATTY ACID IS ACTIVATED TO acYL COA VIA enzyme acyl coa synthase then transferred across the mitochondrial membrane via carnitine shuttle which involve three enzymes . Fatty acyl Coa undergoes beta oxidation to form acetyl CoA. each beta oxidation cycle removes two carbon atoms from the fatty acyl coa and gives it to FADH and NAD, to form FADH2 and NADH and release 1 acetyl coa. For eg 16 carbon atoms palmitoleic acid under goes 7 cycle of beta oxidation forming 8 acetyl Coa The longer the chain the more the acetyl coa . More the acetyl coa , more the ATP
- VLCADD Severe early-onset cardiac and multiorgan failure form. Hepatic or hypoketotic hypoglycemic form Later-onset episodic myopathic form with intermittent rhabdomyolysis LCADD: In its severest form this disorder presents with collapse and death in the neonatal period with acidosis and heart and liver disease. Slightly less severe forms may show failure to thrive from an early age with repeated attacks of lactic acidosis and hypoglycaemia often triggered by intercurrent infections and much milder adult onset forms with muscle or neurological problems have been reported MCAD: A previously healthy individual who becomes symptomatic with: Hypoketotic hypoglycemia, lethargy, seizures, and coma triggered by a common illness Hepatomegaly and acute liver disease (sometimes confused with a diagnosis of Reye syndrome, which is characterized by acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction, and fatty infiltration of the liver) Most FAO disorders including MCAD deficiency frequently manifest with sudden and unexpected death [Rinaldo et al 2002]. The following information supports the possibility of MCAD deficiency: A family history of sudden death or Reye syndrome in sibs Evidence of lethargy, vomiting, and/or fasting in the 48 hours prior to death SCADD
- Intermediary Metabolites Free fatty acids/ 3-hydroxy butyrate. A ratio >2 is indicative of a fatty acid oxidation defect. Fatty acids are mobilised but not converted to ketones. This test is really only useful when the sample is taken during a period of hypoglycaemia or fasting. Organic Acid Profile (OA) Urine organic acids are extracted and converted to their TMS esters and detected by GC-MS. Specific organic acids and glycine conjugates will be present in urine from patients with fatty acid oxidation defects. Note these abnormalities are often only seen during crisis Acylcarnitine Profiles Plasma and blood spot acylcarntines are derivatised and detected by tandem mass spectrometry. Specific acylcarnitine species will be present or increased in some disorders of fatty acid oxidation.
- Analysis of FAO in fibroblasts: This value will give a measure of the patients ability to carry out fatty acid oxidation. Several substrates can be used which will require different chain-length specific enzymes to Metabolise them Measurement of enzyme activity in culture fibroblasts Genetic studies for mutation analysis
- the sequential removal of 2-carbon segments in the form of acetyl-CoA VLCADD: Bimodal : first day ( hypoglycemia ) to adolescents ( C, M) VLCAD is highly expressed in liver, heart, and skeletal muscle When this enzyme is completely or partially deficient, phenotypes vary from severe cardiomyopathy and death in the first few days of life, to recurrent hypoketotic hypoglycemia, or to adolescent or adult presentations with myopathy and/or rhabdomyolysis. VLCAD deficiency presents earlier in infancy and has more chronic problems with muscle weakness or episodes of muscle pain and rhabdomyolysis. Cardiomyopathy may be present during acute attacks provoked by fasting. The left ventricle may be hypertrophic or dilated and show poor contractility on echocardiography. Sudden unexpected death has occurred in several patients, but most who survived the initial episode showed improvement, including normalization of cardiac. During an acute metabolic decompensation,increased levels of C 6-12 dicarboxylic acids LCADD: HADHA - hydroxyacyl-CoA dehydrogenase-alpha subunit Toxic effects of fatty acid metabolites may produce pigmented retinopathy leading to blindness, progressive liver failure, peripheral neuropathy, and rhabdomyolysis. Life-threatening obstetric complications, acute fatty liver of pregnancy, and HELLP syndrome are observed in heterozygous mothers carrying homozygotic fetuses affected with LCHAD deficiency. increases in levels of 3-hydroxydicarboxylic acids of chain lengths C 6 -C 14 MCADD: ACADM The main feature is hypoketotic hypoglycaemia following intercurrent illness. This can cause sudden death or may progress to Reye’s Syndrome. Onset tends to be more commonly from 2 months to 4 years of age but may occur at any time even in adulthood. Muscle and liver problems are not a major feature of this disorder. Sometimes there is significant ketosis. Outcome: If untreated there is a high morbidity and mortality associated with the hypoglycaemia. Treatment is by avoidance of fasting and is usually very successful. Acyl glycines: urinary acylglycines including hexanoyl-propionyl, suberyl-propionyl, and 3-phenylpropionyl glycines SCAD: ACADS