Download NME2.34: case 17

NME2.34: CASE 17 – THE BABIES THAT WOULDN’T WAKE UP
CASE OVERVIEW (1 ST CHILD)
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Normal pregnancy, birth and delivery
Developed upper respiratory tract infection
Baby found cold and unresponsive at 7 months
Initial examination found:
o Large anion gap
o Severe hypoglycaemia
o Lactic acidosis
Further examination found:
o Microsteatosis
o Elevated plasma branched-chain amino acids
o Diagnosis: Sudden infant death syndrome (SIDS)
CASE OVERVIEW (3 RD CHILD)
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Normal pregnancy, birth and delivery
Drowsiness before feeding
Baby found pale and unresponsive
Initial examination found:
o Moderate hypoglycaemia
o Elevated non-esterified fatty acids
o Inappropriately low ketone body levels
o Un-recordable insulin levels
Urine test revealed abnormal organic acids– dicarboxylic, suberglycine, hexanoylglycine
Blood test revealed medium-chain acyl-carnitines
Diagnosis: Medium-chain acyl-CoA dehydrogenase deficiency (MCAD)
MEDIUM-CHAIN ACYL-COA DEHYDROGENASE DEFICIENCY (MCAD)
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An inherited disorder of mitochondrial fatty-acid oxidation
Autosomal recessive with UK incidence of around 1 in 8000
Caused by a single enzyme deficiency (medium chain acyl-CoA dehydrogenase)
Significant phenotypic heterogeneity including:
o Asymptomatic
o Hypoglycaemic encephalopathic episodes
o Sudden death – SIDS
Presents with:
o Vomiting and lethargy following fasting
o Prior viral infection
o History of similar episodes
o Asymptomatic between episodes
10/03/08
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Management and treatment:
o Avoid fasting
o Maintain calorific intake of carbohydrates
o Support aggressively in case of infection or fever
o Supplement with L-carnitine during illness
PATHOPHYSIOLOGY IN MCAD
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Lipid metabolism involves:
o Lipolysis – release of free fatty acids and glycerol (see NME 2.29)
o Esterification of free fatty acids with coenzyme-A to form acyl-CoA
o Transport into the mitochondrial matrix using carnitine
o β-oxidation of acyl-CoA to acetyl-CoA which then enters the TCA cycle
Medium-chain acyl-CoA dehydrogenase is one of several key enzymes involved in β-oxidation
o Different enzymes degrade the acyl-CoA chain as it gets shorter
o MCA acts on chains between C6 – C10 in length
MCAD results in a build-up of C6, C8 and C10 acyl-CoA esters
o Some bind to carnitine and leak into the blood as octanoyl- and hexanoyl-carnitine
o Some bind to glycine and are expressed as octanoyl- and hexanoyl-glycine
o Elevated levels of any of the aforementioned organic acids is characteristic of MCAD
MCAD results in an inability to produce sufficient quantities of acetyl-CoA from β-oxidation
o Acetyl-CoA is used in the liver for ketogenesis during fasting
o Acetyl-CoA is also an allosteric activator of pyruvate carboxylase in gluconeogenesis
o MCAD sufferers have a low tolerance of fasting due to their impaired ketogenic and
gluconeogenic abilities
MCAD results in an accumulation of fatty acids which can have toxic effects (e.g. encephalopathy)
DETECTION AND SCREENING OF MCAD
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Investigation should start with an examination of the major body fuels following a controlled fast:
o Glucose levels will be low
o Non-esterified fatty acid levels will be high
o Ketone body levels will be inappropriately low
Subsequently, body fluids should be screened for abnormal metabolites:
o Acyl-carnitines will show high levels of C6 - C8 esters in the blood
o Organic acids (e.g. acyl-glycines) may be present in the blood and urine
Finally the subject should undergo DNA analysis:
o 985AG (single amino-acid residue substitution) is the most common defect
o PCR can be used to detect such mutations