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Mitochondrial fatty acid oxidation provides the main source of
energy for heart and skeletal muscle and, by generating acetyl-CoA
for ketone-body production, provides energy for other tissues when
the supply of glucose is limited. Fatty acids entering the cell
are esterified with carnitine before being transported across the
mitochondrial membrane and being beta-oxidized in the mitochondrial
matrix as CoA esters (Fig. 150-1). Disorders
that decrease β-oxidation by blocking cellular
carnitine uptake or by impairing entry of fatty acids into mitochondria
or β-oxidation limit energy production by heart
and skeletal muscle at rest and lessen the ability of other tissues,
including the brain, to cope with a low-glucose milieu.
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Most patients with such disorders present before the age of 2
years, about 25% of them in the first week of life. Neonates
may present with cardiac arrhythmias or sudden death, occasionally
with facial dysmorphism and malformations, including renal cystic
dysplasia. Symptoms in infancy and early childhood may relate to
the liver or to cardiac or skeletal muscle, and thus include fasting-
or stress-related hypoketotic hypoglycemia or Reye-like syndrome; conduction
abnormalities; arrhythmias or dilated or hypertrophic cardiomyopathy;
and muscle weakness or fasting- and/or exercise-induced
rhabdomyolysis.
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Diagnosis may be difficult even when the presentation is characteristic.
Probably the most important single diagnostic test is analyzing
acylcarnitine esters in serum or plasma by tandem mass spectroscopy
(MS-MS), which identifies characteristic esters in many disorders,
even when patients are symptom-free. Other tests that may be useful
include analysis of urine organic acids and free and total carnitine
in serum and urine, loading tests with medium- and long-chain fats,
and enzyme assays in leukocytes or fibroblasts.
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Treatment of acute encephalopathy associated with hypoketotic
hypoglycemia is with 10% glucose and l-carnitine, given
intravenously. Long-term therapy involves replenishing carnitine
stores with l-carnitine and preventing hypoglycemia. This may be
accomplished by providing a snack before bedtime, but continuous
intragastric feeding may be required. Except for MCAD deficiency
and the disorders that respond dramatically to carnitine (eg, carnitine
uptake defect), the long-term prognosis for most ...