Fatty Acid Oxidation/ Mitochondrial Diseases Flashcards
Describe the chain length classifications of fatty acids.
short chain: 2-8 C
medium chain: 10-12 C
long chain: >12 C (but for this it is less than 16)
How do fatty acids enter the mitochondria?
short and medium chain enter via diffusion
long chain use carnitine shuttle
Why is beta oxidation important?
important for energy production
main source of energy to muscles when fasting
main source of energy to heart
generates ketone bodies which are an alternative energy source for extrahepatic organs (brain)
How do FA oxidation defects present acutely (in general)?
hypoketotic hypoglycemia coma liver failure hyperammonemia cardiomyopathy
How do FA oxidation defects present chronically (in general)?
myopathy
rhabdomyolysis/exercise intolerance
cardiomyopathy
Describe the Carnitine transporter defect/Carnitine uptake defect.
defect of carnitine transporter (first step in the carnitine shuttle)
can present in infancy (hypoketotic hypoglycemia, elevated liver enzymes, hyperammonemia triggered by fasting or illness such as URI/gastroenteritis), childhood (myopathy involving heart and skeletal muscles), or adulthood (fatigue or completely asymptomatic)
good prognosis with carnitine supplementation
How is the Carnitine transporter defect/Carnitine uptake defect diagnosed?
low plasma carnitine (free and total)
high urine carnitine
molecular genetic analysis of SLC22A5
DO NOT use enzyme activity in fibroblasts
What is CPT1A deficiency?
OMM transporter (2nd step in carnitine shuttle)
presents with hepatic encepahlopathy (precipitated by fasting or fever)
rapid onset of symptoms in association with a relatively common infectious disease such as febrile or GI illness
What is CACT defect?
IMM transporter (3rd step in carnitine shuttle)
rare
usually presents in neonatal period with severe hypoketotic hypoglycemia, liver failure, and hyperammonemia
can present later in life
What is CPTII deficiency?
IMM bound enzyme involved in converting acylcarnitine and CoASH to carnitine and Acyl-CoA
most common carnitine cycle disorder
variable presentations as neonate (neonatal hypoglycemia, liver failure, or cardiomyopathy as well as congenital brain and kidney abnormalities), infant (hypoglycemia, liver failure, cardiomyopathy, and myopathy), or adult (recurrent exercise or stress induced myoglobinuria)
How does Acyl-CoA dehydrogenase deficiency for VLCAD present?
early onset (no residual enzyme activity): hepatoketotic hypoglycemia, cardiomyopathy, hepatomegally childhood onset: hypoketotic hypoglycemia and hepatomegally adult onset: recurrent rhabdomyolysis with myoglobinuria
How does Acyl-CoA dehydrogenase deficiency for MCAD present?
hypoketotic hypoglycemia
Reye syndrome
unexpected death (early presentation is less severe due to ability to still process VLCADs for energy)
How does Reye syndrome present?
hypoglycemia hyperammonemia increased transaminase brain edema fatty liver
How does Acyl-CoA dehydrogenase deficiency for SMAD present?
symptomatic patients present with failure to thrive, hypotonia, and a variety of other symptoms (that may or may not be related)
normally only bad if combined with another condition
What is Multiple Acyl-CoA Dehydrogenase Deficiency (MADD)?
allows for transfer of electrons to ETC from FA and other compounds via complex II (electron transfer flavaprotien is the e- accepter) Type I (neonatal onset form with congenital anomalies)- usually lethal Type II (neonatal onset form without congenital anomalies)- usually lethal Type III (late onset form)- variable with recurrent episodes of lethargy, emesis, hypoglycemia, metabolic acidosis, hepatomegally, muscle pain, and weakness lethality due to severe non-ketotic hypoglycemia, metanolic acidosis, multisystem involvement and excretion of large amounts of FA and AA derived metabolites
