metabolic disease in which organic acids accumulate in blood and urine

 leads to activation of alternative pathways in response to the loss of funciton of a specific gene product

biochemically, clinically and molecularly heterogenous

autosomal recessive pattern of inheritance

vomiting, neurological decompensation, failure to thrive,

unusual odors metabolic acidosis, ketonuria, lactic acidosis,

hyperammonemia, hypoglycemia

Relies on Urine organic acid analysis by GC/MS

specific enzyme deficiency can be inferred based on pattern

then definitive diagnosis can be established by specific enzymatic assays

Acute- interrupt catabolic state, reduce protein intake, remove toxins

long-term= diet -protein restriction, suppliementation of aa, vitamins/minerals, carnitine

branched-chain aa metabolism

 propionate metabolism and related cofactors

 miscellaneous disordres of organic Acid Metabolism

removal of the alpha-amino N from aa to make alpha ketoacids all subsequent intermediates are organic acids or their acyl-Coenzyme A esters

focus on taking carbon skeletons to the kreb acid cycle for reutilization and energy production

in the 2nd reaction leucine, isoleucine and valine use the same enzyme so deficiency across the board

elevated branched chain amino acids and their alpha-ketoacids

increased alloisoleucine

mostly deficient in branched-chain alpha ketoacid dehydrogenase

treated by dietary restriction of branched chain aa

leucine is neurotoxic and will see brain swelling very fast leading to developmental delay

highly prevalent in Old Order Mennonites, mutation in E1a subunit

acute clinical- emesis(throwing up alot), acidosis, sweaty feet odor developemntal delay

A282V mutation identified in newborn screen, but babies are asymptomatic

propionyl-CoA carboxylase deficiency

or deficiency of multiple biotin-dependent carboxylases

primarily due to methylmalonyl-CoA mutase deficiency or

secondary if cofactor deficiency (b12) Cobalamin defects due to mutations in genes required for provision of cobalamin cofactor

primary: methylmalonic aciduria

secondary: hypoglycemia mild hyperlacticacidemia hyperammonemia hyperglycinemia

"ethlene glycole/ acetone" on blood test 

primary deficiency in the recycling of biotin leads to a secondary deficieny of four biotin-requiring enzymes

Clinically: seizures, develop delay, hypotonia, dermatologicala  

diagnosis by enzyme analysis in serum

variable age on onset detected by newborn screening

treatment: biotin (b7) supplementation