Metabolic acidosis (increased anion gap)

Ketonuria

Hypoglycemia

Hyperammonemia

Thrombocytopenia

Amino aciduria, organic aciduria

1.         Removal of the a-amino nitrogen (yields corresponding a-ketoacids)

2.         All subsequent intermediates are organic acids or their acyl-Coenzyme A esters.

3.         Goal of these intermediate pathways is to take carbon skeletons to the tricarboxylic acid cycle for reutilization and energy production.

• also known as branched-chain ketoaciduria
• leucine, isoleucine, and valine are the three essential branched-chain amino acids
• these three amino acids undergo decarboxylation by branched-chain alpha-ketoacid dehydrogenase, a complex enzyme consisting of four subunits and requiring thiamine pyrophosphate as a cofactor
• autosomal recesive
• variable clinical presentation depending on level of residual enzyme activity

• screening-elevation of leucine in blood spots
• amino acid analysis and organic acid profiling (increased BCAA in blood CSF, urine: Alloisoleucine)
• Treatment: dietary restriction, monitoring of plasma leu, aggresive intervention during acute metabolic decompensation
• Age at diagnosis is critical factor

• affected enzyme is Isovalery-CoA dehydrogenase
• accumulation of the derivatives of Isovaleryl-CoA

• Acute (life-threatening): emesis, acidosis, sweaty feet odor
• Chronic: developmental delay

• Deficiency of propiony-coA carboxylase(isolated deficiency for mutations at the alpha or beta locus)
• Deficiency of multiple biotin-dependent carboxylases (holocarboxylase synthetase, and biotinidase)

• deficiency of methylmalonyl-CoA mutase
• Mut defects due to mutations in the gene encoding MCM
• Mut ⁰: no detectable activity even in presence of hydroxycobalamin
• Mut: decreased affinity for AdoCbl and reduced stability
• Cbl defects due to mutations in genes required for provision of cobalamin cofactor
• autosomal recessive

• Accumulation of methylmalonyl-CoA-->Inhibition of PC complex
• accumulation of propionyl-CoA and related compounds-->inhibition of PDH complex, N-acetyl-glutamate synthetase, glycine-cleavage enzyme syste
• hypoglycemia, mild hyperlacticacidemia, hyperammonemia, hyperglycinemia

Cofactor defects (cblA, cblB)

•          Often milder, responsive to cofactor supplementation

CRM- positive mutations (mut^-)

•          Mild or severe, depending on specific mutation

•          Some patients respond to cofactor supplementation

CRM-negative mutations (mut^o)

•          More severe, earlier onset

•          Unresponsive to cofactor supplementation

• Diagnosis by enzyme analysis in serum
• Treatment: Biotin supplementation
• Detected by newborn screening