Organic Acids Flashcards
What are organic acids?
- Water soluble compounds containing one or more carboxyl groups and other non-amino functioning groups
- Small MW organic acids are intermediates in most metabolic pathways
What are Organic Acidaemias?
- Generally describes all disorders detectable by the analytical technique
- Detects over 200 compounds. Not all technically organic acids eg glycerol and glycine conjugates, important metabolite group
- Not a distinct group in metabolism – detects disorders a large number of pathways
What are Analytical Methods for Organic Methods?
- HPLC
- Tandem MS - quant specific compounds e.g. HVA, HIAA
- GCMS - Technique of choice for metabolic screening
What are clinical indications of analysis of Organic Acidaemias?
Acute, Intoxication
- Unexplained metabolic acidosis
- Hyperammonaemia
- Hypoglycaemia
- Lactic acidaemia
- Ketonuria
Chronic
- Developmental delay
- Fits or seizures
- Liver disease
What are examples of classical organic acidurias?
- Propionic aciduria (PA)
- Methylmalonic aciduria (MMA)
- Isovaleric aciduia (IVA): Amino acids at the top of these disorders do not accumulate
What are clinical presentations of PA/MMA/IVA?
Severe neonatal onset:
- Acute metabolic decompensation & neurological distress - ketoacidosis, encephalopathy leading to coma, vomiting, lethargy, hypotonia/hypertonia, hyperammonaemia
Acute intermittent late onset form:
- Failure to thrive, with recurrent episodes of metabolic decompensation
Chronic progressive forms:
- Failure to thrive, hypotonia and developmental delay
How are Organic Acidaemia treated?
Acute:
- Prevent catabolism/promote anabolism (fluids/dextrose)
- Possibly bicarb to control the acidosis
- Lowering ammonia: benzoate/phenylbutyate, Dialysis
Long-term:
- Protein restrict
- Carnitine
- B12 (for MMA if responsive)
- Metronidazole (for MMA/PA decreases bacterial propionate production)
- Emergency regimen
What is the prognosis for IVA?
- Normal growth
- Intellectual prognosis depends on early diagnosis and treatment
- Risk of acute decompensation at times of catabolic stress
What is the prognosis of PA/MMA?
- 15% of MMA are B12 responsive => good long term outcome
- Rest severe disease with many encephalopathic episodes
- Morbidity is high – mild to moderate intellectual disability, abnormal neurology (movement disorders, hypotonia)
- Chronic progressive renal impairment in MMA (most need transplant if they survive into adolescence)
- Survival rates into early/mid childhood now exceed 70%
- Liver/combined liver & kidney transplant can be beneficial in MMA
How does Hyperammonaemia occur in organic Acidaemias?
- Accumulation of Proprionyl-CoA, Methymalonyl-CoA and Isovaleryl-CoA
- They competitively inhibit NAGS which makes the co-factor for the enzyme in the first step of the Urea cycle from Glutamate
- Therefore, the ammonia accumulate. The ammonia you get in these disorder can be equivalent to the ammonia in the urea cycle defect
What types of 2-hydroxyglutaric aciduria?
2 x inborn errors of different aetiology
- D-2-hydroxyglutaric aciduria
- L-2-hydroxyglutaric aciduria
What are symptoms of D-2-hydroxyglutaric aciduria?
Clinical symptoms - neurological
- Developmental delay
- Epilepsy
- Hypotonia,
- Abnormalities of cerebrum (controls muscle, movement, speech, vision, etc).
What are symptoms of L-2-hydroxyglutaric aciduria?
Consistently associated with neurological symptoms
- Progressive ataxia
- Mental retardation
- Epilepsy
- Peripheral leukodystrophy (U-fibres)
What is the enzyme defect in L-2-hydroxyglutaric aciduria?
L-2-hydroxyglutarate dehydrogenase
- Located in mitochondria
- Autosomal Recessive (31 different mutations found in 80 patients. Most result in null alleles)
How does toxicity occur in L-2-hydroxyglutaric aciduria?
- L-2-hydroxyglutarate is thought to be a toxic compound
- Normally L-2-OH glutarate dehydrogenase “mops it up” converting it back to α-ketoglutarate
- Therefore, defect is in this enzyme leads to accumulation of the toxic compound
