6s: Metabolic Disorders 2 Flashcards
Urea acid cycle: ammonia → urea
detecting urea cycle defects
7 enzymes in pathway
detecting urea cycle defects:
- ammonia toxic → body removes it (can’t remove HIGH ammonia levels)
- instead, body attaches ammonium group to glutamate → glutamine
to detect urea cycle defects, look for:
- serum glutamine HIGH in hyperammonaemia
- serum amino acids in urea cycle will either be HIGH or ABSENT
- Urine orotic acid
NOTE: LT psych disorders could be an indicator of hyperammonaemia disease → pts may subconsciously reduce protein intake when younger because it made them ill → ‘small build’
How do we treat hyperammonaemia?
remove ammonia (sodium benzoate, sodium phenyl acetate, dialysis)
reduce ammonia production (low protein diet)
Key features of a urea cycle disorder:
- RESPIRATORY ALKALOSIS HYPERAMMONAEMIA
- vomiting without diarrhoea
- neurological encephalopathy
- avoidance or change in diet
3 Autosomal recessive urea cycle defects, 1 X-linked
ALL have HIGH AMMONIA (toxic)
AR:
- lysine protein intolerance
- Hyperornithinaemia-Hyperammonaemia-Homocitrullinuria (HHH)
- Citrullinaemia type III
X-linked:
- Ornithine Transcarbamylase Deficiency (OTC)
Organic acidurias (isovaleria acidaemia): which amino acids and mechanism
defects within complex metabolism of branched chain amino acids:
- leucine, isoleucine, valine
- funny smelling urine (cheesy/sweaty)
leucine breakdown = ammonia group break off (via transaminase), add high energy protein group → isovaleryl CoA
Isovaleryl CoA → isovaleryl CoA dehydrogenase
Molecules with high energy groups CANNOT traverse the membrane so they need to be converted into other molecules:
- export from cell as = isovaleryl carinitine
- excrete as = 3OH-isovaleric acid (cheesy/sweaty smell), isovaleryl glycine
Organic acuduria presentation in neonates
- METABOLIC ACIDOSIS HYPERAMMONAEMIA (high anion gap from ammonia)
- unusual odour
- lethargy
- feeding problems
- truncal and limb hypotonia
- myoclonic jerks
- hypocalcaemia
- neutropenia, thrombopaenia, pancytopenia (red and white cells)
Give a chronic intermittent form of organic aciduria and it’s features
Reye syndrome = recurrent episodes of ketoacidotic coma and cerebral abnormalities
- swelling of LIVER and BRAIN
- vomiting, lethargy, increasing confusion, seizures, decerebration, respiratory arrest
- TRIGGERED by salicylates (aspirin), antiemetics and valproate
Reye syndrome metabolic screen
Reye syndrome metabolic screen
Mitochondrial Fatty Acid Beta-Oxidation (MACDD): features
Causes hypoketotic hypoglycaemia, hepatomegaly and cardiomegaly
- If you are hypoglycaemic, you should be making ketones as an alternative energy source
- If you are unable to make ketones, it suggests that you are unable to break down fatty acids
MCADD (mitochondria fatty acid beta-oxidation) ix’s
Give two carbohydrate disorders
Galactosaemia = mainly Galactose-1-phosphate uridyl transferase (Gal-1-PUT) deficiency
Glycogen storage disease type 1 (von Gierke diseases)
Galactose-1-phosphate uridyl transferase (Gal-1-PUT) deficiency
presentation, ix, tx
3 disorders of galactose metabolism → Gal-1-PUT deficiency (most common and severe)
Raised gal-1-phosphate → liver and kidney disease
Presentation:
- cBR + hepatomegaly
- sepsis (gal-1-phos inhibits immune response)
- D+V
- hypoglycaemia
If not picked up in infancy, can present in early life = Gal-1-pshophate substrate for aldolase (found in eye lens) in high concentrations → bilateral cataracts
ix:
- high galactose in urine
- red cell Gal-1 PUT
tx = avoid galactose (e.g. milk)
Glycogen storage type 1 (von Gierke diseases)
aka G6Pase deficiency pathophysiology
clinical features
glucose → glucose-1-phosphate or glucose-6-phopshate → phosphate groups removed
- P high energy groups (molecule CANNOT get across the membrane)
- without phosphatase, G6P and G1P cannot be exported → glycogen build up in muscles and liver → hypoglycaemia
Clinical features:
- hypoglycaemia
- lactic acidosis
- neutropenia
- hepatomegaly, nephromegaly
Mitochondrial disorders pathophysiology
mtDNA smaller than ncDNA
once certain mtDNA load → develop sx’s
features of mtDNA:
- maternally inherited
- mt disorders present in any organ, any age, any form of inheritance
Defective ATP production → multi system disease esp. organs with high energy requirement
- brain, muscle, kidney, retina, endocrine organs
- if disease affects multiple systems consider mtDNA diseases
examples of mtDNA disorders
Group 1 = toxin accumulation
Reye syndrome (chronic intermittent form of organic aciduria) tx with salicylates (aspirin), antiemetics and valproate
Urea cycle: first 3 AR, last one is X-linked
- Lysinuric protein intolerance
- Hyperornithinaemia-Hyperammonaemia-Homocitrullinuria (HHH) HIGH AMMONIA (toxic)
- Citrullinaemia type III
- Ornithine Transcarbamylase Deficiency (OTC)
Group 2: reduced energy stores
- Galactose-1-phosphate uridyl transferase (Gal-1-PUT) deficiency
Group 3- large molecule synthesis (all dysmorphic)
CDG Type 1a for glycosylation disorders (defect of post-translational protein glycosylation)
Group 4 – defects in large molecule metabolism
Group 5 - mitochondrial
