Chempath - Inborn Errors of Metabolism Flashcards
Deficient enzyme activity leads to:
Lack of end product
Build-up of precursors
Abnormal, often toxic metabolites
PKU
Phenylalanine hydroxylase deficiency
Build up of phenylalanine in the blood - toxic at high levels
Abnormal metabolites: Phenylpyruvate, Phenylacetic acid (urine)
Disadvantage - IQ<50 - toxic to CNS
Common - 1:5000 to 1:15000
Test – blood Phenylalanine
Gene- >400 mutations (can’t to genetic test)
Treatment- Effective if started in first 6 weeks of life - dietary supplements/alternatives
Started screening for this in 1969 (congenital hypothyroidism added in 1970 - PPV+ = approx 60%)
Sensitivity=
True positive / Total disease present
Specificity=
True negative / Total disease absent
Positive predictive value
True positive / Total positive
PPV+ve for classic PKU currently about 80%
Negative predictive value
True negative/Total negative.
Needs to be 100% in screening - better to have a few false positives than miss some when it is treatable
Predictive value depends on
disease prevalence/incidence
Sickle cell started being screened in
2006
CF added in
2008
Incidence 1:2500
Added due to irrefutable evidence that early intervention improves outcome
6 classes of defect.
Failure of Cl- ion movement from inside epithelial cell into lumen –> increased reabsorption of Na+ /H2O viscous secretions –> ductule blockage
Lungs – recurrent infection
Pancreas –malabsorption, steatorrhoea, diabetes
Liver – cirrhosis
Neonate – high blood immune reactive trypsin (IRT)
IRT Test:
If IRT >99.5th centile (>70ng/mL) in 3 bloodspots –> DNA mutation detection (panel of 4):
- 2 mutations - CF
- 1 mutation –> extend panel to 28 mutations –> if there is a second mutation then there is a diagnosis of CF
- 0 mutations –> another IRT at 21-28 days
Testing for phenylalanine
Mass spectrometry
Structure-related fragments separate according
to mass and charge creating a unique fingerprint
MCADD
Added in 2009
Fatty acid oxidation disorder –> don’t get acetyl CoA
Incidence 1 in 10,000
Screened using acylcarnitine levels by tandem MS (mass spectrometry)
Rx - need to make sure babies never become hypoglycaemic
Urea Cycle Deficiencies
1 in 30,000 incidence
Hyperammonaemia - 1 day and your IQ is v bad
10 possible defects
Autosomal recessive except Ornithine transcarbamylase deficiency (OTC) which is X-linked
Often associated with some long term neuro/psych disorder
Body can’t excrete that much ammonia so it gets added to glutamate to make glutamine –> plasma glutamine quite high.
Check plasma amino acids and Urine orotic acid
Rx:
Remove ammonia - sodium benzoate/sodium phenoacetate, dialysis
Reduce ammonia production - low protein diet
Flags:
- Vomiting without diarrhoea
- Resp. alkalosis, Hyperammonaemia
- Neurological Encephalopathy without encephalitis
- Avoidance/Change in diet
Organic Acidurias
Hyperammonaemia with metabolic acidosis and high anion gap
The most important involve the complex metabolism of the branched chain amino acids (leucine, isoleucine and valine) for example:
Leucine metabolism, lacking Isovaleryl CoA –> Isovaleric acidaemia
Export from cell as: Isovaleryl carnitine
Excrete as: 3OH-isovaleric acid (cheesy/sweaty smell), Isovaleryl glycine
Presentation
- Unusual odour
- Neonates: lethargy, feeding problems, truncal hypotonia / limb hypertonia, myoclonic jerks
- Hyperammonaemia with metabolic acidosis and
high anion gap (not accounted for by lactate)
- Hypocalcaemia, Neutropenia, thrombopenia, pancytopenia
Chronic intermittent forms:
- Recurrent episodes of ketoacidotic coma, cerebral abnormalities
- REYE SYNDROME - Vomiting, lethargy, increasing confusion, seizures, decerebration, respiratory arrest. Triggered by: e.g. salicylates, antiemetics, valproate
Reye syndrome metabolic screen (/organic acidurias)
(get these samples when the symptoms are there)
Plasma/blood ammonia
Plasma / urine amino acid
Urine organic acids
Plasma/blood glucose and lactate
Blood spot carnitine profile - this stays abnormal even in remission
Mitochondrial Fatty acid β-oxidation Issues (e.g. MCADD)
Hypoketotic hypoglycaemia, hepatomegaly and cardiomyopathy
Lab:
Blood ketones
Urine organic acids
Blood spot acylcarnitine profile
Galactosaemia
3 known disorders of galactose metabolism. Of these galactose-1-phoshate uridyl transferase (Gal-1-PUT) is the most severe and the most common
Raised gal-1-phosphate causes liver and kidney disease.
Presents with vomiting, diarrhoea, conjugated hyperbillirubinaemia (always pathological in a neonate), hepatomegaly, hypoglycaemia and sepsis (E.coli sepsis as galactose-1-phosphate inhibits immune responses)
If it presents later:
Galactitiol is formed by the action of aldolase (in eye lens) on gal-1-phosphate leading to bilaterial cateracts
Lab- Urine reducing substances, Red cell Gal-1-PUT
Glycogen Storage Disease Type 1
Hepatomegaly Nephromegaly Hypoglycaemia Lactic acidosis Neutropenia
Loads stored but you can’t use it
Mitochondria disorders
Can present in any organ, at any age, with any inheritance
Maternally inherited
Nucelar genome plays a part in mitochondrial functions
Defective ATP production leads to multisystem disease especially affecting organs with a high energy requirement such as brain, muscle, kidney, retina and endocrine organs.
Age vs Disorder:
Birth - Barth (cardiomyopathy, neutropenia, myopathy)
5-15 - MELAS (mitochondrial encephalopathy, lactic acids and stroke-like episodes)
12-30 - Kearns-Sayre (Chronic progressive external ophthalmoplegia, retinopathy, deafness, ataxia)
Ix:
Elevated lactate (alanine) – after periods of fasting (e.g. overnight), before and after meals
(CSF lactate / pyruvate – deproteinised at bedside)
CSF protein (raised in Kearns-Sayre syndrome)
CK
Muscle biopsy
Mitochondrial DNA analysis (not so useful in children)
Congenital disorders of glycosylation
Defect of post-translational protein glycosylation.
Multisystem disorders associated with cardiomyopathy, osteopenia, hepatomegaly and (in some cases) dysmorphia facial or otherwise.
E.g. CDG type 1a - abnormal subcutaneous adipose tissue distribution with fat pads and nipple retraction.
Mortality 20% in first year
Ix: Transferrin glycoforms (serum)
Peroxisomal disorders
Metabolism of very long chain fatty acids and biosynthesis of complex phospholipids
Neonatal:
SEVERE MUSCULAR HYPOTONIA - seizures, hepatic dysfunction including mixed hyperbilirubinaemia
and dysmorphic signs.
Infantile:
retinopathy often leading to early blindness, sensorineural deafness, hepatic dysfunction, mental deficiency, ftt, dysmorphic signs.
Bony changes involve a large fontanel which only closes after the first birthday, osteopenia of long bones, and often calcified stippling especially the patellar region.
Ix:
Very long chain fatty acid profile
Lysosomal Storage Disease
Intraorganelle substrate accumulation leading to organomagaly (connective tissue, solid organs, cartilage, bone and nervous tissue) with consequent DISMORPHIA
also get REGRESSION
Ix:
Urine mucopolysaccharides and/or oligosaccharides
Leucocyte enzyme activities
Rx:
Bone marrow transplant
Exogenous enzyme
Fat Soluble Viatmins
A, D, E, K
Water Soluble Vitamins
B1, B2, B5, B12, C, Folate, B3
Trace Elements
Iron Iodine Zinc Copper Fluoride
