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
A- Retinol
Deficiency:
Colour blindness
Excess:
Exfoliation, hepatitis
Test:
Serum
D- Cholecalciferol
Deficiency:
Osteomalacia/rickets
Excess:
Hypercalcaemia
Test:
Serum
E - Tocopherol
Deficiency:
Anaemia/neuropathy
?malignancy/IHD
Test:
Serum
K - Phytomenadione
Deficiency:
Defective clotting
Excess:
Test:
PPT
B1 - Thiamine
Deficiency:
Beri-beri
Neuropathy
Wernike syndrome
Excess:
Test:
RBC transketolase
B2 - Riboflavin
Deficiency:
Glossitis
Excess:
Test:
RBC glutathione reductase
B6 - Pyridoxine
Deficiency:
Dermatitis/anaemia
Excess:
Neuropathy
Test:
RBC AST activation
B12 - Cobalamin
Deficiency:
Pernicious anaemia
Excess:
Test:
Serum B12
C - Ascorbate
Deficiency:
Scurvy
Excess:
Renal stones
Test:
Plasma
Folate
Deficiency:
Megaloblastic anaemia
Neural tube defect
Excess:
Test:
RBC folate
B3 - Niacin
Pellagra
Iron
Deficiency:
Hypohromic anaemia
Excess:
Haemochromatosis
Test:
FBC, Fe, ferritin
Iodine
Deficiency:
Goitre
Hypothyroidism
Excess:
Test:
TFT
Zinc
Dermatitis
Copper
Deficiency:
Anaemia
Excess:
Wilson’s
Test:
Cu
Caeroplasmin
Fluoride
Deficiency:
Dental caries
Excess:
Flourosis
Energy expenditure comprised of
REE
Exercise
Thermogenesis
Facultative thermogenesis
Body Composition
Normal weight individual: 98% O2, C, H, Na, Ca 60-70% H2O 10-35% fat 10-15% protein 3-5% minerals
Variation body composition considerable, variation in LBM less
Waist Circumference and CHD risk
MEN
Increased risk: >94
Major risk: >102
WOMEN
Increased risk: >80
Major risk: >88
Protein
INTAKE 84gm men, 64gm women
Utility
- Indispensable (e.g. leucine)
- “conditionally” indispensable (e.g. Cysteine)
- Dispensable (e.g. alanine)
Protein synthesis/breakdown/oxidation
Assessment
- N excretion and balance
- Tracer techniques
Lipid
Polyunsaturated fatty acid (PUFA) include essential fatty acids (EFA). They have multiple double bonds e.g. linoleic acid.
Dietary fat determines LDL-C
- saturated fat increases [chol]
- PUFA decreases [chol]
Increased [HDL] associated reduced IHD risk (women, alcohol, obesity)
Carbohydrate
40-80% total energy intake Polymerisation into sugars, oligosaccharides and polysaccharides 80 % complex 20 % simple NSP - non-starch polysaccharides
Metabolic Syndrome Criteria
Fasting glucose >6.0mmol/l
HDL: men <1, women <1.3
HTN: BP >135/80
Microalbumin/insulin resistance
Wait circumference: men >102, women >88
Protein energy malnutrition - Marasmus
Shrivelled
Growth retarded
Severe muscle wasting
No s/c fat
Protein energy malnutrition - Kwashiorkor
Oedematous Scaling/ulcerated Lethargic Large liver - fatty liver, s/c fat Protein deficient
Proportion of infant deaths that have low birth weight
2/3
Common problems in babies of low birth weight
Respiratory distress syndrome (RDS) –> ((Retinopathy of prematurity (ROP))
Intraventricular hemorrhage (IVH) Patent ductus arteriosus (PDA) Necrotizing enterocolitis (NEC)
AXR sign of necrotising enterocolitis
Intramural air
When is functional maturity of GFR reached?
2 years of age
Paeds GFR (infant)
Low GFR for surface area; consequences are:
- slow excretion of a solute load
- limited amount of Na+ available for H+ exchange
Short proximal tubule means there is a lower reabsorptive capability than in the adult although reabsorption is usually adequate for the small filtered load.
Loops of Henle/distal collecting ducts are short and juxtaglomerular giving a reduced concentrating ability with a maximum urine osmolality of 700 mmol/kg.
Distal tubule is relatively unresponsive to aldosterone –> leads to a persistent loss of sodium of c.1.8 mmol/kg/day and potential reduced potassium excretion
Paeds max urine osmolality
700mmol/kg
Serum ULN potassium - neonate
6mmol/L (as opposed to 5.5)
In the first week of life, ECF falls by
40ml/kg in a term neonate
100ml/kg in a prem neonate
Relatively, how much more water/Na+/K+ does a neonate need than an adult?
Water - 6 time
Na+ - 3.5 times
K+ 2 times
Prolonged jaundice
Prolonged jaundice is jaundice that lasts for more than 14 days in term babies and more than 21 days in preterm babies.
Potential causes:
Prenatal infection/sepsis/hepatitis
Hypothyroidism
Breast milk jaundice
Conjugated/direct bilirubin >20 mmol/l is
ALWAYS PATHOLOGICAL
Biliary atresia, choledocal cyst
1/17 000 UK
20% associated with cardiac malformations, polysplenia, sinus inversus
Early surgery essential
Ascending cholangitis in TPN ( total parenteral nutrition)
Related to lipid content
IEM: Galactosaemia, alpha 1-AT def, tyrosinaemia 1, peroxisomal dis
Hypocalcaemia in neonates - cut offs
- 80 mmol/l Total
0. 70 mmol/l Ionised
Osteopenia of prematurity - signs
fraying, splaying and cupping of long bones
Normal calcium but really high ALP (approx 10x ULN)
Rx - phosphate/calcium supplements, 1acalcidol
Be aware of which other disease that can be confused for rickets
Beware transient hyperphosphatasaemia of infancy (benign). Very high ALP – distinguishable by electrophoresis
