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Liv Path > Chempath - Inborn Errors of Metabolism > Flashcards

Chempath - Inborn Errors of Metabolism Flashcards

1
Q

Deficient enzyme activity leads to:

A

Lack of end product
Build-up of precursors
Abnormal, often toxic metabolites

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2
Q

PKU

A

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%)

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3
Q

Sensitivity=

A

True positive / Total disease present

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4
Q

Specificity=

A

True negative / Total disease absent

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5
Q

Positive predictive value

A

True positive / Total positive

PPV+ve for classic PKU currently about 80%

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6
Q

Negative predictive value

A

True negative/Total negative.

Needs to be 100% in screening - better to have a few false positives than miss some when it is treatable

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7
Q

Predictive value depends on

A

disease prevalence/incidence

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8
Q

Sickle cell started being screened in

A

2006

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9
Q

CF added in

A

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

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10
Q

Testing for phenylalanine

A

Mass spectrometry
Structure-related fragments separate according
to mass and charge creating a unique fingerprint

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11
Q

MCADD

A

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

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12
Q

Urea Cycle Deficiencies

A

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
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13
Q

Organic Acidurias

A

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
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14
Q

Reye syndrome metabolic screen (/organic acidurias)

A

(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

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15
Q

Mitochondrial Fatty acid β-oxidation Issues (e.g. MCADD)

A

Hypoketotic hypoglycaemia, hepatomegaly and cardiomyopathy

Lab:
Blood ketones
Urine organic acids
Blood spot acylcarnitine profile

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16
Q

Galactosaemia

A

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

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17
Q

Glycogen Storage Disease Type 1

A 
Hepatomegaly
Nephromegaly
Hypoglycaemia
Lactic acidosis
Neutropenia

Loads stored but you can’t use it

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18
Q

Mitochondria disorders

A

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)

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19
Q

Congenital disorders of glycosylation

A

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)
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20
Q

Peroxisomal disorders

A

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

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21
Q

Lysosomal Storage Disease

A

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

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22
Q

Fat Soluble Viatmins

A

A, D, E, K

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23
Q

Water Soluble Vitamins

A

B1, B2, B5, B12, C, Folate, B3

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24
Q

Trace Elements

A 
Iron
Iodine
Zinc 
Copper
Fluoride
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25
Q

A- Retinol

A

Deficiency:
Colour blindness

Excess:
Exfoliation, hepatitis

Test:
Serum

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26
Q

D- Cholecalciferol

A

Deficiency:
Osteomalacia/rickets

Excess:
Hypercalcaemia

Test:
Serum

27
Q

E - Tocopherol

A

Deficiency:
Anaemia/neuropathy
?malignancy/IHD

Test:
Serum

28
Q

K - Phytomenadione

A

Deficiency:
Defective clotting

Excess:

Test:
PPT

29
Q

B1 - Thiamine

A

Deficiency:
Beri-beri
Neuropathy
Wernike syndrome

Excess:

Test:
RBC transketolase

30
Q

B2 - Riboflavin

A

Deficiency:
Glossitis

Excess:

Test:
RBC glutathione reductase

31
Q

B6 - Pyridoxine

A

Deficiency:
Dermatitis/anaemia

Excess:
Neuropathy

Test:
RBC AST activation

32
Q

B12 - Cobalamin

A

Deficiency:
Pernicious anaemia

Excess:

Test:
Serum B12

33
Q

C - Ascorbate

A

Deficiency:
Scurvy

Excess:
Renal stones

Test:
Plasma

34
Q

Folate

A

Deficiency:
Megaloblastic anaemia
Neural tube defect

Excess:

Test:
RBC folate

35
Q

B3 - Niacin

A

Pellagra

36
Q

Iron

A

Deficiency:
Hypohromic anaemia

Excess:
Haemochromatosis

Test:
FBC, Fe, ferritin

37
Q

Iodine

A

Deficiency:
Goitre
Hypothyroidism

Excess:

Test:
TFT

38
Q

Zinc

A

Dermatitis

39
Q

Copper

A

Deficiency:
Anaemia

Excess:
Wilson’s

Test:
Cu
Caeroplasmin

40
Q

Fluoride

A

Deficiency:
Dental caries

Excess:
Flourosis

41
Q

Energy expenditure comprised of

A

REE
Exercise
Thermogenesis
Facultative thermogenesis

42
Q

Body Composition

A 
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

43
Q

Waist Circumference and CHD risk

A

MEN
Increased risk: >94
Major risk: >102

WOMEN
Increased risk: >80
Major risk: >88

44
Q

Protein

A

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
45
Q

Lipid

A

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)

46
Q

Carbohydrate

A 
40-80% total energy intake
Polymerisation into sugars, oligosaccharides and polysaccharides
80 % complex
20 %  simple
NSP  -  non-starch polysaccharides
47
Q

Metabolic Syndrome Criteria

A

Fasting glucose >6.0mmol/l

HDL: men <1, women <1.3

HTN: BP >135/80

Microalbumin/insulin resistance

Wait circumference: men >102, women >88

48
Q

Protein energy malnutrition - Marasmus

A

Shrivelled
Growth retarded
Severe muscle wasting
No s/c fat

49
Q

Protein energy malnutrition - Kwashiorkor

A 
Oedematous
Scaling/ulcerated 
Lethargic
Large liver - fatty liver, s/c fat
Protein deficient
50
Q

Proportion of infant deaths that have low birth weight

A

2/3

51
Q

Common problems in babies of low birth weight

A

Respiratory distress syndrome (RDS) –> ((Retinopathy of prematurity (ROP))

Intraventricular hemorrhage (IVH)
Patent ductus arteriosus (PDA)
Necrotizing enterocolitis (NEC)
52
Q

AXR sign of necrotising enterocolitis

A

Intramural air

53
Q

When is functional maturity of GFR reached?

A

2 years of age

54
Q

Paeds GFR (infant)

A

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

55
Q

Paeds max urine osmolality

A

700mmol/kg

56
Q

Serum ULN potassium - neonate

A

6mmol/L (as opposed to 5.5)

57
Q

In the first week of life, ECF falls by

A

40ml/kg in a term neonate

100ml/kg in a prem neonate

58
Q

Relatively, how much more water/Na+/K+ does a neonate need than an adult?

A

Water - 6 time
Na+ - 3.5 times
K+ 2 times

59
Q

Prolonged jaundice

A

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

60
Q

Conjugated/direct bilirubin >20 mmol/l is

A

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

61
Q

Hypocalcaemia in neonates - cut offs

A
  1. 80 mmol/l Total

0. 70 mmol/l Ionised

62
Q

Osteopenia of prematurity - signs

A

fraying, splaying and cupping of long bones

Normal calcium but really high ALP (approx 10x ULN)

Rx - phosphate/calcium supplements, 1acalcidol

63
Q

Be aware of which other disease that can be confused for rickets

A

Beware transient hyperphosphatasaemia of infancy (benign). Very high ALP – distinguishable by electrophoresis

Liv Path (24 decks)

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