metabolic disorders 1

Question 1

inherited metabolic disorders - IMD can be in which forms?

Answer 1

chromosomal

polygenic - mendelian

monogenic - mendelian

Question 2

which are the most and 2nd most common metabolic diseases?

Answer 2

1. Autosomal
2. X linked
3. Y linked
4. Metabolic

Question 3

How does screenign for metabolic disorders often take place?

Answer 3

Genetic testing - often last resort

We test for the biochemical hallmarks of disease FIRIST which include checking for the levels of;

1. End product - usually lacking
2. Precursors - usually build up
3. Toxic metabolites

Question 4

list 5 things in the IMD screening criteria?

Answer 4

Important health problem
Accepted treatment 
Facilities for diagnosis and treatment
Latent or early symptomatic stage
Suitable test or examination

RCT to prove that screening would reduce mortality and morbidity

Question 5

What is the disease process in the IMD Phenylketonuria PKU?

Answer 5

Normally:
Phenylalanine is converted to Tyrosine by enzyme Phenylalanine hydroxylase

Phenylalanine hydroxylase deficiency = build up of precursor phenylalanine in blood, thus

an increase in toxic metabolites of this precursor:
Phenylpyruvate and phenylacetic acid (urine)

Question 6

How does phenylketonuria present?

Answer 6

IQ < 50 (phenylalanine is toxic to cns)

seizures, behavioral problems, and mental disorders.

sometimes musty smell (of sweat and urine) and light coloured skin, microcephaly.

can have no physical symptoms

Question 7

how can we ivx for phenylalanine?

Answer 7

Cant do genetic test; too many mutations

Measure blood Phenylalanine levels!

Question 8

epidemiology of phenylketonuria?

Answer 8

common 1 in 5000-15,000

Question 9

treatment for PKU?

Answer 9

Monitor diet:

phenylalanine is an essential amino acid so cant cut from diet but intake must be kept low.

there are special dietary supplements for PKU sufferers.

will be fine on diet control.

Start early - first 6 weeks of life to prevent damage.

Question 10

what is sensitivity in reference to disease?

Answer 10

Sensitivity is about disease present:

True positive / Total disease present

“i have sensitive teeth so i buy sensodine, i wouldnt buy sensodine if the disease was not present”

Question 11

what is specificity in reference to disease?

Answer 11

Specificity is about disease absent:

True negative / Total disease absent

Question 12

what is positive predictive value in reference to disease?

Answer 12

Positive predictive value (PV+ve) only refers to positive tests:
True positive / Total positive

Question 13

what is negative predictive value in reference to disease?

Answer 13

Negative predictive value (PV-ve) only refers to negative tests:
True negative/Total negative

Question 14

how is PKU screened for in the UK?

Answer 14

Neonatal heel prick test @ 5-8 days old.

blood -> Guthrie card/Paper -> lab

PPValue = 80%

Question 15

what other test was added to the Guthrie test shortly after PKU?

Answer 15

congenital hypothyroid - not an IMD -

due to thyroid agenesis/dysgenesis -> High TSH

PPV is lower - 60%

Question 16

what is the mechanism of cystic fibrosis?

Answer 16

autosomal recessive

Failure of Cl- ion movement from outside epithelial cell into lumen -> increased reabsorption of Na+ /H2O -> viscous secretions -> ductule blockage

mutations:
Delta508 - most popular (phenylalanine deletion at 508th locus of cftr gene on chromosome 7)

over 500 mutations though

Question 17

how is cystic fibrosis screened for?

Answer 17

In neonates:

High blood immune reactive trypsin - IRT

then check DNA mutations on them - starting with paneel of 4

Question 18

in cystic fibrosis IRT screen, what happens in the following circumstanmces;

2 mutations found

1 mutation found

0 mutations found

Answer 18

2 mutations found - diagnosed with CF

1 mutation found - check with panel of 28 -> diagnosis

0 mutations found - repeat IRT at 3-4 weeks old

Question 19

which test allows for screening of 30+ IMD?

Answer 19

tandem mass spectrometry - not done in uk often

Question 20

name one disorder of fatty acid oxidation?

Answer 20

Medium chain AcylCoA dehydrogenase (MCADD) deficiency

particulalrly Mitochondrial Fatty acid β-oxidation

Question 21

what is the carnitine shuffle - briefly?

Answer 21

invovles the transport of fat into the mitochondrai for breakdown

Question 22

give brief overview of Mitochondrial Fatty acid β-oxidation?

Answer 22

it is fatty acid breakdown by enzymes. there are enzymes for different lengths of the fatty acid.

Long fatty acids (Acyl-coA) C >12 are broken by LCAD (long chain acyl dehydrogenase) into medium length c6-10

C6-10 Acyl-coa – MCAD -> c4-6 acyl-coa – SCAD -> Acyl-coA +*

+* = acetyl coenzyme A (produced at each step of shorter fatty acid formation)

Question 23

what is acetyl coA used for?

Answer 23

Ketonesis

TCA cycle akak Krebs cycle

Question 24

how is Medium chain AcylCoA dehydrogenase (MCADD) deficiency screened for?

Answer 24

Screen for MCAD using acylcarnitine levels by tandem MS

Question 25

Lens dislocation
Mental retardation
Thromboembolism at early age

is caused by which IMD?

Answer 25

Homocystinuria

Question 26

what is the aetiology of homocystinuria?

Answer 26

autosomal recessive

Either the deficiency of folic acid, vitamin B12 or pyridoxine (b6)

Or
Cystathionine beta synthase deficiency:

this is the enzyme that converts homocystine into cystathionine (sister thionine)

causes build up of homocysteine in serum and thus high excretion in urine

Question 27

what is the role of folic acid, vitamin B12 or pyridoxine (b6) in homocystinuria?

Answer 27

supposed to help convert homocysteine back to methionine

deficiency = build up of homocysteine