Inborn errors of metabolism

Question 1

What happens to urine in alkaptonuria(AR)?

Answer 1

Urine turns black on standing

Question 2

What deficiency is present in alkaptonuria(AR)?

Answer 2

Homogentisic acid oxidase deficiency

Question 3

What replacement is needed as the patient with alkaptonuria gets older?

Answer 3

Need to have joint/valve replacements as you get older

Question 4

What happens in cystinuria?

Answer 4

Defective transport of cystine and dibasic AAs through epithelial cells of renal tubule and intestinal tract

Question 5

Why do dibasic acids form stones?

Answer 5

Dibasic acids are insoluble so form stones

Question 6

What does a low solubility of cysteine cause the formation of in renal tract?

Answer 6

Cystine has low solubility -formation of calculi in renal tract

Question 7

What mutations cause cystinuria and how can we see this?

Answer 7

• Mutations of SLC3A1 aa transporter gene (Chr 2p) & SLC7A9 (Chr 19)
• Infrared spectroscopy can be done to see this

Question 8

How do we treat a patient with cystinuria?

Answer 8

Treat this by making sure the patient remains hydrated

-3L of water everyday to stop stones forming

Question 9

What is albinism a defect of?

Answer 9

Defect of metabolism of tyrosine

Question 10

What is the phenotype of albinism?

Answer 10

Pink eyes, white hair

Question 11

Tyrosinase negative albinism

Answer 11

• Type 1a - complete lack of enzyme activity due to production of inactive tyrosinase
• Type 1b - reduced activity of tyrosinase

Question 12

Tyrosinase positive albinism

Answer 12

Type II

• AR, biosynthesis of melanin reduced in skin hair and eyes
• most individuals do acquire a small amount of pigment with age

Question 13

What do patients with pentosuria excrete in urine?

Answer 13

Excrete 1-4g pentose sugar L-xylulose daily in urine

Question 14

State of pentosuria

Answer 14

Benign

Question 15

What is the one gene one enzyme concept?

Answer 15

Each gene directly produces a single enzyme, which consequently affects an individual step in a metabolic pathway

Question 16

What are inborn errors of metabolism caused by?

Answer 16

Inborn errors of metabolism are caused by mutations in genes which then produce abnormal proteins whose functional activities are altered

Question 17

What are the 5 mechanisms of inheritance?

Answer 17

• Autosomal recessive
• Autosomal dominant
• X-linked
• Codominant
• mitochondrial

Question 18

What is the most common form of inheritance?

Answer 18

Autosomal recessive

Question 19

What does consanguinity do in autosomal recessive inheritance?

Answer 19

Consanguinity increases risk of autosomal recessive conditions

Question 20

What are the chances in carrying mutation in autosomal dominant?

Answer 20

50% chance of carrying mutation

Question 21

What is X-linked inheritance characterised by?

Answer 21

Characterised by carrier females passing on condition to their affected sons

Question 22

Transmission in X-linked inheritance

Answer 22

No male to male transmission

Question 23

What is co-dominant inheritance?

Answer 23

Two different versions (alleles) of a gene are expressed, and each version makes a slightly different protein

Question 24

What is mitochondrial inheritance inherited from?

Answer 24

Inherited exclusively from mother

Question 25

What can only contribute mitochondria to developing embryo?

Answer 25

only the egg contributes mitochondria to the developing embryo

Question 26

Which parent can only pass on mitochondrial mutations to their children?

Answer 26

only females can pass on mitochondrial mutations to their children

Question 27

What is the criteria for screening inborn errors for metabolism?

Answer 27

- Condition should be an important health problem - Natural history of the condition should be understood - Should be a recognisable latent or early symptomatic stage - Should be a test that is easy to perform and interpret, acceptable, accurate, reliable, sensitive and specific - Should be an accepted treatment recognised for the disease - Treatment should be more effective if started early - Should be a policy on who should be treated - Diagnosis and treatment should be cost-effective - Case-finding should be a continuous process

Question 28

Who criteria for good screening test for inborn errors for metabolism?

Answer 28

- Condition screened for should be an important one - There should be an acceptable treatment for patients with the disease - Facilities for diagnosis and treatment should be available - There should be a recognised latent or early symptomatic stage - There should be a suitable test or examination which has few false positives -specificity - and few false negatives - sensitivity - Test or examination should be acceptable to the population - Cost, including diagnosis and subsequent treatment, should be economically balanced in relation to expenditure on medical care as a whole - Screening programme shouldn’t have too many false postives/negatives

Question 29

What is the national programme for newborn blood spot screening?

Answer 29

- PKU - Congenital hypothyroidism - Cystic fibrosis - MCADD - Haemoglobinopathies - Maple syrup urine disease (MSUD) - Homocystinuria (pyridoxine unresponsive) (HCU) - Isovaleric acidaemia (IVA) - Glutaric aciduria type 1 (GA1)

Question 30

Steps involved in prick heel of baby

Answer 30

1. Samples should be taken on day 5 (day of birth is day 0) 2. All four circles on card need to be completely filled with a single drop of blood which soaks through to the back of the Guthrie card - Can get very different results if not done properly

Question 31

Presentation of IEM from neonate to adult

Answer 31

- Neonatal presentation often acute | - Often caused by defects in energy metabolism

Question 32

Presentation of IEM in adults(Wilson's)

Answer 32

Build up of copper

Question 33

Presentation of IEM in adult(Haemochromatosis)

Answer 33

Men will present before women as women lose blood monthly whereas in men, iron will begin depositing

Question 34

Neonates with IEM

Answer 34

Most are born at term with normal birthweight and no abnormal features

Question 35

What are clues of IEM in neonates?

Answer 35

- Consanguinity - FH of similar illness in sibs or unexplained deaths - Infant who was well at birth but starts to deteriorate for no obvious reason

Question 36

Classic presentation of IEM

Answer 36

- Symptoms - can be very non-specific - Poor feeding, Lethargy, Vomiting, Hypotonia, Fits - Specific symptoms - Abnormal smell (sweet, musty, cabbage-like) - Cataracts - Due to galactosaemia - Hyperventilation due to metabolic acidosis - Hyponatraemia and ambiguous genitalia - Neurological dysfunction with respiratory alkalosis

Question 37

Biochemical abnormalities of IEMs

Answer 37

- Hypoglycaemia - Hyperammonaemia - Unexplained metabolic acidosis / ketoacidosis - Lactic acidosis

Question 38

What are the routine laboratory investigations of IEMS?

Answer 38

- Blood gas analysis - Blood glucose - Plasma ammonia

Question 39

What are specialist investigations of IEMS?

Answer 39

- Plasma amino acids - Looking at phenylketonuria - Urinary organic acids + orotic acid - Blood acyl carnitines - Blood lactate and pyruvate - Mitochondrial disorders - Urinary glycosaminoglycans - Plasma very long chain fatty acids - Peroxisomal disorders

Question 40

What are confirmatory investigations for IEMs?

Answer 40

- Enzymology - Red cell galactose-1-phosphate uridyl transferase - Lysosomal enzyme screening (if suspicious of lysosomal disorder) - Biopsy (muscle, liver) - Fibroblast studies - Complementation studies - Mutation analysis – whole genome sequencing