Metabolic disorders and screening

Question 1

What are the patterns of inheritence of metabolic disorders?

Answer 1

Chromosomal

Mendelian:

• Polygenic
• Monogenic

Question 2

What may deficient enzyme activity be due to?

Answer 2

Deficient enzyme activity may be due to lack of enzyme or reduced enzyme activity due to defects of post-translational modification, assembly or transportation or to defects of cofactor activation.

Question 3

What can deficient enzyme activity lead to?

Answer 3

Lack of end product

Build-up of precursors

Abnormal, often toxic metabolites

Question 4

What are the screening criteria for inherited metabolic disorders?

Answer 4

1. Important health problem
2. Accepted treatment
3. Facilities for diagnosis and treatment
4. Latent or early symptomatic stage
5. Suitable test or examination
6. Test should be acceptable to the population
7. Natural history understood
8. Agreed policy on whom to treat as patients
9. Economically balanced
10. Continuing process

Question 5

What is phenylketonuria (PKU)?

Answer 5

Phenylalanine hydroxylase deficiency

Question 6

What are the features of classic PKU?

Answer 6

Disadvantage: IQ<50

Common: 1:5000 to 1:15000

Test: Blood Phe

Gene: >400 mutations

Treatment: Effective

Question 7

What is the heel prick test?

Answer 7

5-8 days of life (in UK).

Heel prick capillary from posterior medial third of foot.

Blood spotted onto Guthrie card (thick filter paper).

Question 8

What is congenital hypothyroidism?

Answer 8

Incidence 1:4000 (wrong on handout)

Inherited in only 15%

Usually dysgenesis/agenesis of thyroid gland

Not always detected clinically

Based on high TSH (in UK)

PPV+ve c.60-70%

Question 9

What does the Guthrie heel prick test test for?

Answer 9

• PKU from 1969
• Congenital hypothyroidism added 1970
• Sickle cell disease added 2006
• Cystic fibrosis added 2007
• Medium chain AcylCoA dehydrogenase (MCADD) added 2009

Question 10

What should you consider in hyperammonaemia with metabolic acidosis and high anion gap?

Answer 10

Organic acidurias

The most important involve the complex metabolism of the branched chain amino acids (leucine, isoleucine and valine).

Question 11

What is the presentation of organic acidurias in neonates?

Answer 11

Unusual odour

Lethargy, feeding problems, truncal hypotonia/limb hypertonia, myoclonic jerks.

Hyperammonaemia with metabolic acidosis and high anion gap (not lactate).

Hypocalcaemia

Neutropenia, thrombopenia, pancytopenia

Question 12

What is Reye’s Syndrome?

Answer 12

Recurrent episodes of ketoacidotic coma, cerebral abnormalities.

Vomiting, lethargy, increasing confusion, seizures, decerebration, respiratory arrest.

Triggered by: e.g. salicylates, antiemetics, valproate.

Question 13

What is investigated in Reye’s Syndrome?

Answer 13

Collect during acute episode:

Plasma/blood ammonia

Plasma/urine amino acid

Urine organic acids

Plasma/blood glucose and lactate

Stays abnormal in remission:

Blood spot carnitine profile

Question 14

What are signs of mitochondrial fatty acid β-oxidation?

Answer 14

Hypoketotic hypoglycaemia, hepatomegaly and cardiomyopathy.

Question 15

What are laboratory findings of mitochondrial fatty acid beta-oxidation?

Answer 15

(Blood ketones)

Urine organic acids

Blood spot acylcarnitine profile

Question 16

What are carbohydrate disorders?

Answer 16

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 hyperbilirubinaemia, hepatomegaly, hypoglycaemia and sepsis.

Question 17

Why can galactosaemia lead to cataracts?

Answer 17

Galactitiol is formed by the action of aldolase on gal-1-phosphate leading to bilaterial cataracts.

Question 18

What are lab findings of galactosaemia?

Answer 18

Urine reducing substances

Red cell Gal-1-PUT

Question 19

How does glycogen storage disease type 1 present?

Answer 19

Hepatomegaly

Nephromegaly

Hypoglycaemia

Lactic acidosis

Neutropenia

Question 20

What are mitochondrial diseases?

Answer 20

Any organ, any age, any inheritance. mtDNA is small cf to nuclear DNA.

Heteroplasmy means that clinical manifestations become evident at a certain threshold of mutant DNA.

Mitochondrial DNA is maternally inherited – although nuclear genomes plays a huge role in mitochondrial function.

Question 21

What is the pathophysiology of mitochondrial diseases?

Answer 21

Defective ATP production leads to multisystem disease especially affecting organs with a high energy requirement such as brain, muscle, kidney, retina and endocrine organs.

Question 22

Which mitochondrial disorder presents at birth?

Answer 22

Barth: Cardiomyopathy, neutropenia, myopathy

Question 23

Which mitochondiral disease presents between the ages of 5-15?

Answer 23

MELAS (mitochondrial encephalopathy, lactic acids and stroke-like episodes)

Question 24

Which mitochondrial disorder presents between the ages of 12-30?

Answer 24

Kearns-Sayre

Chronic progressive external ophthalmoplegia, retinopathy, deafness, ataxia.

Question 25

What are laboratory findings of mitochondrial disorders?

Answer 25

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)

Question 26

What are congenital disorders of glycosylation?

Answer 26

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.

Question 27

What is the prognosis of congenital disorders of glycosylation?

Answer 27

Mortality 20% in first year.

Question 28

What are laboratory findings of congenital disorders of glycosylation?

Answer 28

Transferrin glycoforms (serum)

Question 29

What are peroxisomal disorders?

Answer 29

Metabolism of very long chain fatty acids and biosynthesis of complex phospholipids.

Question 30

What are signs and symptoms of peroxisomal disorders in neonates?

Answer 30

Severe muscular hypotonia Seizures Hepatic dysfunction including mixed hyperbilirubinaemia Dysmorphic signs

Question 31

What are signs and symptoms of peroxisomal disorders in infants?

Answer 31

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 in the patellar region.

Question 32

What are lab investigations for peroxisomal disorders?

Answer 32

Very long chain fatty acid profile

Question 33

What are lysosomal storage disorders?

Answer 33

Intraorganelle substrate accumulation leading to organomagaly (connective tissue, solid organs, cartilage, bone and nervous tissue) with consequent dysmorphia.

Question 34

What are lab investigations for lysosomal storage disorders?

Answer 34

Urine mucopolysaccharides and/or oligosaccharides Leucocyte enzyme activities

Question 35

What is the treatment for lysosomal disorders?

Answer 35

Bone marrow transplant Exogenous enzyme