Metabolic Disorders and Genetic Screening

Question 1

What three types of individuals is genetic screening meant to identify?

Answer 1

1) those affected by the disease (i.e. confirm Dx)
2) those at risk for developing the disease
3) those at risk for having children who may develop the disease

Question 2

What are the three main Wilson and Jungner criteria for approving genetic screening?

Answer 2

1) There should be a detectable early stage
2) Treatment at that early stage should be of more benefit than at later stages
3) Risks (physical and psych) should be less than the benefits

Question 3

Why is hperphenylalaninemia bad?

Answer 3

Some of the excess phenylalanine is metabolized to other compounds such as phenylpyruvate (a keto acid), which is excreted in the urine (phenylketonuria), but other products are toxic to neurons.

Question 4

What is PAH and what essential cofactor does it require?

Answer 4

Phenylalanine Hydroxylase converts phenylalanine to tyrosine and requires BH4 as a cofactor (which is also important for production of Dopa, NE, E, and serotonin).

Question 5

True or false: all PKU disorders can be solved by lowering dietary Phe.

Answer 5

False: some disorders are the result of defective BH4 recycling or synthesis and require supplemental substrates in addition to a low Phe diet to help with symptoms.

Question 6

True or false: even if PKU is detected later in life (after first month), all symptoms are reversible by simply lowering Phe in the diet.

Answer 6

False: all symptoms but mental retardation are reversible.

Question 7

Which of the following is not a symptom of PKU?
Fair skinned (low Tyr-->melanin)
Mousy odor (accum. phenylacetate)
Thick, brown urine
Mental retardation

Answer 7

Thick, brown urine is not seen in PKU patients

Question 8

What are the blood Phe levels in classic PKU, mild PKU, and mild hyperphenylaninemia? Also, what is the Phe/Tyr ratio?

Answer 8

Classic PKU = >20 mg/dl
Mild = 10-20
Hyperphenylaninemia = 3:1

Question 9

How is it determined whether the patients PKU is caused from a defect in PAH (99-97% of patients) or BH4 (1-3% of patients)?

Answer 9

Cofactor defects are excluded by urine/blood pterin analysis.

Question 10

What mode of inheritance, world wide incidence, and mutation are associated with PKU?

Answer 10

Autosomal recessive affects 1/15,000.

Mutation of PAH (12q22-q24.1) is severe if 5%.

Question 11

Which of the following does PKU not display?
Allelic heterogeneity (most patients are compound heterozygotes with both alleles mutant but b/c of different mutations), Locus heterogeneity (affects PAH vs BH4), Late age of onset (affected individuals can have onset of symptoms years after birth) or Pleiotroy (a single gene mutation affects multiple traits)

Answer 11

Late age of onset.

Question 12

How many hours after birth should PKU screening be done? By how many weeks should a dietary restriction be set in place?

Answer 12

Do screening within 24-48 hours (not earlier). Delay in dietary restriction beyond 4 weeks can profoundly impact intellectual development of patient.

Question 13

What is maternal PKU?

Answer 13

Mom stopped her low Phe diet in mid-childhood because it was assumed that her nervous system was matured and immune to Phe damage. But mom gets preggers, and even though her baby may be heterozygous for PKU, the baby still will have mental retardation, microcephaly, and malformations (esp. heart) due to elevated Phe during pregnancy.

Question 14

What is the defected enzyme in lysosomal defects? What is the result of this defective enzyme?

Answer 14

Hydrolase; defect results in accumulation of substrates in the lysosome, enlargment of the affected tissue, and eventual cell death (e.g. neurodegeneration) that is relentlessly progressive.

Question 15

How many hydrolase disorders have been described and what mode of inheritance do they show?

Answer 15

> 50, most of which are autosomal recessive and untreatable.

Question 16

In Tay-Sachs disease, what is the defect, what does it lead to, and what are the three forms?

Answer 16

Defect is an inability to degrade GM2 gangliosides because of a non-functional Hexosaminidase A enzyme, which leads to neuron death. There are three forms: infantile (death by 4; most common form), juvenile (death by 5-15), and adult/late onset (neurodegeneration begins in 20s/30s but usually not fatal).

Question 17

List the five progressional milestones of Tay-Sachs listed in the notes.

Answer 17

1) Normal at birth but neuronal degeneration at 3-6 mo.
2) Motor development plateaus at 8-10 mo (loss of voluntary movement by 2 yo)
3) Progressive blindness by 12 mo.
4) Seizures by 12 mo.
5) Death by 4

Question 18

What is the cherry red spot associated with Tay-Sachs?

Answer 18

A red spot on the retina surrounded by tissue that has been whitened by accumulated GM2 ganglioside.

Question 19

True or false: clinically indistinguishable Tay-Sachs disorders result from mutations in two other genes, but the exact mutation can be distinguished by enzyme assay.

Answer 19

True.

Question 20

In what population is Tay-Sachs most common? (what is the incidence compared to N.American caucasians?)

Answer 20

Ashkenazi Jews (99% of affected Ashkenazi Jews have one of three mutations)
(1/30 Jews carry the mutated HEXA gene, but only 1/250 N.Americans do)

Question 21

What is the Tay-Sachs pseudodeficiency?

Answer 21

It’s a false positive because there is still 20% enzyme activity, which is sufficient to prevent the disorder.

Question 22

True or false: Tay-Sachs is suitable for newborn screening.

Answer 22

False: there is nothing you can do about a positive result.

Question 23

Describe the carrier screening for Tay-Sachs.

Answer 23

Use HEXA enzyme assay: use serum from males and nonpregnant/non-oral contraceptive women OR leukocytes in pregnant/oral contraceptive women. 1/3 of identified heterozygotes actually have the pseudodeficiency allele, so follow up a positive test with a pseudodeficiency test.

Question 24

What about prenatal screening for Tay-Sachs?

Answer 24

Yes if both parents carriers and pseudodeficiency ruled out. If mutation not identified: Use HEXA enzyme assay. If mutation not identified: Use HEXA molecular test. (both by chorionic villus sampling at about 11 weeks or amniocentesis at 17 weeks).