more genetics

Question 1

what is Duchenne muscular dystrophy?

Answer 1

• Primarily a disease of skeletal muscle

–Deficiency of the protein dystrophin

• Other tissues are involved
–Smooth and cardiac muscle
–Central nervous system

Question 2

typical history of duchene muscular atrophy (DMA)

Answer 2

No close family history of any muscle disease

• Normal pregnancy and birth of boy
• Some vague concern about motor and/or general development
• Late walking, falls easily, never earns to run, difficulty on stairs
• Average age of diagnosis: > 4 yrs

Question 3

diagnosis of DMA

Answer 3

• History
– including family
history
• Examination
–Weakness
– calf hypertrophy
–waddling gait
–Gower’s sign ( indicates weakness of the proximal muscles, namely those of the lower limb. The sign describes a patient that has to use his hands and arms to “walk” up his own body from a squatting position due to lack of hip and thigh muscle strength.)

Question 4

investigations for DMA

Answer 4

Serum creatine kinase
–Muscle enzyme; escapes into
bloodstream
• Muscle biopsy
–Decreased or absent dystrophin

Question 5

genetic test for DMA

Answer 5

Dystrophin is a huge gene

• Short arm of X - Xp
• 2.4 million base pairs
• 79 exons
• Finding a mistake is not easy

Question 6

mitochondrial genome

Answer 6

2 rRNA genes
• 22 tRNA genes
• 13 protein coding sequences
• 103 – 104 copies of mtDNA per cell

Question 7

UPD syndromes

Answer 7

1. Maternal UPD14 syndrome (growth failure)
2. • Paternal UPD14 syndrome (dwarfism)
3. • Maternal UPD2 (growth failure)
4. • Maternal UPD16 (growth failure)
5. • Paternal UPD6 (neonatal diabetes)

Question 8

Human imprinted genetic diseases

Answer 8

1. • Prader-Willi Syndrome on 15q11-q13
2. • Angelman’s Syndrome on 15q11-q13
3. • Beckwith-Wiedeman Syndrome on 11p15
4. • Silver-Russell Syndrome on 7p13-p11.2
5. • Albright hereditary osteodystrophy (Chr 20)
6. • Transient neonatal diabetes (TNDM) (Chr 6)

Question 9

cancer epigenetics

Answer 9

• Hypo-methylation and loss of imprinting
(LOI) have both been associated with tumor
formation

• Epigenetic changes are the most common
alterations in human cancer, but it is
difficult to sort out cause & effect
• Epigenetic changes are heritable and
potentially reversible, thus opening up
opportunities for therapeutic intervention

Question 10

Albright’s hereditary osteodystrophy

Answer 10

GNAS is a heavily imprinted locus, with different expression of its isoforms in different tissues dependent on the parental origin of the gene

Parathyroid glands are intrinsically normal
• Abnormality resides in endorgan (renal) response to parathyroid hormone
• Short metacarpals, metatarsals and phalanges, and wide bones
• Thickening of the calvaria are also seen

Question 11

UK, 2006. Adverse Drug Reactions (ADRs) account for….

Answer 11

1 million hospitalizations (6.5% of total), with an annual cost to the NHS of nearly £2 billion.

Question 12

Abacavir gneetics

Answer 12

Reverse transcriptase inhibitor, used to treat HIV and AIDS.

Severe ADR (immune hypersensitivity) in ~5% of patients
• In 2002, very large association of ADR with HLAB*
5701 found, providing strong (but not 100%) prediction

• In 2006 a relatively cheap test for HLA-B*5701 became
available
• Both US and UK have altered label to require genetic
testing

Question 13

Azathioprine

Answer 13

Induces T-cell apoptosis (cell death)
• Used in various treatments where reduction in immune response required (leukemia / transplants / auto-immune dieases (steroid adjunct))

• Thioprine S-methytransferase (TPMT) is an mportant metabolizing enzyme for this drug

Ifn no TPMT, then: AZT >>6-MP >>ThhioGUanine Nucleotides (cytoxicity, immune supression, leukopenia)

• Mutations in TPMT cause complete inactivity in homozygotes (0.3% of Europeans) and reduced activity in heterozygotes (11% of Europeans)
• Contraindicated in homozygotes (risk of fatal toxicity), reduced dose indicated for heterozygotes
• US has altered label to require genetic testing, UK has not
• In UK (2007), it’s estimated about half of all patients given AZA have TPMT genetic testing, half don’t

Question 14

Warfarin

Answer 14

• Widely used to prevent blood clotting in patients (e.g. strokes, deep vein thrombosis, pulmonary embolism, serious coronary malfunctions).

Warfarin (metabolised by CYP2C9) inhibits vit K cycle via enzyme VKORC1, which is required for regeneration of active vit K >> essential for gama-carboxylation of several blood clotting factors.

• Therapeutic dose varies from patients to patient (20-fold difference in effective dose among Caucasian patients)
• Can trigger fatal haemorrhaging if dose too high, or stroke if dose too low
• Warfarin is carefully monitored via regular INR
(International Normalised Ratio) measurements (of blood clotting time)
• Key polymorphisms in VKORC1 (drug action) and CYP2C9 (drug metabolism) influence optimal dose
• Genetic testing is recommended in US (but not in UK) to adjust the starting dose

Question 15

Warfarin and clinical practice

Answer 15

In the UK, there is no such recommendation, and warfarin dosing largely proceeds via careful monitoring of INR rather than via genetic pre-testing.
• Despite considerable evidence for a strong effect of known genetic variants on drug dose, evidence for a link to ADRs less clear.
• New drug (Dabigatran) offers same therapeutic effect without a need for genetic testing

Question 16

Why not more eg’s of clinical practice?

Answer 16

• Clinical practice lags behind academic findings
• Much still not known
– Difficult to get good sample sizes (ADRs are rare)
– Little research in populations of non-European ancestry
• Time delay in waiting for genetic test results
• If ADR not severe and easily monitored, gradual adjustment of dose may be more cost-effective
• Biomarkers may be better than genotypes at predicting ADR
• Economics