CPC On Genetic Disease

16.2.07

Case 1
• Male aged 24.
• Family history of colon cancer.
• Been on screening since aged 10.
• Now colectomy.

Familial adenomatous polypoposis (FAP)
• Autosomal dominant.
• APC gene - tumour suppressor gene.
• Dominant inheritance, but woks as recessive gene.
• Compare RB gene (retinoblastoma).
• Clinically: polyps in large intestine increased during childhood.
• Malignancy inevitable by late 20s.

Normal
APC loss/mutation
Metaplastic polyp
Loss of DNA methylation
Adenoma
Ras mutation (12p)
Adenoma
Loss of DCC (18q)
Late adenoma
Loss of p53
Carcinoma


Other tumour suppressor genes
• NF-1: neuroblastoma.
• NF-2: Schwannoma, meningioma.
• RB: retinoblastoma, osteosarcoma.
• p53: Li Fraumeni syndrome.
• WT-1: Wilms tumour (renal).
• BRCA-1, 2: Breast, ovary carcinoma.

Case 2
• Female, aged 42, well.
• Patient's uncle died from ischaemic heart disease aged 62.
• Sudden death, therefore, autopsy.
• Liver looked nodular.
• Histology taken.

Next…
• Patient has liver investigations and biopsy.
• LFTs normal.
• Ferritin high, serum iron high.

Autosomal recessive
• Genetic Haemochromatosis.
• Example of "founder" gene mutation (800AD, Celtic population).
• Iron overload due to increased absorption.
• May exceed 50g total (normal <6g).
• Commoner/earlier in men (no blood loss).
• Carrier 1:9 in Northern Europe, homozygotes 1:220 (but penetrance only ~20%).

Haemochromatosis
• Iron in toxic excess (catalyses free radicals).
• Results in:
-Cirrhosis.
-Pancreatic fibrosis.
-Cardiomyopathy.
-Tumours, especially hepatocellular carcinoma.

Other founder mutations - all recessive
Mutation Heterozygote resists
CF Diarrhoea
Sickle cell Malaria
FV Leiden (clotting) Sepsis
ALDH2 (alcohol) Alcoholism (?)
Lactose tolerance Allows milk use
GHB2 (deafness, Middle East) Unknown

Case 3
• Ghanaian (black) male aged 23.
• Episodes of severe abdominal and joint pain.
• Bad enough to need opiates.
• Last attack precipitated by bronchitis.

Sickle cell anaemia
• Recessive (autosomal).
• Point mutation at position 6 of beta globin chain.
• West Africa.
• Homozygote - crises caused by hypoxia ± infection.
• Autosplenectomy.
• Danger from hypoxia.
• Danger from infection, especially pneumonia.
• Joint damage from sickle crises.

Case 4
• Male aged 37 with family history of early cardiac death.
• Father died aged 42.
• Uncle died aged 44.
• Patient overweight (BMI = 34).
• And has xanthelasmata.

Investigations
• Cholesterol 12 mmol.
• LDL 8 mmol.
• FBC and clotting normal.
• U+Es and LFTs normal.

Familial hypercholesterolaemia
• Heterozygote 1:500.
• Typical cholesterol >7.5 mmol.
• Risk of early heart disease and stroke.
• Homozygote much rarer, but more severely affected.
• Cholesterol can be as high as 30!

Case 5
• Male patient aged 41 develops heart failure.
• Tall, thin, blue sclerae, long spidery fingers, pectus excavatus, high arched palate.
• Valve replacement.
• Died suddenly 2 years later.

Marfan's syndrome
• Incidence 1:5000.
• 75% cases familial autosomal dominant.
• Remainder sporadic (new mutation).
• Defect in fibrillin-1: abnormal form due to missense mutations.
• Tall with long gingers and toes.
• Relatively shorter upper body and long legs.
• Double-jointed digits.
• Eye.
• CVS.
• Sudden death from CVS causes.

X-linked recessive: fragile X
• Causes learning difficulties.
• Next commonest after Down's.
• IQ 20-60. Long face, large jaw and ears.
• Macro-orchidism.
• ~20% carrier males normal, but can transmit disorder.
• ~50% carrier females not affected.
• FMR-1 gene at Xq27.3 has CGG repeats in 5' untranslated region.
• Normally 10-55 repeats (average 29).
• Transmitter males pass on permutation without much amplification.
• Carrier females pass on dramatically amplified mutation.
• Amplification probably occurs in oogenesis, but not spermatogenesis.

Future prospects
• Better understanding of diseases (known genetic and postulated environmental), with application of Human Genome Project.
• Genetic tailoring of drug therapy.
• Common drugs like statins and anti-inflammatories may benefit.
• Tailored cancer treatment.