Pathology Of Genetic Disease

16.2.07

Developments
• Human Genome Project.
-Polymorphisms.
-0.1% (3mBp) variable.
-Imprinting ?role.

Congenital and genetic
• Congenital: existing at or before birth - may not become apparent until later.
• Genetic: inherited.

Genetic diseases
• >1000 known to affect humans.
• Diseases with at least some genetic component will affect 2/3 of population during lifetime.

Mutations
• Different scales.
-Whole chromosome gain/loss.
§Monosomy/trisomy.
+Mostly not transmitted.
-Chromosome rearrangement.
-Gene level (submicroscopic).

Cytogenic autosomal disorders
• Trisomies:
-Down's syndrome (trisomy 21).
§Average incidence 1/700 (1/25 if mother >45 years).
§95% cases maternal origin.
§40% patients have congenital heart disease.
§Rate of acute leukaemia increases 10-20X.
§Many get Alzheimer's after age 40 years.
-Edwards (trisomy 18) and Patau's (trisomy 13) rarer.

Sex chromosome disorders
• Two most common:
-Kilnefelter's (47, XXY/variants), 1:500 male.
§Hypogonadism, infertility.
§Mild learning difficulties (not all).
§Effect of extra X probably mitigated by lyonisation.
-Turners (45, X), 1:2000 female births.
§Many (?all) mosaics with XX, XY, XXX etc.
§Hypogonadal, short stature, skin webs.
§IQ often in normal range.

Mutations
• Gene level.
-Deletion (partial/complete).
-Point mutation (single base).
-Insertions/deletions → frame shift.
§Base pair gain/loss.
-Mutations in promoter/enhancer regions.
§Non-coding, but can interfere with transcription.
§Trinucleotide repeats (usually C and G bases).
-Mutation/deletions of MMR genes (HNPCC).

Mendelian disorders: autosomal dominant
• Affect 50% children.
• Parent often affected.
• May be late onset of effect.
• Variable penetrance (incidence).
• Variable expressivity (effect).
• Enzymes not usually involved because ~50% remains (other copy).
• Loss of function due to:
-Regulatory proteins involved in feedback.
-Key structural proteins.
• Gain of function e.g. overexpression.
• Colon: FAP.
• Chemistry:
-Acute intermittent Porphyria.
-Familial hypercholesterolaemia.
• Bones:
-Marfan.
Ehlers-Danlos.
-Osteogenesis imperfecta.
-Achondroplasia.
• Renal: polycystic kidneys.
• Blood:
-Hereditary spherocytosis.
-Von Willebrand's.
• CNS:
-Huntington's disease.
-Von Recklinghausen.
-Myotonic dystrophy.
-Tuberous sclerosis.

Mendelian disorders: autosomal recessive
• Everybody carries 5-8 recessive harmful genes.
• Parents phenotypically normal, but 25% siblings affected.
• Usually complete penetrance.
• Early onset.
• Blood:
-Sickle cell.
-Thalassaemias.
• Bone:
-Some Ehlers-Danlos.
-Alkaptomina.
• Endocrine: congenital adrenal hyperplasia.
• CNS.
• Chemistry:
-CF.
-PKU.
-Galactosaemia.
-Homocystinuria.
-Lysosomal storage disorders.
-Alpha-1-anti-trypsin deficiency.
-Wilson's disease.
-Haemochromatosis.
-Glycogen storage diseases.

Sex chromosomes
• Y chromosome has:
-Genes related to spermatogenesis (with internal copies).
-A few genes homologous to those on X, but no syndromes known from these.
• X chromosome (in female) is randomly inactivated (lyonisation) - mosaic state.

X-linked (recessive) disorders
• Males affected:
-Females may be partly affected due to lyonisation.
-Males described as hemizygous as no paired Y-chromosome gene generally exists.
-Affected males transmit disorder to daughters as carriers, but not to sons.
• Chemistry:
-Diabetes insipidus.
-Lesch-Nyhan (uric acid).
• Muscle: Duchenne's.
• Blood:
-Haemophilia A and B.
-Chronic granulomatous disease.
-G-6-PD deficiency.
-Agammaglobulinaemia.
-Wiskott-Aldrich (immunodeficiency).
• CNS: fragile X syndrome.

Single gene disorders: effects
• Enzyme defects:
-Substrate build-up.
§Mucopolysaccharidoses.
§Lysosomal storage diseases.
-Lack of product.
§Albinism.
§A-1-A-T deficiency.
• Structural alterations in other proteins - haemoglobinopathies - sickle cell anaemia (not thalassaemias).
• Altered reaction to drugs.
• Defects in membrane receptors.

Multifactorial genetic disorders
• Interaction with environment likely.
• Could be 7-10 genes involved.
• Congenital malformations easily observable model.
-Cleft lip/palate.
-Heart.
• IHD.
• Hypertension.
• Diabetes mellitus (especially type II).
• Pyloric stenosis.
• Gout.

Non-Mendelian disorders
• Triplet repeats: fragile X.
• Mitochondrial genes:
-Maternal inheritance.
-37 genes (24 translating and 13 code for metabolic enzymes).
-Several conditions:
§Leber optic neuropathy.
§Mitochondrial myopathy.