Robbins Chapter 6: Genetic Disorders

50% of spontaneous abortions during early gestation have a demonstrable chromosomal abnormality.
Hereditary, by definition, means familial. Congenital means "born with" and may not be genetic (e.g. congenital syphilis).
Mutation def. permanent change in DNA.
Genome mutations def. loss or gain of whole chromosomes.
Chromosome mutations. def. give rise to visible structural changes in the chromosomes.
Gene mutations def. partial or complete deletion of a gene.
Point mutations within a coding sequence: missense (alter meaning of code), nonsense (stop codon)
Point mutations within noncoding sequences: may interfere with transcription factor binding, promoter sequences or lead to defective splicing.
Deletions and Insertions: frameshift mutations.
Trinucleotide repeat mutations: e.g. Fragile X gene FMR-1, normally 29 CGG, abnormal 250-400! Amplification during gametogenesis.

Mendelian Disorders def. expressed mutations in single genes of large effect:
It is estimated that each individual carries 5-8 deleterous genes, but most are recessive so have no effect. 80-85% familial.
Codominance def. both alleles of a gene pair are fully expressed. e.g. histocompatibility or blood group antigens.
Pleiotropism def. a single, mutant gene may lead to many end effects. e.g. Sickle cell anemia.
Genetic heterogeneity def. mutations at many different loci may produce the same trait. e.g. childhood deafness.
Enzyme defects: leads to accumulation of a substrate (lysosomal storage disorders), decreased end product (lack of tyrosinase leads to melanin deficiency & albinism), failure to inactivate a tissue damaging substrate (a1-AT deficiency)
Membrane receptors and transport systems
Non-enzyme proteins: structure, function or quantity (e.g. globin genes)
Mutations resulting in unusual drug reactions (G6PD deficiency)

Autosomal Dominant Disorders
Some patients do not have affected parents - new mutations involving egg or sperm.
Some inherit the mutant gene but are normal - reduced penetrance/variable expressivity.
In many conditions age at onset is delayed.
AD disorders usually involve:
Nonenzymatic proteins involved in regulation of complex metabolic pathways that are subject to feedback inhibition e.g. LDL receptors
Key structural proteins e.g. collagen
Rare gain of function mutations e.g. Huntington's Disease trinucleotide repeat mutation leads to an abnormal protein which is toxic to neurons.

Autosomal Recessive Disorders
One chance in four of being affected.
Expression of the defect tends to be more uniform.
Complete penetrance is common.
Onset frequently early in life.
Enzyme proteins are often affected by a loss of function. e.g. all inborn errors of metabolism.

X Linked Disorders
All sex-linked disorders are X linked and almost all are recessive.
Male is said to be hemizygous.
All daughters are carriers.
Heterozygous female expresses the disorder partially. e.g. G6PD deficiency
X linked dominant are rare e.g. Vitamin D-resistant rickets.

Defects in Structural Proteins
Marfan Syndrome

Congenital Contractural Arachnodactyly
Clinical: Skeletal abnormalities
Transmission: AD
Pathophysiology: Abnormalities in fibrillin 2 (component of extracellular matrix)
Cytogenetics: FBN2 on 5q3

Ehlers-Danlos Syndromes

Defects in Receptor Proteins
Familial Hypercholesterolemia
Clinical:
Heterozygotes have 2-3x elevation in plasma cholesterol; Homozygotes have 5-6 x.
Heterozygotes: tendinous xanthomas and premature atherosclerosis
Homozygotes: skin xanthomas, coronary, cerebral and peripheral vascular atherosclerosis at an early age. MI before age 20.
Pathophysiology: Mutation in gene encoding LDL receptor; loss of feedback control leads to elevated cholesterol
Cytogenetics: Chromosome 19; more than 150 mutations.
Class I: null allele (complete failure of synthesis)
Class II: proteins accumulate in e.r., can't get to Golgi.
Class III: LDL binding domain affected
Class IV: LDL receptors fail to localize in coated pits.
Class V: acid-dependent dissociation of receptor and bound LDL fails to occur
Treatment: Statins suppress intracellular cholesterol synthesis by inhibiting HMG CoA reductase; allows greater synthesis of LDL receptors.


Defects in Enzymes

Lysosomal Storage Diseases
Lysosomal enzymes catalyze the breakdown of complex macromolecules.
Autophagy: def. breakdown of intracellular organelles
Heterophagy: def. phagocytosis
Synthesis of a catalytcally inactive enzyme but that cross-reacts with immunoassays so normal levels of enzyme are detected.
Defects in post-translational processing of the enzymes (e.g. addition of mannose-6-phosphate "marker": enzyme secreted instead of ending in lysosome)
Lack of an enzyme activator or protector protein
Lack of a substrate activator protein
Lack of a transport protein required for egress of digested material out of lysosome
Tay-Sachs Disease
Niemann-Pick Disease
Gaucher Disease
Mucopolysaccharidoses: Hunter Syndrome, Hurler Syndrome
Long-chain complex proteoglycans abundant in ground substance of connective tissue. All except Hunter's are AR. Progressive disorders characterized by involvement of multiple organs including liver, spleen, heart and blood vessels. Most associated with coarse facial features, clouding of the cornea, joint stiffness and mental retardation, HSM, skeletal deformities, valvular lesions and subendothelial arterial deposits, particularly in coronary arteries. MI impt cause of death.

Glycogenoses:
Hereditary deficiency of one of the enzymes involved in the synthesis or degradation of glycogen.
Hepatic forms: Von Gierke Disease
Myopathic forms: McArdle Disease, muscle phosphofructokinase (Type VII)
Deficiency of a-glucosidase (acid maltase): Pompe Disease
Brancher glycogenosis: (Type IV) lack of branching enzyme with widespread deposition of abnormal glycogen in brain, heart, skeletal muscle and liver.

Alkaptonuria (Ochronosis)


Defects in Proteins that Regulate Cell Growth
Neurofibromatosis I
Neurofibromatosis II

Multifactorial Inheritance

Hair color, eye color, skin color, height and intelligence.
Diabetes Mellitus, obesity, cleft lip or palate, congenital heart disease, coronary heart disease, hypertension, gout, pyloric stenosis.
The risk of inheriting a multifactorial disorder is greater in sibs of pts. having severe expression of the disorder.
Concordance for identical twins is 20-40%
If one child is affected, 7% risk for next child; if two, 9%.

Normal Karyotype
46 chromosomes. 46,XX female; 46,XY male.
Arrest mitosis in metaphase with colchicine and stain chromosomes. Giemsa stain: G banding. Resolution improved by getting cells in prophase.
p: short arm (petit); q: long arm.
Regions numbered 1,2,3 from centromere outward.
Limits to karyotyping: applicable only to cells that are dividing.
FISH: flouresence labelled probes recognize chromosome-specific sequences, or demonstarte subtle microdeletions.
Euploid. def. any exact multiple of haploid.
Aneuploid def. chromosome # is not an exact multiple of 23.
Nondisjunction def. homologous pairs of chromosomes fail to disjoin at first meiotic division or the two chromatids fail to separate at either the second meiotic division or at somatic mitotic divisions. This results in two aneuploid cells.
Anaphase lag def. one homologous chromosome is left behind and is excluded from cell nucleus in meiosis or mitosis. This results in one normal cell and in one cell with monosomy.
Mosaicism def. two or more populations of cells in the same individual.
Mosaicism affected the sex chromosomes is fairly common. e.g. 45X/47,XXX mosaic (phenotype: Turner Syndrome)
Chromosomal breakage: structural change in chromosomes followed by loss or rearrangement of material:
(e.g. Fanconi anemia, Bloom Syndrome, Ataxia-Telangiectasia)