When a person has only one good gene where most people have two, the person can expect to make 50% as much of the good protein as do most other people. Sometimes, that isn't enough. Therefore, the known autosomal dominant diseases fall into five categories.
(1) Problems with the quantity or arrangement of large structural proteins
(2) Problems with regulator proteins and receptors, which permit relatively good quality of life.
(3) Deficiency in proteins which are in short supply even in health.
(4) Anti-oncogene deletion syndromes, in which a "second hit" on the normal allele of a normal cell turns it to a tumor cell. More about this last category later.
(5) The mutant gene makes a harmful protein. Today, the best-understood of these are the prion-related diseases, in which an altered protein begins a terrible chain reaction that can even be transmitted to genetically normal creatures, even across species lines.
The common autosomal dominant diseases do not kill or disable until the patient has had a good chance of having a family. Why? Hint: Most genetic diseases do not result from new mutations. The major exceptions are Von Recklinghausen's neurofibromatosis and achondroplastic dwarfism (both are genes with very high mutation rates).
The autosomal dominant disorders are mostly of variable penetrance and/or expressivity, since they are modulated by other genes and/or environment. Two doses of a bad autosomal dominant gene produces some severe exaggeration of the single-dose syndrome, or else death in the womb. Obviously, consanguinity does not play a role in autosomal dominant disease.
The major autosomal dominant disorders which you'll meet in this course:
-- Marfan's syndrome family
-- Many Ehlers-Danlos variants, and plain old familial double-
-- Hereditary spherocytosis
-- The not-so-bad kinds of epidermolysis bullosa (abnormal
keratin in intermediate fibers)
-- Familial hypertrophic cardiomyopathy (some; Reggie Lewis,
mutant beta-myosin chain)
-- Achondroplastic dwarfism (fibroblast growth factor receptors,
-- Hereditary hemorrhagic telangiectasia (presumptive)
-- Osteogenesis imperfecta (collagen)
-- Pelger-Huet's non-disease (presumptive)
-- Familial hypercholesterolemia
-- Benign familial tremor (presumptive)
-- Glucocorticoid-suppressible aldosteronism (ACTH turns on
Short-supply protein deficiency syndromes
-- Von Willebrand's disease
-- Maturity onset diabetes of the young (glucokinase)
-- Acute intermittent porphyria
-- Familial amyotrophic lateral sclerosis (superoxide dismutase)
Anti-oncogene deletion syndromes
-- Retinoblastoma gene syndrome
-- Neurofibromatosis I & II
-- Familial polyposis coli
(including its variant Gardner's syndrome)
-- Lynch's hereditary non-polyposis colon cancer
-- Multiple endocrine neoplasia syndrome I, IIa & IIb
-- Li-Fraumeni cancer syndrome
-- Tuberous sclerosis (presumptive)
-- Von Hippel-Lindau disease (presumptive)
-- Familial dysplastic nevus syndrome (?)
-- Peutz-Jegher's syndrome (presumptive)
-- Adult polycystic kidney disease
-- BRCA-1 breast-and-ovary cancer syndrome
-- Prion diseases (more about these later!)
-- Hereditary amyloidosis C
-- Gilbert's (harmless unconjugated hyperbilirubinemia; the
mutant gene product ties up the good copy)
-- Familial dysplastic nevus syndrome (? the melanin generates,
rather than protects from, free radicals)
Molecular biology being worked out
-- Huntington's disease ("Huntington's chorea")
-- Friedreich's ataxia
-- Familial psoriasis
-- Treacher-Collins (variably malformed face, "Johnny Handsome")
-- Waardenburg's (deafness, different-colored eyes, white
-- Stein-Leventhal (probably)
Semi-diseases, heterozygotes for bad diseases
-- beta-thal minor
-- sickle-cell trait
-- hemoglobin C trait
-- one-dose hemochromatosis
-- alpha-thal is special, since there are four loci.
Marfan's syndrome: A heterogeneous group of genetic disorders with connective tissue problems. Marfan patients are tall, with very long extremities, and long fingers ("arachnodactyly"). The arm span exceeds the height. Joints are hyper-extensible. Double-jointed. Chest- deformities. Funny-looking face. Bones slim, muscles wiry, body habitus slender. "Ectopia lentis" of eye (lax suspensory ligaments). Elongate globe, flat cornea (progressive myopia). Weak central area of thoracic aortic media predispose to aortic dissection ("cystic medial necrosis"). Barlow mitral valve. Lax ligament around aortic valve, causes regurgitation later in life. One gene is fibrillin, a connective tissue protein. Semi-Marfan's abound. Related to Marfan's: (1) Lathyrism, from feeding sweet peas to turkeys and resulting in fatal aortic dissection, results from á-aminopropionitrile inhibiting lysine oxidase, which cross-links collagen and elastin fibers. (2) Menke's kinky hair disease, on the X-chromosome, which prevents normal handling of copper, prevents function of lysine oxidase. (3) Stickler's, a common Marfan variant, results from a premature termination codon on the type II procollagen gene.
Ehlers-Danlos syndrome ("rubber man", "human pretzels") is a family of variably-inherited diseases which leave a person with poorly-woven collagen; easy to hurt, poor healers. Some have overly-extensible (even "cigaret-paper") skin; most have overly-mobile joints which often slip out of place. Type IV: various problems with type III collagen ("reticulin"); colon and arteries often rupture. Type VI: reduced lysyl hydroxylase (autosomal recessive), ruptured corneas, detached retinas. Type VII: inability to turn type I procollagen into collagen.
Familial hypercholesterolemia: Very common. Most of these patients lack enough good apoprotein B-100 ("LDL") receptors. Therefore, they have trouble with (1) hepatic clearance of VLDL leftovers ("IDL's") for recycling, leaving them in the plasma to turn into LDL's; (2) hepatic clearance of LDL's from the plasma, leaving high plasma LDL levels; (3) receptor-mediated uptake of LDL's by other cells (do you remember "coated pits"?), leaving more around to be taken up by the mononuclear phagocytes by their receptor-independent method (which doesn't burn LDL's very well). Xanthomas. Precocious atherosclerosis.
Stein-Leventhal syndrome is a mysterious very common woman's problem. The combination is (1) secondary amenorrhea; (2) hyperandrogenism. Usually also (3) relative tissue resistance to insulin; (4) big ovaries with thick fibrous capsules ("polycystic ovaries"; the cysts are follicles that could not rupture). The male phenotype is the super- hairy guy who goes bald very early.
Note: Copyrights: "The Pathology Guy" - Ed Friedlander MD. Reproduced with permission.