• mendelian
• multifactorial disorders
• single-gene disorders with nonclassic inheritance
• chromosomal (cytogenetic) disorders 

what is:

 -penetrance

 -variable expressivity

 -codominance

 -polymorphism

 -pleiotropism

 -genetic heterogeneity 

1. penetrance: the percentage of individuals carrying an autosomal dominant gene and expressing the trait
2. variable expressivity: variable expression of autosomal dominant trait in affect individuals
3. codominance: full expression of both alleles of a given gene pair in a heterozygote
4. polymorphism: multiple end effects of a single mutant gene
5. genetic heterogeneity: production of a given trait by different mutations at multiple loci.

• mutations affect structural (collagen) or regulatory (receptor) proteins.  in some instances the prodcut of the mutant allele interveres with the function of the normal protein (collagen).  such mutant alleles, called dominant negative, can produce severe deficiency of protein, as in osteogenesis imperfecta.
• there is a reduced penetrance and variable expressivity
• onset of clinical features may be later than in autosomal recessive disorders

include most inborn errors of metabolism.

• age of onset frequently early in life
• clinical features tend to be more uniform
• in many patients, enzyme proteins, rather than structural proteins, are affected 

1. marfan syndrome
2. ehlers-danlos syndromes

disorder of connective tissue primarily affecting the skeletal, ocular, and cardiovascular systems.

• skeletal changes
  • tall stature with long extremeties
  • long, tapering fingers and toes
  • laxity of joint ligaments, producing hyperextensibility
  • spinal deformities (kyphosis and scoliosis)

• ocular changes
  • bilateral dislocation of lenses (ectopia lentis)
  • increased axial length of the globe, giving rise to retinal detachments

• cardiovascular lesions
  • mitral valve prolapse is most common, although not life threatening: affected valves are soft and billowy, producing a floppy valve associated with mitral regurgitation
  • cystic medionecrosis of the aorta is less common than mitral valve lesions but clinically more important.  cystic medianecrosis predisposes to an intimal tear through which the blood dissects into the media; cleavage of the aortic wall may extend proximally or distally, often resulting in rupture of the aorta

• MS results from mutations in the fibrillin-1 gene.  Fibrillin , a glycoprotein secreted by fibroblasts, is a component of microfibils that provides a scaffolding for the deposition of elastin.  there is secondary weakness of he connective tissue, particularly in the aorta, mitral valve, and ciliary zonules.  gene has been mapped to 15q21.1 

clinically and genetically heterogeneous group of disorders that result from some defect in collagen.  divided into 12 variants on basis of predominant clinial manifestations and pattern of inheritance.  following features are common to most variants:

• skin is hyperflexible, extremely fragile, and vulvnerable to trauma; surgical repair of wounds is markedly impaired owing to defective collagen
• joints are hypermobile and prone to dislocation
• affect several organs rich in collagen; manifestations include rupture of the colon and large arteries, ocular fragility with corneal rupture and retinal detachment, and diaphragmatic hernias

the biochemical bases of abnormalities in collagen are extremely varied.  some of the better characterized defects are as follows:

• reduced activity of lysyl hydroxylase, essential in crosslinking collagen fibers, is noted in type VI EDS, the most common autosomal recessive form.  Collagens I and III lack structural stability.
• abnormalities of type III collagen, resulting from several distinct mutations in the structural gene, characterize type IV EDS.  Because a structural rather than an enzyme protein is affected, the patternof inheritance is autosomal dominant.  Blood vessels and intestines, known to be rich in type III collagen, are prone to rupture.
• Defective conversion of type I procollagen to collagen characterizes type VII EDS.  It is caused by mutations affectin type I collagen genes.  THe mutant procollagen chains resist cleavage of N-terminal peptides, essential for the formation of normal collagen.  Even if only one of the two allele is mutant, their abnormal products interfere with the formation of normal collagen helices, and hence heterozygotes have sever disease.
• defective copper metabolism is the basis of EDS type IX.  Intracellular copper levels are high, but serum copper is low.  abnormality of copper mtabolism secondarily reduces the activity of the enzyme lysyl oxidase.  it is inherited as an x-linked recessive trait.

-results from mutation in the gene encoding the recepto for LDL.  at least 150 mutations that can be classified into 5 groups have been discovered.

• class I mutations: impair transcription, resulting in failiure of synthesis of receptor proteins
• class II mutations:  prevent transport of the receptors from the endoplasmic reticulum to the golgic complex
• class III mutations:  associated with production of a receptor protein that has reduced binding capacity
• class IV mutations:  give rise to proteins that can bind LDL but cannot internalize the bound LDL
• class V mutations:  give rise to LDL proteinst hat are expressed and interalized but are trapped int he endosome and cannot be recyled.

-apoprotein b-100 on LDL binds receptor to be internalized

-about 70% of plasma LDL is cleared by the liver.  the remaining 30% is transported into other cells, especially mononuclear phagocytes, by binding scavenger receptors for a chemically altered (acylated) form of LDL

-LDL binds to surface receptors and is internalized

-fuses with  lysosomes, which leads to the release of free cholesterol into the cytoplasm

• free cholesterol inhibits cholesterol synthesis in cell by inhibiting enyme hydroxymethylglutaryl coenzyme A reductase.
• it activates enzymes that favor exterification of cholestrol
• it suppresses synthesis of LDL receptors, thereby preventing excessive transport of cholesterol into cells

-familial hypercholesterolemia - very common - 1 in 500.  heterozygotes have the following features:

• cells possess 50% of the normal number of high-affinity LDL receptors.  plasma LDL cholesterol level is two to three times higher than normal, resulting from both impaired clearance of plasma LDL and increased synthesis.  The latter is secondary to decerased hepatic uptake of IDL, the immediate precursor of plasma LDL.
• hypercholesterolemia leads to premature atherosclerosis and accumulation of cholesterol in soft tissues and skin, producing xanthomas.

1. lysosomal storage diseases
2. tay-sachs disease (GM2-Gangliosidosis: Hexosaminidase alpha-subunit deficiency)
3. niemann-pick disease types A and B
4. gaucher disease
5. mucopolysaccharidoses
6. glycogen storage diseases
7. alkaptonuria

-result from inherited lack of functional lysosomal enzymes or other proeins essential for their function.  catabolism of complex substrates is impaired, leading to accumulation of partially degraded insoluble metabolites within lysosomes.

-the lysosomes become packed with undigested macromolecules, are enlarged and interfere with normal cell fucntion

-classified based on biochemical nature of the accumulated metabolite.

-distribution of stored material and resultant clinical features depend on:

• the site where most of the material to be degraded is normally found
• the site where most of the degradation normally occurs

-organs rich in phagocytic cells like liver and spleen, are often enlarged

-lysosomal storage diseases include:  tay-sachs, niemann-pick, gaucher,  and mucopolysaccharidoses 

-results from mutations that affect the alpha-subunit of the hexosaminidase enzyme complex.

-result prevents degradation of GM2-ganglioside.

-the clinical features, which derive primarily from accumulation of GM2-ganglioside in neurons of the central autonomic nervous systems and retina, include:

• motor and mental deterioration commencing at about 6 months of age
• blindness
• a cherry-red spot in the retina
• death by 2 to 3 years of age

morphologic features include:

• ballooning of neurons with cytoplasmic vacuoles that stain positive for lipids
• whorled configurations in the cytoplasmic vacuoles, revealed by electron microscopy
• progressive destruction of neurons with proliferation of microglia
• accumulation of lipids in retinal ganglion cells, rendering them pale in color, thus accentuating the normal red color of the macular choroid (cherry-red spot)

-two related disorders that are associated with a deficiency of sphingomyelinase and accumulation of sphingomyelin in mononuclear phagocytes and many other cells.

-must be distinguished from N-P dieases type c, which results from a defect in intracellular cholesterol esterification and transport

-type A variant is most common form and is associated with:

• diffuse neuronal involvement, leading eventually to cell death and shrinkage of the brain; there is a retinal cherry-red spot similar to that in Tay-Sachs disease
• massive accumulation of lipids in cells of the mononuclear phagocytic system, giving rise to massive splenomegaly, enlargement of liver and lymph nodes, and infiltration of bone marrow
• visceral involvement affecting the gastrointestinal tract and lungs

-refers to a cluster of autosomal recessive disorders in which mutations affecting the glucocerbrosidease locus reduce the levels of this enzyme.

-consequently, cleavage of ceramide derived from cell membranes of senescent leukocytes and red cells as well as from turnover of gangliosides in the brains of neonates is impaired.

-accumulation of glucocerebroside s occurs in the mononuclear phagocytic system and, in some forms, in the CNS.

-patterns run in families 

type 1:

• most common form, occurs in adults
• chronic, non-neuropathic
• storage of glucocerebrosides in the MN phagocytic system
• massive splenomegaly
• involvement of bone marrow produces small or large areas of bone erosions can cause pathologic fractures
• pancytopenia or thrombocytopenia results from hypersplenism; life span not affected.

type 2:

• acute neuronopathic form
• associated with hepatosplenomegaly as well as CNS involvement
• symptoms such as convulsions and mental deteriorations dominate the clinical picture; death occurs at a young age. 

-MPS are a group of disorders resulting from inherited deficiencies of enzymes involved in the degradation of MPS.

-the mucopolysaccharides that accumulate in the cells include heparan sulfate, dermatan sulfate, keratan sulfate, and chondroitin sulfate.

-histologically, affected cells are distended with clear cytoplasm (balloon cells) that contains PAS-positive material.

-accumulation found in many cell types, including: MN phag. cells (giving rise to hepatosplenomegaly), fibroblasts throughout the body; endothelial cells and intimal smooth muscle cells (giving rise to narrowing of coronary arteries); and neurons 

-classified as MPS I-VII, each resulting from the deficiency of one specific enzyme.

-in general all forms are progressive disorders characterized byo ne or more of the following:

• coarse facial features
• hepatosplenomegaly
• corneal clouding
• lesions of cardiac valves
• narrowing of coronary arteries
• joint stiffness
• mental retardation

-autosomal recessive disorders resulting from defects in the synthesis or catabolism of glycogen.

-3 major groups

1. hepatic forms:
   1. prototype is vonv Gierke disease (type 1 glycogenosis)
   2. results from deficiency of the heptaic enzyme glucose-6-phosphatase.
   3. accumulation of glycogen because it cannot be broken down to free glucose
   4. low blood glucose

1. myopathic forms:
   1. result from deficiencies of enzymes that fuel glycolysis in striated muscles
   2. McArdle disease (type V glycogenosis), most important example, is caused by lack of muscle phosphorylase.
   3. deficiency of enzyme leads to:
      1. storage of glycogen in skeletal muscles
      2. muscle weakness
      3. muscle cramps after exercise
      4. failure of exercise-induced rise in blood lactate

1. miscellaneous forms:
   1. there are several of these, the most important being type II glycogenosis (pompe disease)
   2. results from deficiency of the lysosomal enzyme acid maltase.
   3. many organs are involved, but storage of glycogen is mos prominent int he heart.
   4. affected neonates have massive cardiomegaly, and death results from cardiac failure by 2 years of age. 

-lack of homogentisic oxidase blocks the metabolism of phenylalanine and leads to accumulation of homogentisic acid.

-excess of homogentisic acid is associated with:

• excretion in urine, imparting to it a black color if allowed to stand.
• ochronosis-a blue-black pigmentation of the ears, nose, and cheeks resulting from binding of homogentisic acid to connective tissue and cartilage.
• arthropathy associated with deposition in articular cartilage; the pigmented cartilage loses resilience and is readily eroded; the vertebral column, knee, shoulders, and hips are usualy affected. 

-two genetically distinct autosomal dominant disorders, both characterized by the presence of tumors of the nerves.

-Neurofibromatosis type 1 (also called von Recklinghausen disease) is characterized by 3 main features:

• multiple neural tumors involve nerve trunks in skin as well as internal organs.
  • 3 types of lesions are found: cutaneous, subcutaneous, and plexiform (subcutaneous tumors that contain numerous tortuous thickened nerves)
  • sometimes cause massive enlargement of a limb or other body parts.
  • histologically, neurofibromas reveal proliferation of neurites, schwann cells, and fibroblasts, embeded in loose myxoid stroma

• cutaneous pigmentations
  • present in more than 90% of patients, take the form of light brown macules located over nerve trunks

• Lisch nodules
  • pigmented iris hamartomas are present in almost all cases.

-several associated abnormalities are present; the important ones are as follows:

• there are skeletal lesions in 30 to 50% of patients
• there is an increased risk of the development of othe tumors , especially meningiomas, optic gliomas, and phechromocytomas.
• there is a tendency toward reduced intelligence.

-loss by mutation of tumor suppressor genes underlies these conditions

• NF-1 on Ch17 encodes neurofibromin, a protein that regulates the fucntion of the p21 ras oncoprotein.  NF-1 is a tumor suppressor gene.
• The NF-2 locus on chromosome 22 also encodes a tumor-suppressor gene, of unknown function.
• these patients have the following features:
  • bilateral acoustic nerve tumors in all cases
  • gliomas, particularly ependymomas
  • cafe' au lait spots
  • absence of lisch nodules 

-disorders with multifactorial inheritance result from the combined effects of two or more mutant genes combined with environmental factors and exhibit the following characteristics:

• risk of expression is conditioned by the number of mutant genes inherited.  environmental influences sgnificantly modify the risk of expression; hence the concordance rate in identical twins is 20-40%
• the risk of recurrence of the disorder in first-degree relatives is 2-7%