Mendelian Genetic Disorders

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Autosomal dominant

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heterozygous state. no skip generation, no sex preference, when affected person marries normal person, each child w/ 50% chance develop disease, some affected individuals do not have affected parents -> owe disorder to new mutation either involving egg or sperm
*displays incomplete penetrance, variable expressivity
*new mutations, siblings not affected

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Autosomal recessive

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-skip generation, no sex prediction, each child has 1/4 chance of being affected, consanguinity common among parents of affected children , gene should be present in "double dose"
*parents are usually carries of disorders, normally in reg. population trait is not shown
-manifested in homozygote stage, need double dose to express conditions
*complete penetrance common, onset freq early in life, expression of defect more uniform, in new mutations, ind affected is Asxtic

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Incomplete penetrance

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ability of persons carrying abnormal gene NOT to express trait, inherit gene but phenotypically normal, they can pass gene to offspring who may then have condition

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variable expressivity

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difference in w/c trait is expressed by persons carrying the gene, some carrying abnormal gene may be affected like
-mild condition
-classic features
-severe conditions
new mutations → siblings not affected
delayed age onset not until adulthood

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Sex-linked dominant

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no skip generation, w/ sex predilection, affected males transmit to all daughters, not sons, affected females transmit to half her sons and half her daughters

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Sex-linked recessive:

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Mutation in X chrom
-skip generation, presence sex predilection, affected male does not transmit to sons, all daughters carriers
-carriers transmit 50% to sons, unaffected males never transmit the gene
-gene is only needed in single dose to manifest bc other chromosome doesn't have complement necessary for inhibition of x chrom

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Sex linked disorders in general

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all x linked, almost all are x-linked recessive, only gene assigned w/ certainty to Y chrom is determinant for testes, males w/ any mutation on Y-linked genes usually infertile, hence no Y-linked inheritance

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Point mutation

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affect only a single base
UGA, UAG, UAA-stop codons you are gone, you are away, you go away
-nonsense- stops and protein no longer develops- thalassemia-absent globin chain

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Mendelian disorders

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Results of expressed mutation in single genes of large effects
Categories:
-defects in structural proteins
-defects in receptor proteins
-enzyme defects

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Enzyme defects

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1) Accumulation of substrate→accum intermediates (galactosemia)
2) ↓ amt important end product thru missing enzyme –albinism
3) Failure to inactive tissue damaging substance-alpha antitrypsin deficiency

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Pleiotropism

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Single gene mutations leading to many end effects
Eg sickle cell anemia- defect in hemoglobin

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defects in receptor/transport sys

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1) Receptor mediated endocytosis=familial hypercholestemia
2) Transport protein=cystic fibrosis

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deletions/insertions

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frameshift-change seq of a.a., insert or remove more than 3, every time base read, a.a. entirely different
3-base deletion = missense mutation, add or delete on 3 bases, only single group of a.a will be changed-sickle cell anemia

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Biochemical mechanism autosomal dominant

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1) loss of fxn - loss of protein
2) gain of fxn mutation

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loss of fxn mutation- autosomal dominant

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enzyme protein- heterozygotes normal, reduced enzyme # lead to enough # for normal fxn
-non-enzyme protein
----- regulatory protein ex familial hypercholesterolemia
reduced syn/fxn of LDL receptors
defective transport LDL into cells
secondary to excessive cholesterol synth by complex intermediary mechanism
------ structural proteins ex collage -> EDS, fibrillin-> marfan, spectri -> spherocytosis

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gain of fxn mutation-auto dom

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result in new proteins that are usually toxic
*most mutations lead to loss of gene products and to lesser extent, gain of fxn mutation, transmission disorder produced by gain fxn mutations and almost always autosomal dominant

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marfan's syndrome

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deficient or abnormal fibrillin ( - to bone growth and) 15q21.1,
skeletal abnormalities:
-unusually tall, ratio of upper to lower is low, long extremities, long head, deformities in chest/spine, loose jointedness, ocular change, cvs lesions, skin

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fibrillin

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maj component extracellular glycoprotein provides framework for elastin -abundant in tendons, bv, lens) and inhibits TGF in bones
FBN1 = marfans aka fibrillin 1, m
FBN2 at 5q23.31 = congenital contractual arachnodactylyl

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Ocular change in marfan

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Ectopia lentis-bilateral, up or down dislocation of lens
Severe myopia
Retinal detachment

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Cvs lesions marfan

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Mitral valve prolapse, cystic mediionecrosis-aortic dilatation of ascending aort****

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ehler-danlos syndrome

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EDS
-defective collagen
-affects joints, skin, small BV
-skin extremely stretchable , fragile, prone to trauma, joints hypermobile-extend many ways
-shows molecular heterogeneity -> clinically variable disorder w/ several patterns of inheritance
**lysyl hydroxylase deficiency-enzyme for hydroxylation of lysine residues in collagen synthesis

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familial hypercholesteremia

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(19) 1/500
-inc cholesterol in blood stream, genetically determined
-loss of inhibitory mechanism, activation of scavenger system
- ↓ or defective receptors, receptor d/s due to mutation in gene encoding receptor for LDL (transport/metab cholesterol)
+ scavenger system

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2 mechanisms familial hypercholesteremia

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1) dec receptor: LDLS cleared thru liver 80%, muscle, adrenals, scavenger pathway exists-mo and lymph, if no receptor for IDL = leads to severe cholesterol elevation
2) loss of inhibitory mechanism- HMG coA inhibit cholesterol prod, acetly coA stimulate storage, esterification, inhibit LDL receptors

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Clinical manifestation F- hyperchol

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Xanthoma formation, atherosclerosis

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Molecular genetics F-hyperchol

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manifests in- genetic insertions, missense, variable mutiation affecting different aspects of receptor prod and activity- production, transportation, attachment, enclosure
-delestions, insertions, missense
****autosomal dominant pattern inheritance

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Autosomal recessive biochemical mechanisms

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1) Enzyme defect: accumulation abnormal substance, ↓ amt impt end product, failure to inactivate tissue damaging substance
2) Defects in non enzyme protein: transport protein (thallassemia), hemostasis, structural protein

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albinism

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inability to synthesize melanin, absent Tyrosinase enzyme-converts DOPA to melanin, enzyme defect → metabolic block, ↓ amt end product for fxn
*autosomal recessive

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Clinical significance albinism

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1) inc sensitivity to solar exposure, wrinkles, solar keratosis, squamous cell carcinoma
2) impaired visual acuity

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Alkaptonuria-ochronosis

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Inborn error or metabolism, lack of homogentisic oxidase -> inc homogenistic acid w/c binds to CT staining them blue black
-tissues or eyes look blue/black like bruised-ears, nose, cheeks
**conseqeuence of deposits of pigment in articular cartilages of joints → lose normal resilency and become brittle, fibrillated
Homogenistic oxidase enzyme converts homogentisic acid to methylacetoacetic acid in tyrosine degradation pathway
clin sig: cartilage brittle, degenerative neuropathy
*autosomal recessive

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lysosomal storage diisease

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Grp disorders w/ lack or abnormality of protein essential for normal function of lysosomes- intracellular digestive track, many hydrolytic enzymes
-glycogenosis, mucopolysaccharidoses, sphingolipidosis, tay sachs, sulfatidoses, neimann-pick d/s

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Glycogenosis

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pompe-generalized, ex: glycogen storage in all organs but cardiomegaly prominent, def acid maltase, lysosomal storage of glyc
myopathic-McArdle's disease ex: ms cramps after exercise, skeletal ms ms phosphoryalse, phosphofructokinase, ↑ lactate
hepatic form-von Gierke's dis- hepatomegaly and renomegaly hypoglycemia, hyperlipidemia, hyperuricemia, liver impt-storage, glu 6 phosphatase
deficient: lysosomal glucosidase – accumulates glycogen

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Sphingolipidosis

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Tay Sachs-aka Sandhoff d/s, lack enzyme hexosaminidase-build up gangliosides in CNS, AND, retina-> destruction neurons
LM: ballooned neurons, cytoplasmic vacuoles
EM: whorled gangliosides in lysosomes
clinical pic-ssx @ 6 months, progressive motor and mental deterioration, vegetative in 2, death 3
background of retina- light, macula looks like cherry red spot in tay sachs bc of the light colored background
neurons-ballooned w/ cytoplasmic vacuoles, lysosome filled
ganglioside beta galactosidase, accum ganglioside

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sulfatidoses

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Gaucher's disease, niemann-picks

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Gaucher’s d/s

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lack glucocerebrosidase, accumulates glucocerebrosides-gaucher cell, location in chrom 1q21
-most common lysosomal storage disorder
-enzyme usually cleaves glucose residue from ceramide, def→ accumulates in phagocytes
Type 1-99%, storage glucocerebrosides limited to mononuclear phagocytes throughout body w/out brain mostly spleen/skeletal

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Niemann pick d/s

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-type b-organomegaly w/o CNS involvement, live to adulthood, majority have this
type a- progressive infantile neurologic involvement and marked visceral enlargement, death 2 yrs, missense mutation –SPLEEN ENLARGED
type c- defective cholesterol transport from plasma, heterogeneous clinical pic- still birth, neonatal hepatitis, chronic neurologic-NPC1 involved in transport freee chol from lysosome→cytoplasm (more common than a+b)
Lack sphingomyelinase accumulate sphingomyelin – component of cellular membranes, deficiency blocks degradation of lipid
Chrom 11p15.4

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single gene disorder w/ non classic inheritance

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1) Triple repeat mutation
2) Mutations in mitochondrial genes
3) Genomic imprinting
4) Gonadal mosaicism

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triple gene mutations

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-expansion of a stretch of nucleotides from numerous repeats
CAG repeat- huntington’s chorea, GAA- freidrichs ataxia, Fragile x= CGG
ACC CGG CGG CGG CAG GAA CTG
-tendency of expansion depends upon sex of transmitting parent
-similar to sex linked recessive except w/ these patterns:
1) presence of carrier males
2) female transmission > carriers fem can transmit to affected daughters, > 30-50% carriers’ affected
3) ANTICIPATION- clinical features worsen and d/s occurs w/ generation