3. MUTATIONS
• PERMANENT change in DNA
–GENOME MUTATION: (whole
chromosome)
–CHROMOSOME MUTATION: (visible
chromosome change)
–GENE MUTATION: (may, and often, result
in a single base error)
6. GENE MUTATION
• POINT MUTATION within a coding sequence:
VAL-GLU
• MUTATIONS in NON-coding sequences
defective transcription, regulation
• DELETIONS/INSERTIONS frameshift
mutation, involvement is NOT a multiple of 3
• Tri-nucleotide REPEATS, e.g., CGG repeats
many times in fragile X syndrome
7. GENE MUTATIONS
• INTERFERE with protein synthesis
• SUPPRESS transcription, DNARNA
• PRODUCE abnormal mRNA
• DEFECTS carried over into TRANSLATION
• ABNORMAL proteins WITHOUT
impairing syntheses
8. GENETIC DISORDERS
• SINGLE gene mutations, following
classical MENDELIAN inheritance
patterns the most
• MULTIFACTORIAL inheritance
• CHROMOSOMAL disorders
10. AUTOSOMAL DOMINANT
• Disease is in HETEROZYGOTES
• NEITHER parent may have the disease (NEW mut.)
• REDUCED PENETRANCE (env?, other genes?)
• VARIABLE EXPRESSIVITY (env?, other
genes?)
• May have a DELAYED ONSET
• Usually result in a REDUCED PRODUCTION
or INACTIVE protein
13. AUTOSOMAL RECESSIVE
• Disease is in HOMOZYGOTES
• More UNIFORM expression than AD
• Often COMPLETE PENETRANCE
• Onset usually EARLY in life
• NEW mutations rarely detected clinically
• Proteins show LOSS of FUNCTION
• Include ALL inborn errors of metabolism
• MUCH more common that autosomal dominant
16. SEX (“X”) LINKED
• MALES ONLY
• HIS SONS are OK
• ALL his DAUGHTERS are CARRIERS
• The “Y” chromosome is NOT homologous to
the “X”, i.e., the concept of
dominant/recessive has no meaning here
• HETEROZYGOUS FEMALES have no
phenotypic expression (carriers)….usually,
this means autosomal “recessive”, right?
17. SEX (“X”) LINKED
• DUCHENNE MUSCULAR DYSTROPHY
• HEMOPHILIA , A and B
• G6PD DEFICIENCY
• AGAMMAGLOBULINEMIA
• WISKOTT-ALDRICH SYNDROME
• DIABETES INSIPIDUS
• LESCH-NYHAN SYNDROME
• FRAGILE-X SYNDROME
19. SINGLE GENE DISORDERS
• ENZYME DEFECT (Most of them, e.g., PKU)
– Accumulation of substrate
– Lack of product
– Failure to inactivate a protein which causes damage
• RECEPTOR/TRANSPORT PROTEIN DEFECT (Familial
Hypercholesterolemia)
• STRUCTURAL PROTEIN DEFECT (Marfan, Ehl-Dan)
– Structure
– Function
– Quantity
• ENZYME DEFECT WHICH INCREASES DRUG
SUSCEPTIBILITY: G6PDPrimaquine
20. STRUCTURAL PROTEIN DEFECTS
• Marfan Syndrome
– Fibrillin-1 defect (not -2 or -3)
– Tall, dislocated lens, aortic arch aneurysms, etc.
– Abraham Lincoln?, Osama bin-Laden
• Ehlers-Danlos Syndromes (AD, AR)
– Multiple (6?) different types
– Classical, Hypermob., Vasc., KyphoSc., ArthChal., Derm
– Various collagen defects
– Hyperelastic skin, hyperextensible joints
21. RECEPTOR PROTEIN DEFECTS
• FAMILIAL HYPERCHOLESTEROLEMIA
– LDL RECEPTOR defect
– Cholesterol TRANSPORT across liver cell impaired
– ergo, CHOLESTEROL BUILDUP IN BLOOD
• “Scavenger System” for CHOL kicks in, i.e.,
MACROPHAGES
• YOU NOW KNOW THE REST OF THE STORY
• YOU KNOW WHY MACROPHAGES are “FOAMY”
22. ENZYME DEFICIENCIES
• BY FAR, THE LARGEST KNOWN
CATEGORY
–SUBSTRATE BUILDUP
–PRODUCT LACK
–SUBSTRATE could be HARMFUL
• LYSOSOMAL STORAGE DISEASES
comprise MOST of them
24. GLYCOGEN STORAGE DISEASES
• MANY TYPES (at least 10)
• Type 2 (Pompe), von Gierke, McArdle, most
studied and discussed, and referred to
• Storage sites: Liver, Muscle, Heart
25. SPHINGOLIPIDOSES
• MANY types, Tay-Sachs most often referred to
– GANGLIOSIDES are ACCUMULATED
– Ashkenazi Jews (1/30 are carriers)
– CNS neurons a site of accumulation
– CHERRY RED spot in Macula
26. SULFATIDOSES
• MANY types, but the metachromatic
leukodystrophies (CNS), Krabbe, Fabry,
Gaucher, and Niemann-Pick (A and B) are
most commonly referred to
• SULFATIDES, CEREBROSIDES,
SPHINGOMYELIN are the accumulations
27. NIEMANN-PICK
• TYPES A, B, C
• SPHINGOMYELIN BUILDUP
• MASSIVE SPLENOMEGALY
• ALSO in ASHKANAZI JEWS
• OFTEN FATAL in EARLY LIFE, CNS, ORGANOMEGALY
29. MUCOPOLYSACCHARIDOSES
• HURLER/HUNTER, for I and II, respectively
• DERMATAN sulfate, HEPARAN sulfate
buildup
– coarse facial features
– clouding of the cornea
– joint stiffness
– mental retardation
– URINARY EXCRETION of SULFATES COMMON
31. ALCAPTONURIA
• NOT a LYSOSOMAL ENZYME DISEASE
• FIRST ONE TO BE DESCRIBED
• HOMOGENTISIC ACID
• HOMOGENTISIC ACID OXIDASE
–BLACK URINE
–BLACK NAILS (OCHRONOSIS), SKIN
–BLACK JOINT CARTILAGE (SEVERE ARTHRITIS)
36. MULTIFACTORIAL INHERITANCE
• Multi-”FACTORIAL”, not just multi-GENIC
• “SOIL” theory
• Common phenotypic expressions governed by
“multifactorial” inheritance
– Hair color
– Eye color
– Skin color
– Height
– Intelligence
– Diabetes, type II
37. FEATURES of
multifactorial inheritance
• Expression determined by NUMBER of genes
• Overall 5% chance of 1st degree relatives having it
• Identical twins >>>5%, but WAY less than 100%
• This 5% is increased if more children have it
• Expression of CONTINUOUS traits (e.g.,
height) vs. DISCONTINUOUS traits (e.g., diabetes)
39. KARYOTYPING
• Defined as the study of CHROMOSOMES
• 46 = (22x2) + X + Y
• Conventional notation is “46,XY” or “46,XX”
• G(iemsa)-banding, 500 bands per haploid
recognizable
• Short (“p”-etit) arm = p, other (long) arm = q
40.
41. More KARYOTYPING info
• A,B,C,D,E,F,G depends on chromosome length
– A longest
– G shortest
• Groups within these letters depend on the p/q
ratio
• ARMREGIONBANDSub-BAND,
numbering from the centromere progressing
distad
42.
43. F.I.S.H. (gene “probes”)
greatly enhances G-banding
•Fluorescent In-
Situ
Hybridization
• Uses fluorescent
labelled DNA
fragments, ~10,000
base pairs, to bind (or
not bind) to its
complement
51. TRISOMY-21
• Most trisomies (monosomies, aneuploidy) are
from maternal non-disjunction
• (non-disjunction or anaphase lag are BOTH
possible)
• #1 cause of mental retardation
• Maternal age related
• Congenital Heart Defects, risk for acute leukemias,
GI atresias
• Most LOVABLE of all God’s children
52.
53. Chromosome 22q11.2
Deletion Syndrome
• Because of a DELETION, this cannot be
detected by standard karyotyping and
needs FISH
• Cardiac defects, DiGeorge syndrome,
velocardiofacial, CATCH*
54.
55. SEX CHROMOSOME DISORDERS
• Problems related to sexual development and
fertility
• Discovered at time of puberty
• Retardation related to the number of X
chromosomes
• If you have at least ONE “Y” chromosome,
you are male
56. KLINEFELTER (XXY, XXXY, etc.)
• Hypogonadism found at puberty
•#1 cause of male infertility
• NO retardation unless more X’s
• 47, XXY 82% of the time
• L----O----N----G legs, atrophic testes,
small penis
57.
58. TURNER (XO)
• 45, X is the “proper” designation
• Mosaics common
• Often, the WHOLE chromosome is not
missing, but just part
• NECK “WEBBING”
• EDEMA of HAND DORSUM
• CONGENITAL HEART DEFECTS most
FEARED
59.
60. HERMAPHRODITES
• GENETIC SEX is determined by the PRESENCE or ABSENCE
of a “Y” chromosome, but there is also, GONADAL
(phenotypic), and DUCTAL sex
• TRUE HERMAPHRODITE: OVARIES AND TESTES, often on
opposite sides (VERY RARE)
• PSEUDO-HERMAPHRODITE:
– MALE: TESTES with female characteristics (Y-)
– FEMALE: OVARIES with male characteristics (XX)
61. SINGLE GENE, NON-Mendelian
• Triplet repeats
–Fragile X (CGG)
–Others: ataxias, myotonic dystrophy
• Mitochondrial Mutations: (maternal)
(LEBER HEREDITARY OPTIC NEUROPATHY)
• Genomic “IMPRINTING”: (Inactivation of
maternal or paternal allele, contradicts Mendel)
• Gonadal “MOSAICISM”: (only gametes have
mutated cells)
62. MOLECULAR DX by DNA PROBES
• BIRTH DEFECTS, PRE- or POST- NATAL
• TUMOR CELLS
• CLASSIFICATIONS of TUMORS
• IDENTIFICATION of PATHOGENS
• DONOR COMPATIBILITY
• PATERNITY
• FORENSIC
Most of the classical “genetic” diseases are autosomal RECESSIVE, rather than autosomal DOMINANT, by far.
Fibrillin-1 is a major component of the microfibrils that form a sheath surrounding the amorphous elastin. It is believed that the microfibrils are composed of end-to-end polymers of fibrillin.
The concept is extremely simple: If an enzyme cannot convert A B, then A builds up abnormally.
You will probably never see any of these disorders personally, but nevertheless, you should have familiarity with the process behind each disease.
Tay-Sachs disease (abbreviated TSD, also known as GM2 gangliosidosis or Hexosaminidase A deficiency) is an autosomal recessivegenetic disorder. In its most common variant known as infantile Tay-Sachs disease it presents with a relentless deterioration of mental and physical abilities which commences at 6 months of age and usually results in death by the age of four.
Sphingomyelin (SPH), (sphin-go-my-e-lin (sfi ng gōˈmīəlin)), is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath which surrounds some nerve cell axons. It usually consists ofphosphorylcholine and ceramide. In humans SPH represents ~85% of all sphingolipids.
Cerebrosides are glycosphingolipids which are important components in animal muscle and nerve cell membranes. Myelin is the most well known cerebroside. Glucocerebroside (also called glucosylceramide) is any of the cerebrosides in which the monosaccharide head group is glucose.
Gaucher's disease is the most common of the lysosomal storage diseases. It is caused by a hereditary deficiency of the enzyme glucocerebrosidase (also known as acid β-glucosidase). The enzyme acts on a fatty substance glucocerebroside (also known as glucosylceramide). When the enzyme is defective, the substance accumulates, particularly in cells of the mononuclear cell lineage.
Note this is heparAn, NOT heparIn.
Fucosidosis, also called alpha-l-fucosidase deficiency, is a rare autosomal recessive lysosomal storage disease in which the enzymefucosidase is not properly used in the cells to break down fucose.
Mannosidosis is a deficiency in mannosidase, an enzyme.
Aspartylglucosaminuria (AGU), also called aspartylglycosaminuria, is a rare, autosomal recessive lysosomal storage disorder caused by deficient activity of the enzyme N-aspartyl-beta-glucosaminidase (aspartylglucosaminidase). This enzyme normally cleaves long sugar chains known as oligosaccharides in the lysosome.
Wolman disease (also known as Wolman's disease, Wolman's syndrome, and acid lipase deficiency) is a rare autosomal recessive lipid storage disease that is usually fatal at a very young age. It is in the family of lysosomal storage diseases.
Acid phosphatase deficiency is caused by mutations in the ACP2 (beta subunit) and ACP3 (alpha subunit) genes.
Alkaptonuria (black urine disease or alcaptonuria) is a rare inherited genetic disorder of phenylalanine and tyrosine metabolism. This is an autosomal recessive condition that is due to a defect in the enzyme homogentisate 1,2-dioxygenase (EC 1.13.11.5), which participates in the degradation of tyrosine.
Endogenous pigment looking like ANY other endogenous pigment, e.g., hemosiderin, melanin, bile, lipofucsin
Neurofibromatosis (commonly abbreviated NF) is a genetically-inherited disease in which the nerve tissue grows tumors (i.e., neurofibromas) that may be harmless or may cause serious damage by compressing nerves and other tissues. The disorder affects all neural crest cells (Schwann cells, melanocytes, endoneurial fibroblasts). Cellular elements from these cell types proliferate excessively throughout the body forming tumors and the melanocytes function abnormally resulting in disordered skin pigmentation.The tumors may cause bumps under the skin, colored spots, skeletal problems, pressure on spinal nerve roots, and other neurological problems.
We are now moving the discussion up from ONE gene MULTI-genes Parts of chromosomes WHOLE chromosomes.
If a disease or condition is scalable, rather than on or off, it is probably multigenic, or multifactorial, just part of the spectrum of HOMO-zygous diseases being HOMO-geneous, and HETERO-zygous diseases being VARIABLE.
You might imagine that the list of “multifactorial” disorders blends in with the entire list of human diseases. Hence are “all” diseases “genetic”?
The Giemsa stain, named after Gustav Giemsa, is a VERY common stain in pathology, often used to identify organisms in cells such as malaria and helicobacter, and MANY other things such as parts of cells and connective tissue. It is a VERY simple stain to do.
The “official” notation for the normal male pattern is: “46, XY”
Is it surprising that the “regions” of the “X” chromosome are the same as the list of sex-linked diseases? Ans: NO
Have you see this list before? Ans: YES
Awesome research technique, used often in everyday pathology too, fluorescently “labels” pieces of DNA which connect to the corresponding strand during DNA replication. In situ hybridization (ISH) is a type of hybridization that uses a labeled complementary DNA or RNA strand (i.e., probe) to localize a specific DNA or RNA sequence in a portion or section of tissue (in situ)
FISH is POWERFULLY more sensitive, accurate, and specific, than G-banding.
Common applications for FISH. Examples of diseases that are diagnosed using FISH include Prader-Willi syndrome, Angelman syndrome, 22q13 deletion syndrome, chronic myelogenous leukemia, acute lymphoblastic leukemia,Cri-du-chat, Velocardiofacial syndrome, and Down syndrome, but, IN GENERAL, diseases with partial or whole chromosome abnormalities.
This technique is used to identify structural chromosome aberrations in cancer cells and other disease conditions when Giemsa banding or other techniques are not accurate enough. Each chromosome has a different color, sort of, although some of this is digital false color techniques, much in the same way, electron microscopy can generate “false” colors.
Just about everything you can imagine which can happen to that piece of string------does!
Maternal “nondisjunction” is the classical explanation of Trisomy 21.
You do not have to see many trisomy-21 patients until you can recognize them very quickly and easily. There is NO way you can learn from a textbook how to recognize these patients quickly. If you KNOW one or are RELATED to one, you NEVER fail to recognize the face.
22q11.2 deletion syndrome, also known as DiGeorge Syndrome, Velocardiofacial Syndrome, conotruncal anomaly face syndrome, Congenital Thymic Aplasia, Strong Syndrome, Thymic hypoplasia, and DiGeorge anomaly. It also has the mnemonic C-A-T-C-H, for :
Cardiac Abnormality (especially Fallot's Tetralogy) Abnormal facies Thymic aplasia Cleft palate Hypocalcemia
Cute smiles?
Sexuality can be defined in many ways, having at least ONE “Y” chromosome is a good definition of being male.
“STREAK” ovaries are the rule, neck webbing and cardiac structural abnormalities are also at the top of the list.
“Pseudo”-hermaphrodites are MUCH more common that TRUE hermaphrodites.
The fragile X syndrome is a genetic disorder caused by mutation of the FMR1 gene on the X chromosome. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 females. (Incidence of the disease itself is about 1 in every 4000 females.)
Leber’s hereditary optic neuropathy (LHON) or Leber optic atrophy is a mitochondrially inherited (mother to all offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. However, LHON is only transmitted through the mother as it is primarily due to mutations in the mitochondrial (not nuclear) genome and only the egg contributes mitochondria to the embryo.
Genomic imprinting is a genetic phenomenon by which certain genes are expressed in a parent-of-origin-specific manner.
My #1 peeve, is people who identify pathology with forensic pathology. It shows they have been watching WAY too much TV.
