This document discusses genetics and human diseases caused by genetic mutations. It begins with an introduction to genetics, noting that humans have around 30,000 genes. It then discusses different types of genetic mutations including point mutations, frameshift mutations, and trinucleotide repeat mutations. The document outlines different patterns of genetic inheritance including autosomal dominant, autosomal recessive, and sex-linked inheritance. It provides examples of diseases that follow each pattern of inheritance. The document concludes by discussing specific genetic diseases in more depth, including phenylketonuria (PKU), galactosemia, and how mutations in enzymes, receptors, and structural proteins can cause disease.

1. GENETICS

2. INTRODUCTION
 Humans have only about 30,000 genes
 Genetics is study of single or few genes and their
phenotypic effects.
 Genomics is the study of all the genes in the
genome and their phenotypic effects

3.  Any 2 individuals share greater than 99.5% of
their DNA sequences.
 Remarkable diversity of humans is encoded in
less than 0.5% of our DNA

4. DISEASES
 time-honored classification of human diseases
 (1) those that are genetically determined,
 (2) those that are almost entirely
environmentally determined,
 (3) those to which both nature and nurture
contribute.

5. MUTATIONS
PERMANENT change in
DNA
 GENE MUTATION: (may, and often,
result in a single base error)
 CHROMOSOME MUTATION:
(visible chromosome change)
 GENOME MUTATION: (whole
chromosome)

6.  Those that affect germ cells are transmitted to
the progeny and may give rise to inherited
diseases.
 Mutations in somatic cells are not transmitted to
the progeny but are important in the causation of
cancers and some congenital malformations.

7.  Point mutations result from the substitution of a
single nucleotide base by a different base,
resulting in the replacement of one amino acid by
another in the protein product.
 EX: sickle cell anemia.
 "nonsense" mutations interrupt translation, and
the resultant truncated proteins are rapidly
degraded.

8. POINT MUTATION

9.  Frameshift mutations occur when the insertion or
deletion of one or two base pairs alters the
reading frame of the DNA strand
 Trinucleotide repeat mutations
 mutations are characterized by amplification of a
sequence of 3 nucleotides.

11. MENDELIAN INHERITANCE
PATTERNS
AUTOSOMAL DOMINANT
AUTOSOMAL RECESSIVE
SEX-LINKED (recessive),
involving “X” chromosome

12. AUTOSOMAL DOMINANT
 Disease is in HETEROZYGOTES
 NEITHER parent may have the disease (NEW mut.)
REDUCED PENETRANCE
(environment?, other genes?)
VARIABLE EXPRESSIVITY
(environment?, other genes?)

DELAYED ONSET
May have a

Usually result in a REDUCED
PRODUCTION or INACTIVE protein

13. AUTOSOMAL DOMINANT
•HUNTINGTON
DISEASE
•POLYCYSTIC •NEUROFIBROMATOSI
KIDNEY S
•MYOTONIC
DYSTROPHY
•TUBEROUS
•HEREDITARY SCLEROSIS
SPHEROCYTOS
IS
•VON
WILLEBRAND
•MARFAN SYNDROME
DISEASE
•EHLERS-DANLOS SYNDROMES
(some)
•OSTEOGENESIS IMPERFECTA
•ACHONDROPLASIA
•ACUTE INTERMITTENT
PORPHYRIA
•FAMILIAL
HYPERCHOLESTEROLEM
IA

14. AUTOSOMAL DOMINANT
PEDIGREE
1) BOTH SEXES INVOLVED
2) GENERATIONS NOT SKIPPED

15. AUTOSOMAL RECESSIVE
 Disease is in HOMOZYGOTES

UNIFORM expression than AD
More

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. AUTOSOMAL
RECESSIVE
 CF Hgb S
 PKU
THALASSEMIAS
 GALACTOSEMIA
CONG. ADRENAL HYPERPLASIA
 HOMOCYSTINURIA
EHLERS-DANLOS (some)
 LYSOSOMAL
STORAGE
ALKAPTONURIA
 Α-1 ANTITRYPSIN NEUROGENIC MUSC. ATROPHIES
 WILSON DISEASE FRIEDREICH ATAXIA
 HEMOCHROMATOSIS SPINAL MUSCULAR ATROPHY
 GLYCOGEN STORAGE
DISEASES

17. AUTOSOMAL RECESSIVE PEDIGREE
1) BOTH SEXES
INVOLVED
2) GENERATIONS
SKIPPED

18. SEX (“X”) LINKED
 MALES ONLY
 HIS SONS are OK, right?
 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?

19. SEX (“X”) LINKED
DUCHENNE MUSCULAR
DYSTROPHY
HEMOPHILIA , A and B
G6PD DEFICIENCY
AGAMMAGLOBULINEMIA
WISKOTT-ALDRICH SYNDROME
DIABETES INSIPIDUS
LESCH-NYHAN SYNDROME
FRAGILE-X SYNDROME

20. SEX LINKED
PEDIGREE
1) MALES ONLY, sons of affected males are OK
2) GENERATION SKIPPING DOESN’T MATTER

21. 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
 ENZYMEDEFECT WHICH INCREASES DRUG
SUSCEPTIBILITY: G6PDPrimaquine

22. MARFAN SYNDROME
 autosomal dominant disorder of connective tissues,
 the basic biochemical abnormality affects fibrillin 1.
 This glycoprotein, secreted by fibroblasts, is the major
component of microfibrils found in the extracellular
matrix.
 Microfibrils serve as scaffolding for the deposition of
elastin and are considered integral components of
elastic fibers.
 Fibrillin 1 is encoded by the FBN1 gene, which maps
to chromosome 15q21.
 Mutations in the FBN1 gene are found in all patients
with Marfan syndrome.

23. ABRAHAM LINCOLN

25. SKELETAL ABNORMALITIES
 Patients have a slender, elongated habitus with
abnormally long legs, arms, and fingers
(arachnodactyly);
 a high-arched palate;
 hyperextensibility of joints.
 A variety of spinal deformities, such as severe
kyphoscoliosis, may appear.
 The chest is deformed, exhibiting either pectus
excavatum (i.e., deeply depressed sternum) or a
pigeon-breast deformity.

27.  ocular change is bilateral dislocation, or
subluxation, of the lens owing to weakness of its
suspensory ligaments.
 It should be noted that the ciliary zonules that
support the lens are devoid of elastin and are
made up exclusively of fibrillin

28. SUBLUXATION OF LENS

30.  cardiovascular system.
 Fragmentation of the elastic fibers in the tunica
media of the aorta predisposes to aneurysmal
dilation and aortic dissection
 The cardiac valves, especially the mitral and, less
commonly, the tricuspid valve, may be
excessively distensible and regurgitant (floppy
valve syndrome), giving rise to congestive cardiac
failure
 Death from aortic rupture may occur at any age
and is the most common cause of death. Less
commonly, cardiac failure is the terminal event.

31. EHLERS-DANLOS SYNDROMES
 (EDSs) are characterized by defects in collagen
synthesis or structure.
 30 distinct types of collagen, and all of them have
characteristic tissue distributions and are the
products of different genes.
 the clinical heterogeneity of EDS can be
explained by mutations in different collagen
genes.

32.  tissues rich in collagen, such as skin, ligaments,
and joints, are frequently involved in most
variants of EDS.
 Because the abnormal collagen fibers lack
adequate tensile strength, skin is hyperextensible
and joints are hypermobile.
 These features permit grotesque contortions,
such as bending the thumb backward to touch
the forearm and bending the knee upward to
create almost a right angle.


35.  The skin is extraordinarily stretchable, extremely
fragile, and vulnerable to trauma.
 Minor injuries produce gaping defects, and
surgical repair or any surgical intervention is
accomplished only with great difficulty because of
the lack of normal tensile strength.

36.  The basic defect in connective tissue may lead to
serious internal complications, including
 rupture of the colon and large arteries (vascular
EDS);
 ocular fragility, with rupture of the cornea and
retinal detachment (kyphoscoliosis EDS);
 diaphragmatic hernias (classic EDS),

37. MOLECULAR BASE
 Deficiency of the enzyme lysyl hydroxylase.
 Decreased hydroxylation of lysyl residues in
types I and III collagen interferes with the
normal cross-links among collagen molecules.

38.  Diseases Caused by Mutations in Receptor
 Familial Hypercholesterolemia

39. FAMILIAL
HYPERCHOLESTEROLEMIA
 is among the most common mendelian disorders; the
frequency of heterozygotes is one in 500 in the
general population.
 It is caused by a mutation in the gene that specifies
the receptor for LDL, the form in which 70% of total
plasma cholesterol is transported.
 Dietary triglycerides and cholesterol are incorporated
into chylomicrons in the intestinal mucosa, which
drain via the gut lymphatics into the blood.
 These chylomicrons are hydrolyzed by an endothelial
lipoprotein lipase in the capillaries of muscle and fat.
 The chylomicron remnants, rich in cholesterol, are
then delivered to the liver

41.  Some of the cholesterol enters the metabolic pool
and some is excreted as free cholesterol or bile
acids into the biliary tract.
 The endogenous synthesis of cholesterol and LDL
begins in the liver
 The first step in the synthesis of LDL is the
secretion of triglyceride-rich very-low-density
lipoprotein (VLDL) by the liver into the blood.
 In the capillaries of adipose tissue and muscle,
the VLDL particle undergoes lipolysis and is
converted to intermediate-density lipoprotein
(IDL).

43.  In familial hypercholesterolemia, mutations in
the LDL receptor gene impair the intracellular
transport and catabolism of LDL, resulting in
accumulation of LDL cholesterol in the plasma.
 In addition, the absence of LDL receptors on liver
cells also impairs the transport of IDL into the
liver, and hence a greater proportion of plasma
IDL is converted into LDL.

44.  Thus, patients with familial
hypercholesterolemia develop excessive levels of
serum cholesterol as a result of the combined
effects of reduced catabolism and excessive
biosynthesis
 In the presence of such hypercholesterolemia,
there is a marked increase of cholesterol traffic
into the monocyte macrophages and vascular
walls via the scavenger receptor.
 This accounts for the appearance of skin
xanthomas and premature atherosclerosis

45.  Diseases Caused by Mutations in Enzyme
Proteins
 Phenylketonuria

46.  affects 1 in 12,000 live-born Caucasian infants.
 Homozygotes with this autosomal recessive
disorder classically have a severe lack of
phenylalanine hydroxylase, leading to
hyperphenylalaninemia and PKU.
 Affected infants are normal at birth but within a
few weeks develop a rising plasma phenylalanine
level, which in some way impairs brain
development.
 Usually by 6 months of life severe mental
retardation becomes all too evident;
 fewer than 4% of untreated phenylketonuric
children have IQs greater than 50 or 60..

47.  About one-third of these children are never able
to walk, and two-thirds cannot talk.
 Seizures, other neurologic abnormalities,
decreased pigmentation of hair and skin, and
eczema often accompany the mental retardation
in untreated children.
 Hyperphenylalaninemia and the resultant
mental retardation can be avoided by restriction
of phenylalanine intake early in life.
 Hence, several screening procedures are
routinely performed to detect PKU in the
immediate postnatal period

49.  Many female PKU patients, treated with diet
early in life, reach childbearing age and are
clinically normal.
 Most of them have marked
hyperphenylalaninemia, because dietary
treatment is discontinued after they reach
adulthood.
 Children born to such women are profoundly
mentally retarded and have multiple congenital
anomalies, even though the infants themselves
are heterozygotes.

50.  This syndrome, termed maternal PKU, results
from the teratogenic effects of phenylalanine that
crosses the placenta and affects the developing
fetus.
 Hence, it is imperative that maternal
phenylalanine levels be lowered by dietary
means before conception.
 Maternal hyperphenylalaninemia also increases
the risk of spontaneous abortions.

51.  The biochemical abnormality in PKU is an
inability to convert phenylalanine into tyrosine.
 In normal children, less than 50% of the dietary
intake of phenylalanine is necessary for protein
synthesis.
 The remainder is converted to tyrosine by the
phenylalanine hydroxylase system

 When phenylalanine metabolism is blocked
because of a lack of phenylalanine hydroxylase,
minor shunt pathways come into play, yielding
several intermediates that are excreted in large
amounts in the urine and in the sweat.

52.  These impart a strong musty or mousy odor to
affected infants.
 It is believed that excess phenylalanine or its
metabolites contribute to the brain damage in
PKU.
 Concomitant lack of tyrosine ,a precursor of
melanin, is responsible for the light color of hair
and skin

53. GALACTOSEMIA
 is an autosomal recessive disorder of galactose
metabolism that affects one in 30,000 live-born
infants.
 Normally, lactase splits lactose, the major
carbohydrate of mammalian milk, into glucose and
galactose in the intestinal microvilli.
 Galactose is then converted to glucose in several
steps, in one of which the enzyme galactose-1-
phosphate uridyltransferase is required. Lack of this
enzyme is responsible for galactosemia.
 As a result of this lack of transferase, galactose 1-
phosphate and other metabolites, including galactitol,
accumulate in many tissues, including the liver,
spleen, lens of the eye, kidney, and cerebral cortex.

54.  The liver, eyes, and brain bear the brunt of the
damage.
 The early-developing hepatomegaly is due largely
to fatty change,
 Opacification of the lens (cataracts) develops,
probably because the lens absorbs water and
swells as galactitol, produced by alternative
metabolic pathways, accumulates and increases
its tonicity.
 Nonspecific alterations appear in the central
nervous system (CNS), including loss of nerve
cells, gliosis, and edema.

56.  Almost from birth, these infants fail to thrive.
 Vomiting and diarrhea appear within a few days of
milk ingestion.
 Jaundice and hepatomegaly usually become evident
during the first week of life.
 Accumulation of galactose and galactose 1-phosphate
in the kidney impairs amino acid transport, resulting
in aminoaciduria.
 There is an increased frequency of fulminant
Escherichia coli septicemia.
 Without appropriate dietary therapy, long-term
complications such as cataracts, speech defects,
neurologic deficits, and ovarian failure may occur in
older children and adults.

57.  Most of the clinical and morphologic changes can
be prevented by early removal of galactose from
the diet for at least the first 2 years of life.
 The diagnosis is established by assay of the
transferase in leukocytes and erythrocytes.
 Antenatal diagnosis is possible by enzyme assays
or DNA-based testing of cultured amniocytes or
chorionic villi.

58. ENZYME
DEFICIENCIES
BY
FAR, THE LARGEST
KNOWN CATEGORY
SUBSTRATE BUILDUP
PRODUCT LACK
SUBSTRATE could be
HARMFUL
LYSOSOMAL STORAGE
DISEASES comprise MOST
of them

59. LYSOSOMAL STORAGE DISEASES
 GLYCOGEN STORAGE DISEASES
 SPHINGOLIPIDOSES (Gangliosides)
 SULFATIDOSES
 MUCOPOLYSACCHARIDOSES
 MUCOLIPIDOSES
 OTHER
 Fucosidosis,
Mannosidosis, Aspartylglycosaminuria
 WOLMAN, Acid phosphate deficiency

60. LYSOSOMAL STORAGE DISEASES
 Lysosomes contain a variety of hydrolytic
enzymes that are involved in the breakdown of
complex substrates, such as sphingolipids and
mucopolysaccharides, into soluble end products.
 These large molecules may be derived from the
turnover of intracellular organelles that enter the
lysosomes by autophagocytosis, or they may be
acquired from outside the cells by phagocytosis.

61.  With an inherited lack of a lysosomal enzyme,
catabolism of its substrate remains incomplete,
leading to accumulation of the partially degraded
insoluble metabolites within the lysosomes
 They are divided into broad categories based on
the biochemical nature of the substrates and the
accumulated metabolites, but a more mechanistic
classification is based on the underlying
molecular defect

62. PATHOGENESIS

63. TAY-SACHS DISEASE (GM2
GANGLIOSIDOSIS)
Gangliosidoses are characterized by
accumulation of gangliosides, principally in the
brain, as a result of a deficiency of a catabolic
lysosomal enzyme.
 Depending on the ganglioside involved, these
disorders are subclassified into
 G and G categories.
M1 M2
 Tay-Sachs disease is characterized by a mutation
in and consequent deficiency of the α subunit of
the enzyme hexosaminidase A, which is
necessary for the degradation of GM2.

64.  most affect protein folding or intracellular
transport.
 The brain is principally affected, because it is
most involved in ganglioside metabolism.
 The storage of G occurs within neurons, axon
M2
cylinders of nerves, and glial cells throughout the
CNS.
 Affected cells appear swollen, possibly foamy
Electron microscopy reveals a whorled
configuration within lysosomes
 These anatomic changes are found throughout
the CNS (including the spinal cord), peripheral
nerves, and autonomic nervous system

65.  infants appear normal at birth,
 but motor weakness begins at 3 to 6 months of
age,
 followed by mental retardation, blindness, and
severe neurologic dysfunctions.
 Death occurs within 2 or 3 years

66. 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

67. NIEMANN-PICK DISEASE, TYPES A
AND B
 characterized by a primary deficiency of acid
sphingomyelinase and the resultant
accumulation of sphingomyelin.
 In type A, characterized by a severe deficiency of
sphingomyelinase, the breakdown of
sphingomyelin into ceramide and
phosphorylcholine is impaired, and excess
sphingomyelin accumulates in all phagocytic
cells and in the neurons..

68.  The macrophages become stuffed with droplets or
particles of the complex lipid, imparting a fine
vacuolation or foaminess to the cytoplasm
 Because of their high content of phagocytic cells,
the organs most severely affected are the spleen,
liver, bone marrow, lymph nodes, and lungs

69.  The splenic enlargement may be striking.
 CNS:
 The affected neurons are enlarged and
vacuolated as a result of the storage of lipids.
 This variant manifests itself in infancy with
massive visceromegaly and severe neurologic
deterioration.
 Death usually occurs within the first 3 years of
life.

70.  patients with the type B variant have
organomegaly but no neurologic symptoms.
 Niemann-Pick Disease Type C
 primary defect in lipid transport.
 Affected cells accumulate cholesterol as well as
gangliosides such as GM1 and GM2.
 NPC is clinically marked by ataxia, vertical
supranuclear gaze palsy, dystonia, dysarthria,
and psychomotor regression

71. NIEMANN-PICK
• TYPES A, B, C
• SPHINGOMYELIN BUILDUP
• Sphingomyelinase (ASM), is the missing enzyme
• MASSIVE SPLENOMEGALY
• ALSO in ASHKANAZI JEWS
• OFTEN FATAL in EARLY LIFE, CNS,
ORGANOMEGALY

72. GAUCHER DISEASE
 This disease results from mutation in the gene
that encodes glucosylceramidase.
 deficient activity of a glucosylceramidase that
normally cleaves the glucose residue from
ceramide.
 This leads to an accumulation of
glucosylceramide in the mononuclear phagocytic
cells and their transformation into so-called
Gaucher cells.
 Normally the glycolipids derived from the
breakdown of senescent blood cells, particularly
erythrocytes, are sequentially degraded.

73.  In Gaucher disease, the degradation stops at the
level of glucosylceramides, which, in transit
through the blood as macromolecules, are
engulfed by the phagocytic cells of the body,
especially in the liver, spleen, and bone marrow.

 These phagocytes (Gaucher cells) become
enlarged, with some becoming as large as 100
μm, because of the accumulation of distended
lysosomes, and develop a pathognomonic
cytoplasmic appearance characterized as
"wrinkled tissue paper"

74.  High levels of macrophage-derived cytokines,
such as interleukins (IL-2, IL-6) and tumor
necrosis factor (TNF) are found in affected
tissues.

76.  type I :-- the chronic non-neuronopathic form,
 accounts for 99% of cases of Gaucher disease.
 It is characterized by clinical or radiographic
bone involvement (osteopenia, focal lytic lesions,
and osteonecrosis) in 70% to 100% of cases.
 Additional features are hepatosplenomegaly and
the absence of CNS involvement.
 The spleen often enlarges massively, filling the
entire abdomen.

77.  Gaucher cells are found in the liver, spleen,
lymph nodes, and bone marrow.
 Marrow replacement and cortical erosion may
produce radiographically visible skeletal lesions,
as well as a reduction in the formed elements of
blood.
 Bone changes are believed to be caused by
macrophage-derived cytokines

78.  Types II and III variants are characterized by
neurologic signs and symptoms.
 In type II, the symptoms start before 2 years of
age and are more severe, whereas in type III, the
symptoms appear later and are milder.
 Although the liver and spleen are also involved,
the clinical features are dominated by neurologic
disturbances.
 In addition to these, there is a perinatal-lethal
form characterized by hepatosplenomegaly, skin
lesions, and non-immune hydrops . In the so-
called cardiovascular form, there is involvement
and calcification of mitral and aortic valves.

79. MUCOPOLYSACCHARIDOSES (MPSS)
 characterized by defective degradation (and
therefore excessive storage) of
mucopolysaccharides in various tissues.
 Recall that mucopolysaccharides form a part of
ground substance and are synthesized by
connective tissue fibroblasts.
 Most of the mucopolysaccharide is secreted into
the ground substance, but a certain fraction is
degraded within lysosomes.

80.  Several enzymes are involved in this catabolic
pathway; it is the lack of these enzymes that
leads to accumulation of mucopolysaccharides
within the lysosomes.
 Several clinical variants of MPS, classified
numerically from MPS I to MPS VII, have been
described, each resulting from the deficiency of
one specific enzyme.

81.  The mucopolysaccharides that accumulate within
the tissues include
 dermatan sulfate,
 heparan sulfate,
 keratan sulfate,
 chondroitin sulfate

82.  Most are associated with coarse facial features,
clouding of the cornea, joint stiffness, and mental
retardation.
 Urinary excretion of the accumulated
mucopolysaccharides is often increased.
 All of these disorders except one are inherited as
autosomal recessive conditions; the exception,
Hunter syndrome, is an X-linked recessive
disease.

84.  Mucopolysaccharidosis type I caused by a
deficiency of α-L-iduronidase.
 In Hurler syndrome, affected children have a life
expectancy of 6 to 10 years.
 they develop coarse facial features associated
with skeletal deformities.
 Death is often due to cardiac complications
resulting from the formation of raised endothelial
and endocardial lesions by the deposition of
mucopolysaccharides in the coronary arteries and
heart valves.

85.  type II, or Hunter syndrome, (X-linked),
 results from a deficiency of L-iduronate sulfatase.


86. GLYCOGEN STORAGE DISEASES
(GLYCOGENOSES)
An inherited deficiency of any one of the enzymes
involved in glycogen synthesis or degradation can
result in excessive accumulation of glycogen or
some abnormal form of glycogen in various
tissues.
 Regardless of the tissue or cells affected, the
glycogen is most often stored within the
cytoplasm, or sometimes within nuclei.
 Most glycogenoses are inherited as autosomal
recessive diseases, as is common with "missing
enzyme" syndromes.

87.  Hepatic type.
 Liver contains several enzymes that synthesize
glycogen for storage and also break it down into
free glucose.
 Hence, a deficiency of the hepatic enzymes
involved in glycogen metabolism is associated
with two major clinical effects:
 enlargement of the liver due to storage of glycogen
and hypoglycemia due to a failure of glucose
production

88.  Von Gierke disease (type I glycogenosis),
resulting from a lack of glucose-6-phosphatase, is
the most important example of the hepatic form
of glycogenosis

89.  Myopathic type.
 In striated muscle, glycogen is an important
source of energy.
 When enzymes that are involved in glycolysis are
deficient, glycogen storage occurs in muscles and
there is an associated muscle weakness due to
impaired energy production.
 Typically, the myopathic forms of glycogen
storage diseases are marked by muscle cramps
after exercise, myoglobinuria, and failure of
exercise to induce an elevation in blood lactate
levels because of a block in glycolysis

90.  McArdle disease (type V glycogenosis), resulting
from a deficiency of muscle phosphorylase, is the
prototype of myopathic glycogenoses.
 Type II glycogenosis (Pompe disease) is caused by
a deficiency of lysosomal acid maltase and so is
associated with deposition of glycogen in
virtually every organ, but cardiomegaly is most
prominent.
 Brancher glycogenosis (type IV) is caused by
deposition of an abnormal form of glycogen, with
detrimental effects on the liver, heart, and

91.  Accumulation of dermatan sulfate and heparan
sulfate is seen in cells of the mononuclear
phagocyte system, in fibroblasts, and within
endothelium and smooth muscle cells of the
vascular wall.
 The affected cells are swollen and have clear
cytoplasm, resulting from the accumulation of
material positive for periodic acid-Schiff stain
within engorged, vacuolated lysosomes.
 Lysosomal inclusions are also found in neurons,
accounting for the mental retardation

92. 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

93. 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)

94. “MULTIFACTORIAL”
DISORDERS
Cleftlip, palate
Congenital heart disease
Coronary heart disease
Hypertension
Gout
Diabetes
Pyloric stenosis
MANY, MANY, MANY, MANY
MORE

95. 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

97. 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
ARMREGIONBANDSub-
BAND, numbering from the centromere
progressing distad

99. 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

100. FISH
 SUBTLE MICRODELETIONS
 COMPLEX TRANSLOCATIONS
 AND TELOMERE ALTERATIONS

101. TRIPLE CHROMOSOME #20 A DELETION in
CHROMOSOME #22

102. SPECTRAL
KARYOTYPING

103. CYTOGENETIC
DISORDERS
DEFINITIONS:
EUPLOID
ANEUPLOID (NOT AN EXACT
MULTIPLE OF 23)
MONOSOMY, AUTOSOME OR SEX
TRISOMY, AUTOSOME OR SEX
DELETION
BREAKAGE

104. MORE DEFINITIONS

105. COMMON CYTOGENETIC DISEASES
 AUTOSOMES
TRISOMY-21 (DOWN SYNDROME)
8, 9, 13 (Patau), 18 (Edwards), 22
22q.11.2 deletion
 SEX CHROMOSOMES
KLINEFELTER: XXY, XXXY,
etc.
TURNER: XO

106. TRISOMY-21

107. 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

109. 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*

111. 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

112. 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

114. 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

116. 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)

117. 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)

118. MOLECULAR DX BY DNA PROBES
 BIRTH DEFECTS, PRE- or
POST- NATAL
 TUMOR CELLS
 CLASSIFICATIONS of TUMORS
 IDENTIFICATION of
PATHOGENS
 DONOR COMPATIBILITY
 PATERNITY
 FORENSIC

119. H&E tissue
structures
Immuno-
Antigen
Proteins
GENES that
MAKE those
PROTEINS

120. TRIPLET-REPEAT MUTATIONS:
FRAGILE X SYNDROME
Fragile X syndrome is the prototype of diseases
in which the mutation is characterized by a long
repeating sequence of 3 nucleotides.
 Other examples of diseases associated with
trinucleotide repeat mutations include
Huntington disease and myotonic dystrophy.
 amplification of specific sets of 3 nucleotides
within the gene disrupts its function

121.  Fragile X syndrome is characterized by mental
retardation and an abnormality in the X
chromosome.
 It is one of the most common causes of familial
mental retardation.
 Clinically affected males have moderate to severe
mental retardation.
 They express a characteristic physical phenotype
that includes a long face with a large mandible,
large everted ears, and large testicles (macro-
orchidism).

122.  Fragile X syndrome results from a mutation in
the FMR1 gene, which maps to Xq27.3. Like all
X-linked recessive disorders, this disease affects
males

123. GENOMIC IMPRINTING: PRADER-
WILLI AND ANGELMAN
SYNDROMES
 All humans inherit two copies of each gene,
carried on homologous maternal and paternal
chromosomes.
 genomic imprinting
 certain genes are differentially "inactivated"
during paternal and maternal gametogenesis.
 Thus, maternal imprinting refers to
transcriptional silencing of the maternal allele,
whereas paternal imprinting implies that the
paternal allele is inactivated.
 Imprinting occurs in ovum or sperm and is then
stably transmitted to all somatic cells derived
from the zygote

124. GENOMIC IMPRINTING

125. PRADER-WILLI SYNDROME
 characterized by mental retardation, short
stature, hypotonia, obesity, small hands and feet,
and hypogonadism.
 In 60% to 75% of cases, an interstitial deletion of
band q12 in the long arm of chromosome 15 can
be detected.
 It is striking that in all cases the deletion affects
the paternally derived chromosome 15.
.

126.  Angelman syndrome are born with a deletion of
the same chromosomal region derived from their
mothers

127.  Patients with Angelman syndrome are also
mentally retarded, but in addition they present
with ataxic gait, seizures, and inappropriate
laughter.
 Because of the laughter and ataxia, this
syndrome is also called the happy puppet
syndrome.