Medical Genetics
Robert F. Waters, Ph.D.
Pathology, Etiology, Pathogenesis,
Pathophysiology
Aneuploidy
Metabolic
Mutations
Adducts
Porphyrias
Produced mainly in:
Porphyrin Rings
– Liver
– Erythrocyte producing cells of bone marrow
Not mature erythrocytes (lack of mitochondria)
Initial step and last three steps are in the
mitochondria
Glycine and Succinyl CoA are precursors
Hemin is feedback inhibitor of  -aminolevulinic
dehydrase (ALA) ( -delta)
– Lead is inhibitor of this pathway
Porphyrin Uses
Cytochromes
– P450, b5, ETS
Hemoglobin
Porphyrins Cont:
Addition of ferrous iron in
mitochondria
– ferrochelatase
Porphyrias
Usually hereditary porphyrin production
defects
General Classification
– Erythropoietic (defect in RBCs)
– Hepatic (Defect in liver)
Usually autosomal dominant
Heme Degradation
First product is biliverdin (open ring)
– Heme oxygenase
Biliverdin plus CO yields bilirubin
– Biliverdin reductase
NADP
Bilirubin
– Gut (microbial enzymes act on bilirubin)
Produce Urobilinogen
– Absorbed and carried to liver to produce Urobilin
Yellow color
– Large intestine further microbial enzymes produce
Stercobilin
Characteristic brown color
– Liver
Conjugation with 2 moles of glucuronic acid
– Glucuronyl bilirubin transferase
– Forms bilirubin diglucuronide (polar and soluble)
detox
Hemoglobin
Porphyrin ring
Iron
Oxygen Binding
Two alpha chains and two beta chains
– 1 2  1 2
Thalassemias
Structure of Hemoglobin
Thalassemias
 and  types
Alpha Thalassemias
Thalassemias-Cont:
Alpha thalassemia usually more severe
– Thalassemia major
– Variety of deletions (usually)
Beta thalassemia usually less severe
– Thalassemia minor
– Usually single nucleotide substitutions
Thalassemia Tx
Red Blood Cell Transfusions
Chelation
Hemoglobinopathies-Cont:
Thalassemias (thalassa-sea:many cases
around Mediterranian Sea)
– + 0 (some production vs. none)
– + 0(some production vs. none)
Alpha thalassemias affect fetal and postpartum
hemoglobin
Beta thalassemias affect only postpartum
Genetics of Hemoglobin
12
– Chromosome 16
Diploid designation 12/12
– Produced in utero
1 2
– Chromosome 11
– Produced postpartum only
Alpha-like chains ()
–
pre- & post-natal
–  (zeta)
Beta-like chains ()
– Essentially post-natal
– (sigma, epsilon, gamma)
Hemoglobinopathies
Very common
AR-Sickle Cell Anemia
– HbA vs HbS (6 GluVal)
Life long hemolytic anemia
Sickle Cell Anemia (AR)
Sickle cell anemia is the most common inherited blood
disorder in the United States, affecting about 1 in 500
African Americans. SCA is characterized by episodes of
pain, chronic hemolytic anemia and severe infections,
usually beginning in early childhood.
Autosomal recessive disease caused by a point mutation
in the hemoglobin beta gene (HBB) found on
chromosome 11p15.5. called HbS.
Though, as yet, there is no cure for SCA, a combination
of fluids, painkillers, antibiotics and transfusions are used
to treat symptoms and complications. Hydroxyurea, an
antitumor drug, has been shown to be effective in
preventing painful crises. Hydroxyurea induces the
formation of fetal Hb (HbF)—a Hb normally found in the
fetus or newborn—which, when present in individuals
with SCA, prevents sickling.
Other HbS Anemia Tx
Vaso-occlusive treatments
Folic acid and penicillin
Hydroxyurea
Bone marrow transplants
Sickle Cell Cont: HbS
Renal Failure
Iron and Iron Storage Diseases
Association with copper
– Absorption from lumen in intestine
Ceruloplasmin
– Cupric to cuprous, ferrous to ferric
– Vitamin C
– Wilson’s disease
1:100,000
– Lack of copper transport proteins
Copper in Enzymes
Iron Contained in….
Some Examples
Hemoglobin, myoglobin
NO binding, guanylate cyclase
ETS hemes
Cytochrome b5 in desaturation
Iron-sulfur (Complex I, aconitase, xanthine
oxidase, ferrochelatase (heme synth.)
Phenylalaine hydroxylase, tyrosine hydroxylase,
dioxygenases
Etc.
Transferrin
Plasma protein
– Glycoprotein synthesized by liver
– Single polypeptide (~700 AA’s)
High affinity for ferric iron
No affinity for ferrous iron
Serum levels about 30umol/L
– Serum has excess iron binding capacity
Transferrin Cont:
Transferrin production increased during
– Iron deficiency
– Pregnancy (high estrogen levels)
– Women taking oral contraceptives
Transferrin production decreased
–
–
–
–
–
Excess iron
Infection
Inflammation
Neoplasia
Protein catabolic state
Transferred to recipient cells by– Transferrin-binding Receptors
Ferritin
Store iron in ferrous non-toxic state
Relatively short term storage
Handoff to/from transferrin
Handoff to/from hemosiderin
Mainly intracellular
– Not usually in the serum unless iron storage
saturation
Hemosiderin
Long term storage
Handoff to/from ferritin
Exist in times of iron overload
Probably a form of iron-ferritin complexes
in a type of micelle formation in tissues
Hypochromic Microcytic Anemia
Pale RBCs due to low levels of
hemoglobin
Hemochromatosis (AR)
Excess iron (free iron due to saturation of
tranferrin)
Arthritis, liver cancer, coronary occlusions
Early diagnosis and treatment
AR inheritance with gene on chromosome 6
Treatment
– Venesection (removal of blood)
Removal of 500ml of blood over specified frequency and
period of time to lower iron reserves
High frequency is 500ml per week over 1-2 year period of
time
– Chelation
Hereditary Hemochromatosis
What are the symptoms of hemochromatosis?
Joint pain is the most common complaint of people with hemochromatosis.
Other common symptoms include fatigue, lack of energy, abdominal pain,
loss of sex drive, and heart problems. However, many people have no
symptoms when they are diagnosed.
If the disease is not detected and treated early, iron may accumulate in
body tissues and eventually lead to serious problems such as…
arthritis
liver disease, including an enlarged liver, cirrhosis, cancer, and liver failure
damage to the pancreas, possibly causing diabetes
heart abnormalities, such as irregular heart rhythms or congestive heart
failure
impotence
early menopause
abnormal pigmentation of the skin, making it look gray or bronze
thyroid deficiency
damage to the adrenal glands
Hemochromatosis Dx
Blood tests can determine whether the amount of iron
stored in the body is too high. The transferrin saturation
test reveals how much iron is bound to the protein that
carries iron in the blood. Transferrin saturation values
higher than 45 percent are considered too high.
The total iron binding capacity test measures how well
your blood can transport iron, and the serum ferritin test
shows the level of iron in the liver. If either of these tests
shows higher than normal levels of iron in the body,
doctors can order a special blood test to detect the HFE
mutation, which will confirm the diagnosis.
A liver biopsy may be needed, in which case a tiny piece
of liver tissue is removed and examined with a
microscope.
Hemochromatosis Tx
Phlebotomy
Should be more dietary resolution
Alpha-1-Antitrypsin Deficiency (AR)
Alpha-1 antitrypsin deficiency (Alpha-1) is a
hereditary genetic disorder which may lead to
the development of lung and/or liver disease. It
is the most common genetic cause of liver
disease in children. Adults can also be affected
by Alpha-1 and may develop lung conditions
such as emphysema as well as liver problems.
Fortunately, many persons diagnosed with
Alpha-1 never develop any of the associated
diseases.
Alpha-1-Continued
Liver Cancer
COPD
Latent manifestation
Tx
– Steroids
– Herbs????
Albinism-Lack of Melanin Pigment
Tyrosine production
Tyrosine transport
Autism
Insistence on sameness; resistance to change
Difficulty in expressing needs; using gestures or pointing instead of words
Repeating words or phrases in place of normal, responsive language
Laughing (and/or crying) for no apparent reason; showing distress for reasons not
apparent to others
Preference to being alone; aloof manner
Tantrums
Difficulty in mixing with others
Not wanting to cuddle or be cuddled
Little or no eye contact
Unresponsive to normal teaching methods
Sustained odd play
Spinning objects
Obsessive attachment to objects
Apparent over-sensitivity or under-sensitivity to pain
No real fears of danger
Noticeable physical over-activity or extreme under-activity
Uneven gross/fine motor skills
Non-responsive to verbal cues; acts as if deaf, although hearing tests are in normal
range
Carnitine Deficiency
Muscle metabolism is impaired, causing
myopathy, hypoglycemia, or
cardiomyopathy.
Most often, treatment consists of dietary Lcarnitine, avoid strenuous exercise, avoid
fasting.
G6PD Deficiency (XR)
Partial protection against malaria???
X-Linked Recessive
Favism (Fava Beans)
Insufficient formation of NADPH
– High oxidative stress in erythrocytes
– Lipid metabolism affected
Phenylketonuria
Lack of tyrosine production
Form neurotoxic phenylketones
– Phenylalanine dehydrogenase
Feed with tyrosine
– T3, T4 thyroxines
– L-Dopa
– Dopamine
– Epinephrine
– Melanin Pigment, etc.
Galactosemia
Problems with speech, language, hearing,
fine-motor coordination, hemorrhage of the
gel-like substance of the eye, tremors,
stunted growth, and certain learning
disabilities.
Types associated with galactose kinase
and galactose-1-phosphate uridyl
transferase
Klinefelter syndrome
(XXY syndrome)
Some affected boys will have more features of the syndrome than
others and there will be a difference in the degree of severity
In some cases, a diagnosis of XXY syndrome is not made until a
boy approaches puberty and some men may never be diagnosed
with the condition
The most common features include learning difficulties and a
tendency to grow at a slightly quicker rate than their peers so that
their final height may be more than expected, but is usually within
the normal range; reduction in body hair, beard growth and testicular
size that can be treated with the male hormone testosterone; while
sexuality is normal men with the syndrome may be infertile
Having a son with XXY syndrome does not appear to be related to
either the age of the mother or the father at the time of conception
Those with 47,XXY in all their cells usually are infertile
Turner Syndrome XO
The victim in question possesses a genetic
structure in which one or many parts of the X
chromosome remains absent in the cell
formation.
Symptoms
–
–
–
–
–
–
–
Small fingernails
Horseshoe shaped kidney
Low Hairline
Poor body development
Increased weight
Absence of a menstrual cycle, and
Sterility of the reproductive organs.
Down’s Syndrome Triplo-21
The reasons for this disease are known
Types
– a)Trisomy 21: In most cases (95%), all the body cells
of the patient have three chromosomes 21, which
happens due to the meiosis non-disjunction.
– b)Mosaic Down Syndrome: Only some body cells
have an extra chromosome 21 (non disjunction in
mitosis).
– c)Translocation Down Syndrome: In this case, a
part of chromosome 21 is attached to another
chromosome. So the patients have 2 chromosomes
21 plus a part of a third chromosome 21.
Down’s Continued
The level of superoxide disimutase-1, which is coded by a gene on
chromosome 21, is on average, 150% of the values found in normal
individuals’ blood as well as other cells.
The high enzyme activity results in a high rate of conversion of
superoxides to peroxides, resulting in high levels of peroxides that
may damage DNA and lipids.
Over expression of lymphocyte function associated antigen-1(LFA1), which is also coded on chromosome 21, may lead to an
abnormal interaction between cells from the thymus, resulting in
aberrant T-cell maturation and selection.
Overexpression of the interferon receptor gene also located on
chromosome 21 is common in Down syndrome and may also
contribute to immune deficiency.
Low serum zinc common in Down syndrome, may also cause weak
immunity.
Down’s Continued
The most significant abnormality of the immune
system in Down syndrome is a 30-fold increase
in the incidence of acute leukemia
200-fold increase in acute megakaryocytic
leukemia.
30% of adults with Down syndrome are deficient
in IgG-2 and/or IgG-4 and these deficiencies are
also common in children with Down syndrome.
---selenium supplementation may increase
Cystic Fibrosis (AR)
Sinus Infections
Poor Growth
Diarrhea
Infertility
Difficulty breathing
Hemophilia (XR)
Deep internal bleeding
Joint damage
Transfusion transmitted infection
Poor reactions which can result from the
treatment of the clotting factor
Intracranial hemorrhage
Klinefelter’s Syndrome
XXY, XXXY
Symptoms
–
–
–
–
–
The most important symptom is the male infertility.
small testes
inability to produce sperms
rounded body type
difficulties in reading, writing, or even language
problems
Tx
– Testosterone (Early)
Urea Cycle Disorders
Examples
– Argininemia
– Citrullinemia
– Argininosuccinic aciduria
Symptoms
– Clinical features are the result of the development of
hyperammonemia
– encephalopathy and include poor feeding,
– lethargy leading to coma
– Hyperventilation
– muscle tone abnormalities and,
– death.
Spina bifida
Folate (folic acid) DEGRADES BY
COOKING!
Folate occurs naturally in food.
Cereals, baked goods, leafy vegetables
(spinach, broccoli, lettuce), okra,
asparagus, fruits (bananas, melons,
lemons), legumes, yeast, mushrooms,
organ meat (beef liver, kidney), orange
juice, and tomato juice.
Alzheimer's, Parkinson’s and
Dementia
Curcuminoids
Turmeric
Glutathione
Tay-Sachs Disease
lethal genetic disorder
Mutation lies in the gene Hex A --hexaminidase A on Chromosome
15
The most important ganglioside for Tay-Sachs is the Ganglioside
GM2. This material is found in the nerve cells of the brain and
especially in the cell membranes. In the case of Tay-Sachs Disease
there is no enough activity of the enzyme and the gangliosides are
accumulated with destructive results.
The accumulation of GM2 in the nervous tissue causes a gradual
destruction of the nervous system. The apparently healthy baby
gradually stops laughing, crawling, smiling, grasping, turning
around. Later people with Tay-Sachs becomes blind and paralyzed
and unable to shallow and contact with its surrounding. One of the
most common symptom is a red spot in the eyes. The death seems
to be fatal (in the classic Tay-Sachs Disease) and comes around
age of 5.
Tay-Sachs Inheritance (AR)
Amyotrophic Lateral Sclerosis
Lou Gehrig’s disease also known as
familial amyotrophic lateral sclerosis (ALS)
ISIS-SOD1Rx is an antisense drug
designed to inhibit the production of
SOD1.
ALS Continued
Muscles in the body are damaged first
Speech problems
Problems with moving, swallowing (dysphagia), and
speaking or forming words (dysarthria)
Exaggerated reflexes (hyperreflexia) including an
overactive gag reflex
Does not affect cognitive abilities, patients are aware of
their progressive loss of function and may become
anxious and depressed.
Eventually lose the ability to breathe on their own and
must depend on ventilatory support for survival
GILBERT’S SYNDROME
Alagille syndrome
Often affects the liver and other organs, including the
heart, eyes, spine and kidneys.
Jaundice, usually present at birth (yellowing of the skin)
Severe itching (caused by the buildup of bile salt in the
body)
Pale, loose or clay-colored stools (this happens because
there is little or no bile reaching the intestine to color the
bowel movements)
Poor weight gain (due to a lack of bile needed to digest
and absorb fat)
Poor growth
Marfan’s Syndrome
Bones (arms, legs, fingers, and toes) that are longer than normal
A long, narrow face
Crowded teeth because the roof of the mouth is arched
A breastbone that sticks out or caves in
A curved backbone
Flat feet
Nearsightedness
Glaucoma (high pressure within the eye) at a young age
Cataracts (the eye’s lens becomes cloudy)
A shift in one or both lenses of the eye
A detached retina in the eye
Stiff air sacs in the lungs.
A collapsed lung if the air sacs become stretched or swollen
Snoring or not breathing for short periods (called sleep apnea) while
sleeping
Inborn Errors of Metabolism
Enzymatic defect (structure)
Enzyme substrate problem
Enzyme co-enzyme malfunction
Enzyme co-factor (metal) malfunction
Build up before—feed after
Usually autosomal recessive
– Otherwise would probably be lethal
Some are hemizygous (XY)
Consequences-Overview
Accumulation of a precursor
– Accumulated precursor may be toxic
E.g., pyruvate
– Alternate minor pathways may start producing other
toxic metabolites
E.g., PKU
Deficiency of product
– Product may be precursor to other substance.
E.g., tyrosine and thyronines
– Feedback inhibition may be impaired due to lack of
product
Causes lack of feedback inhibition
PDH Complex
Build up of lactate and pyruvate
May be E1, E2, E3 lesion
Also affects alphaketoglutarate
dehydrogenase
Cystinuria
Increased secretion of cystine, lysine,
arginine, ornithine
Aminoaciduria
AR (variable expressivity)
Renal failure
Glycogen storage diseases
Type I (von Gierke’s)
– Hepatomegaly, mental retardation, hypoglycemia
– Glucose-6-phosphatase deficiency
– AR
Type VIII (Glycogen Storage Disease)
– Hepatomegaly,mild acidosis, hypoglycemia
– XR
– Phorphorylase kinase
McArdle’s Disease Type V
– myophosphorylase C deficiency
– AR
difficulty during physical activities like jogging, walking up hills or
stairs, swimming, or anything moderately intense
Tay-Sachs Disease
Onset at 4 to 6 months
Death 2 to 4 years
AR
Degenerative neurological changes
– Gangliosidosis
Reduced hexosaminidase
Hartnup Disease
Tryptophan transport
Neurological change
AR
Homocystinuria
Dislocated lenses
AR
Accumulation of methionine and
homocystine
Lesch-Nyhan Syndrome
Uric Aciduria
Self-mutilation
Mental retardation
Cerebral palsy
XR
Mucopolysaccharidoses I
Hurler’s Syndrome
“Gargoyle” Appearance
Mental retardation
Corneal clouding
Cardiovascular degeneration
Dwarfism
Mucopolysaccharide accumulation
Mucopolysaccharidoses II
Hunter’s Syndrome
– Less severe than Hurler’s
– No evidence of corneal clouding
Pentosuria
AR
“False Diabetes”
Congenital Spherocytosis
Episodes of hemolytic anemia
Defect in RBC membrane
AD
– Patients are heterozygous
Wilson’s Disease
Cirrhosis of liver
Neurological damage
Improper copper metabolism
AR
Build up of stored copper
Decreased serum levels of ceruloplasmin
Treatment by Penicillamine removes
stored Cu
Maple Syrup Urine Disease
BCAA dehydrogenase
Alcaptonuria
Dark Urine Disease
Homogentisic acid
AR
Vitamin Pathways
holoenzyme carboxylase
– pyruvate carboxylase
CoA
NAD
FAD, FMN
Huntington's disease
AD
Chorea
Latent gene
Neurodegenerative
disease
– The neuron in the center
(yellow) contains an
abnormal intracellular
accumulation of huntingtin
called an inclusion body
(orange).
Duchenne Muscular Dystrophy
DMD
XR
Muscle deterioration early in life
Muscles eventually “explode”
Fatigue
Mental retardation (possible, but does not
worsen over time)
Muscle weakness
Progressive difficulty walking
– May be lost by age 12
(Myotonic) Muscular Dystrophy
(MD)
fat and connective tissue often replace
muscle fibers
Steinert's disease
AD
Many other types of inherited muscular
dystrophy
TYPE I Diabetes
Diabetic Ketoacidosis (DKA)
Beta cell destruction or deterioration
Juvenile onset
Type II Diabetes
Chromosome I and IV
Vasculitis
NIDDM to IDDM
Systemic Lupus Erythematosus
(SLE or Lupus)
Autoimmune disease
DNase1 deficiency
– normally eliminates what is called "garbage
DNA" and other cellular debris by chopping
them into tiny fragments for easier disposal.
Rashes
Infection
Pain…especially joint pain