Age-related genetic disorders
Includes Huntington disease, dominant Polycystic Kidney Disease, genetic
hemochromatosis, and other complex disorders.
Huntington Disease (HD)
Mutation: 4pI6.3. Dominant inheritance pattern. CAG sequence triples repeat, expand.
NL: up to 40 repeats CAG. Those affected have more than CAG repeats. Premature
death of brain cells and accumulation of cholesterol in the brain. Physical disability:
'chorea' loss of motor control, gait, and function. Mental disability: serious dementia.
Psych expression includes depression and paranoia. High suicide risk. Problems with
muscle coordination. Physical symptoms are very similar, but cognitive/psych symptoms
vary from person to person. Fatal with neuronal death. The more CAG repeats, the
more of the mutant protein that increases decay rate of neurons.
chorea
Characteristic of Huntington disease. Uncontrollable, writhing movement. Jerky,
random. Initially exhibited by general restlessness, small unintentionally initiated or
uncompleted motions, lack of coordination, or slowed saccadic eye movements.
progression of Huntington Disease
Symptoms become noticeable at 35-44 years. Physical symptoms are first to be
noticed. Mild chorea comes first before more obvious signs. Writhing motions and
abnormal posturing appear as the disorder progresses. Psychomotor functions become
increasingly impaired; difficulties chewing, swallowing, speaking.
juvenile Huntington Disease
Occurs much early on. Generally progresses faster, and chorea is exhibited briefly, if at
all, with rigidity being the dominant symptom. Seizures are also common.
anticipation
Symptoms of the genetic disorder become apparent at an earlier age as the disease
passes from one generation to the next. I.e. Grandpa had it at 55 years, Mother had it at
48 years, I had it at 41 years.
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Huntington Disease ethical considerations
Diagnosis usually occurs in the 40s. Predictive pre-symptomatic testing is 100%. But,
important to consider that patient may not want to know the results because no
preventive measures/cures. Psychological assessment and counseling is a special
protocol for genetic testing and informed consent. May have guilt, anxiety, and
hopelessness.
adult dominant polycystic kidney disease
Autosomal dominant inheritance. Adult onset. One of the most common inherited
disorders (1:300). Accounts for 10% of dialysis patients. Cysts form throughout the
kidney. Causes progressive renal dysfunction and ultimately renal failure. Symptoms
begin in mid-adulthood with pain in the abdomen, blood in urine, frequent urination, and
intense pain from kidney stones. 50% of patients with this have hypertension at time of
diagnosis. Hepatic cysts, cerebral aneurysms, cardiac abnormalities. Morality related to
subarachnoidal hemorrhage, hypertension/stroke, intracranial aneurysms. Focal
expression because less than 5% of nephrons become cystic.
genetic hemochromatosis
Recessive: HFE gene on chromosome 6. Mutation: "iron overload disease". More iron
absorption and storage leading to organ damage. 1:300 affected with 1:9 carriers.
Northern European men and women over 50 years. Diagnosis through high serum
saturation of transferring and high serum ferritin. Fatigue and joint/abdomen pain are
early symptoms. Other symptoms include vertigo, hair loss, memory loss, heart
degeneration, hepatomegaly, cirrhosis (elevated liver enzymes), bronze skin, diabetes
mellitus, testicular atrophy, arthritis. Treatment includes removal of 500ml blood q-3-4
months; no vitamin C or iron supplements; avoid iron rich foods; no raw oysters. High
levels of free iron have increased growth/lethality of V. vulnificus.
multifactorial adult onset disorders
Includes diabetes, hypertension, coronary heart disease, cancer, aging & Alzheimer's
disease, schizophrenia, and addictions.
common complex diseases
hypertension, stroke, cardiovascular disease. Phenotype is always an issue. Use the
HuGE investigator and gene prospector (CDC) to find significant studies and genes of
interest for these.
human genome epidemiology (HuGE)
establish and information exchange that promotes global collaboration in developing
peer-reviewed information on the relationship between human genomic variation and
health and on the quality of genetic tests for screening and prevention.
sporadic cancer
form that consists of 75% of all cancers
familial cancer
form that consists of 15% of all cancers
hereditary cancer
form that consists of 10% of all cancers
oncogenes
altered forms of proto-oncogenes (due to mutation, chromosome rearrangement, gene
amplification or viral insertion). Cause overproduction of growth factors and
unrestrained cell growth driven by elevated levels of transcription factors.
tumor suppressor genes
normally function to inhibit cell growth. Must be mutations in both alleles of this before
tumor formation occurs. May require two separate mutational events (two-hit theory).
Includes BrCa 1 & 2 (normal versions).
genes implicated in cancer
include oncogenes, tumor suppressor genes, and DNA repair genes.
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DNA repair genes
inherited mutations in DNA repair genes lead to accumulation of mutations in other
genes (because DNA damage is not repaired). Eventually, there is an "unrepaired"
mutation that leads to tumor formation. Example includes hereditary colon cancer.
age-specific penetrance
percentage of individuals with an altered disease gene who develop the disease that is
directly related to their age. Ex. as age increases, there are more HNPCC mutation
carriers.
penetrance
the observable expression (or lack of it) of a mutant gene.
germline mutations
cancer arises from cells present in the egg or sperm of parents. This is heritable.
Causes cancer family syndromes.
somatic mutations
occurs in nongermline tissues. These are non-heritable.
loss of heterozygosity (LOH)
when a group of cells initially had Mm for example, and then it become recessive,
leading to all the cells having mm and becoming cancerous.
genetic heterogeneity
when mutations in different genes can cause the same disease
cancer gene linkage analysis
Compare DNA from different family members. They should share many genes in
common. Carefully compare DNA patterns of those in the family with cancer to those in
the family who do not have the cancer. Look for DNA markers that are located very near
the cancer gene and are consistently inherited by people with the disease but are not
found in relatives who are disease free.
assessment of genetic risks of cancer
includes multiple cases of same type of cancer (at least two close relatives); early age
of cancer onset; bilateral cancer in paired organs; multiple primary tumors in the same
person; a specific spectrum of tumors.
hereditary cancer syndromes
include breast/ovarian cancer, familial adenomatous polyposis (colon), HNPCC (colon),
Li-Fraumeni syndrome, Wilm's tumor (kidney), and retinoblastoma.
gene therapy
treatment of disease using the instructions encoded within the genes. To replace or
repair a defective gene that is causing disease. To provide a new or changed function to
a cell. Modes of delivery include in vivo and ex vivo.
in vivo gene therapy delivery
through IV; allowing for systemic delivery to multiple affected tissues. Possible issue
may include lack of adequate ability to target tissues and control delivery.
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ex vivo gene therapy delivery
currently the most common mode of gene delivery; allows for specific targeting of
delivery. limited to one tissue at a time.
viral vectors
used to transfer genes into all types of cells for millions of years. Advantages include
specific cell-binding and cell entry properties, efficient targeting of the transgene to the
cell nucleus, and ability to avoid intracellular degradation. Viruses insert their genes into
host cell and take over cell machinery. Target replication (safer for experimental therapy
protocols) or pathogenesis (disease formation). Significant portion of virus is removed in
order to insert the therapeutic gene for delivery. Virus is no longer complete and cannot
replicate itself
non-viral gene therapy
uses lipids fused to the therapeutic gene in order to make changes and get it into the
DNA.
severe combined immunodeficiency (ADA-SCID)
first human gene therapy. Inherited as autosomal recessive. Rare disorder. Primarily
affects the white blood cells. Severely affects the immune system. Affected children
similar to the "boy in the bubble". Used bone marrow and peripheral blood and a mouse
retrovirus. Patients still have cells containing the therapeutic gene. Peripheral blood
cells were removed from the patient. White blood cells were incubated with virus
containing the "normal" version of the ADA gene. Blood cells containing the gene were
returned to the patient from who them originated.
cancer gene therapy
virus directly injected into brain tumor cells. Virus contained a "suicide" gene that when
activated would produce a toxic product. Patients were treated with a drug that activated
the gene and the toxin killed many tumor cells. Can be used in addition to traditional
cancer therapies (chemo, radiation, etc.).
pharmacogenetics
will allow individualized medication use based on genetically determined variation in
effects and side effects. Use of medications otherwise rejected because of side effects,
and more accurate methods of determining appropriate dosage. Works by identifying
gene sequence variations (SNPs) that affect drug response. Identifying disease
susceptibility genes which represent potential new drug targets. Identifying gene
sequence variations that can cause adverse drug reactions. Variation can lead to this
working well or not well.
variation in drug responses
due to variations in absorption rates, drug metabolism, drug inactivation/elimination, and
target receptors. Essentially, if there are naturally different ways the body makes
enzymes, gene specific drugs will not work effectively, either not working at all or
causing many adverse effects. May look like drug "resistance" when in fact it is just a
mutant receptor.
warfarin
intended to prevent and treat thromboembolisms. Includes a-fib, recurrent stroke, DVT,
pulmonary embolism, heart valve prosthesis. Multi source anticoagulant with many mg
table strengths. Significant increase in prescription to elderly recently. Major risk of
bleeding. Purple-toe syndrome and skin necrosis are rare adverse reactions to this.
Narrow therapeutic index - small separation between dose-response curves for
preventing emboli and excess coagulation. Nonlinear dose-response (INR) - small
changes in dose may cause large changes in INR with time lag. Want to achieve target
INR of 2-3, but dependent on patient intrinsic and extrinsic factors.
warfarin metabolism
two polymorphic genes, CYP2C9 and VKORC1, affect this. Allelic frequencies of these
two genes are usually associated with ethnicity. Concerns with prescribing warfarin to
patients with these genes include overdose that can result in bleeding which can be
fatal and under dose which can result in thrombosis which can be fatal.
VKORC1 variants
may explain up for 25% of patient variability in response to warfarin. Patients with this
have an exaggerated anticoagulant response.
CYP2C9 variants
take more time to achieve stable dosing, and are associated with increased risk of
bleeding events. If this creates low activity, then it results in higher plasma levels of
warfarin so the patient is at risk for bleeding.
warfarin sensitivity DNA test
determines the presence of specific variations in the CYP2C9 and VKORC1 genes that
confer sensitivity to warfarin and thus significantly reduce the required maintenance
dose. CYP2C9 is involved in warfarin metabolism and VKORC1 influences warfarin's
anticoagulation effect through vitamin K.
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thiopurine methyltransferase ("null variants")
incidence 1/300. Pts cannot metabolize chemo drugs used to treat leukemia into their
inactive methylated forms. Pts can be treated with 10-15 times less chemo than
commonly prescribed. Geneotyping and functional enzyme assay is now the standard
practice in cancer centers.
slow acetylator phenotype
results in peripheral neuropathy in patients treated with anti TB drug (isoniazid). Causes
slow clearance of the drug and associated toxicity. This is found in 40-60% of
Caucasians, 80% of Middle Easterns, but only 20% of Japanese populations.
Gleevec
used to treat chronic myelogenous leukemia (CML). Designed to block the activity of
BCR-ABL protein, which is a fusion protein produced by the 9;22 translocation
associated with this leukemia. Normal blood counts are restored in patients with
chemotherapy resistant CML. Good response and low side effects. Blocks the making
of a cancer protein in CML.
Amyotrophic Lateral Sclerosis (ALS)
Progressive neurodegenerative disease in which the nerve cells of the central nervous
system die. Neurons that control voluntary muscles die. Patients will therefore present
with muscle weakness. Typically, patients die from respiratory failure 3-5 years after
onset of the disease. Interventions include total care and diaphragm pacer. Sporadic
and rarely familial. Autosomal dominant seen more commonly but autosomal recessive
is seen sometimes and sometimes X-linked dominant. SOD1 in familial. Positive
babinski sign, normal intelligence. No treatment - Riluzole may slow progression.
Military veterans are twice as likely to develop it. Ultimately die from respiratory failure.
Cleidocranial Dysplasia
risk for osteoporosis, scoliosis, short stature, recurrent ENT infections, abnormal
dentition. Autosomal dominant pattern. Mutations with RUNX2, but mostly de novo. High
penetrance and variable expressivity. Encourage Calcium and Vitamin D. Diagnosed via
clinical and radiological findings.
Cockayne Syndrome
type 1 (classical form) has progressive symptoms showing up at age 1; mutation on
gene ERCC8 with progressive neurologic degeneration with death at 20-30. Type 2
(congenital) has symptoms at birth, mutation of ERCC6, and death by age 6-7. Type 3
(late form) presents later in child's development and is more mild. Premature aging,
small stature, kyphosis, microcephaly. Autosomal recessive. Genes are involved in
making proteins that deal with damaged genes. No cure, with treatment involves
managing symptoms.
familial adenomatous polyposis
involves the APC (adenomatous polyposis coli) gene that, when mutated, causes an
increased risk for developing colorectal cancer. Autosomal dominant inheritance. 30%
de novo. Asymptomatic in early stages, with intermittent and painless rectal bleeding.
Inevitable by 30-40 years if untreated. Diagnosed with patient has 100+ polyps and the
mutation. Colectomy at early age, Sulindac (NSAID or COX-2 inhibitor) to help decrease
polyps. Surgical removal of polyps.
G6PD Deficiency (glucose-6-phosphate-dehydrogenase)
genetic disorder that results in hemolytic anemia. Involves an enzyme that is deficient; it
normally helps produce RBCs and destroys reactive oxidative enzymes. With this
disorder, the toxins buildup in the bloodstream and can cause RBC hemolysis much
faster. Pts can be asymptomatic. X-linked inheritance; men more commonly affected.
Asymptomatic sometimes but can have some triggers. Symptoms include fatigue,
weakness, pallor, SOB. Diagnoses via rapid fluorescent spot test. Supportive care
because good outcome. Infections are most common triggers, along with certain foods
like fava beans and certain drugs (sulfa drugs). Not part of newborn test.
Thrombocytopenia with Absent Radius Syndrome (TARS)
autosomal recessive. Wither two copies of mutated RBM8A gene, or RBM8A with
deletion on other chromosome (most cases). Variable degrees of expressivity. Detected
through cordocentesis and ultrasound (absent arms). Clinical manifestations include
thrombocytopenia (brain bleeds), other blood abnormalities, bone abnormalities, short
stature, cardiac abnormalities (ASD, VSD, etc.), dysmorphic facial features, and milk
allergy. Will still have thumbs though. Only physical limitations.
Spinal Muscular Atrophy (type 1)
inherited condition causing nerve cells in the lower portion of the brain and spinal cord
to breakdown and cease to function; degeneration and then complete atrophy of muscle
function. May start to choke because cannot cough up secretions - suction, O2 sats,
etc. Autosomal recessive. Seen in Caucasians more frequently. Mutation of SMN1 and
SMN2 genes. Affects mouth and throat muscles. Leads to impaired breathing. Occurs at
6 months of age. No cure, just comfort care. Will die quickly.
Wilson's disease
prevents excess copper from being excreted, which causes issues through liver and
creation of free radicals. Autosomal recessive mutation of ATP7B gene. 95% of patients
with neurological symptoms will have Kayser-Fleischer rings (in eyes). Others will have
only hepatic symptoms. Initial symptom is hepatic disease with neurologic impairment
occurring later. Detected/diagnosed through urine sample and blood test with eye exam.
Medications to promote excretion and prevent absorption; dietary changes.
hereditary spastic paraplegia
pure = lower limb spasticity. Complex = lower limb spasticity along with neurological
symptoms (seizures, cognitive decline, etc.). Anticholinergic drugs to prevent spasticity.
Many different types: X-linked, autosomal recessive, autosomal dominant (most).
Diagnosis is clinical and involves ruling out other options and use of MRI.
Lesch-Nyhan Syndrome
disease of basal ganglia, hypertonia with superimposed dystonia. Self-injurious
behavior, kidney stones (from high levels of uric acid), developmental delay, verbal
communication issues. X-linked recessive - HPRT1 (causing low activity of this
enzyme). Cannot be cured; meds like allopurinol (for the uric acid) and anticholinergics
for spasticity.
Peter's Anomaly
rare genetic condition that affects anterior segment of the eye - cornea fails to
separation from iris which leads to cloudiness and blurriness and a lazy eye. Legally
blind. Sporadic usually. Autosomal recessive - CYP1B1 or autosomal dominant -
FOXC1, FOXE3, PAX6, or PITX2 gene. Abnormal red reflex with clinical diagnosis.
Keratoplasy is gold standard of treatment (cornea transplant).
Progeria
progressive genetic disorder that causes children to age rapidly. Most do not live past
13 years. Due to de novo mutation in Lamin A (LMNA) gene, leading to build up of
progerin which causes accelerated aging. Normal intelligence. Generalized alopecia,
premature cardiac disease, atherosclerosis*. No cure, treat symptoms. High mortality
from heart attacks. Lonafarnib is a clinical trial drug to try to help. Keep hydrated, high
calorie meals, dim lights (can get headaches).
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