Download DISEASE GENETICS DEFICIENCY EPIDEMIOLOGY SYMPTOMS TREATMENT Sickle

DISEASE
Sickle Cell Disease (SCD)
GENETICS
Autosomal recessive: missense
mutation (GAG → GTG) of βglobin in E6V
DEFICIENCY
EPIDEMIOLOGY
1/200 to 1/650 in African
American births
E6V hemoglobin S (HbS) possess a highly ordered and
rigid β-globin, distorting the shape of the RBCs
Exception: compound heterozygote inheritance
High carrier rate: Africa
(8%), Mediterranean, Middle East, India, Caribbean
SYMPTOMS
TREATMENT
Infants appear healthy until HbF levels decrease and HbS levels increase: delayed
growth, hemolysis with chronic anemia,
intermittent vascular occlusion, autoinfarction of the spleen, chronic organ dysfunction
Reduced α-globin synthesis, affecting HbF (α2γ2) and
HbA1/HbA2 (α2β2) by causing a chain imbalance and
subsequent O2-carrying deficiency
Autosomal recessive: deletion
in HbA1 and/or HbA2 gene
α-Thalassemia
Carrier states: α0-Thalassemia (dysfunction of 2 αglobin genes) and α+-Thalassemia (dysfunction of 1 αglobin gene, resulting in a silent carrier state)
Most common: mutation in the
STOP codon of HbA2, extending
Hb Bart (Hydrops Fetalis Syndrome): loss of all 4 α31 amino acids more than
globin alleles, causing an off-balance of γ-globin with a
normal
high affinity for O2 which cannot be released to the fetal
tissues
HbH: loss of 3 α-globin alleles, causing an off-balance of
β-globin that precipitate in RBCs
High rate in Africa, Mediterranean, Arabic, India,
and southeast Asia
Hb Bart: 1/200 in India
HbH: 1/50 in India
α+-Thalassemia: 1/6 in
Sardinia
β0-Thalassemia Major: microcytic hypochromic hemolytic anemia, nucleated RBCs,
growth delays, hepatosplenomegaly
(requiring blood transfusions)
β+-Thalassemia Intermedia: mild hemolytic
anemia with a risk of iron overload
Thalassemia Minor: asymptomatic with
possible very mild anemia (yet visible RBC
abnormality)
Reduced β-globin synthesis, affecting HbA (α2β2) by
causing a chain imbalance and subsequent O2-carrying
deficiency
β-Thalassemia
Autosomal recessive: 200+
possible missense or frameshift
mutation in HbH gene
X-linked recessive: F8 gene
mutation by gene inversion of
intron 22-A (45%)
Hemophilia A
Exceptions: missense or
frameshift mutations, complete
or partial deletion, RNA splicing, insertions, duplications
β0-Thalassemia Major: loss of β-globin, causing an
excess of α-globin that precipitates in RBC precursors
β+-Thalassemia Intermedia: reduced synthesis of βglobin
Thalassemia Minor: heterozygous carriers
Reduction in coagulation Factor VIII of the intrinsic
hemostasis pathway for blood clotting (with normal von
Willebrand Factor), leading to poor blood clotting
1/10,000 in U.S.
Severe Form: <1% active Factor VIII
Moderately Severe Form: 1-5% active Factor VIII
Mild Form: 6-35% active Factor VIII
α0/α+-Thalassemia: normal to moderate
symptoms
Hb Bart: fetal onset of generalized edma,
ascites, pleural and pericardial effusions,
severe hyperchromic anemia → neonatal
death
HbH: mild microcytic hypochromic hemo
lytic anemia, hepatosplenomegaly
Severe Form: By age 1—prolonged and
renewed (abnormal) bleeding after injuries ,
large goosebumps with head injuries, 2-5
episodes of spontaneous joint bleeding
(without treatment)
Moderately Severe Form: By age 6—
prolonged and renewed (abnormal) bleeding after injuries
Mild Form: Later in life—prolonged and
renewed (abnormal) bleeding after injury,
minimal bleeding episodes
Infusion of gene corrected bone marrow to
reach threshold protein
levels
DISEASE
Hemophilia B
GENETICS
X-linked recessive: F9 gene mutation by missense, nonsense,
frameshift, complete or partial
deletion, RNA splicing
DEFICIENCY
Reduction in coagulation Factor IX of the intrinsic
hemostasis pathway for blood clotting (with normal von Willebrand Factor), leading to poor blood
clotting
Severe Form: <1% active Factor IX
Moderately Severe Form: 1-5% active Factor IX
Mild Form: 6-35% active Factor IX
Reduced von Willebrand Factor (vWF) synthesis or
functionality, leading to poor platelet aggregation
Autosomal disorder: missense
von Willibrand Disease (VWD) mutation (Cys → Arg) in C386R
(VWF gene)
Autosomal dominant (with anticipation): >40 CAG repeats (poly Q
expansion) in the 5’ region of IT15
gene for huntingtin
Huntington’s Disease
Premutation: 27-35 CAG repeats,
acting as a reservoir for new mutations due to instability (higher risk
in males)
Autosomal dominant (with anticipation): >50 CTG repeats (poly L
expansion) in the 3’ UTR of DMPK
gene
Myotonic Dystrophy (MD)
Severe form: >2000 CTG repeats
for more severe form)
Type 2: 3q1 CCTG repeats in intron
1 of ZNF9
Type 1—autosomal dominant: reduced synthesis
of vWF (75%)
Type 2—autosomal dominant/recessive: reduced
functionality of vWF (2A/2B, 2M, 2N) (10-15%)
Type 3—autosomal recessive: reduced synthesis
of vWF and Factor VIII
EPIDEMIOLOGY
1/25,000 males in U.S.
Associated with the
European and Russian
royal families
Expanded mRNA accumulates in the cell nucleus,
binding to CUG-BP (a CUG RNA-binding protein)
Mother: transmits early onset form
Father: transmits juvenile onset form
TREATMENT
Severe Form: By age 1—prolonged and
renewed (abnormal) bleeding after injuries ,
large goosebumps with head injuries, 2-5
episodes of spontaneous joint bleeding
(without treatment)
Moderately Severe Form: By age 6—
prolonged and renewed (abnormal) bleeding after injuries
Mild Form: Later in life—prolonged and
renewed (abnormal) bleeding after injury,
minimal bleeding episodes
Infusion of gene corrected bone marrow to
reach threshold protein levels
Type 1: Any age—lifelong ease of bruising,
heavy menstrual bleeding (but may be
asymptomatic)
Type 2: Any age—lifelong ease of bruising,
1/10,000 worldwide
nose bleeds, heavy menstrual bleeding
1/200 in Venetian region Type 3: Rare—nose bleeds, severe skin
bleeding, muscle hematomas, severe joint
of Italy
bleeding
Most common bleeding
disorder
1/10,000 worldwide
Shows anticipation, making it more severe in
succeeding generations
SYMPTOMS
Onset @ 30-50 years of
age
1/8,000 worldwide
Higher risk in German
descendants
Adult: chorea (subtle involuntary muscle
movement), dementia, anxiety, mood
changes and associated depression, alcohol
abuse
Juvenile (5%): rigidity of muscles and associated clumsiness, dementia
Adult: progressive weakness in the neuromuscular tissues, myotonia (tonic muscle
spasms with prolonged relaxation), cataracts, cardiac conduction defects, disturbed
GI peristalsis
Earlier onset: more severe symptoms
Genetic counseling and
prenatal diagnosis
Caspase inhibitors
Stem cell transfer in
affected brain regions
Genetic counseling and
prenatal diagnosis
DISEASE
GENETICS
DEFICIENCY
EPIDEMIOLOGY
Autosomal dominant/recessive or
X-linked
Hereditary Sensory and Motor
Neuropathy (HMSN)
(or Carcot-Marie-Tooth Disease/
Peritoneal Muscle Atrophy)
Neurofibromatosis (or Recklinghausen Syndrome)
Duchenne Muscular Dystrophy
(DMD) (and Becker Muscular
Dystrophy (BMD))
Cystic Fibrosis (CF)
HMSN-Ia: autosomal dominant
point muta- tion in PMP-22 or
duplication of 17p (containing
PMP-22) during spermatogenesis
HMSN-Ib: myelin protein zero
(MPZ) muta- ti
X-linked dominant HMSN: GJB1
connexin 32 mutation in males
HMSN-II: possible mitofusion
(MFN2), neu- rofilament protein,
and
light peptide (NEFL)
mutation
NF1: autosomal dominant
HMSN-I—nerve biopsy: seg- mental
demyelination → “onion” bulb formation
HMSN-II—nerve biopsy: axon- al degredation
17q11.2 for neu- rofibromin
(tumor suppressor) mutation
(shows homology with GTPaseactivating protein that down
regulates RAS)
NF2: 22q for scwannomin (a
membrane cytoskeletal
scaffold tumor suppressor)
MDM—X-linked recessive:
deletion (66%) of dystrophin gene
during maternal unequal crossMales rarely reproduce due to incredibly low
over at “hot spot” exons 1-20 and
genetic fitness
45-53
Exceptions: nonsense,
frameshift, splicing, and
promoter mutations
BMD: point mutations
during paternal meiosis,
translating full dystophin
gene
Autosomal recessive: deletion
of 508F (Phe508del) in CFTR
gene (70%)
Exceptions: G551D mutation
(3%) in North Americans and
G542X mutation (12%) in
Ashkenazi Jews
Mutation rate: 1/10,000 gam- etes
1/2,500 worldwide
NF1: 1/3,000 world- wide
NF2: 1/35,000 world- wide
DMD: 1/3,500 males
BMD: 1/20,000
1/2,000 to 1/3,000
worldwide
Reduced or loss of Cl– chan- nel function,
increasing NaCl concentration which, in turn,
inhibits defensin activity (due to thickened
mucus) → chron- ic bacterial lung infections
1/15,000 in AfricanAmericans
1/31,000 in AsianAmericans
Higher risk in western
European descendants
SYMPTOMS
TREATMENT
HMSN-I: slowly progressive distal
muscle weakness and wasting
followed by the upper limb
involvement, ataxia, and tremors
(generating “inverted champagne
bottle” low- er limbs)
X-linked dominant HMSN:
typical HMSN symptoms
(but milder in females)
HMSN-II: Later onset—milder
distal muscle weakness and
wasting (but possibly asymptomatic)
NF1: By age 5 (100%)—Café au lait
HMSN-III:
Rare early onset—
spots
delay
in
reaching
( minimum of 6 >5motor
mm pigmented
milestones
lesions with truncal freckling),
neurofibromas (soft and fleshy
benign tumors that increase in
preva- lence with age)
NF2: early development of
vestibular “schwannomas”
(acoustic neuromal tumors),
café au lait spots, neurofibromas
DMD: By age 3-5—slowly
Segmental NF: manifests in 1 area
progressive
of the body muscle weakness,
awkward gait development which
prevents running, Gower’s sign
(inability to get up from the floor
without climbing the legs
and thighs), pseudohypertrophy
(replacement of muscle fibers by
fat and connective tissue)
→ cardiorespiratory failure and
death by age 18
BMD: By age 11—milder
Chronic lung disease from
symptomology (possibly
recurrent infections produces
asymptomatic)
fibrotic changes → secondary
cardiac failure (cor pulmonale)
Others: impaired pancreatic
function (85%), leading to
malabsorption; rectal prolapse;
nasal polyps; cirrhosis; diabetes
mellitus type 2
Sterility in males due to
congenital absence of vas
Carrier detection for serum
Creatine Kinase (higher in
DMD patients)
Physical therapy to maintain
muscle
Gene therapy: myoblast
implants from stem cells,
intramuscular injection of
dystrophin, or geneswitching to utrophin
Symptom specific: heartlung transplant, pancreatic
enzyme supplements
Gene therapy: adenoviral or
liposome delivery systems
Genetic counseling and
prenatal diagnosis
Disease
Genetics
47xy + 21, Trisomy 21
Downs syndrome
Deficiency
Can be due to translocation or nondisjunction, mosaicism accounts for 1-2%
Familial downs syndrome is due
to Roberstonian translocation
where a piece of 21 get on 14
or 13 and it appears to be a
trisomy.
Female with this translocation
have a 10% risk of producing
Down’s offspring
Epidemiology
Symptoms
Increased prevalence as Intellectual and developmental
disabilities, flattened nose and
mom increases in age
face, upward slanting eyes,
single palmer crease, short 5th
finger that curves inward, wide
spaced toes, increased skin
creases
Trisomy 13, Mom is responsible Can be partial or entire chromosome
85% of the time.
Characterized by small head,
absent eyebrows, cleft palate,
malformed ears, clenched
hands
Trisomy 18, Mom is responsible can be partial or entire chromosome
90% of the time.
Characterized by large occiput,
malformed ears, small jaw,
small mouth, upturned nose,
flexed big toe, prominent heels,
shield chest, prominent
sternum and wides set nipples
Inversion/Duplication - 22q11
coloboma of the iris, anal
atresia with fistula, frequent
occurrence of heart and renal
malformations, normal or near
normal mental development
Patau Syndrome
Edward's Syndrome
Cat Eye Syndrome
(Schmid-Fraccaro
Syndrome)
Partial chromosome increase or deletion
Treatment
Disease
Genetics
Deficiency
Deletion - 4p- Deletion of short 85-90% of cases occur as the result of a de
arm (p) of chromosome 4
novo deletion, meaning the parents did not
have this. In the remaining cases one of the
parents carries a balanced translocation
Epidemiology
Symptoms
Developmental delays,
characteristic facial appearance,
variety of birth defects
Wolf-Hirschhorn
Syndrome
Deletion of 5p or 5p monosomy 90% of cases de novo, the rest are due to a
parental with an unequal crossing over of a
balanced translocation
Newborns have a cat-like cry,
underdeveloped
larynx,
difficulty
swallowing
and
sucking,
poor
growth,
behavioral problems
Deletion of 22q11.2
Palatal defects, heart defects
(Tetrology of Fallot), hearing
loss, abnormal ears exams,
malformed
kidney,
hypocalcemia, small head,
mental retardation, severe T
cell defects
Cri Du Chat
DeGeorges critical region includes 30 genes.
DiGeorge Syndrome
Female monosomy (45, x) due
to non-disjunction, father 80% Loss of X chromosome in females
responsible
Turner Syndrome
Treatment
Disease
Genetics
Deficiency
Epidemiology
Symptoms
47, XXY or 48, XXXY, father
responsible 100%
Klinefelter Syndrome
47, xxx- mom 95% responsible
Triple X
These are both due to
uniparental disomy
The presence of two homologus
chromosomes inherited from 1 parent
Angelman’s syndrome A-syndrome 2 copies of 15/DAD
PW-syndrome 2 copies of
And
15/Mom
Prader Willi syndrome
Autosomal Ressesive
Tay-Sachs Disease
GM2-gangliosidosis
the Ashkenazic Jews
(northern European
descent vs Sephardic
Jews-Mediterranean
descent) the carrier
frequency is 1/30 (10x
higher than a control
population of the non
Ashkenazic
Neurological degenerative
disorder resulting in death by 6
months.
Treatment
Disease
Retinitis pigmentosa
Genetics
Epidemiology
Locus Heterogenicity
Genes where mutations
involving RP have been found:
Rhodopsin (RHO:20-30%);
U4/U6 small nuclear
riboprotein (PRPF31:5-10%);
peripherin-2 (PRPH2: 5-10%)
Allelic Heterogenicity
Cystic Fibrosis
Sex influenced missense
mutation Cys282Tyr
Hemochromatosis
X-Linked
Rett Syndrome
Deficiency
Mutation in MECP2- a DNA
binding protein- usually
spontaneous mutation. Males
that are 47,xxy or 46 (der x) can
survive
Symptoms
Common cause of visual
impairment caused by
photoreceptor degeneration
with autosomal dominant,
autosomal recessive and Xlinked forms
Caucasian population
1/2000 children has the
disease (virtually nonexistent in Asian population
and rare in African
Americans) frequency of
carriers: 1/29
A mutation in the HFE gene (missense
Occurs in approx.0.5% of
Cys282Tyr) that is homozygous Cys282Tyr European ancestry
HFE mutation permits enhanced absorption
of iron
classic cystic fibrosis: severe
progressive lung disease,
pancreatic insufficiency
and congenital
absence of the male vas
deferens
Provides advantage to females
that may have higher iron
requirements due to
menstruation and dietary
habits
Normal prenatal and neonatal
growth; rapid onset of
neurological symptoms Loss of
milestones between 6-18
months Children become
spastic , some autistic,
purposeless flapping or arms
and legs, 50% cases see
seizures (after a couple years
deterioration stops and child
lives with severe disabilities)
Treatment
Disease
Genetics
Deficiency
Loss of function mutation in
RET gene (receptor tyrosine
kinase)
Failure to develop colonic ganglia-defect in
colon motility and severe constipation
(dominant)
Fragile site marker at Xq.27.1
Fragile site marker at Xq.27.1 chromatin
does not condense properly mitosis-CCG
repeat located in 5’ untranslated region of
gene FMR1-normal repeat =60 > 1000
repeats seen in patients (excessive
methylation interferes with chromatin
condensation or DNA replication or bothtriplet repeats of 60-200 premutation –
unstable in mother  child transmission.
Shows anticipation
Epidemiology
Symptoms
Severe constipation
Hirschsprung Disease
Fragil X Syndrome
Autosomal dominant
CTG triplet repeat
Myotonic Dystrophy
(DM):
Autosomal recessive Triplet
repeat: AAG (poly Lysine)
located in intron of frataxin
Friedreich Ataxia
(FRDA)
Largest kindred of HD
patients –Lake Maracaibo
Venezuela-shows founder
effect-descendants of a
single individual with either
mutation or permutation.
Adults with premuation—
onset of fragile X associated
tremor/ataxia syndrome
25% Females with
premutation premature
ovarian failure by age 40
Congenital form: severe-child offspring of
an affected female who may only be mildly
affected Repeat unit: CTG triplet located in
3’ untranslated region of protein kinase
DMPK normal repeat range=5-30
premutation range=38-54 ) asymptomatic
severely affected >2000 repeats almost
always transmitted by affected mother.
Shows anticipation
Myopathy, cataracts ,
hypogonadism, diabetes and
frontal balding.
Triplet repeat: AAG (poly Lysine) located in
intron of frataxin (encodes mitochondrial
protein)-normal repeat: 7-34 copies
repeat expansions: 100-1200 copies.
Expansion in the intron interferes with
normal expression.
1-2% of FRDA patients are compound
heterozygotes one allele is expansion allele
one is a nucleotide change in FRDA
Manifests before adolescence,
incoordination of limb
movements, cardiomyopathy,
scoliosis, speech difficulty,
diminished tendon reflexes,
foot deformities.
Lack of penetrance, pleiotropy
and variable expression of
clinical severity and age of
onset
Treatment
Disease
Marfan Syndrome
Burkitt’s Lymphoma
Genetics
Epidemiology
T(8;14). C-myc is on 8q24 and it Reciprocal translocation puts the IGH
is moved to 14q24 where the Ig promoter driving c-myc expression in an
heavy chain enhancer is found. uncontrolled fasion- uncontrolled cell
proliferation and tumor formation.
A rarer translocation position cmyc to be driven by the lg light
chain enhancer on 22 and 2
1
translocation (Ph ) t(9;22)
proto-oncogene ABL (tyrosine kinase) is
moved from normal position on
chromosome 9 to the “break point cluster
region” (BCR) –unknown function---at
chromosome 22q.
Result: a chimeric fusion protein larger than
normal Abl protein with enhanced kinase
activity
ABL
BCR-ABL
210
, BCR-ABL
Seen in children in
equatorial Africa,
Treatment
B cell derived tumor of the jaw
Cancer
190
, BCR-
185
Chromosome translocation BCL2 (mitochondrial inner membrane
protein linked to apoptosis regulation) is
seen in B cell lymphoma
translocated from 18 to IgH enhancer
t(14;18)
Follicular B Cell
Lymphoma
Symptoms
Autosomal dominant- defect in Autosomal dominant disease effects the
the fibrillin 1 gene.
eye, the skeleton and the cardiovascular
system Fibrillin 1 gene encodes a
component of connective tissue that is
expressed in the tissues affected by
Marfan’s where unusually strechable tissue
is found.
Philadelphia chromosome
Chronic Myelogenous
Leukemia
Deficiency
region on 14 (another fusion protein with
dysregulated expression. Drives up
expansion of B cells because normal
apoptosis is inhibited
Cancer
Potential “drug target” for
therapy is the associated
kinase activity imatinib has
been developed to inhibit
this kinase activity shown
to be effective in treating
CML
Disease
Genetics
Germline mutation TP53
gene
Deficiency
Epidemeology
P53 mutation causes multiple types of
cancer, heritable
Symptoms
Cancer
Li-Fraumeni
Genes involved in nucelotide excision
repair (XPC, ERCC2, POHL) XPC
Xerodoma Pigmentosa
Franconi’s anemia
Potentially 15 genes autosomal
seen in Ashkenazi Jews
recessive and X-linked (FRACB)
and Afrikaners of S.
complex of proteins that deal with DNA Africa incidence
repair—defective complex
1/350,000
PLOG (DNA polymerase Mitochondiral Depletion Syndrome
gamma), A467T mutation - loss of fidelity in mitoDNA
replication
Alpers Syndrome (4A)
and MNGIE (4B)
Predominately mutated Sensitivity to UV light
in US patients
increased incidence of skin
cancer by age 10 in some
patients neurological issues
too.
acute myelogenous
leukemia and bone
marrow
failure, other congenital
abnormalities (short stature)
Mitochondrial DNA
depletion and loss of
mitochondrial function
Treatment
Disease
Lynch Syndrome
Genetics
Deficiency
Lynch syndrome in
MSH2 and MLH1 defects may account Lebanese family
MSH2 mutation (DNA repair) for up to 60% of cases also endometrial
involvement in women
Hereditary
Nonpolyposis
Colorectal cancer type
1
Kearns-Sayre
Syndrome (KSS)
Symptoms
early onset (25-40 yrs)
colorectal cancer; at least
two relatives with it
estimated to account for 46% of early onset HNPCC
BLM is defective gene (recQ helicase)
check integrity of DNA and DNA
stability
short stature and sun
sensitive skin can develop
any cancer type but earlier
than general population
Mitochondrial Disease mtDNA mutation
Complex I: NADH dehydrogenase,
mtDNA tRNA (MT-TL1)
affects the nervous system
and muscles, muscle
weakness, headaches,
seizures, lactic acidosis
Mitochondrial tRNA gene MTTL1
Mitochondrial Disease mitochondrial deletions
opthalmoplegia, pigment
denegeration,
cardiomyopathy, facial
weakness, deafness, small
stature
Bloom’s Syndrome
Mitochondrial
myopathy,
encephalmyopathy,
lactic acidosis and
stroke (MELAS)
Epidemiology
Treatment
Disease
Leber's Hereditary
Optic Neuropathy
(LHON)
Genetics
Deficiency
Mitochondrial
Develops young adult with painless,
Most LHON patients (90%) have bilateral subacute visual failure males
one of 3 identified point
5X more likely than females to be
mutations in the mtDNA
affected
m. 3460G>A, m. 11778G>A or
females with the disease may go on to
m.14484T>C mutations affect
develop an MS-like illness.
different respiratory chain
complex I subunit genes
ATP6 - ATP synthase
Mitochondrial disease
Mitochondrial Disease - mutation, can't
make ATP
Epidemiology
Symptoms
Legally blind
Nervous system: sensory
neuropathy, muscle
weakness, ataxia, vision loss
Neuropathy, ataxia,
retinitis pigmentosa
(NARP)
TYMP (thymidine
phosphorylase)
Mitochondrial Disease Mitochondrial
Neurogastrointestinal autosomal recessive
2nd to 5th decade of life,
multisystem disorder, GI
tract - poor mobility,
pseudo-obstruction with
peristalsis, malabsorption,
weight loss; neurological neuropathy and
myopathy
Encephalopathy
Syndrome (MNGIE)
multiple mtDNA
mutations
Myoclonic epilepsy
with ragged red fibers
(MERRF)
Mitochondrial Disease - consistent
with heteroplasmy, deficiencies in
Complex I and IV
Elevated serum levels of
pyruvate and/or lactate,
deficiencies in enzyme
complexes of respiratory
chain
Treatment
Largely supportive,
provision of visual aids,
occupational therapy
Families with known
risk: members should be
encouraged to avoid
alcohol and smoking
or other environmental
exposures that might
exacerbate disease
Leigh Syndrome (LSP)
Mutations have also been Mitochondrial respiratory complex
noted in mitochondria tRNA defects mutations have been noted in
proteins (MTTV, MTTK,
both mtDNA and nuclear encoded
MTTW, MTTL1)
genes functioning in the mitochondria
respiratory chain.
X-linked recessive and
autosomal recessive modes
of inheritance
(involvement of
nuclear genes)