Genetic Diseases Flashcards
autosomal dominant diseases
- myotonic dystrophy 1
- achondroplasia
- neurofibromatosis
- HNPP
- Marfan syndrome
- polycystic kidney disease
- Huntington’s
- osteogenesis imperfecta
- charcot marie-tooth type 1A
autosomal recessive
- PKU
- ATD
- Tay-Sachs Disease
- Sandhoff Disease
- AB-variant of Tay-Sachs
- Sickle cell
- cystic fibrosis
- congenital adrenal hyperplasia
- 5-alpha reductase deficiency
x-linked dominant
-Fragile X syndrome
x-linked recessive
- Duchenne Muscular Dystrophy
- Hemophilia A
- testicular feminization
- dosage sensitive sex reversal
- Fabry disease
mitochondrial
- Kearns-Sayre
- MELAS
- MERRF
Duchenne muscular dystrophy
- Onset around 2 yrs, lose motor function, in wheelchair by 18 yrs, median age at death is 18 yrs; high CK levels, large calves
- deletions in many exons in Xp21.2 (dystrophin gene); nonsense frameshift
HNPP (hereditary neuropathy with liability to pressure palsies)
- limbs “go to sleep”
- Deletion of PMP22 gene due to unequal crossing over (PMP22 is integral glycoprotein in nerves)
osteogenesis imperfecta type 1
- Brittle bones, increased fractures, blue sclerae
- Loss of Function: nonsense frameshift in COL1A1 (important for collagen strength)
charcot-marie-tooth type 1A
- Demyelinating motor and sensory neuropathy
- Gain of Function: duplication of of PMP22 gene
osteogenesis imperfecta types 2,3,4
- Brittle bones, increased fractures, blue sclerae
- Novel Property Mutation: the COL1A2 protein has new property due to new/different folding, forming collagen trimers
Huntington’s disease
- Progressive neurodegenerative disorder with adult onset
- Polyglutamate disease; increased CAG repeats
- Parental transmission bias—trinucleotide expansion more likely to come from father
myotonic dystrophy
- Droopy eyes, intellectual difficulty, hypotonia
- Increased CTG repeats (in 3’ UTR) of DMPK gene
PKU
- Epilepsy, mental retardation, hyperactivity
- Defect in PAH-phenylalanine hydroxylase enzyme (common) or BH4 cofactor (rare, also have high neurotransmitter imbalance)
- high phenylalanine in blood
ATD (alpha1-antitrypsin deficiency)
- Late onset: increased risk of developing emphysema, liver cirrhosis/cancer
- Defective alpha1-AT protein (normally protease inhibitor of elastase; elastase recruited by neutrophil) increased elastase activity decreased elastin in lungs emphysema and lung damage
Tay Sachs
- Progressive neurodegeneration of CNS
- Screen enzyme activity (at low temp, both enzymes active, at high temp HexA degrades and B still functions) test and DNA test (three mutant alleles account for 95% of cases)
- Inability to degrade GM2 ganglioside, which aggregates in lysosomes
Sandhoff disease
- symptoms like Tay-Sachs
- Screening enzyme activity shows that both HexA and HexB are inactive (just Hex A in Tay-Sachs)
AB variant of Tay-Sachs
-HexA and HexB are normal but GM2 accumulates due to defect in the GM2 activator protein (GM2AP), which facilitates interaction between the lipid substrate and the HexA enzyme within the cell
cystic fibrosis
- thick, sticky mucus, frequent chest infections, and coughing or shortness of breath
- Mutation of CFTR gene; CFTR protein needed to regulate components of sweat, digestive juices, and mucus by regulating movement of chloride and sodium ion across epithelial membranes
achondroplasia
- rhizomelic limb shortening
- spinal cord compression; 3-7% die suddenly in during first year
- Gain of Function:Gly380Arg mutation in FGFR3 Gene (hot spot for mutation)
- incomplete dominance (homozygous is lethal)
neurofibromatosis type 1
- cafe au let spots, lisch nodules, neurofibromas
- 100% penetrance
- variable expressivity
- Mutation on chr. 17 on NF1 gene
marfan syndrome
- Connective tissue disorder
- risk of aortic aneurism
- tall and skinny
- Mutation in FBN1 mutations (codes for fibrillin)
Fragile X syndrome
- mental deficiency, dysmorphic facies, autism-like
- premutation can lead to FXTAS or premature ovarian failure
- Trinucleotide CGG expansion (>200 penetrant, hypermethylation)
- maternal gene anticipation
hemophilia A
- factor VIII deficiency (clotting)
- can supplement with factor VIII
Turner Syndrome
- 45X
- Gonadal dysgenesis, short stature, heart defects, fused kidneys, webbed neck, brown nevi, widely spaced nipple, infertility, social difficulty etc.
- meiotic nondisjunction
Klinefelter’s syndrome
- 47XXY
- Gonadal dysgenesis/hypogonadism, infertility, tall stature, gynecomastea, high frequency of sterility, language impairment
- meiotic nondisjunction, failure of recombination
XYY Syndrome
- usually fertile
- increased risk of behavioral and educational problems, delayed speech and language skills
- meiotic nondisjunction
- errors in paternal meiosis II (produce YY)
testicular feminization
-feminine features (unresponsive to testosterone)
Absence or abnormality of cytosolic androgen receptor protein
congenital adrenal hyperplasia
- Ambiguous genitalia, masculization of females
- overproduction of androgen
dosage sensitive sex reversal
- development of ovaries even in the presence of expressed SRY
- due to duplication of DAX1 gene
5-alpha reductase deficiency
-5-alpha reductase needed to covert tetosterone to active DHT
nonsyndromic deafness
- congenital deafness (AR)
- progressive childhood deafness (AD)
- allelic heterogeneity
- GJB2 most commonly mutated
deafness + retinitis pigmentosa
Usher syndrome (AR)
deafness + arrhythmia or sudden death
Jervell and Lange-Neilson (AR)
8th nerve schwannoma
neurofibromatosis type II
Fabry Disease
- reduced sweating, risk of heat stroke; progressive renal failure, heart problems
- deficiency of alpha-galactosidase
- chaperone-based or enzyme replacement therapy
Down Syndrome
- trisomy 21
- Mid-face hypoplasia, short stature, hypotonia, moderate intellectual disability
- nondisjunction in maternal meiosis I (some robertsonian translocation or mosaic)
Patau’s syndrome
- trisomy 13
- characteristic face, severe intellectual disability
Edward’s syndrome
- trisomy 18 (often translocation 14;18)
- growth retardation, characteristic facies, severe intellectual disabilities, characteristic hand positioning, hypertonicity
Prader-Willi syndrome
- obesity, excessive eating, short stature
- Paternal Del(15q11-q13) accounts for 70% of cases (also uniparental disomy, imprinting center mutation)
Angelman syndrome
- Seizures, intellectual disability, unusual facial appearance, short stature, severe intellectual disabilities, prominent chin
- Maternal Del(15q11-q13)
WAGR syndrome
- Wilms tumor, Aniridia, Genitourinary anomalies, Intellectual disability
- Del(11p13)
- large enough to test with chromosome testing
DiGeorge’s syndrome
- Absent or hypoplastic thymus and parathyroid’s, congenital heart disease
- Del(22q11.2)
acute lymphomatic leukemia (ALL)
- hyperdiploidy
- enlarged spleen, increased susceptibility to infections, anemia
- detected by FISH fusion probe
chronic myelogenous leukemia (CML)
- Bcr-Abl translocation (9;22) is diagnostic
- detected by FISH fusion probe
- treated with Gleevec (tyrosine kinase inhibitor)
acute promyeloid leukemia (APL/PML)
- PML-RARA translocation (15;17) is diagnostic
- Viewing Auer rods (cytosolic precipitation) is diagnostic
- detected by FISH fusion probe
- treated with retinoic acid
maternally inherited interstitial duplication
- chr15 duplication
- MATERNALLY inherited
- seizures, autism, no dysmorphia
IDIC15
- chr15 duplication
- seizures, autism, no dysmorphia
Gaucher disease
- Hepatosplenomegaly, thrombocytopenia, anemia, join pain, CNS issues
- autosomal recessive
- type 1 most common (no CNS issues)
- Build up of glucocereborsides in macrophage lysosomes due to lack of glucocerebrosidase function
- treat with ERT
Pompe disease
- muscle failure
- Accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme
- ERT every two weeks
Progeria
- premature aging
- point mutation yielding abnormal progerin protein
Hb Kempsey
- Gain of Function: Asp99Asn missense mutation
- Binds oxygen too tightly
Hb Kansas
- anemia
- weak binding of oxygen
Sickle cell (HbS)
- Novel Property Mutation: Single base mutation at codon#6 in the β-globin gene changes glutamate to valine
- Diagnosis: when the sequence changes at codon 6, lose a restriction site for MstII
- liquid chromatography for diagnosis
- autosomal recessive
HbCC
- autosomal recessive
- single base mutation at codon#6 of the β-globin gene, changing glutamate to lysine
- milder than sickle cell
(–/–)
- common in SE Asia
- stillborn
(aa/–)
-mild anemia
(a-/a-)
- Africa, Mediterranean, Asia
- mild anemia
(a-/–)
- HbH disease
- severe anemia
Hb Constant Spring
-mRNA and protein of constant spring are unstable
B-thalassemia major (Cooley’s anemia)
- severe anemia
- autosomal recessive
- MCV (circumference of RBC) is low
- two severely abnormal or absent genes
- blood transfusions needed
B-thalassemia intermediate
- Mild to moderate anemia
- Low MCV
- sometimes need transfusions
B-thalassemia minor
- heterozygous
- Almost no clinical presentation (very mild anemia)
- Normal or low MCV
B+-thalassemia
-Some β-globin is made so some HbA present
B0-thalassemia
- Zero β-globin synthesis so that no HbA is present. (95% is α2γ2 with 5% α2δ2)
- deletion of the β-globin gene, nonsense or frameshift mutations
HPFP
- Symptom free b/c adequate levels of γ chains still made due to the disruption of the perinatal globin switch from γ to β. 100% of hemoglobin is HbF (α2γ2).
- Increased γ-globin expression:
(1) extended deletion brings cis-acting enhancer element closer to γ-globin gene
(2) destroy binding site of a repressor, thereby relieving postnatal repression of γ
