Genetic diseases Flashcards
1
Q
Ehlers-Danlos Syndrome
A
- Autosomal dominant inheritance
- problem with genes that make collagen or interact with collagen
- Hyper mobile joints that are unstable
- soft velvety skin that is highly elastic and fragile
- easy bruising and abnormal scarring
2
Q
Cystic fibrosis
A
- autosomal recessive inheritance
- ( more in pulmonary medicine)
3
Q
Albinism
A
- autosomal recessive
- gene mutation for tyrosinase
- synthesis of melanin pigment altered, little in hair, skin, or eyes
- besides cutaneous findings melanin is required for normal deviation optic fibers–>nystagmus, strabisumus,, reduced visual acuity
4
Q
Autosomal dominant inheritance
A
- 50% inherited
- vertical transmission, phenotype seen generation after generation
- Male= female
5
Q
Autosomal recessive
A
- 25% inherited
- Horizontal: phenotype in multiple siblings; less likely in prior generation
- male = female
- consanguinity makes more likely
6
Q
Achondroplasia
A
- a new mutation (de novo)
- dwarfism
- a result of a DNA change in one of parent gametes, no family history
7
Q
polydactyly
A
- new mutation
- many toes or fingers
8
Q
Retinoblastoma
A
- most common childhood tumor
- begins during embryonic development
- example or reduced penetrance
- 10% of obligate carriers do not have the disease
9
Q
Reduced penetrance
A
person who has the disease genotype does not develop the disease
10
Q
Germline mosacism
A
germline present in an individual contains an allele that is not present in somatic cells
11
Q
Variable expression
A
penetrance may be complete but severity of disease can vary greatly
12
Q
Marfan syndrome
A
- autosomal dominant disorder
- pleiotropy ( more than one effect on the body)
- affects the fibrillin forming component
- found in the aorta, suspensory ligaments, lens, periosteum
- leads to myopia, displaced lens, increased elasticity of bone, pectus carinatum/excavatum , scoliosis, joint hypermobility
- issues with the cardiovascular system- ascending aorta dissection
13
Q
adult polycystic kidney disease
A
- example of heterogenity
- more in nephrology
14
Q
Hereditary non-polyposis colorectal cancer
A
- example of heterogenity
- more in GI
15
Q
heterogenity in disease
A
- refers to multiple origins causing the same disorders in different individuals
- Allelic heterogenity
- locus heterogenity
16
Q
Genomic imprinting
A
differential activation of genes depending on parent from which they are inherited
17
Q
Prader-Willi Syndrome
A
- example of genomic imprinting
- micro-deletion of chromosome 15
- inherited from the father
- short stature, hypotonia, small hands/feet, obesity, mild to moderate developmental disabilities, hypogonadism
18
Q
Angleman Syndrome
A
- inherited from the mother
- severe developmental disabilities, ataxic gait, uncontrolled laughter
19
Q
Repeat expansion
A
mutation that increases the number of times a short DNA sequence is repeated, resulting in protein dysfunction
20
Q
Myotonic dystrophy
A
- set of genetic disorders caused by tri-nucelotide repeats in certain genes
- muscular dystrophy, cardiac arrythmias, testicular atrophy, cataracts
- most common nuclear dystrophy disorder that affects adults
- number of repeats strongly correlated with severity of disease
21
Q
Genetic anticipation
A
severity increases with each successive generation that inherits them
22
Q
hemophilia A- genetic background
A
- X linked recessive disorder
- most common of severe bleeding disorders
- deficient factor VIII –> fibrin formation affected–> easy bleeding
23
Q
Hemophilia A clinical presentation
A
- bruising/ bleeding into muscles
- hemarthroses
- intracranial bleeding
24
Q
Hemophilia A treatment
A
- until 1960s was a fatal disease
- purified factor 8 from donor plasma that infected people with HIV, HBV
- now recombinanat factor 8 available
25
Duchenne Muscular dystrophy - genetic background
- example of X-linked recessive disease
- most common and severe form of muscular dystrophy
- progressive weakness and loss of muscle
- mutation in DMD gene--> altered dystrophin
- dystrophin works to maintain structural integrity of muscle cell cytoskeleton--> muscel cells gradually die as they are stressed by contractions
26
Duchenne Muscular Dystrophy- clinical presentation
- usually seen before 5 years old
- parents note clumsiness and muscle weakness
- calf pseudohypertrophy occurs early on, fat connective tissue infiltrate muscle
- all skeletal muscle degeneartes and are wheel chair bound by age 11
- death usually from respiratory or cardiac failure
- survival beyond 25 years is uncommon
27
Rett syndrome
- X linked dominant disorder
- nuerodevelopmental disorder characterized by autistic behavior, developmental delays, seizures, and gait ataxia
- occurs spontaneously in most affected individuals
- loss of function mutations in MECP2 result in inappropriate expression of genes that appear to be involved in brain development
28
Fragile X syndrome - genetic background
- X chromosome is deficient in folic acid
- most common cause of X linked developmental disease
- tri-nucleotide repeat disorder, severity depends on the number of repeats
- single most common cause of inherited delay - not a new mutation like Downs syndrome
29
Fragile X syndrome clinical presentation
- developmental delay
- distinctive facial appearance (long ears and long face)
- hypermobile joints
- macroorchidism
30
X linked recessive disease
- most commonly a carrier female and normal male
- carrier mother transmits diseased gene to 50% of her sons and 50% of her daughters
- 50% of sons will be affected, no daughter will be affected
31
X linked dominant inheritance
- less in prevelance and numbers than X-linked recessive
- females 2x> males
- no father--> son transmission ; all daughters will innherit diseased gene
- affected females usually heterozygotes and have a 50% chance of passing to both male and female offspring
32
Y-linked inheritance
- transmission is strictly father--> son
| - clinical examples: hypertrichosis pinnae auris, male infertility
33
mitochondrial inheritance
- mutation rate 10x higher than than that of nuclear DNA
- inherited exclusively through the maternal line
- therefore males cannot pass it on
34
heteroplasmy
- DNA heterogenity
- each cell contains multiple mtDNA molecules a singel cell can harbor some molecules that have mtDNA mutation and other molecules that do not.
35
Leber Hereditary Optic neuropathy
- missense mutation in protein coding mtDNA genes
- rapid loss of vision in central vision field as a result of optic death--> usually irreversable
- typically start in 30s
36
chromosome
thread-like structure consisting of chromatin; genes are arranged along chromosomes
37
chromatin
combination of proteins an nucleic acids
38
telomere
tip of each chromosome
39
cytogenetics
study of chromosomes and their abnormalities
40
euploid
cells whose chromosome number is a multiple of 23 ---> haploid gametes and diploid somatic cells are euploid
41
polyploidy
presence of a complete set of extra chromosomes in a cell
42
triploidy
- 69 chromosomes
- example: 69, XXX
- most common cause is dispermy
43
tetraploidy
- 92 chromosomes in each cell nucleus
- 92, XXXX
- much more rare than triploidy, both conception and birth
44
anueploid
- cells that don't contain multiples of 23 for chromosomes
- usually one chromosome affected but can be more than 1
- most clinically important
45
trisomy
- 3 copies of a chromosome
| - much more common than monosomies, the body handles extra genetic information much better
46
Trisomy 21- genetic back ground
- Down syndrome
- most common anueploid condition compatible with life
- 95% caused by disjunction
- extra chromosome contributed by mother in 90-95 of cases ( strong correlation of maternal age and risk)
- although 75% of Down syndrome babies are born to mothers <35 ( more babies being born to mothers that age)
47
Trisomy 21- clinical manifestations
- craniofacial: low nasal bridge, upslanting palpbrel fissures, small overfolded ears, macroglossia, round cheeks, short neck with redundant skin at nape of neck
- musculoskeletal: hands and feet are broad and short, deep flexion crease, hypotonia (highly consistent, good for dx) , hypermobile joints
- structural heart defects: AV septal defects, this contributes to decreased survival
48
Trisomy 21 - other associated medical conditions
- eye disorders
- conductive and sensorineural hearing loss
- moderate-severe developmental delay
- hypothyroidism
- leukemia
- reproductive: 50% are sterile
49
Trisomy 21- anticipatory guidance
- evaluation of heart defects --> TEE as newborn
- opthalmological exam before 4 years
- check thyroid function tests
- hearing test at 6-8 months and as needed afterwords
- refer for early childhood programs to provide intervention for developmental disabilities
50
Tirsomy 18 (Edward syndrome) - genetic background
- 2nd most common autosomal trisomy
- mostly from non-disjuntion
- maternally contributed extra chromosome most common (having to due with age)
51
Trisomy 18- clinical manifestations
- prenatal growth deficiency
- strawberry shaped head; microcephaly
- small low set ears; helices may be unraveled
- micrognathia (jaw hard to open)
- short sternum
- rocker bottom feet
52
Trisomy 18- other associated health issues
- marked developmental delay >>>>>>> downs syndrome
- congenital heart defects
- omphalocele (protrusion of the viscera into the umbilical cord)
- 50% of infants die within the first several weeks of life
53
Trisomy 13 (Patau Syndrome)
- associated with maternal age
- oral-facial clefts
- microopthalmia
- postaxial poldactyly
- malformations of the CNS, heart, kidneys
- prognosis similar to those with trisomy 21
54
Sex chromosome aneuploides
- because of X inactivation consequences are less severe than chromosomal aneuploides
- with the exception of complete absence of X chromosome most are compatible with life
55
Turner syndrome - genetic background
- monosomy of the X chromosome
- karyotype 45, X
- most cases caused by absence of paternally derived sex chromosome
56
Turner syndrome- clinical manifestations
- proportionate short stature
- genital/ sexual infantilism and ovarian dysgenesis common
- traingle-shaped face with broad webbed neck, broad chest, hand/foot lymphedema, Congenital heart defects ( bicuspid AV, coarctation of the aorta), structural renal deficit
57
Kleinfelter's Syndrome
- 47, XXY
- Usually due to non- disjunction
- 48, XXY and 49, XXXXY have been reported, the more X chromosomes the higher the degree of disability
- Y chromosome- male phenotype
- prevalence increases with maternal age
58
Chromosomal rearrangement
- unbalanced rearrangement causes gain or loss of chromosomal material , may produce serious disease
- balanced rearrangement does not produce loss or gain of genetic material often no serious health consequence
59
Translocation
- interchange of material between non-homologous chromosomes
60
Reciprocal translocation
- caused by 2 breaks on different chromosomes --> exchange of material
- carriers of balanced reciprocal translocation usually have normal phenotype
61
Robertsonian translocation
- occur when 2 long arms of accocentric chromosomes fuse at the centromere
- carriers of balanced robertsonian translocation can produce conceptions of monosomy or trisomy
62
Inversion ( balanced/ unbalanced)
- chromosomal abnormality in which a segment of chromosome has inverted from end to end and re-inserted into chromosome at same breakage site
- balanced: no net loss or gain of genetic material occurs; usually not associated with phenotypic abnormalities
- unbalanced: loss or gain of chromosome material occurs, nearly always yields an abnormal phenotype
63
Deletions ( interstitial and terminal)
- when a chromosome breaks and there is loss of generic material
- terminal: and end of a chromosome breaks off and is lost
- interstitial: there are 2 breaks in the chromosome and the material in the middle of the breaks is lost
64
Cri-du-chat syndrome
- deletion of 5p arm
- distinctive cry ("cry of the cat")
- developmental delays, microcephaly, and characteristic but not distinctive facial features
- living to adulthood is unlikely
65
microdeletion
- chromosome deletion that is too small to see under the microscope
- anglemans and prader willi are an example
66
DiGeorge anomaly - genetic background
- microdeletion of chromosome 22
| - alterations in gene or genes produce variable phenotype from DiGeorge anomaly--> VCF syndrome
67
DiGeroge anomaly- clinical symptoms
- structural defects of the thymus---> immunodeficiency
- hypoparathyroidism with 2 degree hypocalcemia
- various congenital heart defects
68
Velocardialfacial syndrome (VCF)
- microdeletion chromosome 22 (70% of patients)
- 2nd most common genetic syndrome behind down syndrome
- most common disorder with cleft palate associated
- characteristic facial anomaly- retinoganthia and a long face with a prominent nose
- 99% will have some developmental delay
69
Williams Syndrome - characteristics
- caused by varying gene microdeletions on chromosome 7 (26-28 genes)
- pixie like facial appearance, older people have slightly course features - wide smile and full nasal tip
- CV abnormalities: stenosis often above the aortic valve, HTN
- Polyendocrinopathy: hypercalcemia, DM, thyroid disorders
- Personality: "cocktail party" very friendly, but often socially isolated
- near universal enjoyment of music, but sensitive to loud noises
- nuerodevelopmental abnormalities- decreased IQ , delayed motor skills and intellectual inability
70
Williams syndrome - organs system evaluation and management
- FISH often used to detect
- there is no genetic test to predict the severity
- CVD: echo, endocrine: TSH, A1c, Ca++
- most adults require ongoing supervision at home,. medication for HTN, may require surgery for aortic stenosis, anticipatory guidance, inter professional team care
- presence or absence of emotional issues determines QOL
71
subtelomeric rearrangements
- deletion of duplication near the telemores results in genetic disease
72
Monosomy 1p36 syndrome
- deletion of several thousand bases of 1p36
- characterized by developmental delays, seizures, hearing impairment, heart defects
- facial features: horizontal eyebrows, deep set eyes, broad nasal root, pointed chin
73
Common metabolic disorders
- diabetes, heart disease, stroke, cancer
| - multi-factorial still unsure of the genetic role played int these diseases
74
Galctosemia
- CHO deficiency disorder
- lacks ability to turn galactose into glucose
- GAL-1-P uridyl transferase
- treatment: avoid dietary galactose
75
Glucose disorders -
- issues with CHO metabolism
- diabetes is a result of genetic and environmental factors
- possible genetic component: mutations in insulin receptor gene, mutation in mitochondrial DNA
76
Lactose
- CHO metabolism disorder
- people lack LAH ( lactase phlorzin hydrase)
- unable to digest dairy (some sources are better tolerated than others)
- treatment: avoid dietary lactose
77
Phenylalanine
- AA deficiency
- PKU- phenylketoneuria
- mutation of PAH
- elevated levels of phenylalanine disrupt essential cellular processes in the brain
- tx: avoid dietary phenylalanine
78
Tyrosine
- AA deficiency
- Tyrosine is a starter to synthetic pathways involved in catecholemines, melanin pigment, thyroid hormones
- elevated levels of tyrosine lead to severe liver damage
- HT1 most common form , caused by deficiency in FAH
79
HT1- tyrosine metabolism disorder
- dysfunction of renal tubules
- acute episodes of nueropathy
- progressive liver disease leading to cirrhosis
- at high risk for hepatocellular carcinoma
80
Tyrosine metabolism disorder - tx
- liver transplant
| - dietary restriction of phenylamine and tyrosine
81
BCCAs
- branched chain amino acids
- 40% of pre-formed amino acids required by mammals are BCAAs
- source of energy
82
Maple syrup urine disease
- common in Mennonite community
- accumulation of BCCAs lead to progressive nuerodegeneration and death in first few monthsof life
- early detection is key and can prevent severe physical impairment.
- even a moderate increase in enzyme activity dramatically improves course of disease
- Tx: dietary restriction of BCAAs to the minimum for required growth , Thiamine can be used as a co-factor of BCKAD ( enzyme used to break up BCCAAs)
83
lipids
- lipid are important part of cell membranes
- important part of steroid hormones
- intracellular messengers , serve as energy substrate
- disorders in metabolism are rare
84
Smith- Lemil Opitz (SLO) syndrome
- autosomal recessive disorder
- reduced levels of cholesterol and increased levels of 7-dehdrocholesterol
- various congenital anomalies of the brain, heart, genetalia, and hands
- tx: supplementing diet with cholesterol can growth and feeding problems, but maybe not cognitive development
85
Congenital Adrenal Hyperplasia (CAH)
- steroid disorder- most common cause of ambigous genitalia, 21-hydroxylase deficiency
- disruption of cortisol synthesis
- variation in aldosterone synthesis
- excessive androgen production
- tx: suppress androgens, cortisol replacement, mineralcorticoid replacement
86
OTC deficiency
- X linked disorder
- enzymatic defects in this pathway lead to accumulation of urea products
- lead to progressive neurological defects and death if untreated
- tx: provide sufficient calories and protein while avoiding hyperammonia states
87
Hereditary hemachromatosis- background
- autosomal recessive disorder of iron metabolism
- single missense mutation substitute tyrosine for cysteine
- excessive iron absorption and accumulation in tissues
88
Hereditary hemachromatosis - Clinical presentation, dx, tx
Clinical presentation: fatigue, diabetes, cardimyopathy, liver enlargement and cirrhosis
Diagnoses: histochemical staining for hemosiderin
Tx: phlebotomy or iron chelating agent ( deferoxamine)
89
Achrodermatitis enteropathica ( AE)
- defect in the absorption of zinc from the GI tract
- clinical presentation: diarrhea, rash that covers buttocks and genital area , growth retardation, dysfunction of the immune system
- tx: high doses of supplementak zinc (curative)
90
Menkes disease
- X linked recessive
- copper can be absorbed by GI tract but cannot be moves from the cells to bloodstream
- clinical presentation: intellectual disabilities, hypothermia, seizures, lose skin, arterial rupture, pili tori
- tx: SQ injections of copper
91
Wilson's disease
- defective excretion of copper from the billiary tract
- autosomal recessive disorder
- Kaiser-Fleischer ring copper at the limbus conrea in 95% patients
- can cause arthropathy, cardiomyopathy, kidney damage, hypoparathyroidism
- tx: copper chelating agents
