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Flashcards in Single Gene Disorders Deck (30)
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AD diseases

- familial hypercholesterolemia (LDL receptor deficiency)
- Huntington's
- Neurofibromatosis Type 1
- Marfan
- Acute intermittent porphyria


X-linked recessive diseases

- Duchenne muscular dystrophy
- lesch-nyhan syndrome (HGPRT deficiency)
- Glucose 6PDH deficiency
- Hemophilia A and B
- red-green color-blindness
- menke's disease
- OTC deficiency
- SCID (IL-receptor gamma chain deficiency)


How to calculate recurrence risk in X-linked recessive diseases when the sex of the fetus is unknown

- if the sex of the fetus is not known, then the recurrence rate is multiplied by 1/2, the probability that the fetus is male vs a female
- ex) if, for a couple the recurrence rate for a daughter is 0, and the recurrence rate for a son is 50%, then the recurrence risk for the unsexed fetus is 25%



- occurs in the blastocyst
- when inactivated, its DNA is not transcribed into mRNA.
- seen microscopically as a Barr body
1. it is random: in some cells of the female embryo the X-chromosome from dad is inactivated, in others the x-chromosome from mom is inactivated
- most women have their paternal X chromosomes active in approx 50% of cells; mom's X is active in 50%
= women are mosaics wrt the active X chromosome
2. it is fixed. once inactivation occurs, the same x chromosome is inactivated in all descendants of the cell
3. it is incomplete: there are regions throughout the X chromosome (including the tips of both the long and short arms) that are not inactivated
4. all X chromosomes are inactivated except 1. if a woman has 3, 2 will be inactivated


X-inactivation is mediated by

1. XIST = primary gene that causes x-inactivation
- XIST produces an RNA product that coats the chromosome, helping product inactivation
2. Condensation into heterochromatin
3. methylation of gene regions on the X chromosome


genetic mosaicism

a condition in which cells w different genotypes or chromosome constitutions are present in the same individual


x-linked dominant

- males and females may be affected differently (have different degrees of penetrance)
- seen about 2x as often in females as in males
- phenotype seen in multiple generations of pedigree (like AD); skipped generations relatively unusual
- An affected male's children: none of sons will be affected, but all daughters will have disease
- Ex) Fragile X Syndrome
- Ex) hypophosphatemic rickets


Fragile X Syndrome

- Males = 100% penetrance
- mental retardation
- large ears
- prominent jaw
- macro-orchidism (usually post pubertal)
2. females = 60% penetrance (causes mental retardation


Examples of mitochondrial diseases

1. leber hereditary optic neuropathy
2. MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes)
3. myoclonic epilepsy with ragged red muscle fibers
- only passed from a female to her children
- diseases are typically neuropathies/myopathies



- single mutation affects multiple organ systems
- ex) marfans (AD)


affect of allelic heterogeneity

- different mutations in the disease-causing locus may cause more/less severe expression
- usually results in phenotypic variation BETWEEN families, not WITHIN one family
- ex) missense mutations in factor VIII gene produce less severe hemophilia than nonsense mutations (which truncate the protein, so it produces very little (or no) factor VIII)



- bc a typical cell contains hundreds of mito in the cytoplasm,
- sometimes a specific mutation is seen in only some of the mitochondria
= heteroplasmy
- variations can result in substantial variation in the severity of expression of mitochondrial diseases


incomplete penetrance

= when some people who have the disease GENOTYPE do not display the disease PHENOTYPE
- these are diseases where a secondary event is required to cause expression of the disease
- differs from variable expression in that the nonpenetrant gene has NO PHENOTYPIC EXPRESSION AT ALL
- ex) an unaffected male has an affected father and two affected sons; he must have the disease-causing mutation
- both dominant and recessive diseases can show incomplete penetrance
- Rb (AD) is an example of incomplete penetrance in familial cancer
** hereditary hemochromatosis is an example of incomplete penetrance AND variable expression
- among individuals with at least some phenotypic expression, the symptoms can be more or less severe (variable expression)
- however, 85% of ppl homozygous for the mutation never have any sx (nonpenetrance)


locus heterogeneity

when the same disease phenotype can be caused by mutations in different loci


Locus heterogeneity in osteogenesis imperfecta Type 2

- the severe perinatal form of OI (T2) is the result of a defect in type 1 collagen; 100% result from new mutations
- T1 collagen = trimeric molecule that has a triple helix structure
- 2 members of the trimer are encoded on Chromosome 17
- 3rd is encoded on chromosome 7
- pts with chromosome 17 mutations are often clinically indistinguishable from pts with mutations on chromosome 7
= locus heterogeneity


- Triplet repeat found in Huntington Disease
- location of repeat
- mode of inheritance
- symptoms

- 5' coding
- normal huntingtin genes have fewer than 27 CAG repeats in the 5' coding region; start developing symptoms when have 39 repeats
- AD
- movement abnormality,
- emotional disturbance,
- cognitive impairment
- death 10-15 years after onset (aspiration pneumonia, head trauma (resulting from loss of motor control), suicide)
- produces a buildup of toxic protein aggregates in neurons, eventually results in neuronal death


- Triplet repeat found in Fragile X syndrome
- location of repeat
- mode of inheritance
- symptoms

- 5' UTR
- X-dominant
- mental retardation
- large ears and jaw
- post-pubertal macro-orchidism (males)
- ADD (females)


- Triplet repeat found in Myotonic dystrophy
- location of repeat
- mode of inheritance
- symptoms

- 3' UTR
- AD
- muscle loss
- cardiac arrhythmia
- testicular atrophy
- frontal baldness
- cataracts


- Triplet repeat found in Friedreich ataxia
- location of repeat
- mode of inheritance
- symptoms

- intron 1
- AR
- early onset progressive gait and limb ataxia
- Areflexia in all 4 limbs
- hypertrophic cardiomyopathy
- axonal sensory neuropathy
- kyphoscoliosis


Diseases with delayed age of onset

- acute intermittent porphyria (peri or post-pubertal)
- huntington disease (30s-40s)
- hemochromatosis
- familial breast cancer


Disease caused by a CAG repeat in the 5' coding region

Huntington Disease (AD)


Anticipation in Huntington Disease

- gain-of-function mutation on Ch 4
- normal huntingtin genes have fewer than 27 CAG repeat in the 5' coding region
- symptoms develop when there are 39 repeats
- pts (generally males) may transmit an expanded number of repeats to their offspring
- age of onset is correlated w the # of repeats:
- 39 repeats = 66 yo; more than 70 repeats = 20 yo


Prader-Willi results from a deletion

from paternal 15q


Disease caused by a CGG repeat in the 5' UTR

Fragile X syndrome (X-Dominant)


Prader-Willi Syndrome

- affects M and F
- neonatal hypotonia
- poor feeding in neonatal period
- behavior problems
- moderate mental and developmental retardation
- hypogonadism, undeveloped genitalia
- hyperphagia and obesity by 2-4yo
- small hands and feet
- deletion from paternal 15q (and the gene that is SUPPOSED to be expressed is on the paternal chromosome; the maternal chromosome has been silenced)
- Paternal 15q codes gene SNRPN, involved in mRNA splicing
- very low recurrence risk
- possibly a result of unequal crossing over during gametogenesis



- symptoms depend on whether the mutant gene was inherited from the mother or father
- occurs bc a small # of genes are only transcriptionally active when transmitted by one of the 2 sexes
- the monologues locus in the other parent is rendered transcriptionally inactive
- imprinted = methylated = transcriptionally INACTIVE
- occurs in gametogenesis, is maintained in all somatic cells of the offspring
- during gametogenesis in the offspring, is erased and re-established according to the sex of the individual


Disease caused by a CTG repeat in the 3' UTR

myotonic dystrophy (AD)


Angelman Syndrome results from a deletion

from maternal 15q


Angelman Syndrome

- "happy puppet"
- Affects M/F
- severe mental retardation
- seizures
- ataxia
- puppet-like posture of limbs
- happy disposition
- deletion from maternal 15q (and the gene that is SUPPOSED to be expressed is on the maternal chromosome; the paternal chromosome has been silenced)
- Maternal 15q encodes gene UBE3A (involved in the ubiquitin pathway)
- very low recurrence risk
- possibly a result of unequal crossing over during gametogenesis


Disease caused by a GAA repeat in intron 1

Friedrich ataxia (AR)