Chapter I: Single Gene Disorders (continued) Flashcards
List some X-linked dominant disorders
- hypophosphatemic rickets
- fragile X syndrome
Create a basic decision tree for determining the mode of inheritance in a pedigree.
Create flow tree
What are some key strategies to help deduce if a person has a mitochondrially inherited condition? What types of conditions are common when assessing mitochondrially inherited conditions?
- disease are transmitted only from affected females to their offspring
- both males and females are affected
- none of the offspring of the affected male are affected
- disease are typically neuropathies and/or myopathies
Heteroplasmy
when a specific mutation occurs in some of the mitochondria, it can be unevenly distributed into daughter cells during cell division
Some cells may inherit more mitochondrial DNA that is normal
What is the inheritance pattern shown in this pedigree.
mitochondrial inherited disease
List some important mitochondrial diseases.
Leber hereditary optic neuropathy
MELAS: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes
myoclonic epilepsy with ragged red muscle fibers (MERRF)
What does it mean to have variable expression of a gene?
when genes vary in their degree of phenotypic expression
What is a modifier loci?
when disease expression is affected by the action of other loci, termed modifier loci
What is incomplete penetrance?
disease-causing mutation is said to have incomplete pentrance when some individuals who have the disease genotype (e.g. one copy of the mutation for an AD disease or 2 copies for an AR disease) do not display the disease phenotype
What is the inheritance pattern of the pedigree shown?
incomplete penetrance
Penetrance must be taken into account when predicting what value?
recurrence risks
How is penetrance calculated?
by examining a large number of families and calculating the percentage of individuals who are known to have the disease causing genotype who display the disease phenotype
How do you calculate recurrence risk if penetrance is involved?
multiply penetrance with the recurrence risk
T/F. Incomplete penetrance can only be seen in dominant disorders?
False.
Can be seen in dominant or recessive disorders
What is an example of a condition that can lead to incomplete penetrance?
hereditary hemochromatosis
Pleiotropy?
when a single disease causing mutation affects multiple organ systems
What is an example of a condition showing pleiotropy?
Marfan syndrome
What are some signs/symptoms of Marfan syndrome?
- skeletal abnormalities (thin, elongated limbs; pectus excavatum; pectus carinatum),
- hypermobile joints,
- ocular abnormalities (frequent myopia and detached lens),
- cardiovascular disease (mitral valve prolapse and aortic aneurysm)
Where is fibrillin commonly found?
in periosteum and perichondrium, the suspensory ligament of the eye, and the aorta
Pathogenetic reason for why Marfan syndrome has its characteristic effects on certain tissue?
because fibrillin causes connective tissue to be ‘stretchy” and leads to all the observed disease features
What is locus heterogeneity?
when the same disease phenotype can be caused by mutations in different loci
What is an example of a condition that exhibits locus heterogeneity?
OI
What type of inheritance pattern is the pedigree showing?
a new mutation
What are some diseases that exhibit delayed Age of Onset?
- Acute intermittent porphyria (peri or postpubertal
- Huntington disease
- Hemochromatosis
- Familial breast cancer
In this pedigree what does the number on the left and the number in parenthesis mean?
Number on left is age and number on right in parenthesis is the number of repeats.
Name 4 symptoms of Huntingons disease.
- movement abnormality
- emotional disturbance
- cognitive impairment
- death 10-15 years after onset
Name symptoms of fragile X syndrome?
- intelectual disability
- large ears and jaw
- post-pubertal macro-orchidism (males)
- attention deficit disorder (in females)
Name some symptoms of myotonic dystrophy?
- muscle loss
- cardiac arrhythmia
- testicular atrophy
- frontal baldness
- cataracts
Name some symptoms of Friedreich ataxia?
- early onset progressive gait and limb ataxia
- areflexia in all 4 limbs
- hypertonic cardiomyopathy
- axonal sensory neuropathy
- kyphoscoliosis
Repeat and location of repeat found in Huntingtons?
CAG 5’ coding
Repeat and location of repeat found in Fragile X syndrome?
CGG 5’ UTR
Repeat and location of repeat in Myotonic dystrophy?
CTG 3’ UTR
Repeat and location of repeat in Freidreich ataxia?
GAA intron 1
Which shows AR mode of inheritance? Huntington, Fragile X, Myotonic dystrophy or Freidreichs ataxia
Freidreich ataxia
Spinobulbar muscular atrophy repeat?
CAG (polyglutamine disorder) in translating region
Symptoms of spinobulbar muscular atrophy.
weakness, atrophy and fasciculations in the limb and bulbar muscles
Is imprinting normal?
yes
What does imprinting involve?
methylation and possibly other mechanisms to imprint or inactivate the appropriate loci
General pathogenesis of both Prader Willi and Angelman Syndrome?
on rare occasion, the transcriptionally active gene may be deleted from the chromosome (perhaps by unequal crossover)
Prader willi syndrome is caused by loss from which chromosome? Mother or father?
from father
Angelman syndrome occurs because of deletion of father or mother chromsome?
deletion of 15q11-13 from maternal chromsome
What is uniparental disomy? Relation of Angelman’s and Prader Willi
rare condition in which both copies of a particular chromosome are contributed by one parent. This may cause problems if the chromosome contains an imprinted region or mutation
Symptoms of Prader-Willi Syndrome?
- affects males and females
- neonatal hypotonia
- poor feeding in neonatal period
- behavior problems
- moderate intellectual disability and developmental retardation
- hypogonadism, underdeveloped genitalia
- hyperphagia (overeating) and obesity by ages 2-4 years *****
- small hands and feet
- deletion from paternal 15q
- very low recurrence risk
Symptoms of Angelman Syndrome.
- affects males and females
- severe intellectual disability
- seizures
- ataxia
- puppet-like posture of limbs
- happy disposition ****
- deletion from maternal 15 q
- very low recurrence risk
