Robbins Chapter 5 Key Concepts Flashcards
Characteristics of Autosomal dominant disorders
Expression in heterozygous state
They affect males and females equally
Both sexes can transmit the disorder
What do autosomal dominant disorders not affect?
enzyme proteins
What is mostly affected in autosomal dominant disorders?
receptors and structural proteins
Characteristics of Autosomal recessive disorders
Both copies of a gene are mutated
Enzyme proteins are frequently involved
Males and females are affected equally
Characteristics of X-linked disorders
Transmitted by Heterozygous females to their sons who manifest the disease
Female carries usually protected because of random inactivation of X chromosome
Cause of Marfan Syndrome
mutation in FBN1 gene encoding fibrillin
What is fibrillin required for?
structural integrity of connective tissue
regulation of TGF-b signaling
Major tissues affected in Marfan Syndrome
skeleton, eyes, and cardiovascular system
Clinical features of Marfan Syndrome (6)
tall stature, long fingers, bilateral subluxation of lens, mitral valve prolapse, aortic aneurysm, and aortic dissection
Drugs that improve aortic and cardiac function in Marfan Syndrome
drugs that inhibit TGF-b signaling
How many variants of Ehlers-Danlos Syndrome are there?
6
What is EDS characterized by?
defect in collagen synthesis or assembly
What causes the differences in each of the variants of EDS?
distinct mutation involving one of several collagen genes or genes that encode other ECM proteins like tenascin-X
Clinical features of EDS (4)
fragile, hyperextensible skin that is vulnerable to trauma
hypermobile joints
ruptures of the colon, cornea, or large arteries
would healing is poor
Genetics of Familial Hypercholesterolemia
autosomal dominant disorder
Cause of Familial Hypercholesterolemia
mutations in genes encoding the LDL receptor
Consequences of impaired transport of LDL into the cells
develop hypercholesterolemia
Heterozygotes with Familial Hypercholesterolemia
elevated serum cholesterol
increased risk of atherosclerosis and coronary artery disease
Homozygotes with Familial Hypercholesterolemia
elevated serum cholesterol
high frequency of ischemic heart disease
How are Xanthomas formed
cholesterol deposits on tendon sheaths
What are Lysosomal Storage Diseases
inherited mutations leading to defective lysosomal enzyme functions giving rise to accumulation and storage of substates in lysosomes and defects in autophagy
Cause of Tay-Sachs Disease
inability to metabolize GM2 gangliosidases due to lack of alpha subunit of lysosomal hexosaminidase
What and where accumulates in Tay-Sachs Disease
GM2 gangliosides in CNS and caused mental retardation, blindness, motor weakness, and death by 2-3 years
Cause of Niemann-Pick Disease types A and B
deficiency of sphingomyelinase
What accumulates in Type A NP Diseases
sphingomylein in the nervous system resulting in neuronal damage
lipid stored in phagocytes
Difference between Type B NP Disease vs Type A NP Disease
Type B has no neuronal damage
Cause of NP C Disease
defect in cholesterol transport
What accumulates in NP C Disease
cholesterol and gangliosides in nervous system
S/S of affected children with NP C Disease
ataxia, dysarthria, psychomotor regression
Cause of Gaucher Disease
lack of lysosomal enzyme glycocerebrosidase
What accumulates in Gaucher Disease
glucocerebroside in mononuclear phagocytic cells
Type I Gaucher Disease characteristics
Gaucher cells affected phagocytes become enlarged and accumulate in liver, spleen, bone marrow causing hepatosplenomegaly and bone erosion
Type II and III Gaucher Disease characteristics
neuronal invovlement
What accumulates in Mucopolysaccharidoses
mucopolysaccharides in liver, spleen, heart, blood vessels, brain, cornea, and joints
Features of affected patients with MPS
coarse facial features
Hurler Syndrome MPS features
corneal clouding, coronary arterial and valvular deposits and death in childhood
Hunter Syndrome MPS features
milder clinical course than Hurler Syndrome
What is a glycogen storage deficiency
inherited deficiency of enzymes involved in glycogen metabolism
Results of glycogen storage deficiency
Storage of normal or abnormal forms of glycogen in liver, muscles, and other organs
Hepatic form of glycogen storage deficiency
Von Gierke Disease
liver cells store glycogen due to lack of hepatic glucose-6-phosphatase
Myopathic form of glycogen storage deficiency
ex. McArdle disease
lack of muscle phosphorylase gives rise to storage in skeletal muscles and muscle cramps after exercise
Pompe Disease
lack of lysosomal acid maltase and all organs are affected
heart involvement in predominant
Genetics of Down Syndrome
extra copy of genes on chromosome 21
most common is trisomy 21
less frequently from translocation of extra chromosomal material from chromosome 21
Clinical features of patient with Down Syndrome
severe mental retardation, flat facial profile, epicanthic folds, cardiac malformation, high risk of leukemia and infections, and premature development of Alzheimer disease
Clinical features of deletion of genes at chromosomal locus 22q11.2
malformations of the face, heart, thymus, and parathyroids
Diseases associated with deletion of chromosomal locus 22q11.2
DiGeorge Syndrome
Velocardiofacial Syndrome
DiGeorge syndrome characteristics
thymic hypoplasia
diminished T-cell immunity
parathyroid hypoplasia
hypocalcemia
Velocardiofacial Syndrome characteristics
congenital heart disease of outflow tracts
facial dysmorphism
developmental delay
Lyon Hypothesis
in females, one X chromosome, maternal or paternal, is randomly inactivated during development
Cause of Klinefelter syndrome
2 or more X chromosomes with one Y chromosomes resulting from nondysjunction of sex chromosmes
Characteristics of Klinefelter syndrome
testicular atrophy sterility reduced body hair gynecomastia eunuchoid body habitus *most common cause of male sterility
Cause of Turner syndrome
partial or complete monosomy of genes on short arm of X chromosome (45,X most common) from absence of one X chromosome
less common from mosaicism
Characteristics of Turner syndrome
short stature webbing of neck cubitus valgus cardiovascular malformations amenorrhea lack of secondary sex characteristics fibrotic ovaries
Fragile X Syndrome pathology
amplification of trinucleotide repeats causing loss of function
Huntington Disease pathology
amplification of trinucleotide repeats causing gain of function
Fragile X Syndrome genetics
loss of FMR1 gene function
Characteristics of Fragile X Syndrome
mental retardation, macro-orchidism and abnormal facial features
How many CGG repeats in a normal FMR1 gene in comparison to fragile X syndrome CGG
29-200 normal
4000 fragile X syndrome
How does Fragile X tremor/ataxia occur
expression of FMR1 gene with a premutation
Mechanism of Fragile X tremor/ataxia
accumulation of mRNA in the nucleus that binds to proteins that are essential for normal function
What is imprinting
transcriptional silencing of the paternal or maternal copies of genes during gametogenesis
How can disease be caused by imprinting
one gene is silenced by imprinting and the other is active but if the active gene loses the functional allele by deletion, this causes disease
Prader Willi Syndrome cause
maternal imprinting of chromosome 15 and deletion of band on long arm of active paternal chromosome 15
Prader Willi characteristics
mental retardation, short stature, hypotonia, hyperphagia, small hands and feet, and hypogonadism
Angelman Syndrome
paternal imprinting of chromosome 15 and deletion of band on long arm of active maternal chromosome 15
Angelman Characteristics
mental retardation, ataxia, seizures, inappropriate laughter
