5 - Genetic Disorders Flashcards
What is the lifetime frequency of genetic disorders?
670 per 1000
What are the three broad categories of genetic disorders?
Single gene mutations with large effects; chromosomal disorders; complex multigenic disorders (most common)
Multiple variations of the same gene is referred to as:
Polymorphisms
Describe Mendelian disorders.
Disorders passed on by mutations that affect single genes and have large effects
What are the major types of point mutation?
Silent, missense, and nonsense
What are the two types of missense mutation?
Conservative (similar amino acid replacement) and nonconservative (very different amino acid replacement)
What kind of effects can deletions within introns have?
Promoters, enhancers, splicing junctions, and other regulatory genes can be altered (often decreasing gene expression)
In what situation are deletions or insertions of DNA not going to result in a frameshift mutation?
If the deletion or insertion is a multiple of three nucleotides
What are some examples of disorders associated with trinucleotide-repeat mutations? Which trinucleotides are involved in each disorder?
Fragile X syndrome (CGG), Huntington’s disease (CAG), myotonic dystrophy (CTG), Friedrich’s ataxia (GAA)
What disorder types don’t fit neatly into the three main types (chromosomal abnormalities, single gene mutations, and multigenic disease)?
Trinucleotide-repeats, mitochondrial inheritance, imprinting, mosaicism
When do sickle cell heterozygotes manifest red blood cell sickling?
Only after unusual circumstances like lowered oxygen tension
A single mutant gene may lead to many end effects. What is this called?
Pleiotropism
What is it called when mutations at several genetic loci may produce the same trait?
Genetic heterogeneity
What are some forms by which single-gene mutations are transmitted (3)?
Autosomal dominant, autosomal recessive, and X-linked
Do any patients with autosomal dominant disorders not have affected parents?
Yes, these patients are the result of new mutations (seem to occur in the germ cells of relatively old fathers)
Do autosomal dominant diseases display variation in penetrance and expressivity?
Yes
Which protein genes are more likely to be affected in autosomal dominant disorders?
Key structural proteins; metabolic pathway-regulating feedback inhibitors
Which is more common, loss-of-function or gain-of-function mutations?
Loss-of-function
What genetic disorder category is the largest of the Mendelian disorders?
Autosomal recessive disorders
What percentage of sex-linked disorders are X-linked? How many of these are recessive?
All; most
What inheritance pattern does Marfan syndrome show?
Autosomal dominant
What extracellular glycoprotein is deficient in Marfan syndrome?
Fibrillan-1
Lack of fibrillan-1 causes what general effects in Marfan syndrome?
Lack of tropoelastin scaffolding; excessive TGF-beta activation
What are the main abnormalities in Marfan syndrome?
Skeletal abnormalities, subluxation or dislocation of the lens, mitral valve prolapse, and ascending aortic dilation
What is the main course of treatment for Marfan syndrome?
Beta-blockers (reduce heart rate and aortic wall stress)
What group of disorders is characterized by defects in the synthesis or structure of fibrillar collagen?
Ehlers-Danlos Syndromes (VI) (also, osteogenesis imperfect and Alport syndrome)
Which Ehlers-Dalos subtypes are autosomal recessive?
Kyphoscoliosis; dermatosparaxis
Describe vascular Ehlers-Danlos Syndrome.
Thin skin, arterial or uterine rupture, bruising, small joint hyper extensibility; autosomal dominant
Describe classic Ehlers-Danlos Syndrome.
Skin and joint hypermobility, atrophic scars, easy bruising; autosomal dominant
What is familial hypercholesterolemia?
An autosomal dominant disease in which LDL receptors are under expressed
How do patients with familial hypercholesterolemia manifest?
2-3 fold elevation of plasma cholesterol at birth (heterozygotes); tendinous xanthomas and premature atherosclerosis in adult life
AMI before 20 years of age may be indicative of what disease?
Familial hypercholesterolemia
What is the frequency of familial hypercholesterolemia?
1 in 500 individuals
What percentage of body cholesterol circulates in the plasma? What is the predominant form of this circulating cholesterol?
LDL; 7%
Describe the metabolism of LDL.
Liver –> VLDL –> Adipose tissue –> IDL –> LDL –> Liver
What is the immediate and major source of LDL?
IDL (intermediate-density lipoprotein)
What effects does an oversupply of cholesterol have on a cell?
Inhibits LDL receptor synthesis, inhibits cholesterol synthesis, stimulates cholesterol storage
How are recently ER-synthesized lysosomal enzymes (acid hydrolases) segregated in the Golgi and targeted to fuse with lysosomes?
Mannose-6-phosphate;
the phosphorylated mannose residues serve as an “address label” that is recognized by specific receptors found on the inner surface of the Golgi membrane. Lysosomal enzymes bind these receptors and are thereby segregated from the numerous other secretory proteins within the Golgi.
Subsequently, small transport vesicle containing the receptor-bound enzymes are pinched off from the Golgi and proceed to fuse with the lysosomes.
What do lysosomes store? What are some of the effects of lysosomal storage diseases?
Acid hydrolases;
lysosomes do not have sufficient hydrolytic enzymes – autophagy and heterophagy are impaired.
What are four lysosomal storage diseases affecting glycogen storage?
von Gierke’s, Pompe’s, Cori’s, McArdle’s
What enzyme is deficient in von Gierke’s disease?
Glucose 6-phosphatase
What enzyme is deficient in Pompe’s disease?
alpha-1,4-glucosidase
What enzyme is deficient in Cori’s disease?
Debranching enzyme
What enzyme is deficient in McArdle’s disease?
Glycogen phosphorylase
What is the most prominent feature of Pompe’s disease?
Cardiomegaly
What is an example of a hepatic-hypoglycemic form of a glycogen storage disease?
von Gierke
What is an example of a myopathic form of a glycogen storage disease?
McArdle’s disease
What is a common feature of lysosomal storage diseases?
Hepatic and splenic enlargement
What are the most prominent sphingolipidoses deficiency disorders?
Tay-Sachs disease; Niemann-Pick disease (types A, B, and C); Gaucher disease
What are two mucopolysaccharidoses deficiencies?
Hurler’s disease and Hunter’s disease
What are complex multigenic disorders? What is an example?
Disorders caused by interactions between variant forms of genes and environmental factors;
type 1 diabetes mellitus
Name all the examples of lysosomal storage diseases you can.
von Gierke’s disease, Pompe’s disease, Cori’s disease, McArdle’s disease, Tay-Sachs disease, Krabbe disease, Fabry disease, Gaucher disease, Neumann-Pick disease, Hurler’s disease, Hunter’s disease, I-Cell disease,
What enzyme is absent from virtually all tissues in Tay-Sachs disease? What substrate builds up? What structures dominate the clinical picture?
Hexosaminidase A; GM2 ganglioside; involvement of neurons in the central and autonomic nervous systems
Describe the pathology and clinical significance of Tay-Sachs disease.
In time there is progressive destruction of neurons, the proliferation of microglia, and accumulation of complex lipids in phagocytes within the brain substance.
A similar process occurs in the cerebellum as well as in neurons throughout the basal ganglia, brain stem, spinal cord, and dorsal root ganglia and in the neurons of the autonomic nervous system.
A cherry-red spot in the macula; this finding is characteristic of Tay-Sachs disease and other storage disorders affecting the neurons.
What neurologic disorder is especially prevalent among Ashkenazi Jews (1 in 30 are carriers)?
Tay-Sachs disease
Describe the clinical significance of Tay-Sachs disease.
The affected infants appear normal at birth but begin to manifest signs and symptoms at about age 6 months. There is relentless motor and mental deterioration beginning with motor incoordination, mental obtundation leading to muscular flaccidity, blindness, and increasing dementia. Sometime during the early course of the disease, the characteristic, but not pathognomonic, cherry-red spot appears in the macula of the eye in almost all patients.
Over the span of 1 or 2 years, a complete vegetative state is reached, followed by death at age 2 to 3 years.
What builds up in lysosomes in Niemann-Pick diseases types A and B?
Sphingomyelin (due to an inherited deficiency of sphingomyelinase)
What enzyme is deficient in Niemann-Pick disease types A and B?
Sphingomyelinase
What ethnicity is implicated in Niemann-Pick disease Type A and B?
Ashkenazi Jews
What is Gaucher disease?
Gaucher disease refers to a cluster of autosomal recessive disorders resulting from mutations in the gene encoding glucocerebrosidase.
What is the most common lysosomal storage disease?
Gaucher disease
Describe the clinical significance of Gaucher disease.
In type I, symptoms and signs first appear in adult life and are related to splenomegaly or bone involvement. Most commonly there is pancytopenia or thrombocytopenia secondary to hypersplenism. Pathologic fractures and bone pain occur if there has been extensive expansion of the marrow space. Although the disease is progressive in the adult, it is compatible with long life.
What is another name for mucopolysaccharides?
Glycosaminoglycans
(dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate)
What clinical features define mucopolysaccharidoses (deficiencies of enzymes involved in the degradation of mucopolysaccharides (glycosaminoglycans))
?
In general, MPSs are progressive disorders, characterized by coarse facial features, clouding of the cornea, joint stiffness, and mental retardation. Urinary excretion of the accumulated mucopolysaccharides is often increased.
Describe Hurler’s syndrome (most severe type).
Affected children appear normal at birth but develop hepatosplenomegaly by age 6 to 24 months. Their growth is retarded, and, as in other forms of MPS, they develop coarse facial features and skeletal deformities. Death occurs by age 6 to 10 years and is often due to cardiovascular complications.
How is Hunter’s disease different from Hurler’s disease?
The mode of inheritance (X-linked), absence of corneal clouding, and milder clinical course.
How is a normal karyotype done?
Each pair of autosomes arranged according to length, followed by sex chromosomes.
What is the most commonly used chromosome staining technique?
G banding (Giemsa stain)
What are two causes of aneuploidy?
Nondisjunction, anaphase lag
How does mosaicism happen?
Mitotic errors in early development give rise to two or more populations of cells with different chromosomal complement, in the same individual,
What is a ring chromosome?
A break occurs at both ends of a chromosome with fusion of the damaged ends
What are two types of chromosomal inversion?
Paracentric and pericentric
What type of chromosomal inversion involves only one arm of the chromosome?
A paracentric inversion
What type of chromosomal inversion involves breaks on opposite sides of the centrosome?
A pericentric inversion
What is it called when a chromosomal arm is deleted, and so the remaining arm is duplicated?
An isochromosome (with a lost chromosomal arm and duplication of the remaining arm)
What are some types of chromosomal translocations?
Balanced; Robertsonian
What are the three most common trisomies (in order of descending incidence)?
Down syndrome, Edward’s syndrome, Patau syndrome
Name the trisomies involved in Down, Edward’s, and Patau syndromes.
21, 18, 13
What syndrome do the previously separate Velocardiofacial and DiGeorge syndrome comprise?
Chromosome 22q11.2 deletion syndrome
What neurologic disorder will virutally all individuals with Down syndrome develop after the age of 40?
Alzheimer’s Disease
What psychiatric disorder is related to 22q11.2 deletion syndrome?
Schizophrenia
Describe the clinical significance of Down syndrome.
Patients with Down syndrome have severe mental retardation, flat facial profile, epicanthic folds, cardiac malformations, higher risk of leukemia and infections, and premature development of Alzheimer disease.
Which is better tolerated, autosomal or sex chromosome disorders?
Sex chromosome disorders (they are also much more common)
What are two of the most common sex chromosome disorders?
Kleinfelter syndrome (XXY), Turner syndrome (XO)
Describe Klinefelter syndrome.
Patients have testicular atrophy, sterility, reduced body hair, gynecomastia, and eunuchoid body habitus.
It is the most common cause of male sterility.
Describe Turner syndrome.
Short stature, webbing of the neck, cubitus valgus, cardiovascular malformations, amenorrhea, lack of secondary sex characteristics, and fibrotic ovaries are typical clinical features.
Name four trinucleotide-repeats disorders and their repeating triplets.
Friedrich’s ataxia (GAA), Myotonic dystrophy (CTG), Huntington’s disease (CAG), Fragile X syndrome (CGG)
Describe Leber Hereditary Optic Neuropathy.
A neurodegenerative disease that manifests as a progressive bilateral loss of central vision. Visual impairment is first noted between ages 15 and 35, leading eventually to blindness.
(Mitochondrial genes - maternal inheritance)
What is the difference between Prader-Willi and Angelman syndromes?
Paternal or maternal imprinting of chromosome 15
Describe Prader-Willi syndrome.
Patients have mental retardation, short stature, hypotonia, hyperphagia, small hands and feet, and hypogonadism.
Describe Angelman syndrome.
These patients have mental retardation, ataxia, seizures, and inappropriate laughter.
What is true hermaphroditism?
The presence of both testicular and ovarian tissues
What is pseudohermaphroditism?
When there is a disagreement between the phenotypic and gonadal sex
