Ch15. Genetics-1

Question 1

Variable Expressivity

Answer 1

Showing a variety of different problems from patient to patient with the same autosomal dominant disease

Example: MyotonicDystrophy

Question 2

Pleiotropism

Answer 2

Multiple end effects of a single mutant gene
Example: Marfan’sSyndrome

   Skeletal, ocular, and cardiovascular problems        arise from a single mutant fibrillin gene

Question 3

Genetic Heterogeneity

Answer 3

Production of a given trait by different mutations

Example: CharcotMarieToothdisease

Different genet mutations can cause the same disease

Question 4

Autosomal Dominant Diseases

Answer 4

Mutations affect structural or regulatory proteins
50% of offspring will inherit the gene

Reduced penetrance and variable expressivity
come into consideration
Onset of clinical features may occur latter than with autosomal recessive diseases

Question 5

AD Diseases:

Categories of Non-enzyme proteins affected

Answer 5

Proteins involved in the regulation of complex metabolic pathways, subject to feedback inhibition
Key structural proteins
Less common–gain of function mutations

Question 6

Marfan Syndrome

Answer 6

A disorder of connective tissues of the body
Manifestations occur principally in the skeleton, eyes, and cardiovascular system

Prevalence: 1in 5000
~70-85% of cases are familial

Question 7

Marfan Syndrome: Pathogenesis

Answer 7

Defect in fibrillin-1(FBN1)
Extracellular glycoprotein

Major component of microfibrils found in extracellular matrix
Acts as a scaffold on which topoelastin is deposited forming elastic fibers.

Question 8

Marfan Syndrome: Pathogenesis

Answer 8

More than 500 mutations found in the FBN1 gene
Majority are missense mutations, producing abnormal fibrillin

Mutations of the fibrillin 2 (FBN2) also occur, but are much less common
Cause congenital contractural arachnodactyly

Question 9

Penetrance

Answer 9

Percentage of individuals carrying an autosomal dominant gene and expressing the trait

With 100% penetrant diseases: if you carry the gene–you have the disease

Question 10

Marfan Syndrome: Morphology

Answer 10

Skeletal abnormalities-Tall with long extremities,
 Ratio of upper segment of body to lower segment is significantly lower than the norm

 Lax ligaments (double-jointed)
 Kyphosis, scoliosis, pectus excavatum, or pigeon-breast deformity

Question 11

Marfan Syndrome: Morphology

Answer 11

Occular changes- Bilateral subluxation or dislocation of the lens

Cardiovascular-Mitral valve prolapse, Aneurysm of ascending aorta, May become dissecting,
Dilation may involve the aortic ring causing incompetence of aortic valve

Question 12

Marfan Syndrome: Clinical Course

Answer 12

Great variation in clinical expression

Diagnosis: Look for occular, skeletal and cardiovascular changes. Look at family history

COD: 30 - 45% dissecting aortic aneurysm with
rupture through the wall Cardiac failure

Question 13

Achondroplasia

Answer 13

Short limbed dwarfism with large head size 80% of patients are new mutants

Discussed in non-neoplastic bone lecture

Question 14

Huntington Disease

Answer 14

Progressive dementia and choreic movements

Onset typically in 40’s

Covered in neuro lectures

Question 15

Split Hand Split Foot

Answer 15

Gene location: 7q21.3 - q22.1

Reduced penetrance
Variable expressivity
At least five distinct loci implicated

Question 16

Acrocephalosyndactyly (Apert Syndrome)

Answer 16

“Zero fitness”
Therefore–100% are new mutations
Associated with syndactyly of the hands and feet
“mitten hands, sock feet”
Mental deficiency, craniosynostosis, hypertelorism

Question 17

Apert Syndrome

Answer 17

Fusion of 2 fingers or 2 toes or a tab of skin representing an extra digit
Premature closure of the cranial sutures
Mutations of Fibroblast Growth Factor Receptor-2 (chromosome 10)

Question 18

Apert Syndrome

Answer 18

Fusion of 2 fingers or 2 toes or a tab of skin representing an extra digit
Premature closure of the cranial sutures
Mutations of Fibroblast Growth Factor Receptor-2 (chromosome 10)

Question 19

Tuberous Sclerosis

Answer 19

Autosomal dominate disorder

Chromosomes 9 or 16 involved
Characterized by: Seizures
Mental retardation
Sebaceous adenomas

Question 20

Tuberous Sclerosis

Answer 20

Cutaneous lesions: Angiofibromas
Leathery thickenings in localized patches (shagreen patches)
Hypopigmented areas, Subungual fibromas

Kidney:
angiomyolipoma

Question 21

Autosomal Recessive Disorders

Answer 21

Single largest category
Age of onset usually early in life
Enzyme proteins are most often affected
Both alleles at a given gene locus are mutations Complete penetrance is common
More frequent in consanguineous marriages
Expression of the defect tends to be more uniform

Question 22

Phenylketonuria

Answer 22

Deficiency of phenylalanine hydroxylase
Leads to hyperphenylalaninemia; normal at birth; (Within weeks) plasma phenylalanine inc.
brain development, mental retardation
Treatment: strict diet from birth
Diagnosis: routine screening in postnatal period

Question 23

Lysosomal Storage Diseases

Answer 23

Spingolipidoses
Mucopolysaccharidoses Mucolipidoses

Question 24

Lysosomal Storage Diseases

Answer 24

Inherited lack of functional lysosomal enzymes or proteins essential for function
Lysosomes become filled with undigested macromolecules
Normal cell function- inhibit
hepatomegaly, splenomegaly

Question 25

Sphingolipidoses

Answer 25

Tay-Sachs Disease Sandoff Disease Neimann Pick disease Gaucher’s Disease Krabbe’s Disease

Question 26

Tay-Sachs Disease GM2 Gangliosidosis: Hexosaminidase α- Subunit Deficiency

Answer 26

Deficiency of Hexosaminidase A GM2 ganglioside accumulates in many tissues Neurons in the central and autonomic nervous system and retina Most common in Jews of eastern European origin Gene location: Chromosome 15

Question 27

Tay-Sachs Disease

Answer 27

Motor/mental deterioration at ~ 6 months Death by 2-3 years Blindness Cherry red spot on retina Antenatal diagnosis and carrier detection are possible by enzyme assays and DNA- based analysis

Question 28

Tay-Sachs Disease: Morphology

Answer 28

Ballooning of neurons with cytoplasmic vacuoles, which stain positive for lipids Vacuoles are distended lysosomes filled with gangliosides Progressive destruction of neurons EM: whorled configurations within lysosomes

Question 29

Sandhoff Disease

Answer 29

Deficiency of hexosaminidase B Gene location: Chromosome 5

Question 30

Niemann-Pick Disease

Answer 30

Deficiency of sphingomyelinase Accumulation of sphingomyelin Type A -infantile form, severe neurologic involvement and marked visceral accumulations of sphingomyelin. Death (within the first 3 yrs) Type B-organomegaly without CNS involvement

Question 31

Niemann-Pick Disease

Answer 31

Type C: defects in intracellular esterification of cholesterol Accumulation of cholesterol

Question 32

Gaucher Disease

Answer 32

Most common lysosomal storage disorder A cluster of AR disorders Lack glucocerebrosidase Enzyme which normally cleaves the glucose residue from ceramide Accumulation of glucocerebrosides

Question 33

Gaucher Disease

Answer 33

Type I- Most common, ~99% in adulthood Chronic non-neuropathic form Splenic, skeletal involvement Pathologic fractures, splenomegaly shortened lifespan

Question 34

Gaucher Disease

Answer 34

Type II- Acute neuronopathic, infantile no glucocerebrosidase activity Progressive CNS involvement with death at an early age Type III- intermediate between types I and II Juvenile presentation; Progressive CNS involvement

Question 35

Gaucher Disease: Morphology

Answer 35

Accumulation of glucocerebrosides in phagocytic cells throughout the body “Gaucher cells” -in the spleen. Liver, bone marrow, lymph nodes, tonsils, thymus, and Peyer patches. Cytoplasm- fibrillary appearance, Crumpled tissue paper appearance PAS positive

Question 36

Inborn Errors of Metabolism Affecting the CNS

Answer 36

Krabbe’s Disease Metachromatic Leukodystrophy Adrenoleukodystrophy

Question 37

Krabbe’s Disease (Globoid Cell Leukodystrophy)

Answer 37

Deficiency of galactosylceramidase Required for the catabolism of galactocerebroside to ceramide and galactose Some accumulation of galactocerebroside. This is not the toxic agent. It is metabolized by an alternative pathway, generating psychosine (cytotoxic)

Question 38

Krabbe Disease: Clinical Course

Answer 38

Rapidly progressive course Onset- between 3 -6 months Survival beyond age of 2 uncommon Present with motor signs: Stiffness, weakness, problems feeding Morphology: loss of myelin & oligodendrocytes, macrophages filled with cerebroside

Question 39

Metachromatic Leukodystrophy

Answer 39

Deficiency of arylsulfatse A Accumulation of sulfitides, especially galactosyl sulfatide

Question 40

Adrenoleukodystrophy

Answer 40

Progressive disease with symptoms due to myelin loss in the CNS and PNS and adrenal insufficiency Accumulate high levels of saturated, very long chain fatty acids (VLCFA) in the brain and adrenal cortex Most common form is X-linked

Question 41

Mucopolysaccharidoses

Answer 41

``` Hurler Syndrome (MPS I H) Scheie disease (MPS I S) Hunter Syndrome (MPS II) Sanfilippo Disease (MPSIII) Morquio Disease (MPS IV) ```

Question 42

Mucopolycaccharidoses

Answer 42

A group of closely related syndromes Result from genetically determined deficiencies of certain lysosomal enzymes These enzymes are responsible for the degradation of mucopolysaccharides All -AR (exception)Hunter syndrome->X-linked recessive

Question 43

Mucopolysaccharidoses

Answer 43

they are progressive Characterized by: Coarse facial features Clouding of the cornea Joint stiffness Mental retardation

Question 44

Mucopolysaccharidoses: Morphology

Answer 44

Accumulated mucopolysaccharides are usually found in mononuclear phagocytic cells, endothelial cells, smooth muscle cells, and fibroblasts. Affected cells are distended Balloon appearance EM: minutevacuoles Hepatosplenomegaly, skeletal deformities, valvular lesions, and subendothelial arterial deposits common

Question 45

Hurler Syndrome

Answer 45

Deficiency of α-L-iduronidase Severe form Dwarfism Gargoyle facies Other Normal at birth Develop hepatosplenomegaly by age 6 - 24 months

Question 46

Hunter Syndrome

Answer 46

Mode of inheritance: X-linked recessive Milder clinical course than Hurler Syndrome Deficiency of L-iduronate sulfatase

Question 47

Glycogen Storage Diseases

Answer 47

Defects in the synthesis or catabolism of glycogen May be limited to a few tissues or more widespread

Question 48

Hepatic Forms Example: von Gierke’s disease (type I)

Answer 48

Deficiency of glucose-6-phosphatase Inadequate conversion in the liver of glucose-6-phoshpate to glucose Patient suffers hypoglycemia Hepatomegaly

Question 49

Myopathic Forms Example: McArdle’s Syndrome (type V)

Answer 49

If enzymes that fuel the glycolytic pathway are deficient, glycogen stores in the muscle increase Muscular weakness Clinical: muscle cramping after exercise and a failure of exercise-induced lactic acidosis

Question 50

Miscellaneous Example: Pompe Disease (type II)

Answer 50

Deficiency of α-glucosidase Lack of branching enzyme Associated with glycogen storage in many organs

Question 51

Alkaptonuria

Answer 51

Deficiency of homogentisic acid oxidase Blocks metabolism of phenylalanine Black urine Ochronosis -blue-black pigmentation Pigmented cartilage is readily eroded(arthrisis)