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Pathology > Ch15. Genetics-1 > Flashcards

Ch15. Genetics-1 Flashcards

1
Q

Variable Expressivity

A

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

Example: MyotonicDystrophy

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2
Q

Pleiotropism

A

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

   Skeletal, ocular, and cardiovascular problems        arise from a single mutant fibrillin gene
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3
Q

Genetic Heterogeneity

A

Production of a given trait by different mutations

Example: CharcotMarieToothdisease

Different genet mutations can cause the same disease

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4
Q

Autosomal Dominant Diseases

A

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

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5
Q

AD Diseases:

Categories of Non-enzyme proteins affected

A

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

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6
Q

Marfan Syndrome

A

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

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7
Q

Marfan Syndrome: Pathogenesis

A

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.

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8
Q

Marfan Syndrome: Pathogenesis

A

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

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9
Q

Penetrance

A

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

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10
Q

Marfan Syndrome: Morphology

A 
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
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11
Q

Marfan Syndrome: Morphology

A

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

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12
Q

Marfan Syndrome: Clinical Course

A

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

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13
Q

Achondroplasia

A

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

Discussed in non-neoplastic bone lecture

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14
Q

Huntington Disease

A

Progressive dementia and choreic movements

Onset typically in 40’s

Covered in neuro lectures

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15
Q

Split Hand Split Foot

A

Gene location: 7q21.3 - q22.1

Reduced penetrance
Variable expressivity
At least five distinct loci implicated

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16
Q

Acrocephalosyndactyly (Apert Syndrome)

A

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

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17
Q

Apert Syndrome

A

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)

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18
Q

Apert Syndrome

A

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)

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19
Q

Tuberous Sclerosis

A

Autosomal dominate disorder

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

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20
Q

Tuberous Sclerosis

A

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

Kidney:
angiomyolipoma

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21
Q

Autosomal Recessive Disorders

A

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

22
Q

Phenylketonuria

A

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

23
Q

Lysosomal Storage Diseases

A

Spingolipidoses
Mucopolysaccharidoses Mucolipidoses

24
Q

Lysosomal Storage Diseases

A

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

25
Q

Sphingolipidoses

A

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

26
Q

Tay-Sachs Disease

GM2 Gangliosidosis:
Hexosaminidase α- Subunit Deficiency

A

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

27
Q

Tay-Sachs Disease

A

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

28
Q

Tay-Sachs Disease: Morphology

A

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

29
Q

Sandhoff Disease

A

Deficiency of hexosaminidase B

Gene location: Chromosome 5

30
Q

Niemann-Pick Disease

A

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

31
Q

Niemann-Pick Disease

A

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

32
Q

Gaucher Disease

A

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

33
Q

Gaucher Disease

A

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

34
Q

Gaucher Disease

A

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

35
Q

Gaucher Disease: Morphology

A

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

36
Q

Inborn Errors of Metabolism Affecting the CNS

A

Krabbe’s Disease
Metachromatic
Leukodystrophy
Adrenoleukodystrophy

37
Q

Krabbe’s Disease (Globoid Cell Leukodystrophy)

A

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)

38
Q

Krabbe Disease: Clinical Course

A

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

39
Q

Metachromatic Leukodystrophy

A

Deficiency of arylsulfatse A
Accumulation of sulfitides, especially galactosyl sulfatide

40
Q

Adrenoleukodystrophy

A

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

41
Q

Mucopolysaccharidoses

A 
Hurler Syndrome (MPS I H) 
Scheie disease (MPS I S) 
Hunter Syndrome (MPS II) 
Sanfilippo Disease (MPSIII) 
Morquio Disease (MPS IV)
42
Q

Mucopolycaccharidoses

A

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

43
Q

Mucopolysaccharidoses

A

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

44
Q

Mucopolysaccharidoses: Morphology

A

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

45
Q

Hurler Syndrome

A

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

46
Q

Hunter Syndrome

A

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

47
Q

Glycogen Storage Diseases

A

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

48
Q

Hepatic Forms

Example: von Gierke’s disease (type I)

A

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

49
Q

Myopathic Forms

Example: McArdle’s Syndrome (type V)

A

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

50
Q

Miscellaneous

Example: Pompe Disease (type II)

A

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

51
Q

Alkaptonuria

A

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

Pathology (15 decks)

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