Ch5. Genetic Disorders Flashcards Preview

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Flashcards in Ch5. Genetic Disorders Deck (37):
1

pleiotropism

a single mutant gene may lead to many end effects

2

genetic heterogeneity

Genetic heterogeneity: mutations at several genetic loci produce the same trait

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incomplete penetrance vs. variable expressivity

seen in dominant disorders

• incomplete penetrance: individuals inherit the gene but it is not expressed
oex. 50% penetrance means that 50% of those that carry the gene expresses the trait

• variable expressivity: gene is expressed differently among individuals

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o skeletal changes (tall, thin build, long extremities, hyperextensible joints, pectus excavatum or carinatum)
o abnormal eyes (ectopia lentis, characterized by bilateral sublaxation of lens)
o cardiovascular system is vulnerable - see degeneration of elastic arteries with loss of elastic fibers and smooth muscle cells with increased risk of dissecting aortic aneurysm, dilation of aortic ring potentially leading to aortic valve insufficiency and mitral valve prolapse.

Marfan Syndrome: autosomal dominant disorder

• defect in structural proteins
• disorder of connective tissues manifested principally by changes in skeleton, eyes and cardiovascular system
• due to missense mutation of fibrillin gene (FBN1)
oFibrillin is a glycoprotein that fns as a scaffold for the alignment of elastic fibers

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• clinically disease causes hyperextensible skin that is easily traumatized and hyperextensible joints secondary to effect on joint and adjacent ligaments (seen in tissues rich in collagen such as skin, ligaments and joints) – permits grotesque contortions

Ehlers-Danlos Syndromes (EDS): autosomal dominant disorder

group of inherited CT diseases that have a common defect in collagen structure and synthesis

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Clinical manifestations of homozygous individuals have 5-6x increase in plasma cholesterol levels, skin xanthomas and coronary, cerebral and peripheral atherosclerosis at a young age.

Familial Hypercholesterolemia: autosomal dominant disorder

• most common inherited disorder (incidence 1 in 500)
• due to mutation in the low density lipoprotein (LDL) receptor on chromosome 19
• mutation results in elevated levels of cholesterol that induce premature atherosclerosis, leading to greatly increased risk of MI
• Clinical manifestations of homozygous individuals have 5-6x increase in plasma cholesterol levels, skin xanthomas and coronary, cerebral and peripheral atherosclerosis at a young age.
• defect in LDL receptor results in:
o increased plasma level of LDL due to decreased clearance
o impaired IDL transport into liver causes greater proportion of plasma IDL in precursor pool for LDL → increased synthesis of LDL
o increased LDL seen in macrophages, monocytes and phagocytes
• statinssuppress intracellular cholesterol synthesis by inhibiting the enzyme HMG CoA reductase, allowing for greater synthesis of LDL receptors

7

statin

statins suppresses intracellular cholesterol synthesis by inhibiting the enzyme HMG CoA reductase, allowing for greater synthesis of LDL receptors

- given to people with familial hypercholesterolemia

8

lysosomal storage diseases?

Tach sachs
Niemann-Pick, A/b
niemann pick C
Gaucher disease
MPS

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i. cherry-red spot due to accentuation of the macula
ii. dilated neurons with cytoplasmic vacuoles seen in CNS
iii. affected children are normal at birth, but by age 6 show progressive mental deterioration and motor incoordination. death by age 2-3 years

iv. Electron microscopy shows distended lysosomes with whirled membrane

Tay-Sachs disease (GM2 Gangliosidosis: Hexosaminidase alpha-subunit deficiency):

a.due to deficiency of hexosaminidase A- due to HEXA gene
b.leads to accumulation of GM2 ganglioside in lysosomes of CNS and retina
c.most common in Ashkenazi Jews

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c. Common features:
i. retina: cherry red spot
ii. CNS: distended neurons with foamy cytoplasmic vacuolizations
iii. reticuloendotheial system: hepatosplenomegally, lymphadenopathy, bone marrow involvement (*** note difference to Tay-Sachs***)
iv. Electron microscopy shows distended lysosomes containing lamellated figures “zebra bodies”

d. affected children are normal at birth but have symptoms by 6 months and death by age 2, along with mental deterioration

Niemann-Pick Disease, Types A and B

a. due to deficiency in sphingomyelinase which leads to accumulation of spingomyelin within the lysosomes of the CNs and reticuloendothelial system(monocytes and macrophages located in reticular CT)
b. common in Ashkenazi jews

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a. see child that presents with marked ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, psychomotor regression

Niemann-Pick Disease Type C (NPC): autosomal recessive

a. see child that presents with marked ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, psychomotor regression
b. due to defect in lipid transport

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Clinical manifestations:
i. adult hepatosplenomegaly
ii. thrombocytopenia secondary to hyperspelnism
iii. lymphadenopathy
iv. bone marrow involvement → bone pain, deformities, fractures

Gaucher Disease: autosomal recessive

a. most common lysosomal storage disorder
b. deficiency of glucocerebrosidase leads to accumulation of glucocerebroside predominantly in monocytes and macrophages of reticular connective tissue (leading to secretion of TNF and IL-1)
c. Type I is most common and seen in adulthood


Histologically: see presence of “Gaucher Cells”:
1. enlarged macrophages with fibrilary (tissue paper like) cytoplasm
2. have one or more dark and eccentrically placed nuclei

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Clinical features:
i. mental retardation, cloudy cornea
ii. hepatosplenomegaly
iii. skeletal deformities and coarse facial features
iv. joint abnormalities, cardiac lesions
v. Histologically: see “balloon cells” distended cells with clearing of cytoplasm

Mucopolysaccharidoses (MPS): autosomal recessive disorder

a. deficiencies in lysosomal enzymes required for degradation of mucopolysaccharides

14

types of glycogen storage diseases

• glycogen storage disease resulting from a hereditary deficiency of enzymes involved in synthesis or degredation of glycogen

• Hepatic forms: deficiency in hepatic enzymes results in decreased glycogen breakdown, storage in the liver and resulting hypoglycemia
o see hepatic enlargement and hypoglycemia

• Myopathic forms: enzymes that fuel glycolytic pathway are deficient, glycogen storage occurs in muscles and causes muscular weakness due to impaired energy production
o see muscle cramps after exercise, increased lactate levels after exercise

• Random: due to deficiency in alpha-glucosidase or lack of branching enzyme
o see cardiomegaly

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clinical features:
o urine that is pale yellow, but turns black on standing
o black-stained cartilage – discoloration of nose and ears
o degenerative arthritis

Alkaptonuria (Ochronosis); autosomal recessive disorder

• occurs when deficiency of homogentisic acid oxidase results in the accumulation. This homogentisic acid has affinity for CT (especially cartilage), resulting in black discoloration

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types of inversion

• Inversion: rearrangement that involves two breaks within a single chromosome with reincorportation of the inverted intervening segment
o Paracentric: involves only one arm of the chromosome
o pericentric: breaks are on opposite sides of the centromere

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isochomosomes

• Isochromosomes: formation results when one arm of a chromosome is lost and the remaining arm is duplicated resulting in a chromosome consisting of two short arms only or of two long arms

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translocations

• Translocations: a segment of one chromosome is transferred to another
o balanced reciprocal translocation: there are single breaks in each of two chromosomes, with exchange of material
o robertsonian translocation (centric fusion): a translocation b/w two acrocentric chromosomes, typically the breaks occur close to the centromeres and transfer of the segments may lead to one very large chromosome and one extremely small one – usually the small chromosome portion is lost

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Clinical findings:
o severe mental retardation
o abundant neck skin, broad short neck
o intestinal stenosis
o “mongoloid facial features” - epicanthic folds and flat facial profile
o brushfield spots: speckled appearance of iris
o Simian crease on hands
o Congenital heart defects: atriventricular canal
o umbilical hernia
o Hypotonia
o Gap between first and second toes
o *** predisposition to Leukemia

Trisomy 21 (Down Syndrome): 47 XX, XY +21
• most common of chromosomal disorders

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Clinical findings:
o prominient occiput
o mental retardation
o low set ears
o short neck
o overlapping fingers
o congenital heart defects
o renal malformations
o limited hip abduction
o rocker-bottom feet

Trisomy 18: Edwards syndrome
• rarely survive past 1 year

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• Clinical findings:
o microcephaly, mental retardation
o polydactyly
o cleft lip and palate
o cardiac defects
o umbilical hernia, renal defects
o rocker bottom feet

Trisomy 13: Patau syndrome
• rarely survive past 1 year

22

• features: congenital heart defects, abnormalities of palate, facial dysmorphism, developmental delay and T-cell mmunodeficiency and hypocalcemia

Chromosome 22q11.2 Deletion Syndrome
• features: congenital heart defects, abnormalities of palate, facial dysmorphism, developmental delay and T-cell mmunodeficiency and hypocalcemia
• DiGeorge syndrome
• velocardiofacial syndrome

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XIST gene

• XIST gene: the molecular basis of X inactivation involves this gene, whose product is a noncoding RNA that is retained in the nucleus, where it “coats” the X chromosome that is transcribed from and it initiates a gene-silencing process by chromatin modification and DNA methylation

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Laboratory studies:
o show elevated levels of FSH and LH with low levels of testosterone

Clinical findings:
o testicular atrophy, infertility due to azoospermia, eunuchoid body habitus; high-pitched voice, female distribution of hair, gynecomastia
o lower IQ
o increased invidence of DM II, mitral valve prolapse

Klinefelter Syndrome: 47 XXY

• male hypogonadism that occurs when there are two or more X chromosomes and one or more Y chromosomes
• caused by meiotic nondisjunction

mechanism: functional response to androgens is dictated by number of CAG repeats, with shorter CAG repeats the effectis more pronounced. People with Klinefelter’s X chromosome with shortest CAG repeat is preferentially inactivated – this nonrandom X inactivation leaves the allele with longest CAG repeat active and thus accounts for the hypogonadism.

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Clinical findings:
o female with no secondary sex characteristics
o short stature, widely spaced nipples
o gonadal dysgenesis with atrophic “streaked” ovaries
o primary amenorrhea and infertility
o webbing of neck, hypothyroidism, congenital heart disease


Turner Syndrome: 45 XO

• results from complete/partial monosomy of the X chromosome and is characterized primarily by hypogonadism in phenotypic females
• The second X chromosome is necessary for oogenesis and normal development of the ovary – No Barr body is present on histological examination of cells

* Single most important cause for amenorrhea *

• SHOX gene: normal males and females have two copies of this gene. Haploinsufficiency of SHOX gives rise to short stature. SHOX gene is expressed during fetal life in the growth plates of long bones.

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true hermaphroditism

• implies presence of BOTH ovarian and testicular tissue – very rare
• sometimes see testes on one side and ovary on the other
• “ovatestes” – see both ovarian and testicular tissue
• may be 46 XX, Xy or 45 X/XY mosaics

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female pseudohermaphroditism

• refers to an individual with normal female (46 XX) genetic sex; normal female internal organs and abnormal phenotypic sex due to ambiguous or virilized external genitalia
• occurs with exposure of female fetus to andrgoens in utero, by congenital adrenal hyperplasia; androgen-producing tumors (ovarian Sertoli-Leydig cell tumor) or exogenous androgens

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male pseudohermaphroditism

• normal 46XY with male gonadal and ductal sex b/c testes are present
• abnormal phenotypic sex with ambiguous or female genitalia
• testicular feminization (complete androgen insensitivity syndrome)

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Clinical manifestations:
o elongated face with a large jaw, large everted ears, macroorchidism
o later development of tremor ataxia, and parkinsonism

Fragile X syndrome:

• due to triplet NT repeat mutations so that CGG repeats hundreds to thousands of times
• mutation occurs in FMR-1 gene (familial mental retardation-1 gene) on X chromosome
• disease behaves as an X-linked dominant disease that causes mental retardation in all affected males and 50% of female carriers
• second most common genetic disease of mental retardation

molecular basis is due to loss of fn. of familial mental retardation protein (FMRP) – when there are trinucleotide repeats the DNA becomes methylated and can no longer be transcribed. FMRP is seen in the brain and testes, and is required for normal function in these sites.

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anticipation

- seen in fragile X syndrome
• Anticipation: clinicala features of this syndrome worsen with each successive generation, the mutation becomes increasingly deleterious as it is transmitted from a man to his grandsons and great grand-sons
o normal transmitting males and carrier females carry 55-200 CGG repeats, considered premutations
o affected individuals have large expansion of 200-4000 repeats, called full mutations
o full mutations arise from amplification of premutations. When permutation is passed on by a carrier female, there is a highly probability of dramatic amplifications, thus it seems that during oogenesis, but not spermatogenesis, premutations can be converted to mutations by triplet-repeat amplification

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progressive dementia and choreiform movements in middle life

Huntington Disease:
• due to CAG repeat of the Huntington gene that produces an abnormal Huntington protein which is neurotoxic and causes atrophy of caudate nucleus

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neurodegenerative disease that shows progressive bilateral loss of central vision

Leber Hereditary Optic Neuropathy:
• neurodegenerative disease that shows progressive bilateral loss of central vision
• results from problem with mtDNA

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clinical manifestations: mental retardation, short stature, hypotonia, hyperphagia, obesity, small hands and feet, hypogonadism

Prader-Willi syndrome:
• clinical manifestations: mental retardation, short stature, hypotonia, hyperphagia, obesity, small hands and feet, hypogonadism
• del (15) (q11.2q13) from paternal chromosome (maternal imprinting)

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: “happy puppets” mentally retarded, ataxic gait, seizures, inappropriate laughter

Angelman syndrome:
• clinical manifestations: “happy puppets” mentally retarded, ataxic gait, seizures, inappropriate laughter
• del (15) (q11.2q13) from maternal chromosome (paternal chromosome imprinted)

35

cardiomegally and heart failure

pompe disease - glycogen storage disease

36

A 2-year-old child is brought to the physician after having convulsions. The child has a history of failure to thrive.
Physical examination shows hepatomegaly and ecchymoses of the skin. Laboratory studies show a blood glucose level of
31 mg/dL. A liver biopsy specimen shows cells filled with clear vacuoles that stain positive for glycogen.

von gierke disease - glycogen storage disease

37

results from a deficiency of muscle phosphorylase and leads to muscle cramping.

McArdle disease - glycogen storage disease