Friggin' Genetic Disorders Flashcards
What chromosome is affected in CF?
7q31.2
symptoms of CF
lung disease, pancreatic insufficiency, steatorrhea, intestinnal obatruction, male infertility
what population is affected by cf
caucasians
What population is affected by PKU
caucasians, from scandinavian descent, not AA or jewish
What are characteristic symptoms are found in patients with PKU
mousy/musty odor in urine
severe mental retardation and hypopigmentation hair and skin, eczema
What enzyme is affected in phenylketonuria
phenylalanine hydroxylase
What enzyme is affected in tay sachs disease
hexoadminidase
What diseases are Autosomal dominant
huntington disease, Marfan syndrome
Autosomal recessive diseases
CF, sickle cell disease
X linked recessive diseases
hemophilia, Fabry disease
X linked dominant disease
fragile X syndrome
codominant eamples
ABO blood group, alpha -1 antitrypsin deficiency
Mitochondrial inheritance disease example
Leber hereditary optic neuropathy
What enzyme is affected in galactosemia
Galactose 1 phosphate uridyltransferase def
What happens in alpha 1 antitrypsin deficiency
unable to inactivate neutrophil elastase in lung, leads to emphysema from a failre to inactivate a tissue damaging substrate
What is the disease mechanism in Familial hypercholesterolemia
decreased synthesis/function of LDL receptor
What is the structure alteration in Thalassemias
mutation in globin gene affects amount of globin chains synthesized
What is affected by antimalarial primaquine
G6PD, leads to severe hemolytic anemia
What chromosomes are affected in Marfan syndrome
15Q21.1
5Q23.31 (less so)
What genes are affected in Marfan syndrome
FBN1
FBN2 (less so)
What is the mechanism of Marfans’ syndrome
loss of fibrillin leads to loss of structural support in microfibril rich connective tissue, and TGF-B is activated excessively
What syndrome tends to have subluxation/dislocation of the lens?
Marfan syndrome
What is the mechanism of EDS
defect in synthesis/structure of fibrillar collagen
What is a unique feature of EDS compared to Marfans
Skin is stretchable, fragile, and vulnerable to trauma. Leads to internal complications such of rupture of colon and large arteries.
Class I/II inheritance pattern
autosomal dominant
Classic I/II clinical findings
skin and joint hypermobility, atrophic scars, easy bruising
Classic I/II Gene defects
COL5A1, COL5A2
Vascular (IV) clinical findings
thin skin, arterial/uterine rupture, bruising, small joint hyperextensibility
Vascular IV inheritance pattern
Autosomal dominant
Vascular IV gene defects
COL3A1
Kyphoscoliosis VI clinical findings
hypotonia, joint laxity, congenital scoliosis, ocular fragility
Kyphoscoliosis VI inheritance pattern
Autosomal recessive
Kyphoscoliosis VI gene defects
Lysyl hydroxylase
Clinical finding in familial hypercholesterolemia
Tendinous xanthomas, increased plasma cholesterol levels, increased risk of MI
What is primary accumulation in lysosomal storage Dzs
catabolism of substrate of missing enzyme is incomplete, so it accumulates within the lysosome
What are the 2 general approaches to treat lysosomal storage diseases
Enzyme replacement therapy
Substrate reduction therapy
What is the most common form of GM2 gangliosidosis
Tay Sachs disease
What chromosome is affected in tay sachs disease
Chr 15, in alpha subunit locus.
What does Tay Sachs disease manifest with
severe deficiency of hexosaminidase A
What population is affected in Tay Sachs disease
Ashkenazi Jews (Eastern european)
What are the clinical manifestations of Tay SWachs disease
cherry red spot in macula
6 mo motor and mental deterioration, obtunded, flaccidity, blindness and dementia
1-2 yo vegetative state, 2-3 death
Where does GM2 ganglioside accumulate
neurons, retina, heart, liver, spleen
What tests determine if GM2 ganglioside accumulations are present
fat stains oil red O
Sudan black B positive
What causes Niemann-Pick DZ
lysosomal accumulation of sphingomyelin due to inherited deficiency of sphingomyelinase
What population is affected by Niemann Pick DZ
Ashkenazi Jews, AR
What chr is affected in Niemann Pick DZ
Chr 11p15.4 (expressed more on maternal part)
What is the most severe form of Niemann Pick DZ
Type A, severe infantile form.
Clinical manifestations of Niemann Pick DZ type A
extensive neuro involvement, mkd visceral accumulations of sphingomyeline, progressive wasted, symptoms by 6mo, death b4 3 yo
Clinical manifestations of Niemann Pick DZ type B
organomegaly, No CNS involvement, reach adulthood
Clinical manifestation of Niemann Pick DZ type C
Most common, affects NPC1. Progressive neurological damage, ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, psychomotor regression
Morphology of Niemann Pick DZ (histo)
zebra bodies, massive splenomegaly,
Gaucher Dz affects
glucocerebrosidase mutation
Etiology of Gaucher DZ
accumulation of glucocerebroside, activation of macrophages so that IL-1, IL-6 and TNF are released
What are the manifestations of Type 1 gaucher dz
No CNS involvement, spleen and bone sx, slt & slt life span
What population is affected in Type IGaucher DZ
European Jews
Clinical manifestations of Type II lysosomal storage
infantile cerebral pattern, progressive CNS invovlement, early death, hepatosplenomegaly
What population is affected in Type II gaucher DZ
Not jewish europeans
Clinical manifestations of Type III Gaucher DZ
systemic involvement with progressive DNZ dz, begins in adolescence/early adulthood
Morphology of Gaucher DZ
distended phagocytic cells in liver/spleen or BM, which leads to bone erosion, typically see cells that look like crumpled tissue paper.
Spleen is huge.
Treatement of Gaucher DZ
allogeneic hematopoietic stem cell transplant; recombinant enzyme replacement
What is affected in Mucopolysaccharidoses
enzymes degrading glgycosaminoglycans are deficient
Inheritance pattern of MPS
autosomal recessive, except Hunter, which is X linked recessive
Clinical manifestations of MPS
coarse facial features, clouding of the cornea, joint stiffness, mental retardation
Clinical manifestation of Hurler syndrome
hepatosplenomegaly by 6-24 mo, death 6-10 yo, cardiovascular complications, growth retardation, coarse facial features, skeletal abn
Clinical manifestation of Hunter syndrome
MPS II, No corneal clouding, milder clinical course
Morphology of MPS
in mononuclear phagocytic cells, endothelial cells, have balloon cells that have a clear cytoplasm and multiple vacuoles with swollen lysomsomes. Lamellated zegra bodies.
Enzyme deficiency in Von Gierke
glucose 6 phosphatase
Clinical features of Von Gierke
failure to thrive, hepatomegaly, renomegaly, hypoglycemia, hyperlipidemia, bleeding tendency
Pompe disease enzyme deficiency
lysosomal acid maltase
clinical features of pompe disease
massive cardiomegaly, muscle hypotonia, cardiorespiratory failure
Enzyme deficiency in McArdle dz
muscle phosphorylase
Clinical manifestation of McArdle
cramps after exercise, no increased blood lactate after exercise
Morphology of pompe dz
glycogen filled myocardial cells
What is an example of multifactorial inheritance?
cleft lip, cleft palate, and neural tube defects
What is a ring chromosome
break of chr occurs at both ends of the chr, with fusion of the damaged ends.
What is paracentric inversion
inversion involving only one arm of the chromosome
What is pericentric inversion
breaks are on opposite sides of centromere
What is isochromosome
When one arm of the chromosome is lost, so the remaining arm is duplicated. Means you have two short arms only or two long arms only.
What is robertsonian translocation
translocation between 2 acrocentric chromosome, breaks are closer to the centromeres of each chromosome.
What is Trisomy 21 generally caused by
robertsonian translocation
What influences trisomy 21
Robertsonian translocation
Maternal age
What are the clinical manifestations of trisomy 21
flat facial profile, oblique palepebral fissures, epicanthic folds. IQ of 25-50. Congenital heart disease, and have an increased risk of developing acute leukemia.
What kind of immune response do patients with trisomy 21 have
abnormal one, predisposes them to serious infections of lungs and thyWroid autoimmunity
What chromosome is affected in Edward’s syndrome
18
Clinical manifestations of Edwards syndrome
low set ears, overlapping fingers, congenital heart defects, micrognathia, prominent occiput
What chromosome is affected in Patau’s syndrome
13
Clinical manifestations of Patau’s syndrome
Microphthalmia, polydactyly, microcephaly, cleft lip and palate, renal defects
What chromosomal deletion can lead to DiGeorge Syndrome and Velocardiofacial syndrome
22q11.2
Clinical manifestations of DiGeorge syndrome
thymic hypoplasia, T cell immunodeficiency, parathyroid hypoplasia (leads to hypocalcemia, cardia malformations and mild facial anomalies)
Clinical manifestations of Velocardial syndrome
facial dymorphism, prominent nose, cleft palate, cardiiovascular anomalies and learning disabilities
What is CATCH 22 for DiGeorge syndrome
Cardiac abnormality abnormal facies thymic aplasia cleft palate hypocalcemia
What is lyonization
X chromosome is compacted to make a Barr Body, which makes it inactive.
What increases the likelihood of mental retardation
of X chromosomes
Chromosomal abnormalities associated with Klinfelter syndrome
XXY
Clinical manifestations of Klinefelter syndrome
eunuchoid body habitus with long legs, small atrophic testes and small penis, gynecomastia, lower IQ.
Increased risk of Type 2 DM and metabolic syndrome, mitral valve prolapse. Leads to male infertility and increased risk of breast cancer.
Chromosomal abnormality of Turner syndrome
complete/partial monosomy of X chr.
Clinical manifestations of turner syndrome
cystic hygroma, swelling of nape of neck due to lymph stasis. congenital heart disease, cardiovascular abnormalities, short stature, cubitus valgus, amenorrhea, hypothyroidism, glucose intolerance, obesity and insulin resistance.
What kind of ovaries are found in patients with Turner syndrome
Fibrotic ovaries
What gene and locus are affected in Fragile X syndrome
FMRI and X27.3
What gene and locus are affected in Huntington disease
HTT and 4p16.3
What trinucleotide repeat is in Fragile X syndrome
CGG
What trinucleotide repeat is in Huntington disease
CAG
What is a morphological hallmark of trinucleotide repeat mutations
accumulation of aggregated mutant proteins in large intranuclear inclusions
Clinical manifestations of Fragile X syndrome
long face with a large mandible large everted ears large testicles hyperextensible joints high arched palate mitral valve prolapse
What is anticipation
clinical features of fragile X syndrome worsen with each successive generation, and mutation becomes worse with each generation as it is passed on.
What defines carrier males of Fragile X syndrome
20% of males who carry Fragile X mutation but are clinically and cytogenetically normal. Transmit trait through all phenotypically normal daughters to affected grandchildren.
How many females are affected in fragile X syndrome
30-50 percent of carrier females are affected.
What is huntington’s disease characterized by
autosomal dominant disease, that has progressive movement disorders/dementia.
What is huntington’s disease caused by
degeneration of striatal neurons. Fro polyglutamine trinucleotide repeat expansion disease.
What is the threshold effect
minimum number of mutant mtDNA that must be present in a cell/tissue before oxidative dysfunction gives rise to disease
What is an example of a mitochondrial gene disorder
Leber hereditary optic neuropathy
Clinical manifestations of Leber hereditary optic neuropathy
bilateral loss of central vision, started between ages 15 and 35. Leads to eventual blindness. Cardiac conduction and minor neurologic manifestations may also occur.
What is the chromosomal abnormality of Prader-Willi syndrome
Imprinting of paternal allele. Interstitial deletion of band q12 in long arm of chromosome 15.
Chromosomal abnormality of Angelman Syndrome
Imprinting of maternal allele
Clinical manifestations of Prader-Willi syndrome
mental retardation, short stature, hypotonia, profound hyperphagia, obesity, small hands and feet, hypogonadism
Clinical manifestations of Angelman syndrome
mentally retarded, ataxic gait, seizures, and inappropriate laughter. Happy puppets.
