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Dominant Negative
Heterozygote produces a protein that prevents the normal protein from functioning
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Linkage Disequilibrium
alleles at linked loci occur together more frequently than expected (measured in a population, NOT a family)
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Locus Heterogeneity
mutations at different loci can result in similar phenotypes
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allelic heterogeneity
different mutations at the same locus can produce the same phenotype
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uniparental disomy
euploid and often results in a normal phenotype
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heterodisomy
meiosis I error
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isodisomy
meiosis II error or postzygotic chromosomal duplication of one chromosome and loss of the other
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Pleiotropy
multiple seemingly unrelated effects
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XLR Disorders
- Oblivious (Ornithine Transcarbamylase Def)
- Females (Fabry Dx)
- Will (Wiskott-Aldrich)
- Often (Ocular Albanism)
- Give (G6PD Def)
- Her (Hunter)
- Boys (Bruton Agammaglobulinemia)
- Her (Hemophilia A&B)
- XLDs (Lesch-Nyhan Syndrome & Duchenne/Becker Musculodystrophy)
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Huntington (gene)
CAG repeats on chromosome 4
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Fragile X (gene)
CGG repeats on X chromosome
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Myotonic Dystrophy (gene)
CTG repeats on chromosome 19
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Friederich Ataxia (gene)
GAA on chromosome 9
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McCune-Albright Syndrome
1. Inheritance
2. Mutation
3. Presentation
- 1. Mosaicism
- 2. GNAS
- 3. unilateral cafe-au-lait spots with ragged edges, polyostotic fibrous dysplasia, endocrinopathy, ↑IL-6
- ** can be lethal if occurs before fertilization
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Prader-Willi Syndrome
1. Inheritance
2. Mutation
3. Presentation
- 1. Maternal Imprinting
- 2. Maternal Ch.15 is silent, Paternal is deleted
- 3. Hyperphagia, obesity, intellectual disability, hypogonadism, hypotonia
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Angelman Syndrome
1. Inheritance
2. Mutation
3. Presentation
- 1. Paternal imprinting
- 2. paternal ch.15 is silent, maternal is deleted
- 3. inappropriate laughter, seizures, ataxia, severe intellectual disability
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Hypophosphatemic Rickets
1. Inheritance
2. Mutation
3. Presentation
- 1. XLD
- 3. Increased Phosphate wasting at proximal tubule
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Fragile X Syndrome
1. Inheritance
2. Mutation
3. Presentation
- 1. XLD
- 2. Trinucleotide Repeat (CGG)
- 3. intellectual disability, long face, large chin, post-puberty macroorchidism, large everted ears, autism, and mitral valve prolapse
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Alport Syndrome (inheritance)
XLD
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Mitochondrial Myopathies
1. Inheritance
2. Mutation
3. Presentation
- 1. Mitochondrial
- 2. Ox Phos Failure
- 3. Myopathy, Lactic Acidosis, CNS Dx, and Ragged Red Fibers
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Cystic Fibrosis
1. Inheritance
2. Mutation
3. Presentation
- 1. AR
- 2. CFTR (Ch.7) ΔF508
- 3. Recurrent pulmonary infections, pseudomonas, chronic bronchitis, bronchiectasis, opacification of sinuses, pancreatic insufficiency, malabsorption, biliary cirrhosis, liver disease, meconium ileus, male infertility, female subfertility
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Duchenne MD
1. Inheritance
2. Mutation
3. Presentation
- 1. XLR
- 2. Frameshift/Nonsense Mutation in DMD
- 3. myonecrosis, pelvic girdle - superior progression, pseduohypertrophy, dilated cardiomyopathy, ↑CK and Aldolase
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Becker MD
1. Inheritance
2. Mutation
3. Presentation
- 1. XLR
- 2. Non-frameshift deletions
- 3. less severe presentation of DMD
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Myotonic Type 1
1. Inheritance
2. Mutation
3. Presentation
- 1. AD
- 2. CTG repeat in DMPK (myotonin PK)
- 3. myotonia, muscle wasting, cataracts, balding, and gonadal atrophy
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Down Syndrome
1. First Trimester
2. Second Trimester
- 1. nuchal translucency, hypoplastic nasal bone, ↓PAPP-A and ↑βhCG
- 2. ↑βhCG, ↑ Inhibin A, ↓αFP and ↓ estriol
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Edwards Syndrome
1. Chromosome
2. Presentation
3. 1st Trimester
4. 2nd Trimester
- 1. 18
- 2. prominent occiput, rocker-bottom feet, intellectual disability, clenched fists with overlapping fingers, low set ears, micrognathia, congenital heart disease
- 3. ↓ PAPP-A and βhCG
- 4. ↓ βhCG, Inhibin A, αFP, and estriol
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Patau Syndrome
1. Chromosome
2. Presentation
3. 1st Trimester
- 1. 13
- 2. intellectual disability, rocker-bottom feet, micropthalmia, microcephaly, cleft lip/palate, holoprosencephaly, polydactyly, cutis aplasia, congenital heart disease
- 3. ↓ PAPP-A and βhCG
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Chromosome 4
ADPKD (PKD2), Achondroplasia, Huntington Disease
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Chromosome 5
Cri-du-chat, FAP
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Chromosome 6
Hemochromatosis (HFE)
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Chromosome 7
Williams Syndrome & Cystic Fibrosis
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Chromosome 9
Frederich Ataxia
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Chromosome 11
Wilms Tumor, β-globin gene defects (sickle cell and βthal), and MEN1
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Chromosome 13
Patau Syndrome, Wilson Disease, Rb, BRCA2
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Chromosome 15
Prader-Willi, Angelman Syndrome, Marfan Syndrome
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Chromosome 16
ADPKD (PKD1), α-globin gene defects
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Chromosome 17
Neurofibromatosis 1, BRCA1, and p53
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Chromosome 21
Down Syndrome
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Chromosome 22
Neurofibromatosis 2 & DiGeorge Syndrome (22q11)
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Chromosome X
Fragile X Syndrome, X-linked agammaglobulinemia, and Klinefelter's Syndrome (XXY)
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Cri-du-chat
microcephaly, intellectual disability, high-pitched cry, epicanthal folds, VSD
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Williams Syndrome
elfin face, intellectual disability, hypercalcemia, well-developed verbal skills, stranger friendly, cardiovascular problems
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PKU
1. Inheritance
2. Enzyme
3. Presentation
- 1. AR
- 2. Phenylalanine Hydroxylate or BH4
- 3. Tyrosine becomes essential because it cannot be produced from Phe, Intellectual disability, growth retardation, seizures, fair skin, pallor in LC, NucDors, and SN, eczema, and musty body odor
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Alkaptonuria
1. Inheritance
2. Enzyme
3. Presentation
- 1. AR
- 2. Homogentisate Oxidase (Tyr → Fum)
- 3. accumulation of homogentisic acid in tissue (blue black deposits) also joint pain
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Homocystinuria
1. Inheritance
2. Presentation
3. Enzymes
- 1. AR
- 2. ↑ homocysteine in urine, osteoporosis, marfanoid, ocular changes (down/in subluxation), cardiovascular effects, kyphosis, and intellectual disability
- 3. Cystathionine Synthase Deficiency (↑cysteine, B6, B12, and folate)
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Type 1 GSD (Von Gierke Dx)
- G6Pase def
- fasting hypoglycemia, hepatomegaly, ↑blood lactate, and hyperuricemia
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Type II GSD (Pompe Dx)
- Lysosomal α-1,4-glucosidase
- Hypertrophic cardiomyopathy, hypotonia, exercise intolerance, early death
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Type III GSD (Cori Dx)
- Debranching Enzyme
- milder form of Von Gierke with normal blood lactate levels and accumulation of limit dextrans in cytosol
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Type IV GSD (McArdles)
- glycogen phosphorylase
- increased glycogen in muscles, cramps, myoglobinuria with exercise, arrhythmia, and second wind phenomenon
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Hexosaminidase A (GM2 ganglioside)ARneurodegeneratioin, cherry red spot, developmental delay, lysosomes with onion skin, no hepatomegaly
Tay Sachs
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α-galatosidase A (Ceramide Trihexoside)XLRperipheral neuropathy, angiokeratomas, hypohidrosis, progressive renal failure and CV Dx
Fabry Dx
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Arylsulfatase A (Cerebroside Sulfate)ARdemyelination, ataxia, and dementia
Metachromatic Leukodystrophy
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Galactocerebrosidase (Galactocerebroside, Psychosine)ARperipheral neuropathy, developmental delay, optic atrophy, globoid cells
Krabbe Dx
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Glucocerebrsidase
AR
Hepatosplenomegaly, pancytopenia, osteoporosis, avascular necrosis of femur, bone crises, and gaucher cells
Gaucher
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Sphingomyelinase
AR
Neurodegeneration, Hepatosplenomegaly, Foam Cells, and Cherry Red Spot
Niemann Pick
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α-L-iduronidase (Heparan sulfate and dermatan sulfate)
AR
developmental delay, gargoylism, airway obstruction, corneal clouding, hepatosplenomegaly
Hurler Syndrome
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Iduronate Sulfatase (Heparan/Dermatan Sulfate)
XLR
aggressive behavior and no corneal clouding
Hunter
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