Chapter 5: Genetic Disorders Flashcards
1
Q
- List and discuss the three broad categories of human genetic disorders.
A
1. Mutations in a single gene with large effects (Mendelian disorders)
2. Chromosomal disorders
3. Complex multigenic disorders
2
Q
- List and discuss the three broad categories of human genetic disorders.
[mutations in a single gene]
Description:
Common:
Penetrance:
Example:
A
- Mutations with single genes are called Menelian disorders. They have:
- large effects
- rare
- high degree of penetrance.
- An example would be: Sickle cell anemia is prominent in the African-American community and has malaria maintains the mutation in the population.
3
Q
- List and discuss the three broad categories of human genetic disorders.
Chromosomal disorders
Description:
Common:
Penetrance:
A
Chromosomal disorders are structural or numerical alterations in autosomes and sex chromosomes. They are:
- Uncommon
- High penetrance
4
Q
- List and discuss the three broad categories of human genetic disorders.
Complex multigenic disorders
Description:
Common:
Penetrance:
A
Complex multigenic disorders (polymorphic disorders) are caused by multiple interactions between the environment and genes. They are multi/polygenic: maning that each different gene has a small increase in disease risk but no single gene is necessary and sufficient to produce the disease. They are:
More common
Low penetrance
5
Q
What are examples of complex multigenic disorders?
A
- 1. Atherosclerosis
- 2. DB
- 3. HTN
- 4. Autoimmune diseases
- 5. Height and weight
6
Q
What is a mutation?
A
permanent change in the DNA
7
Q
- Germ cells mutations give rise to
- Somatic cells give rise to
A
- Germ cells sex cells) mutations give rise to inherited dz
- Somatic cells give rise to cancer & some congenital malformations
8
Q
What are point mutations and what types are there?
A
Point mutations are changes in which a single base is substituted with another base IN a CODING sequence.
-
Missense: change the meaning of squence in protein.
- Acid -> base
- Nonsense: AA substitution results in a stop codon (chain terminator)
9
Q
Point mutations can be divided into missense mutations or nonsense mutations.
What is an example of both?
A
- Missense mutation: Sickle cell changes [glutamic acid -> valine] in a B-globulin chain of Hb.
- Nonsense mutation: β0 -thalassemia is a point mutation affecting the codon for glutamine (CAG) creates a s_top codon (UAG)_ if U is substituted for C => deficiency of β-globin chains
10
Q
- Discuss the effect of mutations involving noncoding sequences.
A
Mutations in non-coding sequence can alter promotor or enhancer regions .
- May interefere with binding of transcription factors => reduction or total loss of transcription
Mutaion in non-coding sequences can also cause defects of splicing in intervening sequences.
- Causes fa_ilure to form mRNA=_> cannot translate into protein
11
Q
What transcription factors should we be aware of when a mutation occurs in non-coding sequences?
A
1. MYC
2. JUN
3. p53
12
Q
- Describe and discuss the two effects on protein encoding associated with deletions and insertions (figure 5-2, 5-3, and 5-4).
A
Deletions and insertion can alter the reading frame of a protein.
Non-frameshit mutation: 3/multiple of 3 base pairs are deleted or inserted, the reading frame will remain intact -> abnormal protein gaining/lacking 1 or more AA will be made.
Framshift mutation: if the number of bases deleted/inserted is not a multiple of 3
13
Q
- What is trinucleotide repeats (figure 5-23).
A
-
Tri-nucleotide repeats is an amplification of a sequence of 3 nucleotides, almost always containting C & G.
- Tri-nucleotide repeats undergo anticipation: as the genetic order is passed onto generations, the symptoms more severe and m_ore apparent at an earlier age_ with each generation
- Ex. Huntingtons or myotonic drystophy
14
Q
Cystic fibrosis is an example of what kind of mutation?
A
Non-frameshift mutation: 3-base deletion in the CF allele that causes lack of AA 508 (phenylalanine)
15
Q
Anticipation is seen in which of the following?
A. Frameshift mutation
B. Non-framshift mutations
C. Tri-nucleotide repeats
D. Mutations with noncoding sequences
A
C. Tri-nucleotide repeats
Anticipation: as a genetic disoder that is passed on to the next generation, the symptoms become more apparent at an earlier age and more severe.
16
Q
What disorders show anticipation?
A
1. Huntingtons Disease
2. Myotonic dystrophy
17
Q
What type of mutation is the Tay-Sachs disease, often seen in Ashkenazi Jews?
A
Frameshift mutation: insertion of 4 bases (TATC) on hexosaminidase A gene.
18
Q
What leads to the O allele in ABO blood typing?
A
Frameshift mutation: deletion of 1 base (G of valine)
19
Q
- Define “de novo” as related to genetic mutations.
A
It is estimated that every individual is a carrier of 5 to 8 deleterious genes, most that are recessive and have no serious phenotypic effects.
- About 80% to 85% of these mutations are familial.
- The remainder represents new mutations acquired de novo by an affected individual.
20
Q
Mendelian disorders can be described in terms of:
1. Codominance
2. Pleitropism
3. Genetic heterogeneity
A
-
Codominance: both alleles contribute to the phenotype
- Ex. AB blood type
- Pleiotropic: mutation of 1 gene => has many phenotypic affects
- Genetic heterogeneity: mutations at several loci produce the SAME phenotype.
21
Q
- For the autosomal dominant disorders listed in table 5-1, discuss the following;
- manifestation,
- chance of inheritance,
- new mutations
- penetrance
- expressivity
A
- Manifestion: Heterozygous state (only 1 gene is affected so 1 parent most often affected). However, in every autsomal dominant disorder, there is a prop of pts whose parents do have the disorder.
- Chance of inheritance: Age of onset is delayed in many AD conditions, meaning sx appear in adulthooD!
-
New mutations:
- With every autosomal dominant disorder, some proportion of patients do not have affected parents. Such patients get the disorder d/t new mutations that involve either the egg or the sperm from which they were derived. Their siblings are neither affected nor at increased risk for disease development.
- How the disease affects the reproductive fittness determines who develops the disease as a result of a new mutation
- When a disease causes low reproductive fitness => most cases of the disease arise from new mutations that occur in germ cells of relatively older fathers
-
PResentations in Autosomal Disorders can vary d/t variations in penetrance and expressivity.
-
Penetrance:
-
Incomplete penetrance: Pt has the mutation, but are phenotypically normal
- Ex. 50% penetrance meants that 50% who carry genes express the trait
-
Incomplete penetrance: Pt has the mutation, but are phenotypically normal
-
Expressivity:
- Expressivity can vary: All of those + for the trait can express it differently
-
Penetrance:
22
Q
Autosomal dominant disorders
Loss of function mutations:
Gain of function mutations:
A
Loss-of function mutations: more common in AD disorders
- Result in: decreased production of a gene or decreased activity of a protein.
- Ex. Familial hypercholesterolemia
Gain of function: less common
- Cause disease by giving gene toxic properties or increasing normal activity.
- Ex. Huntingtin protein toxic to neuron
- SN: Huntinging trinucleotide repeat that shows anticipation and gain of function
23
Q
As mentioned, most Autosomal Dominant mutations are loss of function.
What are the 2 main patterns we see?
A
- Mutations in structural proteins, like collagen and cytoskeleton elements of RBC
- Mutations in metabolic pathways, subject to feedback inhibition.
Age of onset is delayed in many AD conditions, meaning sx appear in adulthooD!
24
Q
What does a pedigree for somone with an autsomal dominant mutation look like?
A
- If the parent is heterozygous or the trait: will pass down to 50% of children (M or F).
- If the mutation is spontaneous (new), parents are not affected and will affect 25% of children.
If dominant: will not skip a generation
If automal: will affect M and F equally
25
What are the 4 diseases that are **autosomal dominant** and affect the **nervous system**? (hint: there is a mnemonic)
1. - Tuberous sclerosis
2. - Myotonic dystrophy
3. - Huntington disease
4. - Neurofibromatosis
## Footnote
**Touch My Hurt Nerves**
26
What is the largest category of genetic disorders?
**Autosomal recessive disorders**
27
**Autosomal recessive disorders**
1. Manifestation
2. Chance of inheritance
1. Manifestations: homozygous; both alleles are mutated; parents are not usually affected
2. Chance of inheritance
1. Siblings have a 25% chance of inheritance
2. If the mutation does not occur commonly in the population, there is a strong liklihood of consanguineous marriage.
28
How are AR and AD disorders different from one another?
In AR:
**New mutations:**
**Expressivity:**
**Penetrance**
**Onset:**
1. New mutations are rarely detected (would occur after several generations
2. Expressivity is more uniform
3. Complete penetrance
4. Onset is early in life
29
Autosomal recessive disorders usually involve mutations of \_\_\_\_\_\_.
**Enzymes (inborn errors of metabolism);** activity of normal enzyme is decreased or the enzyme is is defected
30
**Cystic fibrosis (aka)**
Transmission pattern:
Mutation:
**_CF= MUCOVISCIDOSIS_**
## Footnote
**Transission pattern:** Autosomal recessive.
**Mutation:** Non-frameshift 3 base deletion (AA 508;
Phenylalanine) mutation CF allele on CFTR (cystic fibrosis transmembrane regulator) gene on chromosome 7, q31.2=\> causing abnormal function of Cl- channel
31
**Cystic fibrosis:**
Effect:
Main cause of death:
**Effect**: (Cl-) cannot be pumped into secretion. B/c it usually draws H20 into secretions and thins them out, this will cause thick secretions in exocrine glands and lungs, intestines and reproductive lining.
* Newborns: thick secretions will affect their meconium (first stool) =\> making it thicc and stick =\> get stuck intestines and form meconium ileus
* Eary childhood: thick secretions can cause pancreatic insufficiency because the thick mucus will block the pancreatic ducts, preventing pancreatic digestive enzymes from going into intestines =\> problem absorbing fats and proteins =\> can cause [failure to thrive, malnutrition and steatorrhea: fatty stools]
* If continue, can damage the pancrease and cause acute pancreatitis/chronic =\> develop cysts and fibrosis in the pancreas.
* Later in childhood: develop lung problems: it is hard to clear thicc mucus =\> create perffff env for bacteria (haemophilus inflenzua and pseudonomas aurginosa) =\> cough and fever
* If cant clear =\> chronic CF =\> bronchiectasis and atelactasis
* =\> overtime, it can cause respitaroy distress and COPD (LEADING COD IN CF)
* Salt-loss syndrome: acute salt depletion
**Main cause of death**: COPD (80-90% of cases)
32
Patients with **Cystic fibrosis** can get \_\_\_\_\_\_\_\_\_\_, secondary to what?
**Chronic lung disease,** secondary to:
* pancreatic insufficiency
* steatorrhea
* intestinal obstruction
* male infertility
33
**Cystic fibrosis:**
Incidence:
Manifestation appear:
**Incidence**: most common lethal genetic disease that affects whites
**Manifestations appear:** at any point in life from b4 birth -\> later in childhood and adolescence.
34
**Cystic fibrosis** is the best-known examples of what? Is this still true?
**ONE GENE -\> ONE DISEASE AXIOM;**
However, there is evidence that genes other than CFTR alter the frequency and severity of organ-specific manifestations.
35
In children with **Cystic Fibrosis,** what is the biggest thing for diagnosis at birth?
1. **Muconium ileus** prevents children from having a bowel movement. Thus, children will have abdominal distension, smelly stouls and failure to thrive/
36
**Chronic CF (sinpulomonary disease)** is manifested by what two bacteria and causes what?
**1. Haemphilus infleunza**
**2. Pseudomas aeruginosa**
**Can cause bronchiestasis and atelectasis.**
37
**What is the criteria for diagnosis of CF?**
1. 1 or more characteristic phenotypic feature
2. OR history of CF in sibling
3. OR a postitive newborn screening test
AND
1. + sweat cholide test: increased Cl- in sweat on 2 or more occasions, causing bby to taste salty
2. OR ID of 2 cystic fibrosis mutations
3. OR abnormal epithelial nasal ion transport
38
**_PKU (found in articifial sweetners)_**
Transmittion pattern:
Mutation:
* **Transmittion pattern:** Autosomal recessive
* **Mutation**: PAH (phenylalanine hydroxylase) =\> decreased of PAH =\> phenylalanine cannot convert to tyrosine & tyrosine cannot become melanin =\> hyperphenylalanemia
* High phenylalanine
* Low tyrosine and melanin
39
**_PKU_**
Effect:
Main cause of death:
Effect: High phenylalanine, low tyrosine and low melanin =\> _toxic_; _severe mental retardation_, _hypopigmentation_ of skin and hair, eczema.
* Pt will have a strong, musty odor in urine and sweat
Main cause of death: N/A
40
**_PKU_**
Incidence:
Manifestation appear:
Other:
* **Incidence**: _1 in 10K Scandanavian_ caucasians (not AA or jewish)
* **Manifestations appear:** Appears early.
* Children are normal at birth
* By 6 months, child has developed severe symptoms.
* **Other**: Tx with dietary restrictions.
41
**X-linked recessive diseas** that affects the MSK system?
**Duchenne muscular dystrophy**
42
**X-linked _recessive_ disorde**rs that affect the blood system (3 of them)?
1. **Hemophilia A and B**
2. **Chronic granulomatous disease**
3. **G6PDH defiency**
43
What **X-linked recessive disorders** affect the immune system?
**Agammaglobinemia\***
44
What 2 **X-linked recessive disorder**s affect the _metabolic system?_
**1. Diabetes insipidus\***
**2. Lesch-Nyan syndrome \***
45
What **X-linked recessive disorde**r affects the nervous system?
**Fragile X syndrome\***
46
**The most common X-linked disorders are \_\_\_\_\_\_\_.**
**_Recessive._**
## Footnote
**- Fully expressed in males because they do not have another counterpart (M are XY)**
**- Heterozygous F, on the othre hand, have another X chromosome so they usually do not express/fully express the disorder.**
47
What is the pattern of transmittance of **X-linked dominant** conditions?
Caused by **dominant alleles on X-chromosome;** there are FEW X-linked dominant disorders.
* Affected heterzygous mom -\> _passes down to 1/2 sons and 1/2 daughters_
* _Afffected dad and unaffected mom_-\> passes to ALL of his daughterss and none of his sons
48
What is an example of X-linked dominant disorders?
**Vitamin D-resistant Rickets**
49
How are **X-linked recessive disorders** expressed in M and F?
**Males**:
* Affected males are hemizygous for the disorder.
* Affected men -\> fully express disorders if they have 1 copy because the gene will not have a Y counterpart.
* Males are usually infertile; meaning that there is no Y-linked inheritance.
**Females:**
* Heterozygous females do not usually express the disease d/t a paired normal allelle.
50
**Mitochondrial Inheritance**
Tranmission pattern
**Mitochondrial DNA is only inherited from the mom.** Thus, an affected mom will pass down the gene to all of their children. However, an affected dad will NOT pass on the genes.
51
What does a mT inheritance pedigree look like?
52
**Single Gene (Mendelian )Disorders** can cause disease by what 2 ways?
Altering a single gene can cause:
## Footnote
**1. Decrease in a production of a normal gene**
**2. Forming abnormal proteins (enzymes, substrates, receptors, and structural proteins)**
53
**What are the 4 main categories of _mendelian disorders?_**
* 1. Production of defective _enzymes_ (which have decreased actiivity) or decreased production of a normal _enzyme_
* 2. _Defects in membrane receptors and transport systems_
* 3. Changes in the *structure*, *function* or *quantity* of proteins that are **NOT enzymes.**
* 4. Mutations that cause unusual reactions to drugs.
54
**Mendelian disorders can cause defects in enzymes.**
What are the **3 consequence**s and give an example of each.
1. **Accumulaton** of a _precursor_, _intermediate_ or _alternative product_ that is toxic.
1. _Ex. Galactosemia_: deficiency of galatacote-1 phosphate uridyltransferse
2. _Ex. Lysosomal storage disease;_ accumulation of substrated in lysosomes d/t a deficiency of degradative enzymes.
2. **Decreased amount of an end product**
1. _Albinism_ occurs d/t lack of tyroninase causing a decrease in melanin.
2. _Lesch-Nyhan_: decrease in end-products =\> increase in intermediate products; when they breakdown =\> TOXIC.
3. **Failure to *inactivate* a substance that damages tissue**
1. a_1-antitrypsin deficienc_y causes us to not be able to *inactivate* neutrophil elastase in lung, causing emphysema.
55
Disorders related to mutations in single genes with large effects are also called?
What is their pentrance and how common?
**- Mendelian disorders**
- Uncommon, but highly penetrant
56
Mendelian disorders can cause defects in receptors and transport systems.
## Footnote
**What are 2 examples of these?**
**1. Familial hypercholesterolemia:** decrease in synthesis/function of LDL receptor =\> defectiev transport of LDL into cells =\> secondary increase of cholesterol =\> can cause arthersclerosis and cardiac problems
**2. CF**: Cl-ion transport in exocrine sweat glands, ducts, lungs and pancrease is defective
57
Mendelian disorders can cause **changes in structure, function or quantity of non-enzyme proteins.**
What are examples of these?
* **HAVE WIDESPREAD SECONDARY AFFECTS**
* 1. **Sickle cell disease:** defect in structure of globin molecule
* 2. **Thalassemias**: mutation in globin gene =\> decrease in globin chains
* 3. **collagen** –\> osteogenesis imperfecta;
* **spectrin** –\> hereditary spherocytosis
* **dystrophin** –\> muscular dystrophies
58
**Mendelian disorders can cause adverse reactions to drugs. How?**
Silent mutations in a single gene are unmasked after we are exposed to that drug.
59
What is the most common adverse reaction to a drug?
**G6PD deficiency:** give pt antimalarial primaquine can cause severe _hemolytic anemia._
60
What disorders are associated with **defects in structural proteins?**
**1. Marfans syndrome**
**2. Ehlers Danlos syndrome**
61
**Marfan Syndrome**
Transmission pattern:
Mutation:
**Transmission pattern:** _Autosomal dominant_
**Mutation**: fibrillin-1 on the _FBN1 gene_ _on_ _Chr 15q21.1_ or _FBN2 Chr5q23.31_ (less common)
62
**_Marfan syndrome_**
Effect:
Main cause of death:
Normally fibrillin sequesters TGF-B, a growth-factor that causes tissue growth, to prevent overgrowth.
**Effect**: Decrease in # of dysfunctional fibrillin-1 =\> causes clinical manfistations via 2 mechanisms
* 1. Decreases structural support and elasticity in microfibrils of CT
* 2. TGF is not seqetered =\> high TGF-B =\> more tissue growth =\> **skeletal**, **eyes** and **heart** problems
* A. Skeletal: Tall; long arms and short legs; arachnodactaly (long digits), Pectus excavatum, flexibile joints
* B. Ocular: Ectopia lentis=\> bilateral dislocation of lens
* D. CV: aortic dissection, _mitral valve prolapse\*,_ dilation of ascending aorta
* \*=most common
* E. HIGH lung capacity; they have the lowest levels of lactate ever -\> _allowing efficient production of NRG_
**Main cause of daeth: N/A**
63
**_Marfans syndrome_**
Incidence:
**1 in 5,000; 70-85% familial passdown**
64
**_Name that disorder:_**
Heterogenous group of 6 conditions that is due to a defect in the synthesis of **fibrillar collagen in CT.**
**Ehlers-Danlos Syndrome**
65
What are the general manifestation of Ehlers-Danlos Syndrome?
Changes in skin and joints
1. **Skin** is stretchy, fragile and vulnerable to trauma. Small injuries will produce a gaping defect, making repair hard.
2. **Joints** are hypermobility =\> makes people more vulnerable to clumsiness and joint sprains/dislocations
3. Because there is a defect in CT, pts have **internal complications**:
* Vascular EDS: rupture of colon and large arteries
* Kyphoscooliosis EDS: eye is fragile: causes cornea ruptures and and retina detaches
* Classic EDS: diaphragmatic hernia
66
What are the **autosomal dominant** types of **EDS**?
**1. Classic (I/II) EDS**
**2. Vascular (IV/4) EDS**
67
What is the **autosomal recessive (AR)** types of _Ehlers-Danlos syndrome?_
What is the gene defect and clinical findings in each?
***Kyphoscoliosis (Type VI)/6 EDS** is the most common AR form*
* **Gene defect:** _lysyl hydroxylase_
* **Clinical findings**: hypotonia (low muscle tone/floppy), joint laxity, c_ongenital scoliosis, ocular fragility_ (causing the cornea to rupture and retina to detach)
68
**_Vascular (IV) EDS_**
Tranmission pattern:
Gene defects:
Clinical findings:
**Tranmission pattern:** autosomal dominant
**Gene defects:** COL3A1
**Clinical findings:** thin skin, arterial/*uterine*/*colon* rupture and easy bruising
69
**Classic (I/II) EDS**
## Footnote
Tranmission pattern:
Gene defects:
Clinical findings:
**Tranmission pattern:** Autosomal dominant
**Gene defects:** COL5A1, COL5A2
**Clinical findings:** *atrophic scars*, *easy bruising*
70
**_Familal Hypercholesterolemia_**
## Footnote
Transmission pattern:
Mutation:
**Transmission pattrn:** Autosomal Dominant
**Mutation**: LDL receptor
71
**_Familial Hypercholesterolemia_**
## Footnote
Effect:
Main cause of death:
**Effect**: Mutation of LDL receptor -\> increase in cholesterol -\> premature atherosclerosis -\> increases risk of MI
**Main cause of death: N/A**
72
**_Familial Hypercholesterolemia_**
## Footnote
Incidence:
Manifestions appear:
Other
**Incidence:**
* Heterozygotes: occur in 1/500 births;
* 1 mutant gene, with 2-3x increase of cholesterol levels,=\>
* *tendinous xanthomas, xanthelesmas, and arcus cornealis* and premature atherosclerosis
* Homozygotes: worse prognosis;
* 2 mutant genes and 5-6x increase of blood cholesterol levels =\>
* skin xanthomas coronary, cerebral, and peripheral vascular atherosclerosis at a early age; MI before 20 yo.
**Manifestions appear:** N/A
**Other**: N/A
73
If a patient comes in before 20 yo with an MI, what should we look for problems with?
**Cholesterol, vascularity, and skin xanthomas**
**=\> patient could be _homozygous_ in _familial hypercholesterolemia._**
74
**VLDLs** released by liver are rich in ______ and contain lesser amounts of \_\_\_\_\_\_\_
VLDLs released by liver are rich in **triglycerides** and contain lesser amounts of **cholesterol esters**
* **Undergo lipolysis via lipoprotein lipase-\> release TAGs -\> stored in fat cells -\> used as source of NRG in skeltal muscle**
* **-\> IDL -\> LDL**
75
Patients with ______ familial hypercholesteremia present with tendinous xanthomas. How does this process occur?
**_Heterozyous_** **familial hypercholesteremia**
* Tendinous xanthomas manifest as first, the **thickening** of, then **depostings** of cholesterol in extensor tendons.
76
**Xanthelasmas** and **arcus cornealis** are most common in ________ familal hypercholesteremia. What are these?
**Heterozygous**
* **Xanthelasmas: deposits of cholesterol around the eye**
* **Arcus cornealis: deposits of cholesterol around the cornea**
* **occur most commonly in ppl younger than 45.**
77
Mutations in the LDL receptor in familial hypercholestermia can be classified as what?
1. Synthesis in the ER (I)
2. Transport to Golgi (II)
3. Binding of apoprotein ligands (III)
4. Clusting in coated pits (IV)
5. Recycling in endosomes (V)
78
\_\_\_\_ is the major transport form of cholesterol in the plasma
**LDL**
79
Which apoprotein is found on LDL and can be recognized by the LDL-recptor for uptake/clearance by the liver?
**ApoB-100**
80
How is plasma LDL most cleared?
**Uptake by the liver**, even though most cells have high affinity receptor for ApoB-100.
81
If LDL is chemically altered, how is it taken up?
**Scavenger receptor**s on mononuclear phagocytes and other cells can uptake chemically altered LDL.
82
What disorders are associated with **defects in enzymes?**
* 1. **Lyosomal storage diseases** (Tay Sachs, Niemann Pick Disease Type A, B and C, Gaucher disease, MSP (mucopolysaccharidoses I H and II)
* 2. **Glyocogen Storage Disease** (hepatic type and miscellaneous type)
*
83
Storage diseases are also called \_\_\_\_\_\_\_.
**Thesaurismoses**
84
Lyosomal storage diseases are d/t the deficiency of \_\_\_\_\_\_\_\_\_; this can cause what?
**_lysosomal enzymes; causing the accumulation of non-metabolized substrates._**
1. **_Primary accumulation:_** breakdown of the substrate of the missing enzyme is incomplete, causing to accumulate in the lysosome -\> lysosomes become large and impair cell functions
2. **_Secondary accumulation:_** lysosome makes substances needed for autophagy. SA is a buildup of substances important in autophagy in the lysosome
85
What are the 3 general approaches to treatment of **lysosomal storage diseases?**
* 1. **Enzyme replacement therapy\***, currenltly used in many diseases
* 2. **Substrate reduction therapy**: reduce the substrate that would be degraded by the enzyme. The remaining enymze activity may be enough to catabolis and prevent build up.
* 3. Consider **molecular basis** of the deficiency: use molecular chaperones to help with mutated proteins fold normally
* Ex. Tx in Gaucher diseaes
86
How can we divide lysosmal storage diseases?
Based on the accumulated metabolite:
## Footnote
**1. Glycogenases**
**2. Sphingolipidoses (lipidoses)\***
**3. MPSs**
**4. Mucolipidoses**
87
**Storage diseases (thesaurismoses)** are most common in _________ and cause \_\_\_\_\_\_. The most common are what?
Storage diseases are most common in **children** and caues **hepatomegaly**. The most common are
* 1. **Sphingolipidoses** (Niemann-Pick, Tay-Sachs and Gaucher disease)
* 2. **Glycogen storage diseases** (von Gierke disease)
88
**GM2 gangliosidoses** are what?
What is the **most common?**
A group of 3 lysosomal storage disorders that make it hard to break out GM2 gangliosides.
## Footnote
**Tay-sachs is the most common.**
89
**_Tay Sachs Disease_**
## Footnote
Transmission pattrn:
Mutation:
**Transmission pattern**: Autosomal Recessive
**Mutation**: alpha-subunit of hexosaminidase on chromosome 15
90
**Tay Sachs Disease**
## Footnote
Effect:
Main cause of death:
**Effect**: Mutation of a_lpha-subunit of hexosaminidase on chr 15_ =\>
* Deficiency of _hexosaminidase_ =\>
* Accumulation of _GM2 gangliosides_ in neurons\*, retina, \<3, liver and spleen =\> cause motor and mental deficits
* \*neurons have the most gangliosides, so they are the cell most affected
* Obtunded, flaccid, blind and dementia
* Cherry red spot in macula
* Lipid filled cytoplasmic vacules
**Main cause of death**: death by 2-3 yo
91
**Tay Sachs Disease**
## Footnote
Incidence:
Manifestions appear:
Other
**Incidence**: Most common in Ashkenazic Jews (1 in 30 have it)
**Manifestions appear:**
* Pts are normal at birth
* 6 months: motor and mental deterioration appear
* 1-2 yo: in a vegetative state
* 2-3 yo: death
**Other:**
92
What is a **cherry-red spot in the macula** and what disorders does it occur in?
* Accumulation of lipids in retinal ganglion cells, causing them to become pale in color and swollen. This makes the red-color of the macula seem brighter.
* Occurs in: **Tay-Sachs** and **Niemann Pick A.**
93
**_Niemann Pick Dz_**
## Footnote
Transmission pattrn:
Mutation:
**Transmission pattrn:** Autosomal recessive
**Mutation**: Chr 11p15.4 of moms chromosomes d/t epigenetic silencing of dads gene.
94
**_Niemann Pick Disease_**
## Footnote
Effect:
Main cause of death:
**Effect**: mutation of _Chr 11p15.4_ =\> inherited _deficiency of sphingomyelinase_ =\> _accumulation of sphingomyelin_ in lysosome.
* C*holesterol and sphingomyelin build up* in cells, causing them to enlarge and have foamy cytoplasm\*
* =\> splenomegaly, build up also occurs in spleen, liver, LN, BM, GI tract, lungs
* *Zebra bodies form*: lysosomes with concentric lamellations
* *1/3-1/2 will have cherry red spot\**
**Main cause of death**: Those with Type A will have extensive neuro deficits and die b4 3 years old.
95
**Niemann-Pick Disease**
## Footnote
Incidence:
Manifestions appear:
Other
Incidence: Most common in Ashkenazi Jews
Manifestions appear:
Other: there are 3 types (A, B, C)
96
Which **NPD** is the most common and which is the most severe and mild?
* **Most common:** C is the most common -\> A -\> B
* **Most severe:** Type A
* **Most mild (best):** Type B
97
**_Niemann Pick Dz Type A_**
Type of mutation:
Characterstitics
**Type of mutation:** missense mutation, causing the compelte lack of sphingomyelinase
**Characteristics**: Type A is a severe infantile form of NPD characterized by sx that appear at 6months old
* e_xtensive neuro deficits_
* _visceral accumulations of sphingomyelin_
* _Progressive muscle wasting_
Patient will die before 3 years old
98
**_Niemann Pick Dz Type B_**
Type of mutation:
Characterstitics
**Type of mutation**: N/A
**Characterstitics**: organomegaly but no CNS involvement. Patients survive until childgood.
* Most mild
99
**_Niemann Pick Dz Type C (NPC)_**
## Footnote
Type of mutation:
Characterstitics
* **Type of mutation:** mutation in _NPC1_ =\> which codes for proteins that transport cholesterol from lysosome -\> cytoplasm
* **Most common**
* **Characterist**: progressive neurological damage that include ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria and psychomotor regression.
100
**Niemann Pick disease** is characterized by a **foamy cytoplasm**. What is this due to?
**Hepatocytes and kupfer cells** will have a high deposition of lipids =\> foamy vacuolated appearance.
101
At the **end stage of Niemann-Pick disease**, neurological damage in can be seen in histo by identifying what?
Blue stains in the **cerebellum** that show **lipid accumulation**
102
What disease is charcterized by a fibrillary type of cytoplasm likened to crumpled tissue paper?
Gaucher
103
**Gaucher Disease**
## Footnote
Transmission pattrn:
Mutation:
**Transmission pattrn**: Autosomal recessive (AR); most common lysosomal storage disorder
**Mutation**: mutation of _glucocerebrosidase_
104
**Gaucher Disease**
## Footnote
Effect:
Main cause of death:
**Effect**: mutation of glucocerebrosidase =\>
* accumulation of glucocerebroside phagocyte's lysosomes =\> creates lipid-laden macrophages (Gaucher cells) that enlarge and accumulate in the [liver, spleen, and BM], causing them to look like crumpled tissue paper. The phagocytes then release IL-1, IL-6, TNF
* Pancytopenia (decrease in all BCs: RCs, WCs and platelets) and hepatosplenomegaly (\>10kg) cause easy bruising and anemia
* Patient develops osteoporosis
**Main cause of death**: Death is most common in Type II (acute neuronopathic) Gaucher disease.
105
**What is the most common form of Gaucher disease?**
Affects primarily?
Found prinicipally in what population?
Affect on longevity?
* - **Type I (**chronic nonneuronopathic form) of Gaucher disease
* - **NO** involving the CNS; thus, life expentancy decreases a LITTLE
* - **Splenic** and **bone involvements** dominate this pattern
* - Found principally in **European jews**
* - Slight decrease in life-span
106
**Type II form of Gaucher disease** has what type of affect and pattern?
Glucocerebrosidase activity?
Clinical picture dominated by?
Affect on longevity?
- **Type 2 (acute neuronopathic form**) is the acute infantile cerebral pattern in **NON-JEWISH PEOPLE**
- THere is virtually no glucocerebrosidase activity in the tissues
- Hepatosplenomegaly seen, but clinical picture dominated by **progressive CNS involvemen**t, leading to death at an early age
107
Describe type 3 Gaucher Disease
**Type 3 GD (intermediate):** systemic involvement with progressive CNS disease that begins in early adolescene or early adulthood.
108
What is the morphology of Gaucher disease?
Dominant cell type visualized?
What is visualized with electron microscope?
What type of stain is positive?
- Accumulation of distended phagocytotic cells (G**aucher cells)** found in _spleen, liver, bone marrow, LN's, tonsils, thymus_, and **Peyers patches**
- Accumulation of glucocerebroside causes the cytoplasm to look like fibrillary, crumpled tissue paper.
* Rarely appear vacuolated
* Eccentric nucleus
- Periodid acid-Schiff (PAS) staining is intensely positive
109
Accumulation of Gaucher cells in the bone marrow in t**ype I disease** leads to?
Gaucher cells in BM =\> secretion of IL-1, IL-6 and TNF by macrophages =\> bone erosion, which can give rise to pathologic fractures
110
The signs and symptoms of **type I Gaucher disease** first appear when and what's involved?
Most commonly there is?
Longevity of these patients?
- In adult life and are related to **splenomegaly (\>10kg)** or **bone involvement**
- Most commonly there is **panocytopenia** or **thrombocytopenia** secondary to hypersplenism
- Progressive in the adult, but IS compatible with long life
111
In **types II and III Gaucher disease** what are the most common dysfunctions and organs involved?
- CNS dysfunction, convulsions, and progressive mental deterioration dominate
- Liver, spleen and LN's are also affected
112
What is the mainstay treatment for Gaucher disease?
1. Allogenic _hematopoetic stem cell_ transplant
2. Recombinant enzyme replacement
113
**Mucopolysaccharidoses (MPS)**
## Footnote
Transmission pattrn:
Mutation:
MPS is a group of disorders: Hunter and Hurley
* **-Transmission pattern:** All MPS disorders are _AR except Hunter syndrome, which is X-linked recessive._
* **Mutation**: Mutations are different for each type, but they affect enzymes that degrade _mucopolysaccharides (glycosaminoglycans)_
114
MPS have mutations in enzymes that degrade glycoaminoglycans (GAGs/mucopolysaccharides)
## Footnote
**Thus; what are the glycosaminoglycans that accumulate in MPSs?**
1. **Dermatan sulfate,**
2. **Heparan sulfate,**
3. **Keratan sulfate**
4. **Chondroitin sulfate**
115
* All the MPSs are classified numerically MPS I to MPS VII (7) and are inherited in a _______ fashion
## Footnote
**What is the exception?**
- AR fashion
- Exception, MPS II (Hunter syndrome), is X-linked recessive trait
* HUNTER DZ: "X-marks the spot" like a hunter"
* X-linked recessive
* No cloudy cornea because how can they shoot with one
116
In general, **MPSs** are _progrssive_ disorders characterized by?
* _Coarse facial features_,
* clouding of the cornea,
* joint stiffness,
* mental retardation
117
**MPS-I-H** is also called?
**Hurler syndrome**
118
**Hurler syndrome (MPS I-H)**
## Footnote
Defiency of what enzyme?
Appears when, cause of death and what are its affects?
What is the cause of death?
**-α-_L-_iduronidase deficiency** -\>accumations of _*mainly* dermatan sulfate and heparan sulfate_
- Hurler syndrome is one of the most severe forms
* Children at normal at birth
* 6 months-2 years: develop _hepatosplenomegaly_
* 6-10 years: death d/t _cardiovascular problems_
-Clouding of the cornea, growth is retarded, coarse facial features and skeletal deformities
119
**Hunter syndrome (MPS II)**
## Footnote
Defiency of what enzyme?
Genetics:
How is different than MPS-I-H?
X- MARKS THE SPOT: X-linked recessive; no clouding of the cornea bc how can they hunt
* **l-lduronosulfate sulfatase deficiency**-\> accumations of mainly dermatan sulfate and heparan sulfate
* **-X-linked recessive**
* **-NO corneal clouding** and a **milder** clinical course
120
How can we diagnose disorders of mucopolysaccharidoses: MPSs have what feature that is different from all other storage disorders?
**Metabolite present in urinalysis**
121
What is the **morpholgy** of MPS?
_Mucopolysaccharides will build up in:_ mononuclear phagocytotic cells, endothelial cells, smooth muscles in intestines and fibroblasts in the [liver, spleen, BM, BV and \<3] =\>
* Affected cells are called **balloon cells**: swollen with clear cytoplasm, swollen lysosomes with **PAS positive material (periodic acid schiff stain).**
* Also have **lamellated zebra bodies.**
122
What disorders have **lamellated zebra bodies?**
**1. Niemann Pick Dz**
**2. Mucopolysaccharides (MSPs)**
123
Glucose molecules in glycogen are linked together via what kind of bonds?
**α-1,4-glucoside bonds**
124
**Glycogen storage diseases** are called what?
**_Glycogenoses_**
125
What are **glycogen storage diseases (glycogenoses)?**
* Hereditary **deficiency** in one of the enzymes involved in **_synthesis_ or _degradation_ of glycogen**
* **=\> storage of normal/abnormal glycogen _mainly in liver_ or muscle.**
126
What are the 3 subgroups of **glycogenoses**?
* **1. Hepatic type:** von Gierke disease (type I)
* **2. Myopathic type:** McArdle disease (type 5)
* **3. Miscellaneous type**: Pompe disease (type 2)
127
What are the **2 glycogen storing** diseases discussed?
1. Hepatorenal **von Gierke disease (type 1)**
2. Generalized glycogenesis - **Pompe Disease (type 2)**
128
**Von Gierke disease (type I glycogenosis)** is deficiency in?
* **Characterized by?**
* **Longevity?**
**Deficiency**: Glucose-6-phosphatase (G6Pase)
* Increase glycogen in liver and decrease in blood glucose (hypoglycemia)
**Characterized by:**
* _Hepatomegaly_ and _renomegaly_ d/t accumulation of glycogen
* _Impaired gluconeogenesis_
* =\> hypoglycemia in blood, hyperlipidemia, and hyperuricemia
**Longetivity**: Most survive and develop late complications (i.e._, hepatic adenomas)_
129
In **Von Gierke disease** where does the glycogen accumulate in the liver and kidney?
- **Intracytoplasmic** and **intranuclear** accumulations in liver
- Intracytoplasmic accumulation in cortical tubular epithelial cells of kidney
130
**McArdle disease (type V)** is deficiency in?
Characterized by?
**Deficiency in:** _muscle phosphorylase (V, VI)_
**Characterized by**: Accumulation of _glycogen in skeletal muscle -\>_
* muscle weakness, cramps and no increase in lactate levels after XRCise
* muscle cramps after excercise
* blood lactate levels do not increase after excercise
131
**Pompe disease (type II glycogenosis**) is a deficiency in?
* Clinical features of this disease
* what is the most prominent clinical feature?
**Deficiency in:** _Lysosomal α-glucosidase (acid maltase_)
* Lysosomal _storage of glycogen in all organs_ (i.e., mild _hepatomegaly_ and _skeletal muscle_) but mostly in _myocardial cell_s, =\> **_massive cardiomegaly_**
* _**muscle hypotonia and cardioresporatory** failure also occur within the first 2 years of life_
* *
132
**Miscellaneous forms** of glycogenoses involve deficiencies of what?
Glycogen accumulates: \_\_\_\_\_\_\_\_\_.
Life expentence: \_\_\_\_\_\_\_\_\_\_
**Deficiency of:**
* 1. Deficiency in glucosidase (acid maltase)
* 2. Lack of branching enzyme
**Glycogen accumulates:**
* many organs
**Life expenctancy:**
* death in early life
133
What are 2 important characteristics of **complex multigenic disorders, which are _VERY common._**
1. **Multifactorial inheritance:** caused by the interaction of the environment and 2 or more genes
2. **There are a _range of levels of severi_ty**, however, _different levels of severity_ can also be d/t v_ariable expressivity and reduced penetrance_ of 1 mutation.
This is why complex multigenic disorders and mendelian are often confused.
134
What conditions are caused by **_multifactorial inheritance?_**
**_1. Cleft lip_**
**_2. Cleft palate_**
**_3. Neural tube defects_**
135
Why is it difficult to distinguish between Mendelian diseases and multifactorial diseases?
**Mulitfactorial diseases** have _a range of levels of severity_, but differeny levels of severity can also be d/t variable expressivity and reduced penetrance of 1 mutation.
136
The fact that the incidence of neural tube defects are DRAMATICALLY reduced by taking folic acid does what?
**undermines the importance of environmental contributions** to multifactorial inheritance.
137
**Euploid vs. aneuploidy?**
**Euploid** = exact multiple of the haploid number of chromosomes (23)
**Aneuploidy** _= error in mitosis or meiosis w_here cell has an abnormal number of chromosomes that is not a multiple of 23
138
Common causes of **aneuploidy** include what?
* **_Nondisjunction_**: can occur in gametogenesis, gamates have an increase or decrease in # chromosomes
* **_Anaphase lag:_** during meiosis or mitosis, one chromatid lags behind and is left out of the nucleus -\> _one normal cell and one monosomy cell_.
139
What is **mosaicism** and what cells are most commonly affected?
Errors in **mitosis** that give rise to 2 or more populations of cells, most commonly in sex chromosomes, with different genotypes, in one person.
140
What is a **ring chromosome?**
Both ends of the chromosome break, then the damaged ends fuse. If too much genetic material is lost =\> phenotypic abnormalities.
Ex. 46, XY,**r(14)**
141
What is an **isochromosome**?
**Isochromosomes** occur when 1 arm of a chromosome is lost and the remaining arm is copied, resulting in a chromosome with only 2 short arms or only 2 long arms. The genetic material in both arms is identical.
i(17q).
142
What is **translocation**?
When a segment of one chromosome is transferred to another.
143
What is a **balanced recipricol translocation?**
2 chromosomes each have a single break and then exchange material. Thus, no **genetic material is lost** and **phenotype is normal.**
144
What is a **robertsonian translocation (centric fusion)**
**Robertsonian translocations (ROBs)** are recipricol translocation between the two accentric chromosomes _that involve the short arm of one_ and th_e long arm of another._
Makes: _one abnormally large chromosome_ and a_n extremely small chromsome._ The e_xtremely small one is usually lost._ bc it as reduntant genes so loss of this =\> NL phenotype
It does not usually cause health difficulties, but can in some cases result in genetic disorderssuch as **Down syndrome and Patau syndrome.**[1] Robertsonian translocations result in a reduction in the number of chromosomes.
145
How common are **robertsonian translocations?**
occur in **1/1000** normal people
146
What is an example of a Robertsonian translocation?
**_3-4% of trisomy 21_** cases are robertsonian translocations:
* q arm of chromsome 21 is translocated to other Chr 22 or 14 =\> fetus has 46 chromosomes but 3 copies of long arm of chromsome 21, which has all the functional genes of the chromosome.
147
How can we indicate in letters **trisomy 21?**
**46, XY, der (15:21)(q10;q10), +21**
148
What is the **most common chromosomal disorder?**
It is a major cause of what?
* **Down syndrome (Trisomy 21): 1/700**
* **Mental retardation**
149
**_Trisomy 21 (Down Syndrome)_**
## Footnote
What are the genetics (mutations) we see in Trisomy 21?
1. **95% of people have a complete extra chromosome 21,** causing them to have 47 chromsomes.
1. In 95% of these, the extra chromosome is **maternal** in origin. Thus, maternal age is a STRONG incidence in Down-syndrome (older=more likely)
2. **4%** of cases receive extra chromosome from **Robertsonian translocation** of the long arm of Chr 21 -\> Chr 22 or Chr 15 that is paternally derived . Thus, maternal age is of no impact.
3. **1% are mosciacs:** have a mixture of cells with either 46 or 47 chromosomes. Sx in these people are more variable and milder
150
What clinical features do we see in people with **Trisomy 21?**
* 1. **Facial features:** Flat face, _oblique palpebral fissues_, _epicanthal folds_
* _simeon crease on_ hand (big crease that run horizontal across the palm
* 2. Severe mental retardation (80% have an **IQ between 25-50)**
* 3. **40% have congenital \<3 disease, particular endocardial cushyions**
* **more likely to get a VSD (ventricular septal defect)**
* **COD**
* 4.By 20: 10-20x increased risk of developing **acute leukemia**
* 5. By 40:almost all Down patients older than 40 have changes assx with premature **Alzheimers (neuropathogenic stages of DS)**
* 6. **Faulty immune system**: predisposes them to infections (mainly lungs) and thyroid autoimmunity.
151
What is responsible for the majority of death in [infancy and early childhood] in Down Syndrome patients?
**Congenital \<3 Disease,**
**in particular: endocardial cushions (VSD)**
152
**Trisomy 21: Down syndrome**
**Incidence:**
Trisomy 21 type: \_\_\_\_\_
Translocation type: \_\_\_\_\_
Moscaic type: \_\_\_\_\_
Incidence: 1/700
**Trisomy 21 type**: 47 **XX**, +21
**Translocation type:** 46 XX, der (14;21)(q10;q10), + 21
**Moscaic type:** _46,XX/47,XX, +21_
153
What are 2 other trisomys besides **trisomy 21?**
* **1. Trisomy 18:** Edwards syndrome
* **2. Trisome 13:** Patau syndrome
154
What are the distinctive clinical features of **Trisomy 18: Edwards syndrome?**
1. Prominent occiput
2. **Horseshoe kidney**
3. **Low set ears and short neck**
4. **Micrognathia (small jaw)**
5. **Overlapping fingers**
6. Limited hip abduction
7. Child will _die at 4 months_
155
What are the distinctive clinical features of **Trisomy 13: Pateau syndrome**?
* **1. Microcephaly (small head)**
* **2. Micropthalmia (small or missing eyeballs)**
* **3. Cleft lip and cleft palate**
* **4. Polydactyl**
* 5. Umbilical hernia
156
In all **Trisomy conditions (21, 13 and 18),** what symptoms are common?
**1. Renal malformations**
**2. Rocker-bottom feet**
**3. \<3 defects**
**4. Mental retardation**
157
What is **Chr 22q11.2 Deletion syndrome**
* Range from DiGeorge Syndrome =\> velocardial facial syndrome
* **Ch.22q11.2** deletion syndrome is a a fairly common mutation (**1/4000**) that occurs due to a deletion of _band q11.2 on the long arm of chromosome 22._
158
symptoms o**f Chr22q11.2 deletion syndrome** are often what?
* **1. Congenital heart defects (affects 2nd, 3rd and 4th brachial arches)**
* **2. Facial abnormalities**
* **3. Developmental delay**
* **4. Various degrees of T-cell immunodeficiency: funny thymus**
* **5.Hypocalcemia (d/t parathyroid hypoplasia)**
159
What are the clinical features of **DiGeorge's syndrome?**
1. - Thymic hypoplasia w/ resultant T-cell immunodeficiency
2. - Parathyroid hypoplasia giving rise tohypocalcemia
3. - Low-set ears, wide-set eyes, small jaw
160
What are clinical manifestations of v**elocardialfacial syndrome?**
1. **Facial**: Long face, prominent nose, retrognathia and cleft palate
2. **Cardiac**: CV anomalies
3. **Developmental delays**
161
What 2 genes are implicated in 22q11.2 deletion syndrome?
- **TBX1**\
- **PAX9**
162
Which are more common: genetic diseases involving autosomes or sex chromosomes?
**SEX SEX SEX**
163
**Which are better tolerated?**
Imbalances (excess or loss) of sex chromosomes or imbalance of autosomes?
**Imbalances of sex chromosomes:** thus, they are more common but better tolerated.
164
Why are abnormalities of sex chromosomes more common but better tolerated?
1. **Only 1 X chromosome is active (others undergoes lyonization)**
2. **Y chromosome carries a MODEST amount of genetic material.**
165
What is the **Lyon hypothesis?**
* Normally, there iac activation of only 1 X chromosome and **random** inactivation of 1 X chromosome (either moms or dads), forming a Barr body.
* Random inactivation of paternal or maternal X chrom occurs on/about _day 5.5 of embryonic life._
* The _inactivation of the SAME X chromosome persists in all cells_ that are derived from precursor.
166
Is there mocaicism in normal females: thus, does the lyon hypothesis hold true?
No.
**Normal females are a moscaic of two population:**
one population of cells can have inactivated maternal X chromosome and the other can have an inactivated paternal X chromsome.
167
**Barr bodies** are inactive X chromosomes that can be seen in \_\_\_\_\_\_\_\_\_\_\_\_phase nucleus as what?
**_INTERPHASE NUCLEUS_**
as a _dark staining small mass_ *that contacts the nuclear membrame*
168
Describe the genes on Barr bodies
**It was originally thought that ALL genes are inactive, however, more recent studies _show that many escape X inactivation._**
169
What determines the male sex
Presence of a **SINGLE Y chromsome**
170
In general, **sex chromosomes disorders** cause problems relating to _______________ and are first recognized at \_\_\_\_\_\_\_\_\_\_\_.
* **_Sexual development_ and _fertility_**
* **_Puberty_**
171
In males and females, the greater the number of __________ = the greater the liklihood of \_\_\_\_\_\_\_\_\_\_\_\_.
**more X chromsomes = more liklihood of mental retardation**
172
What is **Klinefelter syndrome?**
What is the most common?
* **Male hypogonadism** that occurs when a person has 2 or more X chromosomes and at least 1 Y chromosome.
* Most common: **47XXY** is seen 90% of the time
173
What is the only consistent finding in Klinefelter syndrome (XXY)?
**_Hypogonadism_**
174
Most patients with **Kleinfelter syndrome** have a distinctive body habitus characterized by?
1. _- Euchnoid (talll and thin)_
2. _- Abnormally long legs_
3. - Small testes and penis (hyopgonadism)
4. _- Feminine physique_: _gynecomastasia_ (breast tissue), n_o chest hair, fem pubic hai_r
5. _- Lack masculine secondary sexual characteristi_cs
175
You, as a doctor, should be cautious that patients with Klinefelters syndrome have **_INCREASED RISK FOR WHAT?_**
* **_1. Type 2 DM_**
* **2. 50% increased risk for _mitral valve prolapse_**
* **3. _Osteoporosis_ and _fractures_ because of hormone imbalance**
* **4. Male infertility**
* **5. _20% risk_ of breast cancer**
*
176
What is the incidence of ppl with Klinefelters syndrome?
when it is diagnosed?
**1/660** live male births but is usually not diagnosed until after puberty.
It is the **most common cause of hypogonadism** in males
177
What is the most common cause of MALE hypogonadism\>
Klinefelters
178
What is the most common sex chromosome abnormalitiy in females?
**Turner syndrome**
179
What is **Turners Syndrome?**
Turner syndrome is **hypogonadism in _phenotypic_ females** that is due to _complete or partial monosomy of X chromosome._
180
What are the 3 types of karyotypic abnormalities in **Turner syndrome?**
1. 57% of phenotypic females are **completely missing one X (45 X).**
2. **Partial monosomy** of X chromsome
3. **Mosaic (45X/46XX)**: one population with 45 X0 and another with normal or abnormal cell type
181
What mosaics can we see in Turner syndrome?
**_1. 45X/ 46XX_**
## Footnote
**2. 45X/ 46XY**
**3. 45X/47XXX**
182
What clinical manifestions do we see in people with **Turner syndrome?**
1. **Short**
2. **Infants will have cytic hygroma: l****ymphedema in the neck, hands and feet =\> causes w****ebbing of neck**
3. **Congenital \<3 disaese affects 25-50%:**
1. ****ESPPPPP **_coarctication of the aorta and bicuspid aortic valve._**
2. **\*Most common COD**
4. **Lack of secondary sex characteristics**
5. **Primary amenorrhea**
6. **Fibrotic ovaries (Streak ovaries)**** =\> infertility.**
183
Most common cause of death in children with **Turner Syndrome**
**Cardiovascular abnormalities**
184
**1/3 of causes of primary amenorrhea** is due to what?
**Turner syndrome**
185
**"Menopause BEFORE menarche"** is a common phrase for \_\_\_\_\_\_\_\_\_.
**Turner syndrome**
186
People with **Turners syndrome** also have what conditions?
1. **Hypothyroidism**: 1/2 pts will have
2. **_Glucose intoleranc_e, _obesity_, I_nsulin intolerance_ in a minority of paitents**
187
People with **Turners syndrome** often have lymphedema and webbing of the neck. How does this occur
They are born with a **cystic hygroma** (edema and swelling of the nape of the neck),
As the infant gets older, the swellling goes down but leaves bilateral neck webbing and looseness of skin on the back of the beck.
188
What are the 4 categories of **_single-gene disorders with Non-classic inheritance?_**
Diseases caused by:
## Footnote
**1. _Trinucleotides-repeat mutation_**
**2. _Mutations in mT genes_**
**3. associated wit_h genomic imprinting_**
**4. associated with _gonadal mosaicism_**
189
What is the morphologic hallmark of **tri-nucleotide repeat mutations?**
**Accumulation of mutated proteins in NUCLEUS**
190
What are the top **2 most common genetic** causes of **mental retardation**. In order.
**1. Down syndrome**
**2. Fragile X syndrome**
191
**Trinucleotide repeat mutations** is an important cause of ___________ disorders
**NEURODEGENERATIVE**
192
What disorders are caused by **trinucleotides repeats?**
**1. Fragile X syndrome**
**2. Huntingtons disease**
193
**3 principles of trinucleotide-repeat mutations:**
1. **Repeats** of trinucleotides that often have **G and C**
2**. Tendency to expand depends on the SEX** of the parent that transmits it
3. These repeats can cause:
* **_loss of funtion_ (fragile X)**
* **_toxic gain of function_ (huntingtons)**
* **t_oxic gain of function mediated by mRNA_ (fragile X tremor ataxia syndrome)**
194
What gene, locus, protein and repeat is affected in **fragile X?**
**Gene: FMRI (FRAXA),**
**Locus: Xq27.3**
**Protein: FMR-1 protein**
**Repeat: CGG**
195
**Fragile-X syndrome** is a result of what?
What type of mutation?
1. 200- 4000 **CGG** **tricnucleotide** **repeats** on the **non-coding** **part** of **FMR-1 gene** (familial mental retardation-1)
2. Occurs on the X chromosome so: **X-linked recessive**
3. **Loss-of-function** **mutation**
1. **FMR-1 gene stops functioning and is not transcribed**
196
What is the site of expansion for **Huntingtons disease?**
**CAG triplet repeats** in the **_exon_** =\> **misfolded** **expansions** of **polyglutamine**, causing a **toxic gain of function.**
197
What is the characteristic phenotype of someone with **Fragile X syndrome?**
1. - **Long face w/ large mandible**
2. - **Large everted ears**
3. - **Large testicles (_macro-orchidism_**) = most distinctive feature (90% of males)
198
How is **Fragile X Syndrome** transmitted?
1. **Carrier males** are called _normal-transmitting males._
1. They transmit the repeats to their phenotypically normal daughters with SMALL changes in repeats
2. Thus, the premutation is passed on by the carrier female =\> grandchildren
1. _During oogenesis_, premutations (silent) undergo triplet-repeat _amplification_ =\> converted to _mutations_
1. Thus, clincial presentation worsen with each generation (_anticipation_)
3. **Carrier females then affect** almost _all sons_ and _50% of daughters_
1. _30-50% of carrier females are affected and have mental retardation,_ which is higher than any other X-linked recessive disorder.
199
Describ the risk of **phenotypic effects of Fragile X syndrome**
* The risk depends on the position of the individual in the pedigree. It gets more severe in later generations (**anticipation**)
* Brothers of transmitting males have a 9% risk of MR; grandsons of transmitting males have a 40% risk.
200
IN **FRAGILE X SYNDROME,**
THE MUTATIONS BECOME _________ WITH EACH SUCCESSIVE GENERATION AS IT IS TRANSMITTED FROM MAN-\> GRANDSOMES AND GREAT-GRANDSONS.
**INCREASING DELETORIOUS.**
THIS IS CALLED **ANTICIPATION**
201
DESCRIBE PEDIGREE OF FRAGILE X
IN FIRST GENERATION, ALL SONS ARE NORMAL AND ALL FEMALES ARE CARRIERS.
## Footnote
During oogenesis in the carrier female, premutation expands to
full mutation; hence, in the next generation all males who inherit the X with full
mutation are affected. However, only 50% of females who inherit the full mutation are
affected, and only mildly.
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What gene, locus, protein and repeat is affected in **Huntingtons**?
1. **Gene**: HTT
2. **Locus**: Chr 4p16.3
3. **Protein**: Huntingtin =\> toxic to neurons (bc toxic GOF)
4. **Repeat**: CAG triplet in the exon
1. =\> misfolded expansions of **polyglutamine** =\> toxic gain of function
2. =\> Huntingtons
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What is **Huntigtons Disease?**
**_Autosomal dominant d_isease** characterized by progressive movement disorders, _dementia_, and d_egeneration of striatal neurons d/t loss of [head of caudate nucleus =\> flattening of lateral ventricle =\> GP_]
_Calorie intake is 3x more_
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**Gain of function mutations** are almost always what type of inheritance pattern?
Which disease illustrates this type of mutation?
**- Autosomal dominant**
## Footnote
- Huntington's disease gives rise to abnormal protein, _huntingtin_, that is toxic to neurons, and _hence even heterozygotes develop neurologic deficit_
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What parts of the brain are affected in Huntingtons?
1. head of caudate nucleus=\> flatten lateral venticle
2. Body of corpus callosum
3. GP
206
Describe the transmission of **Huntingons**.
Repeat expansion occur during **_SPERMATOGENESIS_**, s_o paternal transmission is associated with early onset in the next generation (**anticipation**)_
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How are mT disorders passed down from mom?
Bc _ova have a shit ton of mT_ in cytoplasm, spermatozoa do not.
208
Describe the _expression of mT disorders_ as they are passed down.
Expression is variable. When a cell that has normal and mutant DNA divides, the proportion of _normal and mutated mtDNA in daughter cells is random and variable (**heteroplasmy**)._ In order for the disease to occur, there must be a minimum number of mutant mtDNA, called the **threshold affect.**
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What is an example of mT disorders?
**Leber hereditary optic neuropathy**
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What is **Leber hereditary optic neuropathy?**
**mTDNA neurodegenerative dissease** that causes _**progressive bilateral loss of central vision** first noted between 15- 35_ =\> _evenentually leading to blindness._
also has: _cardiac conduction defects_ and _minor neurological problems._
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Pedrigree for mT dNA
212
What is genomic imprinting?
**Imprinting INACTIVATES either a maternal allele or a paternal allele .**
**Maternal imprinting:** transcriptional silencing of maternal allele.
**Paternal imprinting:** inactivation of paternal allele
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What 3 ways can genomic imprinting occur?
1. _Deletions_
_3. Uniparental disomy_
_3. Defecting imprinting_
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What is u**niparental disomy?**
_Inheritance of both chromosomes of a pair from 1 parent._ This is seen in normal patients with prader-Willi syndrome, who have 2 maternal copies of chromosome 15. This is the 2nd most common reason for PW.
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What is Prader-Willi syndrome?
**deletion of paternal q12 of chromosome 15q11.2q13**, leaving behind only the silenced mothers gene =\>
mental retardation, short obese, small hands and feet, hypogonadism, hyperphagia, hypotonia.
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What is Angelman syndrome?
**deletion of maternal q12 of chromosome 15q11.2q13**, leaving behind only the silenced paternal gene =\>
"happy puppets": mental retardation, ataxic gait, seizures, inappropriate laughter.
Laughter and ataxia make them happy puppets
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