Gen Path Final Exam Section 6: Genetic and Pediatric Disease Flashcards
1
Q
genome
A
organism’s genetic material
2
Q
gene
A
set of nucleotides; is basic unit of inheritance; and instructs protein synthesis, which influences phenotype
3
Q
Allele
A
alternative form of a gene; single gene locus
Diploid = paired alleles
4
Q
Hereditary
A
transmitted to offspring
5
Q
Perinatal
A
last trimester and 1st month after birth
6
Q
Neonate
A
first 4 weeks (“newborn”)
7
Q
Infant
A
1st year after birth
8
Q
Congential
A
present at birth (unrelated to inheritance)
9
Q
What are the three Mendelian Disorder categories?
A
- Autosomal Dominant (1-22 chromosomes)
- Autosomal Recessive (1-22 chromosomes)
- X-linked Recessive (23 chromosome)
10
Q
What are features of Autosomal Dominant Disorders?
A
- manifest in heterozygous state
- sporadic mutations possible (no family history)
- Reduced Penetrance
- Variable Expressitivity
- Delayed age onset
11
Q
What do Autosomal Dominant disorders effect?
A
- structural proteins
2. membrane receptors
12
Q
What is reduced penetrance?
A
inherit mutated gene but DO NOT ever manifest with condition
13
Q
What is Variable Expressitivity?
A
different people with same mutant gene manifest with widely-variable clinical features
14
Q
What does delated age onset mean?
A
may not notice in infancy; but manifests later childhood, adolescence, or young adulthood
15
Q
What are features of Autosomal Recessive Disorders?
A
- manifest in homozygous state
- Complete penetrance
- early onset (shortly after birth)
- rarely sporadic
16
Q
What does Autosomal Recessive Disorders effect?
A
enzymatic proteins –> result in abnormal metabolic processes
17
Q
What is complete penetrance?
A
expressed completely in individuals affected by such conditions
18
Q
What are features of X-linked Recessive disorders?
A
- sex-linked = allosomal (irregularities on 23rd chromosome)
- All are X-linked (females are protected; males are prime targets)
19
Q
What is the offspring chance of having an X-linked disorder with a heterozygous mother?
A
heterozygous females = asymptomatic “carriers” and the male offspring have 50% chance manifesting with the disorder
20
Q
What is the relationship between hereditary disorders and congenital disorders?
A
NOT all hereditary disorders are congenital
AND
NOT all congenital disorders are hereditary
21
Q
What is autosomal dominant condition of the FBN1 gene and what does affect?
A
Marfan Syndrome; causes Fibrillin to be abnormal
22
Q
What is Fibrillin?
A
- structural protein
- in microfibrils of ECM
- abdundant in many CT, esp. tissues highly elastic
(ass. w/ Marfan Syndrome)
23
Q
What tissues is Marfan Syndrome MC manifest in?
A
- osseous skeleton tissues
- eyes
- cardiovascular tissue
24
Q
What percentage of cases of Marfan Syndrome are inherited? Sporadic? And how many people are affected?
A
85% inherited (familial)
15% results of new FBN1 gene mutations (sporatic)
~1 per 5,000
25
What the clinical features of Marfan Syndrome?
- overgrowth of many long bones
- elongated head/face (dolichoecephaly)
- long hands/fingers (arachnodactyly)
- 1.05 or greater of arm length/ height
- sternal abnormalities (pectus carinatum or excavatum)
- long arms
- long feet/toes
- high-arched palates
- positive Steinburg sign or Wrist sign
- Pes planovalgus
- Scoliosis
- Protrusio acetabuli
- Ectopia lentis
- cardiovascular complications
- dural ectasia
26
What are Ectopia lentis, cardiovascular complications, and dural ectasia features of?
Marfan Syndrome
27
What is an autosomal dominant OR autosomal recessive disoder that affects collagen protein synthesis?
Ehlers-Danlos syndrome
| abnormal collagen lacks tensile strength
28
What tissues are rich in collagen, therefore MC affected by Ehlers-Danlos syndrome?
joint cartilage, skin, and ligaments
29
What are clinical features of Ehlers-Danlos syndrome?
- tissues distend (risk of tissue injury)
- joint hypermobility (dislocations)
- hyperextensible skin
- vulnerable to visceral trauma (injury to colon or large arteries or hiatal hernias)
- vascular fragility (therefore, poor wound healing)
30
What disorder is autosomal dominant and is a loss-of-function mutation in LDLR gene?
Familial Hypercholesterolemia
| - affects ~1 in 500 inds. in US
31
What does the LDLR gene do? and if altered what happens?
- regulates LDL receptors
- mutations impair translocation and breakdown (catabolism) of LDL cholesterols
- is a membrane receptor disease
(ass. w/ Familial Hypercholesterolemia)
32
What are clinical features of Familial Hypercholesterolemia?
- increase levels of LDL cholesterols = hypercholesterolemia
- encourages premature atherosclerotic plaques
- may cause coronary disease and increase risk of lethal myocardial infarctions
33
Heterozygous individuals with Familial Hyperhcolesterolemia
- have elevated LDL levels ~2-3x normal
| - manifest with Xanthomas or coronary artery disease in early adulthood
34
Homozygous individuals with Familial Hypercholesterolemia
- have elevated LDL levels ~5x normal
- more serious and life-threatening presentation
- develop Xanthomas during childhood and commonly die from lethal myocardial infarction
35
What is an autosomal recessive disorder that has mutations in CFTR gene?
Cystic Fibrosis
| - affects ~ 1 in 3,000 caucasians
36
What does the CFTR gene do? If altered, what happens?
(ass. with Cystic Fibrosis)
- regulates CFTR protein complex, which transports CHLORIDE ions across epithelial cells
- when altered; fluid secretion affected and exocrine glands, respiratory tract, and GI tract have viscous or salty secretions
37
What are the clinical features of Cystic Fibrosis?
- thick viscous secretion accumulate in lungs (pulmonary infetions--pneumonia)
- "Salty kisses"
- Pancreatic Obstruciton (~90% patients)
- Cor pulmonale
- Sterility (atrophy of vas deferens)
(highly variable---some may die in infancy while others live a nearly normal life)
38
What causes "Salty kisses" in Cystic Fibrosis?
occur in neonates due to sweat glands affected and accumulation of salts (NaCl) on skin
39
What does Pancreatic Obstruction cause in Cystic Fibrosis patients?
(occurs in ~90% of patients)
| - prevents pancreatic zymogens from reaching SI and results in malaborption
40
What is Cor pulmonale?
(clinical feature of Cystic Fibrosis)
- can be life-threatening involving right-side heart failure
- due to pulmonary conditions resulting in increase pulmonary BP
- right-side of heart cannot withstand these pressures as well as left-side can --> therefore may develop quick
41
What is an autosomal recessive disorder and is a mutation in PAH gene? And what does it lead to?
Phenylketonuria; leads to lack of production of ENZYME phenylalanine hydroxylase (PAH)
~ 1 in 10,000 births
MC in Scandinavians
42
What does the PAH enzyme do? If absent what occurs?
(= phenylalanine hydroxylase)
(ass. with Phenylketonuria)
- metablizes A.A. phenylalanine into tyrosine
- absence of enzyme; results in hyperphenylalaninemia and phenylketouria (in urine)
43
What are clinical features of Phenylketonuria?
- damages CNS (intellectual disability, seizures, behavioral problems, mental disorders)
- ~2/3 never develop ability to talk
- ~1/3 never develop ability to walk
- "Musty or Mousy" odor of urine and sweat
- lack pigment in hair and skin
- increase risk of eczema
- ----appear normal at birth; intellectual disabilities evidence at ~6 months
44
What can help to reduce affects of Phenylketonruia?
- restrict phenylalanine consumption early in life to avoid neurotoxic effects and resulting disabilities
(seems to be neurotoxic effects DO NOT occur after childhood)
45
If the mother has Phenylketonuria (Maternal PKU), what happens?
if mother not adhering to diet; she must eliminate phenylalanine prior to conception to avoid teratogenic effects on fetus
- will have devastating effects on fetus (congenital heart malformations and microcephaly)
46
What is Benign Hyperphenylalaninemia?
have mildly elevated levels of hyperphenylalaninemia and asymptomatic due to PAH gene mutation being less severe
47
What disorder is autosomal recessive and involves mutation in HGD gene?
Alkaptonuria -- lacks/dysfunction in ENZYME homogenetisic oxidase
48
What is Alkaptonuria sometimes called?
the "Black Urine Disease"
| - due to homogentisic acid accumulating in urine and oxidizing when comes in contact with oxygen
49
What does Homogentisic Oxisase do?
(ass. with disorder Alkaptonuria)
- assist in metabolism of typrosine and phenylalanine
- part of this process produces hamogentisic acid and it then accumulates
- when homogentisic acid oxidizes it polymerizes and becomes more pigmented
50
What are clinical features of Alkaptonuria?
- homogentisic acid accumulates in: urine, joints, and heart
- manifest with dark urine shortly after birth or dark earwax
- ~age 30 areas of pigmentation occur on skin (ochronosis)
- Adulthood-- arthritis pain in spine (IVD), hip, knee, and shoulder joints
- predisposed to kidney stones and heart problems
51
What is ochronosis?
= accumulation of dark pigment in CT; such as cartilage and skin
(ass. with Alkaptonuria)
52
What disorder is autosomal recessive and involved a mutation in GALT gene?
Galactosemis
| - causes lack of production of GALT enzyme
53
What does the GALT enzyme do? What occurs when it is mutated?
- metabolizes galactose carbohydrate (produced as component of lactose metabolism)
- when mutated-- will have difficulty shortly after birth when drink milk
54
What are clinical features of Galactosemia?
- increase of galactose and galactose-1- phosphate in many tissues
- problems ass. with difficult feeding, vomiting, diarrhea after newborn consumes milk
- may causes "Failure to Thrive" within first week
- CNS involved (cerebral edema and gliosis)
- Hepatomegaly and jaundice of liver
- Eyes--> cataracts develop
- Spleen --> splenomegaly
55
Can anything be done for Galactosemia?
yes
- remove milk from diet to avoid many damaging effects (important early in life, adults don't seem to be as easily damaged)
- reintroduce milk into diet at ~2 years
- therefore why have standard newborn screenings for galatosemia
56
What disorder is autosomal recessive and lack lysosomal enzyme?
Lysosomal Storage Disease
| - Rare all combined at ~ 1 in 5,000 births
57
What are some clinical features of Lysosomal Storage Diseases?
- inhereted enzyme disorder
- early age onset
- Hepatosplenomegaly
- intellectual disability
58
What are three types of Lysosomal Storage Disease?
1. Tay-Sachs Disease
2. Gaucher Disease
3. Mucopolysaccharidosis
59
What is an autosomal recessive lysosomal storage disease that involves mutation in HEXA gene?
Tay-Sachs Disease (our focus on "infantile Tay-Sachs Disease")
- results in faulty hexosaminidase A enzyme
MC affects Ashkenazi Jews
*normally fatal ~2-3 years of age
60
What does the Hexosaminidase A enzyme do?
(ass. w/ Tay-Sachs Disease)
- catablizes glyclipid Gm2 ganglioside
- when it can't do that it will acculumate in NS, heart, liver, spleen, and retina
61
What are clinical features of Tay-Sachs Disease?
- Gm2 gangliosides acculumate in CNS, PNS, and ANS (neural damage becomes evident ~3-6 months)
- vision, hearing, problems
- immobility and seizures
- failure to meet developmental milestones
- **Characteristic feature = "cheery red" spot on central retinal (the macula)
62
What disorder is an autosomal recessive lysosomal storage disease that involves the GBA gene?
Gaucher Disease
| - results in a faulty glucocerebrosidase enzyme
63
What does a faulty glucocerebrosidase enzyme lead to?
(ass. with Guacher Disease)
- leads to accumulation in glycolipid glucocerebroside in macrophages, which will enlarge and now called "Gaucher cells"
- have "wrinkled tissue paper" appearance
64
What are the Types of Gaucher Disease?
Type I (99% all cases) "chronic neuropathic form"
Type II
Type III
65
What are the clinical features of Type I Gaucher Disease?
- Hepatosplenomegaly and bony involvement (spares CNS)
- osteolysis, osteopenia, osteonecrosis, and Erlenmeyer Flask deformities of extremity long bones
- Pancytopenia
66
What is Pancytopenia?
blood cell deficiencies of:
- decrease in red bone marrow = decrease RBC's (anemia and fatigue)
- decrease in WBC's (infections)
- decrease in platelets (bleeding tendencies)
67
Type II and Type III Gaucher Disease
Rare; ~1% all cases; BUT more devastating
- Hepatosplenomegaly and severe neurodegeneration
- ass. with profound intellectual disability
- ass. w/ 20-fold increase of developing Parkinson disease
68
Type II vs Type III Gaucher Diseases
Type II = more severe and onsets during infancy
| Type III = milder and develops during childhood/ young adulthood
69
What is an autosomal recessive lysosomal storage disease that involves abnormalities in many enzymes involved in ECM breakdown?
Mucopolysaccharidosis
70
What are the two forms of mucopolysaccharidosis?
Hurler Syndrome (MPS Type I) and Hunter Syndrome (MPS Type II)
71
What are the most notable undigested metablites associated with mucopolysaccharidosis?
dermatan sulfate and heparan sulfate
72
What enzyme is deficient in Hurler Syndrome?
alpha-L-iduronidase
autosomal recessive
73
What are the clinical features of Hurler Syndrome?
- "course facial features" (skeletal deformity)
- intellectual disability
- clouding of cornea
- accumulation of mucopolysaccharides within coronary arteries = Coronary Artery Disease --> **most likely to cause lethal myocardial infarction within 1st decade of life
74
What type of inheritence is Hunter Syndrome and what enzyme is deformed?
X-linked mutation
L-iduronate sulfatatase
75
What are the clinical features of Hunter Syndrome?
(=less severe, and slower progression than Hurler Syndrome)
- unlikely to manifest with severe skeletal/facial features
- no clouding of cornea, or intellectual disabilities
- will live a nearly normal lifespan
76
What are Glycogen Storage Diseases?
they are autosomal recessive enzyme disorder that results in intracellular accumulation of glycogen in liver, skeletal muscle, and heart
77
What are the three types of Glycogen Storage Diseases?
1. Von Gierke Disease
2. McArdle Disease
3. Pompe Disease
78
Which is the "hepatic type" of glycogen storage disease?
Von Gierke Disease
- causes glycogen to accumulate in liver
- deficiency in enzymes--> glucose-6-phosphatase
79
What are the clinical features of Von Gierke Disease?
- failure to thrive shortly after birth; typically lethal
- hepatomegaly
- hypoglycemia
- increased risk of gout, xanthomas of skin, and bleeding tendencies
80
Which is the "myopathic type" of Glycogen Storage Disease?
McArdle Disease
- causes glycogen to accumulate within skeletal muscle
- deficiency in enzyme --> muscle phosphorylase
81
What are the clinical features of McArdle Disease?
- muscle cramping and weakness during intense exercise (decrease in muscle glycolysis)
- onset at about age 20; adolescence/young adulthood
- may produce: myoglobinuria and rhabdomyolysis
- inability for exercise to raise lactate levels during intense physical activity
82
What makes Pompe Disease unique and what enzyme is deficient?
unique b/c technically a lysosomal storage disease b/c enzyme deficiency is lysosomal acid maltase
(is considered a Glycogen Storage disease
83
What is Rhabdomyolysis and what disease can causes it?
condition develops after destruction of skeletal muscle tissue and causes large amounts of macromolecules to enter bloodstream and causes damage to CNS and kidneys
--ind. with McArdle Disease has possibility of developing this
84
What is the most common cause of death in individuals with rhabdomyolysis?
lethal renal failure (myoglobin causes obstruction of glomeruli)
85
What can causes rhabdomyolysis?
```
Mechanical trauma to skeletal muscle tissue from:
- motor vehicle accident (MVA)
- surviving earthquake-related trauma
- experiencing physical abuse
Intense physical activity (rare)
```
86
What may rhabdomyolysis cause? Define it.
myoglobinuria = presence of myoglobin in urine; causes dark brown discoloration of urine
may also causes-- muscle pain, confusion, weakness, and Renal Failure
87
What are Complex Multigenic Disorders?
- are multi factorial or polygenic in nature
| - result from complex interactions b/w multiple genetic risk factors AND env. risk factors
88
What is an example of a Complex Multigenic Disorder?
Type II Diabetes Mellitus
