"Degenerative" Genetic Diseases Flashcards
(171 cards)
1
Q
What is the name for skills that include self-control, memory, self-monitoring, organization, control of emotions, starting and completing tasks, etc. (tasks of daily living)?
A
executive function
2
Q
What is it called when someone is using too many words to describe something when fewer would suffice?
A
circumlocution
3
Q
What may be an indicator of reduced function in Alzheimer’s disease?
A
circumlocution
4
Q
What is a mutation that arises where there is no family history of the condition (may be a new genetic variant in a family)?
A
De novo mutation
5
Q
What is the most common cause of dementia in the elderly?
A
Alzheimer’s
6
Q
Alzheimer’s is typically diagnosed over what age in those affected?
A
65
7
Q
What does Alzheimer’s disease result in?
A
progressive memory loss and premature death
8
Q
Alzheimer’s has a ___% mortality per year after diagnosis
A
10
9
Q
Once diagnosed with advanced dementia, half of the AD patients die within?
A
6 months
10
Q
Although Alzheimer’s is not a specific cause of death, it increases their vulnerability to what?
A
illness and infection due to:
-injuries from falls
-poor nutrition or dehydration
-aspiration pneumonia due to inherent swallowing difficulties
11
Q
What is the main common cause of death in Alzheimer’s disease patients?
A
aspiration pneumonia
12
Q
What are the hallmark pathologic changes of Alzheimer’s Disease?
A
- amyloid plaques
- neurofibrillary tangles
13
Q
What are abnormal deposits of the protein beta amyloid in the space between neurons?
A
amyloid plaques
14
Q
What is formed by clumps of tau protein, which is part of the structure of the microtubules that support the structure of the neuron (limit communication between neurons)?
A
neurofibrillary tangles
15
Q
Amyloid plaques and neurofibrillary tangles result in what?
A
-synaptic connections between neurons are lost and many neurons stop functioning and die
-atrophy of the brain occurs
-functioning and memory processes greatly decrease
16
Q
What are the manifestations of Alzheimer’s disease?
A
- memory deficits
- language changes
- visuospatial skills
- neurobehavioral effects
17
Q
What are the memory deficits associated with AD?
A
- recent: unable to remember many events after AD onset
- remote: able to remember some events that occurred prior to AD onset
18
Q
What are the language changes associated with AD?
A
- verbal disfluency and circumlocution
- anomia (forgetting words)
- reduced vocabulary
- diminished comprehension
19
Q
What are the visuospatial skills associated with AD disease?
A
- misplaced items
- get lost frequently
20
Q
What are the neurobehavioral effects associated with AD?
A
- loss of or fragmented sleep
- depression and/or psychosis
- loss of executive function
21
Q
What are the two different types of AD?
A
- early-onset
- late-onset
22
Q
Early-onset AD usually occurs between what ages?
A
30-60, but can occur as young as 20
23
Q
What percentage of AD cases are related to early-onset genes?
A
1-5%
24
Q
Early-onset AD is commonly associated with what inheritance pattern?
A
autosomal dominant
25
What are the genes associated with early-onset Alzheimer's disease?
- amyloid precursor protein gene (APP)
- presenilin 1 (PSEN1)
- presenilin 2 (PSEN2)
26
Which early-onset AD gene has over 30 mutations associated with early-onset AD and may be involved in early neural development, but exact function is unknown?
amyloid precursor protein gene (APP)
27
Which early-onset AD gene has over 150 million mutations and can lead to an overproduction of a longer and more toxic beta amyloid peptide and plaque formation?
presenilin 1 (PSEN1)
28
Which early-onset AD gene is the rarest of the three mutations and has an unknown mechanism but perhaps increases apoptosis in neurodegeneration?
presenilin 2 (PSEN2)
29
What chromosome is the APP gene located on?
chromosome 21
30
Individuals with Down Syndrome have trisomy 21 and an increased expression of what?
the APP protein
31
What increases the development of neurofibrillary tangles and beta amyloid plaques?
down syndrome
32
Individuals with down syndrome have a higher risk of what?
early-onset AD
33
What is the average lifespan of an individual with Down Syndrome?
60 years
34
Late-onset AD typically occurs after the age of what?
65
35
What percentage of cases of AD are late-onset?
over 95%
36
Genetics of late-onset AD represents what types of influences?
genetic and environmental influences
37
How many genes have been identified that are associated with late-onset AD?
20
38
What is the most firmly identified gene involved in late-onset AD?
apolipoprotein E (APOE)
39
What does the APOE variant allele also increase the risk of?
other forms of dementia (including vascular dementia and Lewy Body dementia)
40
What are the risks for late-onset AD in order?
1. age
2. family history of affected (1st degree relative)
3. presence of APOE polymorphism
41
The APOE allele exists in 3 forms, what are they?
1. APOE epsilon 2
2. APOE epsilon 3
3. APOE epsilon 4
42
Which APOE allele is the least common allele, is found in 5-10% of population, and appears to reduce the risk of late-onset AD?
APOE epsilon 2
43
Which APOE allele is the most common allele, is found in 70-80% of population, and plays a neutral role in risk of late-onset AD?
APOE epsilon 3
44
Which APOE allele is found in 10-15% of population, and appears to increase the risk for AD and is associated with an earlier onset?
APOE epsilon 4
45
What increases risk 3 to 8-fold, depending on whether a person has one or two copies?
APOE epsilon 4
46
APOE is a susceptibility gene, not a what?
determinant gene
47
Having 1-2 copies of APOE epsilon 4 does not mean what?
that AD will develop in 100% of cases
48
What is considered a non-reversible, progressive neurodegenerative disease?
Huntington's Disease
49
What occurs primarily in Caucasian people of NW European ancestry and most commonly begins in mid-life but can begin earlier or later?
Huntington's Disease
50
Onset of Huntington's Disease before the age of 20 is considered what?
juvenile HD
51
What is the inheritance pattern of Huntington's disease?
autosomal dominant
52
Affected individuals with HD are considered what?
heterozygous
53
What are some of the neuromuscular coordination manifestations of Huntington's disease?
- chorea
- gait abnormalities
- absence of smooth eye movement
54
What are rapid, involuntary movements of the face, trunk, and limbs?
chorea
55
What are the psychosocial and behavioral manifestations of Huntington's disease?
- irritability, anxiety, depression, disrupted social relationships, paranoia, aggression, delusions
- loss of insight, inflexibility, memory loss, impaired judgement
56
What gene codes for the protein called Huntington?
HTT
57
The mutated form of the HTT gene in HD consists of an expanded what?
CAG trinucleotide repeat
58
What is the codon for glutamine?
CAG
59
The average non-affected individual has how many CAG repeats?
17-20
60
A higher number of CAG repeats correlates to what in HD?
earlier onset and greater severity of disease
61
If inheritance of HTT allele in Huntington's is from the father, what happens?
patients tend to develop disease early by about 3 years (paternal allele is more likely to have more CAG repeats than maternal allele)
62
In HD genetic testing, less than 35 CAG repeats is considered what type of result?
negative test result, so no chance of developing Huntington's
63
In HD genetic testing, 36-39 CAG repeats is considered what type of result?
uninformative test result, so an individual may or may not develop HD but they are at a risk for it; their children are also at risk due to CAG repeat instability across generations
64
In HD genetic testing, more than 40 CAG repeats is considered what type of result?
positive test result, so they will always develop HD
65
Due to the instability of the CAG gene in HD, you may have a family that this arises _____
de novo
66
What is the most common lethal inherited disorder among Caucasians in the US?
cystic fibrosis
67
Cystic fibrosis is more common in persons of what descent?
Northern European descent
68
What is the inheritance pattern of Cystic fibrosis?
autosomal recessive
69
What newborn screening test is done that can determine if a newborn has cystic fibrosis?
heel stick
70
What gene does the Cystic fibrosis mutation occur on?
Cystic fibrosis transmembrane regulator gene (CFTR)
71
What does CF disease severity depend on?
how much of the normal CFTR gene is present
(more absences = more presentation)
72
What is the most common variant of the CFTR gene and results in loss of a CTT along the gene which changes the resulting proteins produced?
delta F508
73
What encodes for a functional transmembrane conductor of ions, especially sodium, chloride, and bicarbonate?
CFTR gene
74
What affects the membranes of the:
- respiratory tract
- pancreas
- liver and gallbladder
- intestinal tract
- sweat glands
- reproductive tract
CFTR gene
75
What is the most common place that CF occurs and affects?
respiratory tract
76
When both parents pass the variant CFTR gene, what fails to work properly?
transmembrane conductor
77
What is the normal function of the CFTR gene?
- chloride is moved from inside the cell to outside via the conductor
- the amount of sodium is regulated
78
What is the variant function of the CFTR gene?
- chloride cannot exit cell
- sodium absorption is unchecked and repeatedly absorbed into the cell in excess
- where sodium goes, water follows, so more water than normal is found intracellularly than along the epithelial/mucus layer
- results in unchecked sodium and water absorption leaving mucus very sticky
79
What are the manifestations of CF in infancy and adolescence?
- malabsorption and failure to thrive
- pancreatitis
80
What are the pulmonary manifestations of CF that are common but variable and typically occur later in life?
- chronic cough
- frequent pulmonary infections (pneumonia)
- dyspnea and exercise intolerance
81
In patients with CF, what can lead to increased pulmonary pressure or pulmonary hypertension?
chronic pulmonary disease
82
The high pressure associated with chronic pulmonary disease in CF patients can lead to?
stretching in the right ventricle so the right ventricle becomes less effective as a pump and can lead to right heart failure
83
What is another name for cor pulmonale?
right heart failure
84
People with right heart failure can develop what?
- dyspnea with exertion
- chest pain
- edema
- possibly cyanosis
85
How does CF affect the pancreas?
- pancreatic digestive enzymes are impaired
- poor absorption of food resulting in poor growth rate
- pancreatic inflammation and pancreatitis
- diabetes mellitus due to pancreatic insufficiency
86
How does CF affect the GI tract?
causes multiple conditions that result from thickened mucus of epithelium
87
How does CF affect the liver?
liver damage and portal hypertension
88
How does CF affect the genitourinary system?
CF males are 98% infertile due to absence of vas deferens
89
What are the two types of neurofibromatosis?
- neurofibromatosis 1
- neurofibromatosis 2
90
Which type of neurofibromatosis is more common?
Neurofibromatosis 1
91
NF1 is due to mutations in which gene?
NF1 gene
92
Normal NF1 gene acts as what?
tumor suppressor gene
93
NF1 gene produces what protein?
neurfibromin
94
What is the inheritance pattern of both NF1 and NF2?
autosomal dominant
95
What percentage of NF1 cases are inherited and what percentage result from new mutations?
- 50% are inherited
- 50% result from new mutations
96
In NF1 and NF2, the variable presentation and onset is based on what?
extent of gene mutations
97
Mutations in what gene is NF2 due to?
NF2 genes
98
The normal NF2 gene is what type of gene?
tumor suppressor gene
99
What protein does the normal NF2 gene produce?
merlin
100
What is the gene penetrance for both NF1 and NF2?
100%
101
What are some of the main manifestations of NF1?
- cafe-au-lait macules
- freckling
- lisch nodules
- cutaneous neurofibromas
- plexiform neurofibroma
- optic glioma
102
In NF1 patients, what appears during the first year of birth 6 or more are highly suggestive of NF1?
cafe-au-lait macules
103
In NF1 patients, what appears by 3-5 years old, and occurs especially in areas of skin opposition, such as axillary and inguinal regions?
freckling
104
In NF1 patients, what are small hamartomas of the iris and are more common in adult NF1 patients and less common prior to age 6?
lisch nodules
105
What results from abnormal neurofibromin production?
NF1
106
Where is neurofibromin found?
- brain
- kidneys
- spleen
- thymus gland
- other tissues
107
What results in multiple benign tumors (neurofibromas) composed of schwann cells, which produce the myelin sheath of axons?
NF1
108
Large deletions that encompass the entire NF1 gene result in more severe (1) and earlier appearance of (2)?
1. mental disability
2. neurofibromatomas
109
What are tumors of the optic pathway and occur in 15% of children with NF1 under age 6 and rarely occur in adults?
optic gliomas
110
The risk for multiple forms of malignant neoplasms (in the brain, nerve sheath and soft tissue tumors especially) increases for individuals with what?
NF1
111
What are these bone abnormalities associated with:
- most commonly, anterolateral bowing of the tibia
- scoliosis
- osteoporosis
NF1
112
What are these neuropsychiatric outcomes associated with:
- intellectual disability
- ADD
- neuromotor dysfunction
NF1
113
What is associated with the development of noncancerous tumors on the auditory and vestibular nerves of the body (known as schwannomas and typically occur bilaterally)?
NF2
114
What are tumors on the nerve sheath or CNS?
schwannomas
115
NF2 has fewer manifestations of what than NF1?
cutaneous manifestations
116
Symptoms of NF2 present earlier or later in life than NF1?
later in life
117
What can also affect vision if schwannomas affect structures of the eye like the retina?
NF2
118
What are bilateral vestibular schwannomas (acoustic neuroma) which can lead to hearing loss, tinnitus, headache, and balance dysfunction associated with?
NF2
119
What can cause tumors of the spine and meninges of the brain (and tumors can cause peripheral neuropathy)?
NF2
120
What are skin lesions such as cutaneous and subcutaneous tumors, and skin plaques associated with?
NF2
121
What are more subtle in presentation in NF2 than in NF1?
skin lesions
122
What do you need to identify NF?
- family history
- thorough physical examination
123
Genetic testing for NF1 cannot predict what?
the severity of the disease
124
What is the inheritance pattern of polycystic kidney disease (PKD)?
autosomal dominant pattern
125
Mutations of PKD can occur in what genes?
PKD1 or PKD2 genes
126
If there are mutations of PKD in both PKD1 and PKD2 genes, what can happen?
earlier presentation of end-stage-renal-disease (ESRD)
127
Rarely, PKD can follow in what type of inheritance pattern?
autosomal recessive
128
When PKD presents in an autosomal recessive, what can present?
- can present at birth and cysts may be seen on prenatal US
- high mortality rate when found newborn
129
Both ADPKD and ARPKD commonly manifest as?
bilateral renal cysts (but is a multi-organ disease)
130
What does PKD1 encode for?
polycystin-1
131
What does PKD2 encode for?
polycystin-2
132
85% of PKD is due to what gene?
PKD1
133
Mutations on which PKD gene can have an increased severity of symptoms such as larger kidneys and more cysts?
PKD1
134
Younger onset of PKD symptoms is associated with which gene mutation?
PKD1 mutations
135
Which PKD gene mutations can lead to a faster progression to ESRD?
PKD1
136
15% of PKD is due to which gene?
PKD2
137
Mutations on which PKD gene can have decreased severity of symptoms compared to PKD1?
PKD2
138
Which PKD gene mutations can lead to a later onset of symptoms?
PKD2
139
What will occur in all patients with PKD but will have varying size and amount?
renal cysts
140
Kidney size in patients with PKD is typically increased more than how many times their normal size?
5x
141
What replaces normal structure of kidneys in patients with PKD and has altered normal processes of filtration, reabsorption, and urine concentration?
cysts and scarring
142
What may be large and palpable on exam with PKD patients?
kidneys
143
What are these manifestations associated with:
- hematuria (grossly vissible)
- proteinuria
- flank pain
- bladder/kidney infections
- hypertensions
- progression to ESRD (50% of patients by age 60)
PKD
144
What are these manifestations associated with:
- polycystic liver disease
- diverticulosis
- dilation of aortic root and cardiac valvular abnormalities
PKD
145
What is the most dangerous clinical manifestation or complication of PKD?
Intracranial aneurysm
146
10-20% of people with PKD end up with what complication?
intracranial aneurysm
147
What can intracranial aneurysm that rupture rapidly cause?
- intense HA
- intracranial bleeding
- can be fatal without surgical intervention
148
In PKD patients, what can easily show cysts once they have formed?
US or CT scan
149
What causes increased intestinal absorption of iron?
hereditary hemochromatosis
150
Increased iron is stored in many organs and causes end-organ damage in which places?
- liver
- pancreas
- skin
- heart
- pituitary gland
151
What is the inheritance pattern of hereditary hemochromatosis?
autosomal recessive
152
What type of penetrance does hereditary hemochromatosis have?
variable
153
Hereditary hemochromatosis is caused by a mutation in what gene?
HFE gene
154
What does the HFE gene encode for?
proteins present in hepatocytes and intestines
155
When functional, what does the HFE gene do?
strictly regulates the amount of iron absorbed by the body
156
The two most common point mutations in hemochromatosis exists at what sites?
C282Y and H63D
157
In hemochromatosis, the point mutation at C282Y causes what?
a single amino acid substitution which results in cysteine changing to tyrosine
158
In humans, GI absorption of iron increases when what happens?
when stored iron decreases
159
Iron is lost in what?
- sweat
- shedding skin
- GI tract
- Menstruation
160
In hemochromatosis, what is not regulated by the amount of iron stored, causing a deadly accumulation of iron?
absorption of iron
161
Hemochromatosis is expressed 10x more in men due to what?
- women have lower dietary intake and menstruate (sex-induced phenotype)
- if women develop disease, it is often a later age than men
162
Affected persons of what disease do not usually present until age 40 because it is related to an excess absorption of iron over a period of years?
hemochromatosis
163
What are these liver abnormalities associated with?
- hepatomegaly
- elevated liver enzymes
- fibrosis and cirrhosis of liver
hemochromatosis
164
An increased risk of hepatocellular carcinoma (20-fold to 200-fold) is associated with what?
hemochromatosis
165
What is potentiated by alcoholic liver disease and infectious hepatitis, especially?
hemochromatosis
166
In hemochromatosis, what is caused by iron deposition into specific tissues/organs?
- diabetes (pancreas)
- arthropathy (joints)
- heart disease (dilated cardiomyopathy, heart failure)
- pituitary gland (hypogonadism and amenorrhea)
- increased risk of bacteria infections
167
In hemochromatosis, what can become more virulent in the presence of iron?
bacteria
examples include Listeria monocytogenes and Yersinia enterocolitica
168
What leads to hyperpigmented skin (bronze color)?
hemochromatosis
169
What leads to hypermelanosis?
increased iron in the system
170
It is believed that the increased melanin in hemochromatosis is from an increase in what?
hemosiderin (an iron-storage complex)
171
In hemochromatosis, some symptoms can be ________
reversible
