Quiz 4 Flashcards
(123 cards)
1
Q
2 sections of PNS
A
1) Autonomic nervous system: Unconscious body functions
2) Somatic nervous system: Conscious control of the muscles
2
Q
3 types of neuron
A
1) Sensory Neuron
2) Interneuron
3) Motor Neuron
3
Q
Clinical Diagnosis of Neuromuscular Disorders
A
1) Medical and Family History
2) Physical Evaluation
Tuning fork, walking evaluation, assessment of muscle strength
3) Creatine Kinase (CK)
Enzyme in heart, brain, skeletal muscles etc
Released into blood when muscles are damaged
4
Q
Testing to Diagnose Neuromuscular Disorders
A
1) Electromyography (EMG)
2) Nerve Conduction Studies (NCS)
3) MRI Imaging, Muscle Biopsy and IHC staining
5
Q
What does Spinal Muscular Atrophy (SMA) affect?
A
Lower motor neurons (anterior horn cells)
6
Q
What does Amyotrophic Lateral Sclerosis
(ALS) affect?
A
Upper and lower motor neurons
7
Q
What does Kennedy’s disease affect?
A
Lower motor neurons
8
Q
What does Hereditary Spastic Paraplegia affect?
A
Upper motor neurons
9
Q
Features of Muscle weakness and atrophy in SMA
A
1) Symmetrical and progressive (gets worse over time)
2) Proximal> distal
3) Lower limbs affected > upper limbs affected
10
Q
Main function of PNS
A
use sensory & motor neurons to connect the CNS to the rest of the body
11
Q
Creatine Kinase (CK)
A
Enzyme in brain, heart and skeletal muscle that is released I to blood when muscles are damaged
12
Q
Electromyography (EMG)
A
the electrical recording of muscle activity
13
Q
Nerve conduction study
A
Measures speed and strength of nerve signals
14
Q
Spinal Muscular Atrophy (SMA)
A
Motor neuron disorder
Autosomal Recessive
progressive loss of lower motor neurons
15
Q
SMA symptoms
A
1) Proximal and lower limb weakness
2) Hypotonia
3) respiratory failure
16
Q
What are the number/types of SMA are there?
A
0-4
17
Q
SMA causative gene
A
SMN1 gene, homozygous deletion of Exon 7 (most common, 2% de novo one allele b/c mis-cut with SMN2), or non deletion mutations in one allele
18
Q
SMA modifying gene
A
SMN2; SNP leads to exclusion of exon 7 in mRNA, so only 10% of SMN protein comes from SMN2 mRNA
Increasing SMN2 copy number decreases SMA severity
19
Q
SMA NBS
A
SMN1 exon 7 deletion only
20
Q
Zolgensma
A
SMA gene therapy for <2 year olds
21
Q
What percent de novo mutations in SMA and why?
A
2% de novo mutations -
de novo mutations much more likely in SMA and CAH than other AR diseases - because pseudogenes are right there
22
Q
What is a silent carrier in SMA?
A
2 copies of SMN1 gene on 1 chromosome
and Zero on the other - but carrier screen doesn’t show it ->
SILENT CARRIER
23
Q
Nusinersen (Spinraza)
A
Taken throughout life - changes splicing to include exon 7 in SMN2 gene
24
Q
amyotrophic lateral sclerosis (ALS)
A
Motor neuron disorder
Autosomal Dominant
Progressive and asymmetrical loss of muscle movement
25
Frontotemporal Dementia
Frontal and temporal regions degenerate
Personality, behavior and language changes
Can occur with ALS
26
ALS causal gene
C9orf72;
Hexanucleotide repeat expansion
Repeat number does not correlate with severity
>30 pathogenic
27
ALS susceptibility genes
VCP and SOD1
28
Spinal and Bulbar Muscular Atrophy (Kennedy Disease)
Motor neuron disorder
X-linked; degeneration of lower motor neurons
29
SBMA symptoms and onset
Proximal and distal muscle weakness, muscle atrophy, difficulty walking, androgen insensitivity in some (females asymptomatic)
18-64 years (most in 30-40s)
30
SBMA genetics
CAG repeat expansion in androgen receptor (AR) gene
>37 repeats is pathogenic
Increasing repeats increases severity and decreases age of onset
31
Hereditary Spastic Paraplegia (HSP)
Motor neuron disorder
most commonly Autosomal Dominant
32
HSP types and onset
Pure/uncomplicated and complicated; early childhood through late adulthood
33
pure HSP symptoms
Impacts lower body, spasticity, atypical gait
34
Complicated HSP symptoms
Symptoms of pure plus other symptoms (cognitive impairment, epilepsy, etc)
35
Dystrophinopathies
Mutations in dystrophin gene (DMD)
X-linked
Elevated CK
Muscle cramps
36
Duchenne Muscular Dystrophy (DMD)
Delayed motor milestones
Abnormal gait
Gower maneuver
Serum CK > 10x normal
Hypertrophic calf muscles
Require wheelchair by age 12
Cardiomyopathy
Life expectancy 24 years
37
Becker muscular dystrophy (BMD)
Similar but less severe than DMD, later onset muscle weakness, cardiomyopathy, median survival 40 year
38
DMD-associated Dilated Cardiomyopathy (DCM)
Left ventricular dilation and congestive heart failure; males 20-40 years, females later
39
Female dystrophinopathy carriers
15-20% have mild-moderate muscle weakness, elevated CK, increased risk for DCM
40
DMD gene
Largest gene
Deletions/duplications most common
2/3 of affected males inherited mutation from their mother
Reading frame rule (in frame cause milder phenotype)
41
Exon skipping treatment
Skips exon that disrupts the reading frame; DMD to BMD phenotype
42
Limb Girdle Muscular Dystrophy (LGMD) types
Type 1, Autosomal Dominant
Type 2, Autosomal Recessive
43
LGMD symptoms and onset
proximal muscle weakness (shoulder and pelvic girdle),
Cardiomyopathy, or
Respiratory problems
Varaible age of onset
44
Facioscapulohumeral muscular dystrophy (FSHD) types
FSHD1 (95%), Autosomal Dominant
FSHD2 (5%), unclear inheritance
45
FSHD symptoms
Weakness and atrophy in the face
Shoulder blades (scapular winging)
Upper arms
Rarely affects cardiac muscles
46
FSHD (Facioscapulohumeral muscular dystrophy) onset
childhood to adult, 50% have symptoms before age 20
47
FSHD1 genetics
Typically, D4Z4 region repeats cause methylation and suppression of DUX4 expression
Deletion/contraction of D4Z4 region (1-10 repeats) plus the deletion on the permissive 4qA haplotype allele that carries the polyA tail leads to DUX4 expression
48
FSHD1 genetics details
DUX4 is demethylated, and then stabilized so it keeps getting expressed - >
deletion (contraction to less than 10 repeats) of D4Z4 causes DUX4 to be demethylated and expressed
if permissive 4A allele which codes for the polyA tail is present, the DUX4MRNA is stabilized so the protein can be expressed
49
FSHD2 genetics
Pathogenic variant in SMCHD1 gene (chromosome 18) makes a protein that removes D4Z4 methylation plus the variant on the permissive 4qA haplotype allele that carries the polyA tail leads to DUX4 expression
50
Myotonic dystrophy type 1 (DM1)
CTG repeat expansion in DMPK gene
Increased repeat sizes increases severity
Autosomal Dominant
Congenital form inherited from moderate size of repeats from mother (anticipation)
51
Classic DM1 (Myotonic Dystrophy Type 1) symptoms and age of onset
1) weakness
2) myotonia
3) cataracts
4) cardiac arrhythmia
5) avoidant/passive-aggressive personality;
10-30 years
52
Congenital DM1 (Myotonic Dystrophy Type 1) symptoms and age of onset
infantile hypotonia, respiratory deficits, intellectual disability, classic signs as adults; birth-10 years
53
Myotonic dystrophy type 2 (DM2)
CCTG repeat within complex repeat motif in CNBP gene; no anticipation and no correlation with repeat size and disease severity
54
DM2 symptoms
myotonia and muscle weakness, cataracts, type 2 diabetes, cardiomyopathy
55
Collagen VI-related muscular dystrophies
affect skeletal muscle and connective tissue; COL6A1, COL6A2, COL6A3 genes
56
Bethlem muscular dystrophy
autosomal dominant; muscle weakness, hypotonia, contractures, slowly progressive
57
Ullrich congenital muscular dystrophy
autosomal recessive; severe muscle weakness beginning soon after birth, respiratory involvement
58
Charcot Marie Tooth
peripheral neuropathy; demyelination, axonal, or both; sensory and motor nerve damage; longer nerves impacted first
59
Charcot Marie Tooth symptoms
numbness and tingling, balance issues, muscle weakness and atrophy, foot drop
60
CMT type 1, 2, 3, and 4
1 demyelinating, 2 axonal, 3 and 4 mixed
When the myelin is damaged (Type 1 CMT), the nerve impulses are conducted more slowly than normal. If the axon itself is damaged (Type 2), the speed of nerve conduction is almost normal, but the strength of the signal is reduced.
61
CMT lettered subtypes
determined by genetic testing
62
CMT1A
most common type, autosomal dominant, PMP22 duplication
63
CMT1X
second most common type, x linked dominant
64
CMT4C inheritance
Autosomal Recessive
65
Hereditary neuropathy with liability to pressure palsies (HNPP)
demyelinating, impacts sensory and motor neurons, onset 20s-30s, episodic symptoms in response to pressure
66
HNPP genetics
Autosomal Dominant
PMP22 loss of function mutations
Most commonly complete PMP22 deletion
67
Ataxia Telangiectasia (AT) symptoms and onset
progressive cerebellar ataxia, jerking, and tremors, swallowing difficulties; immunodeficiency, increased risk for malignancy; onset 1-4 years
68
AT genetics
Autosomal Recessive, ATM gene (ATM serine/threonine kinase), carriers at risk for breast, pancreatic, and prostate cancer
ATM can’t correct mistakes
ATM serine/threonine kinase, symbol ATM, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis
69
Spinocerebellar ataxias (SCAs)
degeneration of the cerebellum and spinal cord; progressive incoordination of walking
70
SCA symptoms
ataxia, poor coordination of hand and eye movements
71
SCA (Spinocerebellar ataxia) genetics
Autosomal Dominant, some types due to repeat expansions
72
Friedreich ataxia
slowly progressive ataxia with onset before age 25
73
Typical Friedreich ataxia symptoms
progressive ataxia, peripheral neuropathy, muscle weakness, dysphagia, cardiomyopathy
74
Atypical Friedreich ataxia
late onset (after 25 years)
75
Friedreich ataxia genetics
Autosomal Recessive, mutations in FXN gene, GAA expansion in intron 1
FXN Frataxin gene codes for a protein that affects mitochondria. Frataxin mRNA is mostly expressed in tissues with a high metabolic rate.
76
Neuronal ceroid lipofuscinosis (NCL, Batten disease)
many types, mostly autosomal recessive, vision loss, epilepsy, dementia
Neuronal ceroid lipofuscinosis is the general name for a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the body's tissues. These lipopigments are made up of fats and proteins.
77
CLN1 (NCL)
Infantile onset, floppy, epilepsy, death by mid-childhood (7 y.o.)
78
CLN3 (NCL)
juvenile onset, vision loss, epilepsy, unsteady gait, death 15-35 years
79
Huntington's disease
progressive breakdown (degeneration) of nerve cells in the brain
mood, memory, movement
80
Huntington's disease genetics
HTT gene, CAG repeat expansion, inverse relationship between disease severity and repeat number, anticipation (most commonly maternal)
81
Epilepsy types of seizures
generalized versus focal/partial
82
Tonic clonic seizure
generalized seizure, unconsciousness, convlusions, muscle rigidity
83
Absence seizure
staring into space
84
Epilepsy genetic testing yield
higher for rare forms, neonatal onset, and uncontrolled types
85
Epilepsy genetic testing options
CMA (Chromosomal Microarray Analysis)
epilepsy panel (del/dup analysis but many VUS (variants of uncertain significance))
WES (Whole Exome Sequencing)
86
Dravet syndrome
prolonged seizures, onset <1 year old, leads to developmental delay and cognitive impairment
87
Dravet syndrome gene
SCN1A
88
General US incidence of CF
1/3,500
89
CF carrier rate, European ancestry
1/25
90
CF symptoms/manifestations
lung disease and infection, liver disease, bowel obstruction, pancreatic insufficiency or pancreatitis, male infertility, diabetes, high Cl- in sweat
91
CFTR mechanism
Mutation of cystic fibrosis transmembrane conductance regulator (CFTR); abnormal transport of chloride, bicarbonate, and sodium
92
Onset of CF symptoms
meconium ileus at birth, malnutrition by 2 months, subtle signs of lung disease by 1-3 months
93
Pancreatic insufficiency in CF
unable to secrete enzymes needed to break down food, leading to nutritional deficiencies
94
Pancreatitis in CF
pancreatic sufficient patients
95
Genotype-phenotype correlation for CF
predicts pancreatic, not lung, function
96
Meconium ileus
when baby doesn't pass first stool
97
Congenital Bilateral Absence of the Vas Deferens (CBAVD)
obstructive azoospermia
98
CF life expectancy 2020
46 years
99
Diagnostic criteria CF
2 CF mutations and/or sweat test >60 mmol/L
100
CF NBS
IRT (measure of pancreatic stress), 43 panel mutation analysis; positive if high IRT and at least one mutation found
Immunoreactive trypsinogen (IRT) is a pancreatic enzyme
101
Sweat test age
4 weeks or older
102
CF NBS false negatives
nursery issues (bad or not obtained sample), testing lab (uncommon mutations, IRT below cut off), error in sweat chloride
103
CF therapies: nutrition
enzymes, formulas and supplements, high calorie diet
104
CF therapies: pulmonary
chest physiotherapy, antibiotics, bronchodilators, steroids, mucolytic agents, sinus surgery
105
Female reproductive issue CF
cervical mucus
106
CF gene
CFTR, 7p31.2, 27 exons
107
Most common CF mutations
delta F508
108
Class I CFTR mutation
No functional CFTR created, nonsense and frameshift mutations
109
Class II CFTR mutation
block in processing so protein doesn't reach cell membrane, missense and deletion mutations
110
Class III CFTR mutation
Block in regulation so protein doesn't move chloride through the cell, missense mutations
111
Class IV CFTR mutation
altered conductance so protein moves chloride through at a reduced rate, missense mutations
112
Class V CFTR mutations
reduced synthesis, missense and alternative splicing mutations
113
R117H mutation polyT tract modification
mild mutation modified by cis 5T polyT tract to be more like a moderate mutation (7T and 9T are benign)
114
R117H mutation TG tract modification
TG 13 modifies 5T to make R117H a more severe mutation when all in cis (11 and 12 TG benign alone)
115
CF ACMG panel
23 mutations
116
CF expanded mutation panel
80-200 mutations
117
CFTR Related Metabolic Syndrome (CRMS) or Cystic Fibrosis Screen Positive Inconclusive Diagnosis (CFSPID)
identified by NBS but lack of diagnostic sweat test and/or less than 2 known CF-causing mutations identified
118
Ivacaftor
potentiator that impacts CFTR protein to open up chloride channels in cell membrane (class III mutations)
119
Ivacaftor + Lumacaftor
corrector and potentiator to move the defective CFTR protein to the cell membrane and open up the channel (homozygous deltaF508)
120
Ivafactor + Tezacaftor
corrector and potentiator to move the defective CFTR protein to the cell membrane and open up the channel (homozygous deltaF508 or heterozygous with other mutations)
121
Ivacaftor + Teacaftor + Elexacafor (Trikafta)
corrector and potentiator to move the defective CFTR protein to the cell membrane and open up the channel (at least one copy of deltaF508)
122
Meconium ileus
when baby doesn't pass first stool
123
SMA silent carrier mutation
c.*3+80T>G
