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GCD 8917 > Quiz 4 > Flashcards

Quiz 4 Flashcards

1
Q

2 sections of PNS

A

1) Autonomic nervous system: Unconscious body functions

2) Somatic nervous system: Conscious control of the muscles

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2
Q

3 types of neuron

A

1) Sensory Neuron
2) Interneuron
3) Motor Neuron

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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

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4
Q

Testing to Diagnose Neuromuscular Disorders

A

1) Electromyography (EMG)
2) Nerve Conduction Studies (NCS)
3) MRI Imaging, Muscle Biopsy and IHC staining

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5
Q

What does Spinal Muscular Atrophy (SMA) affect?

A

Lower motor neurons (anterior horn cells)

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6
Q

What does Amyotrophic Lateral Sclerosis

(ALS) affect?

A

Upper and lower motor neurons

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7
Q

What does Kennedy’s disease affect?

A

Lower motor neurons

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8
Q

What does Hereditary Spastic Paraplegia affect?

A

Upper motor neurons

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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

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10
Q

Main function of PNS

A

use sensory & motor neurons to connect the CNS to the rest of the body

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11
Q

Creatine Kinase (CK)

A

Enzyme in brain, heart and skeletal muscle that is released I to blood when muscles are damaged

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12
Q

Electromyography (EMG)

A

the electrical recording of muscle activity

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13
Q

Nerve conduction study

A

Measures speed and strength of nerve signals

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14
Q

Spinal Muscular Atrophy (SMA)

A

Motor neuron disorder

Autosomal Recessive

progressive loss of lower motor neurons

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15
Q

SMA symptoms

A

1) Proximal and lower limb weakness
2) Hypotonia
3) respiratory failure

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16
Q

What are the number/types of SMA are there?

A

0-4

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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

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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

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19
Q

SMA NBS

A

SMN1 exon 7 deletion only

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20
Q

Zolgensma

A

SMA gene therapy for <2 year olds

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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

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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

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23
Q

Nusinersen (Spinraza)

A

Taken throughout life - changes splicing to include exon 7 in SMN2 gene

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24
Q

amyotrophic lateral sclerosis (ALS)

A

Motor neuron disorder

Autosomal Dominant

Progressive and asymmetrical loss of muscle movement

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25
Q

Frontotemporal Dementia

A

Frontal and temporal regions degenerate

Personality, behavior and language changes

Can occur with ALS

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26
Q

ALS causal gene

A

C9orf72;

Hexanucleotide repeat expansion

Repeat number does not correlate with severity

> 30 pathogenic

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27
Q

ALS susceptibility genes

A

VCP and SOD1

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28
Q

Spinal and Bulbar Muscular Atrophy (Kennedy Disease)

A

Motor neuron disorder

X-linked; degeneration of lower motor neurons

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29
Q

SBMA symptoms and onset

A

Proximal and distal muscle weakness, muscle atrophy, difficulty walking, androgen insensitivity in some (females asymptomatic)

18-64 years (most in 30-40s)

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30
Q

SBMA genetics

A

CAG repeat expansion in androgen receptor (AR) gene

> 37 repeats is pathogenic

Increasing repeats increases severity and decreases age of onset

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31
Q

Hereditary Spastic Paraplegia (HSP)

A

Motor neuron disorder

most commonly Autosomal Dominant

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32
Q

HSP types and onset

A

Pure/uncomplicated and complicated; early childhood through late adulthood

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33
Q

pure HSP symptoms

A

Impacts lower body, spasticity, atypical gait

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34
Q

Complicated HSP symptoms

A

Symptoms of pure plus other symptoms (cognitive impairment, epilepsy, etc)

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35
Q

Dystrophinopathies

A

Mutations in dystrophin gene (DMD)

X-linked

Elevated CK

Muscle cramps

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36
Q

Duchenne Muscular Dystrophy (DMD)

A

Delayed motor milestones

Abnormal gait

Gower maneuver

Serum CK > 10x normal

Hypertrophic calf muscles

Require wheelchair by age 12

Cardiomyopathy

Life expectancy 24 years

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37
Q

Becker muscular dystrophy (BMD)

A

Similar but less severe than DMD, later onset muscle weakness, cardiomyopathy, median survival 40 year

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38
Q

DMD-associated Dilated Cardiomyopathy (DCM)

A

Left ventricular dilation and congestive heart failure; males 20-40 years, females later

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39
Q

Female dystrophinopathy carriers

A

15-20% have mild-moderate muscle weakness, elevated CK, increased risk for DCM

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40
Q

DMD gene

A

Largest gene

Deletions/duplications most common

2/3 of affected males inherited mutation from their mother

Reading frame rule (in frame cause milder phenotype)

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41
Q

Exon skipping treatment

A

Skips exon that disrupts the reading frame; DMD to BMD phenotype

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42
Q

Limb Girdle Muscular Dystrophy (LGMD) types

A

Type 1, Autosomal Dominant

Type 2, Autosomal Recessive

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43
Q

LGMD symptoms and onset

A

proximal muscle weakness (shoulder and pelvic girdle),

Cardiomyopathy, or

Respiratory problems

Varaible age of onset

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44
Q

Facioscapulohumeral muscular dystrophy (FSHD) types

A

FSHD1 (95%), Autosomal Dominant

FSHD2 (5%), unclear inheritance

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45
Q

FSHD symptoms

A

Weakness and atrophy in the face

Shoulder blades (scapular winging)

Upper arms

Rarely affects cardiac muscles

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46
Q

FSHD (Facioscapulohumeral muscular dystrophy) onset

A

childhood to adult, 50% have symptoms before age 20

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47
Q

FSHD1 genetics

A

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

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48
Q

FSHD1 genetics details

A

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

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49
Q

FSHD2 genetics

A

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

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50
Q

Myotonic dystrophy type 1 (DM1)

A

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
Q

Classic DM1 (Myotonic Dystrophy Type 1) symptoms and age of onset

A

1) weakness
2) myotonia
3) cataracts
4) cardiac arrhythmia
5) avoidant/passive-aggressive personality;

10-30 years

52
Q

Congenital DM1 (Myotonic Dystrophy Type 1) symptoms and age of onset

A

infantile hypotonia, respiratory deficits, intellectual disability, classic signs as adults; birth-10 years

53
Q

Myotonic dystrophy type 2 (DM2)

A

CCTG repeat within complex repeat motif in CNBP gene; no anticipation and no correlation with repeat size and disease severity

54
Q

DM2 symptoms

A

myotonia and muscle weakness, cataracts, type 2 diabetes, cardiomyopathy

55
Q

Collagen VI-related muscular dystrophies

A

affect skeletal muscle and connective tissue; COL6A1, COL6A2, COL6A3 genes

56
Q

Bethlem muscular dystrophy

A

autosomal dominant; muscle weakness, hypotonia, contractures, slowly progressive

57
Q

Ullrich congenital muscular dystrophy

A

autosomal recessive; severe muscle weakness beginning soon after birth, respiratory involvement

58
Q

Charcot Marie Tooth

A

peripheral neuropathy; demyelination, axonal, or both; sensory and motor nerve damage; longer nerves impacted first

59
Q

Charcot Marie Tooth symptoms

A

numbness and tingling, balance issues, muscle weakness and atrophy, foot drop

60
Q

CMT type 1, 2, 3, and 4

A

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
Q

CMT lettered subtypes

A

determined by genetic testing

62
Q

CMT1A

A

most common type, autosomal dominant, PMP22 duplication

63
Q

CMT1X

A

second most common type, x linked dominant

64
Q

CMT4C inheritance

A

Autosomal Recessive

65
Q

Hereditary neuropathy with liability to pressure palsies (HNPP)

A

demyelinating, impacts sensory and motor neurons, onset 20s-30s, episodic symptoms in response to pressure

66
Q

HNPP genetics

A

Autosomal Dominant

PMP22 loss of function mutations

Most commonly complete PMP22 deletion

67
Q

Ataxia Telangiectasia (AT) symptoms and onset

A

progressive cerebellar ataxia, jerking, and tremors, swallowing difficulties; immunodeficiency, increased risk for malignancy; onset 1-4 years

68
Q

AT genetics

A

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
Q

Spinocerebellar ataxias (SCAs)

A

degeneration of the cerebellum and spinal cord; progressive incoordination of walking

70
Q

SCA symptoms

A

ataxia, poor coordination of hand and eye movements

71
Q

SCA (Spinocerebellar ataxia) genetics

A

Autosomal Dominant, some types due to repeat expansions

72
Q

Friedreich ataxia

A

slowly progressive ataxia with onset before age 25

73
Q

Typical Friedreich ataxia symptoms

A

progressive ataxia, peripheral neuropathy, muscle weakness, dysphagia, cardiomyopathy

74
Q

Atypical Friedreich ataxia

A

late onset (after 25 years)

75
Q

Friedreich ataxia genetics

A

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
Q

Neuronal ceroid lipofuscinosis (NCL, Batten disease)

A

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
Q

CLN1 (NCL)

A

Infantile onset, floppy, epilepsy, death by mid-childhood (7 y.o.)

78
Q

CLN3 (NCL)

A

juvenile onset, vision loss, epilepsy, unsteady gait, death 15-35 years

79
Q

Huntington’s disease

A

progressive breakdown (degeneration) of nerve cells in the brain

mood, memory, movement

80
Q

Huntington’s disease genetics

A

HTT gene, CAG repeat expansion, inverse relationship between disease severity and repeat number, anticipation (most commonly maternal)

81
Q

Epilepsy types of seizures

A

generalized versus focal/partial

82
Q

Tonic clonic seizure

A

generalized seizure, unconsciousness, convlusions, muscle rigidity

83
Q

Absence seizure

A

staring into space

84
Q

Epilepsy genetic testing yield

A

higher for rare forms, neonatal onset, and uncontrolled types

85
Q

Epilepsy genetic testing options

A

CMA (Chromosomal Microarray Analysis)

epilepsy panel (del/dup analysis but many VUS (variants of uncertain significance))

WES (Whole Exome Sequencing)

86
Q

Dravet syndrome

A

prolonged seizures, onset <1 year old, leads to developmental delay and cognitive impairment

87
Q

Dravet syndrome gene

A

SCN1A

88
Q

General US incidence of CF

A

1/3,500

89
Q

CF carrier rate, European ancestry

A

1/25

90
Q

CF symptoms/manifestations

A

lung disease and infection, liver disease, bowel obstruction, pancreatic insufficiency or pancreatitis, male infertility, diabetes, high Cl- in sweat

91
Q

CFTR mechanism

A

Mutation of cystic fibrosis transmembrane conductance regulator (CFTR); abnormal transport of chloride, bicarbonate, and sodium

92
Q

Onset of CF symptoms

A

meconium ileus at birth, malnutrition by 2 months, subtle signs of lung disease by 1-3 months

93
Q

Pancreatic insufficiency in CF

A

unable to secrete enzymes needed to break down food, leading to nutritional deficiencies

94
Q

Pancreatitis in CF

A

pancreatic sufficient patients

95
Q

Genotype-phenotype correlation for CF

A

predicts pancreatic, not lung, function

96
Q

Meconium ileus

A

when baby doesn’t pass first stool

97
Q

Congenital Bilateral Absence of the Vas Deferens (CBAVD)

A

obstructive azoospermia

98
Q

CF life expectancy 2020

A

46 years

99
Q

Diagnostic criteria CF

A

2 CF mutations and/or sweat test >60 mmol/L

100
Q

CF NBS

A

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
Q

Sweat test age

A

4 weeks or older

102
Q

CF NBS false negatives

A

nursery issues (bad or not obtained sample), testing lab (uncommon mutations, IRT below cut off), error in sweat chloride

103
Q

CF therapies: nutrition

A

enzymes, formulas and supplements, high calorie diet

104
Q

CF therapies: pulmonary

A

chest physiotherapy, antibiotics, bronchodilators, steroids, mucolytic agents, sinus surgery

105
Q

Female reproductive issue CF

A

cervical mucus

106
Q

CF gene

A

CFTR, 7p31.2, 27 exons

107
Q

Most common CF mutations

A

delta F508

108
Q

Class I CFTR mutation

A

No functional CFTR created, nonsense and frameshift mutations

109
Q

Class II CFTR mutation

A

block in processing so protein doesn’t reach cell membrane, missense and deletion mutations

110
Q

Class III CFTR mutation

A

Block in regulation so protein doesn’t move chloride through the cell, missense mutations

111
Q

Class IV CFTR mutation

A

altered conductance so protein moves chloride through at a reduced rate, missense mutations

112
Q

Class V CFTR mutations

A

reduced synthesis, missense and alternative splicing mutations

113
Q

R117H mutation polyT tract modification

A

mild mutation modified by cis 5T polyT tract to be more like a moderate mutation (7T and 9T are benign)

114
Q

R117H mutation TG tract modification

A

TG 13 modifies 5T to make R117H a more severe mutation when all in cis (11 and 12 TG benign alone)

115
Q

CF ACMG panel

A

23 mutations

116
Q

CF expanded mutation panel

A

80-200 mutations

117
Q

CFTR Related Metabolic Syndrome (CRMS) or Cystic Fibrosis Screen Positive Inconclusive Diagnosis (CFSPID)

A

identified by NBS but lack of diagnostic sweat test and/or less than 2 known CF-causing mutations identified

118
Q

Ivacaftor

A

potentiator that impacts CFTR protein to open up chloride channels in cell membrane (class III mutations)

119
Q

Ivacaftor + Lumacaftor

A

corrector and potentiator to move the defective CFTR protein to the cell membrane and open up the channel (homozygous deltaF508)

120
Q

Ivafactor + Tezacaftor

A

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
Q

Ivacaftor + Teacaftor + Elexacafor (Trikafta)

A

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
Q

Meconium ileus

A

when baby doesn’t pass first stool

123
Q

SMA silent carrier mutation

A

c.*3+80T>G

GCD 8917 (5 decks)

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