Muscular Dystrophy (TBL) Flashcards
1
Q
Common presentation of muscular dystrophy?
A
in a wheel chair at 12 and die by 20-30
2
Q
What is muscular dystrophy?
A
Group of inherited, progressive muscle diseases in which
there is necrosis of muscle tissue
3
Q
What is muscular dystrophy caused by?
A
distinct mutations in genes affecting proteins found in the cell membrane (sarcolemma), muscle nuclei, ECM, muscle enzymes and contractile proteins
4
Q
What is the classic Gowers signs?
A
using body to stand up, sign of DMD
5
Q
What is pseudohypertrophic calf muscles indicative of?
A
DMD
6
Q
During muscle dystrophy, fibers get torn away from what?
A
the ECM which creates fibrotic lesions
7
Q
Where are the nuclei located in DMD?
A
in the center!!! (weird cuz usually skeletal muscle have nuclei on the periphery)
8
Q
What is the main reason for DMD mutations?
A
messed up proteins or glycosylation in the attachment area that binds the cell to the ECM
9
Q
What does BMD cause?
A
a truncated form of the protein dystrophin
10
Q
What is DMD?
A
complete lack of dystrophin
11
Q
When you have muscle deterioration what will you labs present as?
A
elevated AST/ALT ratio
elevated creatine kinase
12
Q
What three things should you get first when seeing a patient you suspect of having muscle problems?
A
Ancillary tests-> CK, MRI
Clinical features
Family History
13
Q
What can calf hypertrophy be indicative of?
A
dystropinopathies
sarcoglycanopathies
14
Q
When do you have calf wasting?
A
LGMD2B (dysferlin)
15
Q
Are dystroglycanopathies dominant, recessive or x linked?
A
they are x-linked recessive diseases
16
Q
What gene is dystrophin on?
is it a big or small gene?
A
Xp21
BIG
17
Q
Where do mutations occur on the X gene for DMD?
A
Center (80%)
N-terminal (20%)
18
Q
What is the most common way to get a dystroglycanopathy?
A
- 66% patients show large deletions (>1 million base pairs)
5-10% have point mutations,
5% with duplications
19
Q
What is this:
Appear normal at birth, achieve mile stones,
neck and flexors have some weakness, wide base, waddling gait (2-6 yrs of age), tendency to be toe walkers, calf hypertrophy is often present, Progressive leg weakness leads to increasing falls from 2-6 years of age
Exhibit Gower sign
A
DMD (clinical features)
20
Q
In DMD, Where is weakness worse, proximal or distal, lower or upper limb?
A
PL
proximal, lower
21
Q
By what age do kids have difficulty climbing stairs? When are they in a wheelchair?
A
age 8
age 12
22
Q
What is the cause of death in most patients w/ DMD?
A
respiratory function
23
Q
People with DMD often develop (bank) to their spine and get joint contractures
A
kyphoscoliosis
24
Q
What happens to your reflexes if you have DMD?
A
biceps, brachii, triceps, and quadricep reflexes diminish and are absent in 50% of children by 10 years of age
25
What can occur late in the disease of DMD?
cardiac dysrhythmias and congestive heart failure
26
Does DMD effect the CNS?
yes
27
What are the lab values for DMD and what does the MRI look like?
increased CK
Increased AST/ALT
Fat and CT replacement
28
Do you use electrodiagnostic testing for DMD?
no
29
What do you need to diagnosis DMD?
Genetic screening
30
What kind of mutation does DMD have?
translational
31
What kind of mutation does BMD have?
in frame mutation
32
Tell me about the Histopathology of DMD?
reduced/absent dystrophin
scattered necrotic or regenerating myofibers in variable sizes,
increased CT and addition of small rounded regenerating myofibers
inflammatory infilitrate (cytoxic T cells 2/3 and macrophages 1/3)
33
What can be used to assess the quantitiy and size of dystrophin?
immunoblot (last resort cuz its painful)
34
What does dystrophic tissue look like in DMD?
increased CT
central nuclei
presence of regenerating and degenerating fibers
35
How can you differentiate between duchennes and becker?
quantitiy and amount of protein in specific tissue
| determine size of protein
36
What is the go to for DMD?
gene sequencing
37
What is a milder for of dystroglycanopathy and can be distinguished from DMD clincallly by the slower rate of progression and analysis of dystrophin?
BMD (becker muscular dystrophy)
38
What is the incidence of Beckers?
5/100,000
| 10% cases are spontaneous
39
```
What is this:
Family history compatible with X-linked recessive inheritance
Ambulation past 15 years of age
Limb Girdle pattern of muscle weakness
Calf hypertrophy
Cardiac abnormalities later in life
reduced life expectancy
```
clinical features of BMD
40
What are the lab values and histopathology of BMD?
increased CK
Abnormal EMG
MRI w/ fatty tissue replacement of affected groups
41
What will immunostaining reveal for BMD?
dystrophin with N-terminal reactive antibodies but not c terminal reactive antibodies (truncated dystrophin proteins)
42
What will immunoblot reveal for BMD?
abnormal quantity and reduced size of dystrophin protein
43
Females with translocations at the chromosomal Xp21 site or Turners syndrome may develop (blank)
dystroglycanopathies
44
Manifesting carriers of DMD or BMD typically develop a mild (blank)
limb-girdle phenotype similiar to BMD
45
For a treatment for dystrophinopathies, (blank) has been shown to increase muscle strength and function since as early as 10 days and sustained for up to 3 years.
prednisone
46
What do corticosteroids (prednisone) do and how do they ork?
slow rate of deterioration in children with DMD
| alter muscle metabolism
47
What are these:
Side affects of high dose treatments: weight gain, excessive hair growth, irritability, stunted growth and hyperactivity, increased chance of infection, glucose intolerance, cataract formation, oestoporosis, osteonecrosis AND
problems with Cardiac function
side affects of corticosteroids
48
HOw should you treat dystropinopathies?
Supportive therapy with a
multidisciplinary approach and
physical therapy
49
Treat DMD with a (blank) involving neurologists, psychiatrists, physical therapists, speech therapists, respiratory therapists, dietitians, psychologists and genetic counselors.
Multidisciplinary approach
50
(blank) is critical for DMD and BMD patients because of the contractures that develop early in the disease.
physical therapy
51
(blank) is a common complication of DMD resulting in pain, aesthetic damage and sometimes ventilator compromise.
scoliosis
52
(blank) is considered with patients exeeding 35 degrees scoliosis and in significant discomfort often improves life quality but does not improve respiratory function.
spinal fusion
53
Genes encoding dystrophin, glycerol kinase (GKD), and adrenal hypoplasia congenita (DAX1) can occur (blank)
together as contiguous genes on chromosome Xp21
54
What is the gene order of the X gene?
Xpter-> DAX1-> GKD-> DMD
55
Since dystrophin, GKD, and DAX1 are on the same gene, depending on the extent of the mutation patients may exhibit (blank)
combined diseases (children with DMD and GKD exhibit in addition to severe muscle weakness, severe pyschomoter delay, episodic nausea, vomiting and stupor associated with GKD deficiency.
56
Children with mutations in DAX1 gene that is responsible for AHC can also have life threatening (blank)
adrenal insufficiency
57
Mutations encoding the 3' carboxy terminus of the dystrophin protein usually span the (blank) and should be evaluated for contiguous gene syndrome.
GKD locus
58
How do you get emery-driefuss muscular dystrophy?
x-linked recessive, mutations in emerin
59
What is emerin?
a nuclear scaffolding protein localized to the inner nuclear membrane that is involved in the attachment of heterochromatin
60
What are the effects of emergy-driefuss muscular dystrophy?
wasting and weakness in upper arms, shoulders and legs
61
What happens to the heart during emery-driefuss muscular dystrophy?
cardiac complications are frequent and include ventricular myocardial disease and conduction block leading to sudden death
62
Can carriers of emery-driefuss muscular dystrophy be affected?
female carriers may develop cardiac dysfunction at older age that can lead to sudden death. This is why carriers should get regular ECGs
63
How can you diagnosis emery-driefuss muscular dystrophy?
CK is elevated
Skin biopsy (cuz emerin is found in a bunch of tissues)-> for diagnosis
and DNA testing for confirmation
64
If you have an LGMD1 is it autosomal dominant or recessive?
| LGMD2?
dominant
| recessive
65
(blank) are a heterogenous group of disorders that clinically resemble dystroglycanopathies except genes are autosomal.
LGMD
66
What is the prevalence of LGMD?
8-70 per million!! SO super rare
67
Clinical, laboratory and histopathological features of LGMD’s are (blank).
non-specific
68
(blank) is caused by mutations in the myotilin gene.
LGMD 1A
69
In the case of LGMD1A, if family history is absent, should you still suspect it in a patient showing symptoms?
yes, because spontaneous mutations are common
70
(blank) is a sarcomeric protein that colocalizes with alph-actinin at the z-disk.
myotilin
71
What are these:
Progressive weakness that may begin in early or late adult life
Distal leg and occasional arm weakness
Patients has associated cardiomyopathy
clinical features of LGMD 1A
72
What are the laboratory features of LGMD 1A?
normal or elevated CK levels
| muscle biopsies show rimmed vacuoles and occasional nemaline rod-like inclusions
73
(blank) is caused by mutations in lamin A/C chromosome 11.
LGMD 1B
74
What is lamin A/C required for?
nuclear cytoskeleton organization
75
What are the clinical features of LGMD 1B?
weakness in hip and shoulder girdle
| cardiac conduction abnormalities that can lead to sudden death requiring a pacemaker
76
What are the laboratory features of LGMD 1B?
normal or elevated CK levels
77
(blank) is caused by mutations in caveolin 3 on chr 3. Spontaneous mutations are common so lack of family history does not exclude diagnosis.
LGMD 1C
78
(blank) is located on the sarcolemma and is involved in cell signaling and regulation of sodium channels.
caveolin 3
79
What are these:
Heterogenous phenotype
Present in childhood or adult life with proximal weakness and exertional myalgias
Calf hypertrophy maybe present
Rippling muscle disease and distal weakness
Clinical features of LGMD 1C (caveolin 3)
80
What is the histopathology of LGMD 1C?
non-specific myopathic changes
| EM reveals decreased caveoli
81
What are the laboratory features of LGMD 1C?
normal or elevatd CK
82
(blank) is caused by mutations in the calpain 3 gene.
LGMD 2A (calpain 3)
83
What is the most common LGMD in eastern Europe, Spain, Italy and Brazil?
LGMD 2A (calpain 3)
84
What is this:
Affects pelvic-girdle muscles and posterior thigh muscles
2-5 years later periscapular and humoral muscle weakness
Early contractures at elbows and calves
Approximately 50% of patients non-ambulatory by 20 years of age
Life expectancy is normal
cliical features of LGMD 2A (calpainopathies)
85
What is the histopathology of LGMD2A (calpainopathies)?
myofiber size variation
| endomysial CT
86
What are the laboratory features of LGMD 2A (calpain 3)?
normal or elevated CK
| MRI scan show fat and CT replacement
87
How do you diagnosis calpain 3?
western blot and sequencing (gold standard)
88
What presents with scapula wing?
LGMD 2A (calpain)
89
What is caused by mutations in the dysferlin gene on chrom 2
LGMD2B (miyoshi myopathy)
90
(blank) account ~1% of LGMDs but ~60% of distal myopathies.
dysferlinopathies
91
What are this:
present in adolescene and early adult life
weakness and atrophy of calf muscles
disease progression is slow, some patients lose ambulation in their 20s while others are able to walk late in life.
Clinical features of LGMD2B and miyoshi myopathy
92
What is the histopathology of LGMD2B?
dystrophic muscle features
non-myopathic features in affected muscles
occasional endomysial or perivascular inflammatory process
93
What are the lab features of LGMD2B and miyoshi myopathy?
elevated levels of CK
94
What is the messed up gene in LGMD2B and miyoshi myopathy?
dysferlin
95
What are the 2 distinct phenotypes of messed up dysferlin?
LGMD 2B
| Miyoshi Myopathy
96
How can you tell the difference between LGMD2B and Miyoshi Myopathy?
LGMD 2B has muscle weakness in proximal lower girdle muscles
| Miyoshi Myopathy has muscle weakness restricted to calf muscles
97
What is autosomal recessive with adult onset and slow progression?
dysferline (LGMD2B/ MM)
98
What are the four genes that make up sarcoglycanopathies?
LGMD2C, LGMD2D, LGMDE, LGMDF
99
```
What is this:
onset 1st -3rd decade
loss of ambulation 2nd-4th decade
CK markedly increased
cardiac involvement
elevated CK levels
```
sacoglycanopathies
100
T or F?
| Mutations in any of the four sarcoglycan genes can cause LGMD2C, LGMD2D, LGMD2E and LGMD2F. All are autosomal recessive
True
101
The (blank) are a tightly associated protein complex and loss of one member of the complex often results in loss or reduced levels of the others making exact diagnosis tricky.
sarcoglycans
102
sarcoglycanopathies account for greater than (blank) % of patients with a limb-girdle pattern and positive dystrophin.
10
103
What is the most common sarcoglycanopathy?
alpha-sarcolycanopathy
104
(blank) deficiences may account for up to 50% of patients with muscular dystrophy in North Africa.
sarcoglycan
105
How can you tell that you dont have DMD or BMD, but instead you have a sarcoglycanopathy?
you can tell you have a sarcoglycanopathy if you have normal dystrophin
106
```
What is this:
trunk and limb weakness
high CK
disease is variable (but DMD like)
calf hypertrophy
Cardiac is fine
```
Sarcoglycanopathies
107
(blank) is associated with severe weakness and mimics DMD in its progression and loss of ambulation
LGMD2C
108
In sarcoglycanopathies, what is disease severity dependent on?
whether the protein is absent or reduced
109
```
What is this:
onset variable
commonest form in UK and Germany
Clinical variability
calf, leg, tongue hypertrophy
cardiomyopathy
respiratory failure
increased CK
```
LGMD 2I- FKRP
110
Which is more severe, homo for LGMD2I or hetero?
hetero
111
You get calf hypertrophy in all except for which?
LGMD2B (dysferline, miyoshi myopathy)
112
Which LGMD have cardiac involvement, which is cardiac involvement rare?
sarcoglycan and FKRP
| Calpain and Dysferlin
113
Which have DMD-like phenotypes?
sarcoglycan, calpain, and FKRP
114
Which has a vary wide range of phenotypes?
FKRP (can get absence of symptoms in 4th decade)
115
(blank) are a family of structural basement membrane components with major influences on cells.
laminins
116
What are these clinical features of:
| hypotonia, weakness, onset birth to 6 months, increased CK
congenital muscular dystrophies
117
What is MDC1A?
merosin deficient congenital muscular dystrophy type 1A caused by absence of the lamin 2's
118
(blank) is caused by mutations in the LAMA2 gene on Chr 6 with complete or partial absence of laminin-211 and 221 (merosin)
MDC1A
119
What are these clinical features of:
Severe weakness of the trunk and limbs and hypotonia at birth
Prominent contractures of the feet and hips are present
Although intelligence is normal, the incidence of epilepsy is 12% to 20%
Brain MRI can reveal increased signal in the white matter on T2-weighted images. Computed tomography (CT) of the head reveals lucencies of the white matter.
MDC1A
120
What is the histopathology and lab features of MDC1A?
small muscle fibers, inflammatory cells, myofiber loss and fibrosis and increased CK
121
(blank) is critical for myelinization of neurons so you will see changes in the brain. So people with this deficiency may have seizures. Can see it white matter changes on cerebral MRI. BUT people with this disease still have normal intelligience just lots of seizures.
Merosin (laminin alpha 2 deficiency)
122
Selenoprotein N disorders are associated with 2 autosmal recessive conditions; what are they?
multi-mini core disease (congential myopathy)
| Rigid Spine syndrome (congenital muscular dystrophy)
123
These selenoprotein N disorders (multi mini core disease and rigid spine syndrome) share the same core (blank).
clinical features
124
What are the 2 collagen VI muscular dystrophies?
bethlem myopathy
| ullrich congenital MD
125
Which collagen VI muscular dystrophy is this:
| mild, dominant, early childhood, muscle weakness and wasting, contractures
```
Bethlem myopathy
(Beth is an MD)i.e mild, dominant
```
126
```
Which collagen VI muscular dystrophy is this:
severe and progressive
recessive
from birth
contractures and distal laxity
respiratory muscles
abnormal scarring
```
Ullrich congenital MD
127
What disorders are these:
| rough texture to skin, abnormal teeth, overflexibility.
collagen VI
128
How can you tell you have a collagen disorder via histology?
collagen staining and you can see collagen is all fuzzy
129
What are dystroglycanopathies?
having defective glycosylation w/ alpha dystroglycan
130
Patients with E-H dystroglycanopathies have...?
| patients with I-L dystroglycanopathies have....?
mutations in FKRP
| mutations in LARGE
131
What is this:
Pertains to alpha dystroglycan; there are series of steps it goes through in the golgi to become glycosylated and go hook up with lamina. The early it occurs (towards nucleus) the more severe the disease.
You need glycosylation so they can stick to lamina.
dystroglycanopathies
132
```
What is this:
problems with POMT1 (glycosylation of alpha-dystroglycan)
severe
detected on early antenatal UA
encephaloceles frequent
type II lissencephaly
```
Walker Warburg Syndrome
133
```
What is this:
problems with POMGnT1
seen in all pop, heterogeneous
secondary merosin and alpha DG deficiency (abn glycosyl)
MRI-> T2 abnormal, decreases with time.
```
Muscle-eye-brain disease -POMGnT1
134
```
What is this:
severe phenotype clinically and histopathologically
generalized leg hypertrophy
macroglossia
increased CK
(N) brain, intellect, NCS
LGMD1->allelic varient-> most common LGMD in UK
dilated cardiomyopathy very common
```
MDCIC-FKRP
135
What is this:
| mutations in the fukutin gene on chromo 9. Autosomal recessive inheritance pattern.
Fukuyama
136
(blank) is a glycosyl transferase and part of a pathway involved in the glycosylation of alpha-dystroglycan (laminin binding)
Fukutin
137
What do you get a secondary loss of in fukuyama congenital muscular dystrophy?
laminin-alpha 2 and alpha-dystroglycan
138
What are the clinical features of fukyama?
```
normal at birth,
some floppy babies
joint contractures with hip, knee and ankle
skull asymmetry
often severely mentally retarded
```
139
What is the histopathology and lab values of fukuyama congenital muscular dystrophy?
myofiber size variability, myofiber loss and CLN, muscle fibrosis and inflammation with increased CK levels and brain abnormalities on MRI and CT
140
What is this:
Patients of Japanese origin
homozygous founder mutation
die by average 16y
heterozygotes for point mutation - 13% - severe
no heterozygotes without founder mutation reported - ?embryonic lethal
fukutin = putative glycosyl transferase
fukuyama CMD
141
Do you die of fukyama?
yes by 16
142
What is this:
characterized by progressive muscle wasting
and weakness and myotonia
● Autosomal dominant inheritance with an incidence of
~1/8000 live births
Mutation occurs in untranslated region of DMPK gene which contains CTG repeats
myotonic dystrophy type 1
143
Why does mytonic dystrophy type 1 occur?
Untranslated DMPK gene has CTG repeats that undergo mutation and you get expansion of these and then you get disease :(
144
Does myotonic dystrophy type 1 show anticipation or penetrance?
BOTH!
145
When do you usually see clinical signs of myotonic dystrophy (DMI) and what are the clinical symptoms?
early teenage years-> get weakness in hands and distal muscles and footdrop. Long face with mournal expression.Cardiac disease common
146
Are myotonic dystrophys (type 1 and 2) dominant or recessive?
dominant
147
DM2 and PROMM are (blank) disorders
allelic
148
What is this:
Caused by CCTG expansion in intron 1 of the zinc finger protein ZNF9. As with DM1 the transcribed mRNA with expanded CCTG repeats accumulates as focal collections in the nucleus and are toxic to cells.
Mytonic dystrophy type 2
149
When do people typically manifest DM2?
20-60 years of age
150
What is this:
● Elevated CK, insulin insensitivity in 75% of patients, low testosterone in 29% of patients. Non specific myopathic histology.
myotonic dystrophy type 2
151
Which as more anticipation, DM1 or DM2?
DM2
152
How do you get facioscapulohymeral dystrophy
AD, 1/100,000, caused by deletion in D4Z4 or by hypomethylation of D4Z4 umewhich results in expression of the DUX 4 gene :(
153
Does fascioscapulohumeral dystrophy show anticipation?
yes
