Muscular Dystrophy (TBL) Flashcards
Common presentation of muscular dystrophy?
in a wheel chair at 12 and die by 20-30
What is muscular dystrophy?
Group of inherited, progressive muscle diseases in which
there is necrosis of muscle tissue
What is muscular dystrophy caused by?
distinct mutations in genes affecting proteins found in the cell membrane (sarcolemma), muscle nuclei, ECM, muscle enzymes and contractile proteins
What is the classic Gowers signs?
using body to stand up, sign of DMD
What is pseudohypertrophic calf muscles indicative of?
DMD
During muscle dystrophy, fibers get torn away from what?
the ECM which creates fibrotic lesions
Where are the nuclei located in DMD?
in the center!!! (weird cuz usually skeletal muscle have nuclei on the periphery)
What is the main reason for DMD mutations?
messed up proteins or glycosylation in the attachment area that binds the cell to the ECM
What does BMD cause?
a truncated form of the protein dystrophin
What is DMD?
complete lack of dystrophin
When you have muscle deterioration what will you labs present as?
elevated AST/ALT ratio
elevated creatine kinase
What three things should you get first when seeing a patient you suspect of having muscle problems?
Ancillary tests-> CK, MRI
Clinical features
Family History
What can calf hypertrophy be indicative of?
dystropinopathies
sarcoglycanopathies
When do you have calf wasting?
LGMD2B (dysferlin)
Are dystroglycanopathies dominant, recessive or x linked?
they are x-linked recessive diseases
What gene is dystrophin on?
is it a big or small gene?
Xp21
BIG
Where do mutations occur on the X gene for DMD?
Center (80%)
N-terminal (20%)
What is the most common way to get a dystroglycanopathy?
- 66% patients show large deletions (>1 million base pairs)
5-10% have point mutations,
5% with duplications
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
DMD (clinical features)
In DMD, Where is weakness worse, proximal or distal, lower or upper limb?
PL
proximal, lower
By what age do kids have difficulty climbing stairs? When are they in a wheelchair?
age 8
age 12
What is the cause of death in most patients w/ DMD?
respiratory function
People with DMD often develop (bank) to their spine and get joint contractures
kyphoscoliosis
What happens to your reflexes if you have DMD?
biceps, brachii, triceps, and quadricep reflexes diminish and are absent in 50% of children by 10 years of age
What can occur late in the disease of DMD?
cardiac dysrhythmias and congestive heart failure
Does DMD effect the CNS?
yes
What are the lab values for DMD and what does the MRI look like?
increased CK
Increased AST/ALT
Fat and CT replacement
Do you use electrodiagnostic testing for DMD?
no
What do you need to diagnosis DMD?
Genetic screening
What kind of mutation does DMD have?
translational
What kind of mutation does BMD have?
in frame mutation
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)
What can be used to assess the quantitiy and size of dystrophin?
immunoblot (last resort cuz its painful)
What does dystrophic tissue look like in DMD?
increased CT
central nuclei
presence of regenerating and degenerating fibers
How can you differentiate between duchennes and becker?
quantitiy and amount of protein in specific tissue
determine size of protein
What is the go to for DMD?
gene sequencing
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)
What is the incidence of Beckers?
5/100,000
10% cases are spontaneous
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
What are the lab values and histopathology of BMD?
increased CK
Abnormal EMG
MRI w/ fatty tissue replacement of affected groups
What will immunostaining reveal for BMD?
dystrophin with N-terminal reactive antibodies but not c terminal reactive antibodies (truncated dystrophin proteins)
What will immunoblot reveal for BMD?
abnormal quantity and reduced size of dystrophin protein
Females with translocations at the chromosomal Xp21 site or Turners syndrome may develop (blank)
dystroglycanopathies
Manifesting carriers of DMD or BMD typically develop a mild (blank)
limb-girdle phenotype similiar to BMD
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
What do corticosteroids (prednisone) do and how do they ork?
slow rate of deterioration in children with DMD
alter muscle metabolism
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
HOw should you treat dystropinopathies?
Supportive therapy with a
multidisciplinary approach and
physical therapy
Treat DMD with a (blank) involving neurologists, psychiatrists, physical therapists, speech therapists, respiratory therapists, dietitians, psychologists and genetic counselors.
Multidisciplinary approach
(blank) is critical for DMD and BMD patients because of the contractures that develop early in the disease.
physical therapy
(blank) is a common complication of DMD resulting in pain, aesthetic damage and sometimes ventilator compromise.
scoliosis
(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
Genes encoding dystrophin, glycerol kinase (GKD), and adrenal hypoplasia congenita (DAX1) can occur (blank)
together as contiguous genes on chromosome Xp21
What is the gene order of the X gene?
Xpter-> DAX1-> GKD-> DMD
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.
Children with mutations in DAX1 gene that is responsible for AHC can also have life threatening (blank)
adrenal insufficiency
Mutations encoding the 3’ carboxy terminus of the dystrophin protein usually span the (blank) and should be evaluated for contiguous gene syndrome.
GKD locus
How do you get emery-driefuss muscular dystrophy?
x-linked recessive, mutations in emerin
What is emerin?
a nuclear scaffolding protein localized to the inner nuclear membrane that is involved in the attachment of heterochromatin
What are the effects of emergy-driefuss muscular dystrophy?
wasting and weakness in upper arms, shoulders and legs
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
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
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
If you have an LGMD1 is it autosomal dominant or recessive?
LGMD2?
dominant
recessive
(blank) are a heterogenous group of disorders that clinically resemble dystroglycanopathies except genes are autosomal.
LGMD
What is the prevalence of LGMD?
8-70 per million!! SO super rare
Clinical, laboratory and histopathological features of LGMD’s are (blank).
non-specific
(blank) is caused by mutations in the myotilin gene.
LGMD 1A
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
(blank) is a sarcomeric protein that colocalizes with alph-actinin at the z-disk.
myotilin
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
What are the laboratory features of LGMD 1A?
normal or elevated CK levels
muscle biopsies show rimmed vacuoles and occasional nemaline rod-like inclusions
(blank) is caused by mutations in lamin A/C chromosome 11.
LGMD 1B
What is lamin A/C required for?
nuclear cytoskeleton organization
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
What are the laboratory features of LGMD 1B?
normal or elevated CK levels
(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
(blank) is located on the sarcolemma and is involved in cell signaling and regulation of sodium channels.
caveolin 3
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)
What is the histopathology of LGMD 1C?
non-specific myopathic changes
EM reveals decreased caveoli
What are the laboratory features of LGMD 1C?
normal or elevatd CK
(blank) is caused by mutations in the calpain 3 gene.
LGMD 2A (calpain 3)
What is the most common LGMD in eastern Europe, Spain, Italy and Brazil?
LGMD 2A (calpain 3)
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)
What is the histopathology of LGMD2A (calpainopathies)?
myofiber size variation
endomysial CT
What are the laboratory features of LGMD 2A (calpain 3)?
normal or elevated CK
MRI scan show fat and CT replacement
How do you diagnosis calpain 3?
western blot and sequencing (gold standard)
What presents with scapula wing?
LGMD 2A (calpain)
What is caused by mutations in the dysferlin gene on chrom 2
LGMD2B (miyoshi myopathy)
(blank) account ~1% of LGMDs but ~60% of distal myopathies.
dysferlinopathies
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
What is the histopathology of LGMD2B?
dystrophic muscle features
non-myopathic features in affected muscles
occasional endomysial or perivascular inflammatory process
What are the lab features of LGMD2B and miyoshi myopathy?
elevated levels of CK
What is the messed up gene in LGMD2B and miyoshi myopathy?
dysferlin
What are the 2 distinct phenotypes of messed up dysferlin?
LGMD 2B
Miyoshi Myopathy
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
What is autosomal recessive with adult onset and slow progression?
dysferline (LGMD2B/ MM)
What are the four genes that make up sarcoglycanopathies?
LGMD2C, LGMD2D, LGMDE, LGMDF
What is this: onset 1st -3rd decade loss of ambulation 2nd-4th decade CK markedly increased cardiac involvement elevated CK levels
sacoglycanopathies
T or F?
Mutations in any of the four sarcoglycan genes can cause LGMD2C, LGMD2D, LGMD2E and LGMD2F. All are autosomal recessive
True
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
sarcoglycanopathies account for greater than (blank) % of patients with a limb-girdle pattern and positive dystrophin.
10
What is the most common sarcoglycanopathy?
alpha-sarcolycanopathy
(blank) deficiences may account for up to 50% of patients with muscular dystrophy in North Africa.
sarcoglycan
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
What is this: trunk and limb weakness high CK disease is variable (but DMD like) calf hypertrophy Cardiac is fine
Sarcoglycanopathies
(blank) is associated with severe weakness and mimics DMD in its progression and loss of ambulation
LGMD2C
In sarcoglycanopathies, what is disease severity dependent on?
whether the protein is absent or reduced
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
Which is more severe, homo for LGMD2I or hetero?
hetero
You get calf hypertrophy in all except for which?
LGMD2B (dysferline, miyoshi myopathy)
Which LGMD have cardiac involvement, which is cardiac involvement rare?
sarcoglycan and FKRP
Calpain and Dysferlin
Which have DMD-like phenotypes?
sarcoglycan, calpain, and FKRP
Which has a vary wide range of phenotypes?
FKRP (can get absence of symptoms in 4th decade)
(blank) are a family of structural basement membrane components with major influences on cells.
laminins
What are these clinical features of:
hypotonia, weakness, onset birth to 6 months, increased CK
congenital muscular dystrophies
What is MDC1A?
merosin deficient congenital muscular dystrophy type 1A caused by absence of the lamin 2’s
(blank) is caused by mutations in the LAMA2 gene on Chr 6 with complete or partial absence of laminin-211 and 221 (merosin)
MDC1A
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
What is the histopathology and lab features of MDC1A?
small muscle fibers, inflammatory cells, myofiber loss and fibrosis and increased CK
(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)
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)
These selenoprotein N disorders (multi mini core disease and rigid spine syndrome) share the same core (blank).
clinical features
What are the 2 collagen VI muscular dystrophies?
bethlem myopathy
ullrich congenital MD
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
Which collagen VI muscular dystrophy is this: severe and progressive recessive from birth contractures and distal laxity respiratory muscles abnormal scarring
Ullrich congenital MD
What disorders are these:
rough texture to skin, abnormal teeth, overflexibility.
collagen VI
How can you tell you have a collagen disorder via histology?
collagen staining and you can see collagen is all fuzzy
What are dystroglycanopathies?
having defective glycosylation w/ alpha dystroglycan
Patients with E-H dystroglycanopathies have…?
patients with I-L dystroglycanopathies have….?
mutations in FKRP
mutations in LARGE
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
What is this: problems with POMT1 (glycosylation of alpha-dystroglycan) severe detected on early antenatal UA encephaloceles frequent type II lissencephaly
Walker Warburg Syndrome
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
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
What is this:
mutations in the fukutin gene on chromo 9. Autosomal recessive inheritance pattern.
Fukuyama
(blank) is a glycosyl transferase and part of a pathway involved in the glycosylation of alpha-dystroglycan (laminin binding)
Fukutin
What do you get a secondary loss of in fukuyama congenital muscular dystrophy?
laminin-alpha 2 and alpha-dystroglycan
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
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
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
Do you die of fukyama?
yes by 16
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
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 :(
Does myotonic dystrophy type 1 show anticipation or penetrance?
BOTH!
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
Are myotonic dystrophys (type 1 and 2) dominant or recessive?
dominant
DM2 and PROMM are (blank) disorders
allelic
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
When do people typically manifest DM2?
20-60 years of age
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
Which as more anticipation, DM1 or DM2?
DM2
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 :(
Does fascioscapulohumeral dystrophy show anticipation?
yes
