Muscular Dystrophy-TBL Flashcards
Muscular dystrophies can be caused by mutations to genes coding for proteins in which areas?
sarcolemma muscle nuclei ECM muscle enzymes contractile proteins protein complexes linking the muscle to the ECM
What is dystrophin?
it is a protein found on the sarcolemma that links to laminin in the ECM
Why is it bad when the molecular glue linking the muscle to the ECM is missing?
b/c when the muscle contracts, it tears away from the ECM. Atrophy occurs. Leaks occur.
Mutations to the protein dystrophin account for which 2 main conditions? What are the differences b/w these 2 mainly?
BMD & DMD
DMD is more severe, the complete absence of the dystrophin protein
BMD is less severe–there is still dystrophin present, but it is only partially functional & it is a truncated protein
MDC1A affects which gene? Does it affect girls or boys more?
laminin-2 gene
it is autosomal–affects boys & girls equally
**it codes for a part of laminin…if this gene is mutated–don’t have the important laminin holding the ECM together
Where is the dysferlin protein found? What conditions does a mutation in this gene cause?
found in the sarcolemma–attached to caveolin-3.
2 main conditions: one more severe form of the other
LGMD2B
Miyoshi Myopathy
T/F AST & other liver enzymes have lower levels in patients with muscular dystrophy.
False. They have much higher levels!!
Calf hypertrophy is found in which types of muscular dystrophy?
dystroglycanopathies
sarcoglycanopathies
FKRP
Calf wasting is found in which types of muscular dystrophy?
LGMD2B–where dysferlin protein is messed up!!
What characteristics do all dystroglycanopathies share?
all affect the dystrophin protein
X-linked recessive inheritance
What are the 2 main types of dystroglycanopathies?
DMD & BMD
Aside from DMD & BMD, what are the other forms of dystrophinopathies? These occur at lower incidence.
X-linked dilated cardiomyopathy Isolated quadriceps myopathy Muscle cramps with myoglobinuria Asymptomatic elevation of muscle enzymes Manifesting DMD and BMD carrier females
T/F The dystrophin gene is relatively small.
FALSE! It is the largest gene!
Where is the dystrophin gene found?
xp21
How long is the dystrophin gene in the genomic DNA? How many exons make up the dystrophin gene? How large is the transcript for the dystrophin gene?
2.4 megabases of DNA
79 exons
14kb transcript
Can you see a patient with DMD that doesn’t have a family history of it?
YES! 1/3 cases of DMD occur w/ spontaneous mutation to the dystrophin gene
Which part of the gene is usu mutated w/ dystrophinopathies?
80% of cases mutation is in the center of the gene
20% of cases the mutation is near the N-terminus
T/F More often than not, the mutation to the dystrophin gene in patients w/ DMD is near the carboxyl end.
FALSE! N-terminus, & when not that–center!
What would be considered a large deletion to DNA? How many DMD patients have a large deletion?
large deletion: more than 1 million base pairs
66% of patients
What percentage of DMD patients have a point mutation in their dystrophin gene? What percentage have a duplication?
Point mutation: 5-10%
Duplication: 5%
T/F the course of DMD is very unpredictable.
False. It is very predictable, sadly.
Why might a mom take their child into the doctor initially? If this patient is later discovered to have DMD…
maybe b/c the child was having a hard time holding himself up & was falling down.
What do DMD patients usu die from?
pulmonary dysfunction, perhaps an infection (diaphragm muscle weak)
cardiomyopathy
Is the CNS involved in DMD?
Yes.
What will a DMD patient’s labs likely show?
high CK
high AST & ALT
What would a DMD patient’s MRI show?
fat & CT replacement in muscle
What is electrodiagnostic testing? When would it prove to be useful with DMD patients?
it tests conduction pathways
not useful when there is a family hx of DMD
may be useful in a patient with spontaneous BMD (maybe CK isn’t markedly elevated & this test would help)
What does diagnosis of DMD require?
genetic screening for identifiable mutations of the dystrophin gene
In a patient w/ DMD…what would a western blot of dystrophin protein show?
A complete absence of the dystrophin protein!
Immunohistochemistry includes what kind of staining? What would this show for a DMD & BMD patient?
involves fluorescent antibody staining
DMD: complete absence of dystrophin on the sarcolemma (seen in cross section)
BMD: light staining (some dystrophin)
How is DMD inherited? Where is the mutation found? Which protein is affected? What type of muscular dystrophy is it considered? What is its incidence rate? How many of these cases are from spontaneous mutations? What is the prevalence?
X-linked recessive
Xp21
dystrophin
dystrophinopathies
Incidence Rate: 1/35,000 male live births
Spontaneous? 1/3 cases of DMD no family hx
Prevalence: 1/18K (lower than incidence b/c so many patients die at a young age)
How is BMD inherited? Where is the mutation found? Which protein is affected? What type of muscular dystrophy is it considered? What is its incidence rate?
X-linked recessive Xp21 dystrophin dystroglycanopathy Incidence Rate: 1/18K-1/31K
How is MDC1A inherited? Which gene is affected? Which protein is affected?
Autosomal Recessive
6q22-23
laminin-alpha 2 chain (of laminin)
How does a DMD patient appear at the following ages:
Birth
Slightly after birth
2-6 years
Birth: normal @ birth After birth: meets all initial milestones with a slight delay on close inspection, neck flexors are a little weak 2-6 years: wide-base waddling gait toe walker calf hypertrophy progressive leg weakness-->falls Gower sign
What is the Gower sign?
when rising, a child will walk up with their hands to rise. They will put their hands on their knees & push themselves up.
In patients with DMD, where is their muscle weakness usu focused?
more proximally & in lower limbs (rather than upper limbs)
How does a DMD patient appear at the following ages: 8 yrs 10 yrs 12 yrs 15 yrs Early 20s
8 years: hard to climb stairs 10 years: biceps, triceps, & quad reflexes are weaker or absent 12 years: confined to a wheelchair kyphoscoliosis joint contractures 15 years: definitely scoliosis spine by then Early 20s: respiratory function decreases cardiac dysrhythmias increase congestive heart failure increases
DMD
What will you see in immunocytochemistry?
absent dystrophin
DMD
Muscle biopsies–what will you see?
scattered necrotic & regenerating fibers
DMD
histology of muscle–what will you see?
increased CT increased inflammation central nuclei gaps b/w muscle fibers fibrotic lesions
In the inflammation that is seen in DMD patients’ muscle fibers…what are the cells that are present? What proportion?
cytotoxic T cells (2/3)
macrophages (1/3)
If you want to look @ the quantity & size of dystrophin protein…what do you look @?
immunoblot
What percentage of BMD cases arise from spontaneous mutations?
10% of the cases
T/F DMD has a slower rate of progression than BMD.
FALSE Other way around
What are the clinical features of BMD?
family hx consistent w/ x-linked recessive (many men with the disease) (also seen in DMD)
ambulation past 15 yrs of age (as opposed to 12 in DMD)
Limb Girdle pattern of muscle weakness (also seen in DMD)
calf pseudohypertrophy (also seen in DMD)
cardiac abnormalities (also seen in DMD)
reduced life expectancy (less severe than DMD)
BMD:
What would you see with CK levels? EMG? MRI? Histopath/Immunostaining? Immunoblot
CK levels: elevated
EMG: abnormal conduction in muscles
MRI: fatty tissue replacement of some muscle groups
Histopath/Immunostaining: less severe than DMD, dystrophin w/ N-terminal reactive antibodies but no C-terminal reactive antibodies
Immunoblot: smaller quantity & size of the dystrophin
Why is it that there are no C-terminal reactive antibodies for BMD?
b/c it is a truncated protein. Has the N…but doesn’t get all the way to the C.
Which set of tests would you conduct first to test for DMD/BMD? Why?
Histopath/Muscle Biopsy
EMG/MRI
Definitely EMG/MRI b/c it is much less painful than Histopath/Muscle Biopsy (very painful).
Do women ever experience symptoms of DMD/BMD when they carry an affected X or no b/c it is inherited in an X-linked recessive pattern?
Sometimes, strangely enough, they actually do.
One case: If they have Turner’s syndrome (1 X & it is affected).
Another Case: translocation @ the Xp21 site (in both?)
Another Case: Carriers–Lyon hypothesis–skewed x-inactivation of the normal X chromosome & dystrophin gene
What are the symptoms of a carrier female who seems to have DMD/BMD?
typically they are much closer to a milder form: BMD
they have limb girdle-type muscle weakness
laboratory & histologic features similar to muscular dystrophy patients
What are the treatment options for dystrophinopathies?
Corticosteroids
Supportive therapy: including a number of different mental & physical health specialists & maybe physical therapy & surgery
What type of corticosteroid is often used to treat dystrophinopathies? How long does it work for? What does it do?
Prednisone
works for up to 3 years
alters muscle metabolism (doesn’t seem to work thru immunosuppression)
slows rate of deterioration
What are the negative side effects of long-term & high-dose use of prednisone?
could hurt heart function could also cause: weight gain hair growth irritability stunted growth hyperactivity more susceptibility to infection glucose intolerance cataract formation steroid-induced osteoporosis osteonecrosis
Why is physical therapy especially important for DMD/BMD patients?
b/c of the contractures they experience
When would spinal fusion surgery be necessary for DMD/BMD patients? What would this help? What wouldn’t this help?
When their scoliosis exceeds 35 degrees. This would help their comfort, but not help the resp problems associated w/ scoliosis.
What is contiguous gene syndrome?
this is a syndrome where a deletion is so large that it affects multiple genes. So the patient can have a super complex phenotype, including aspects of multiple diseases. This happens in some patients with DMD.
What is the order of the genes next to DMD that make it susceptible to contiguous gene syndrome?
Centromere-DMD-GKD-DAXI-Xpter
What is GKD? What are some of its symptoms?
glycerol kinase deficiency severe psychomotor delay episodic nausea vomiting stupor
What condition is DAXI associated with? What are the results of a deletion here?
adrenal hypoplasia congenita
lifethreatening adrenal insufficiency
What is Emery-Driefuss Muscular Dystrophy (EDMD)?
a condition caused by a mutation to the gene encoding the emerin protein.
