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