TBL: Muscular Dystrophies Flashcards
Group of inherited, progressive muscle diseases in which
there is necrosis of muscle tissue
muscular dystrophies
Muscular dystrophies are caused by distinct (blank) in genes affecting proteins found in the cell membrane (sarcolemma), muscle nuclei, ECM, muscle enzymes and contractile proteins.
mutations
A mutation in dystrophin can lead to one of these two disorders
Duchenne’s muscular dystrophy
Becker’s muscular dystrophy
A mutation in laminin-2 can lead to this disorder
MDC1A
Ancillary tests for muscular dystrophy
Creatine kinase levels
MRI
X-linked recessive diseases related to dystrophin
dystroglycanopathies
The major dystroglycanopathies
DMD
BMD
The most common form of muscular dystrophy with an incidence of ~1/3,500 live male births. The mutation rate is about 1/3 of the incidence of the disease in males, or about 1/10,000
DMD
Incidence rate of DMD
1/3500
Incidence of BMD
1/18,000 to 1/31,000 male births
X-linked dilated cardiomyopathy Isolated quadriceps myopathy Muscle cramps with myoglobinuria Asymptomatic elevation of muscle enzymes Manifesting DMD and BMD carrier females
Other dystroglycanopathies that occur at lower incidence
a structural protein which provides integrity to the sarcolemma
Dystrophin
The dystrophin gene is on the (blank) chromosome and is a huge gene. What are some kinds of mutations that can cause dystroglycanopathies?
X-chromosome; 66% deletions, 5-10% point mutations, 5% duplications
Incidence of DMD vs prevalence
1/3500 is the incidence
1/18,000 is the prevalence
What fraction of DMD occurs as a result of spontaneous mutations?
1/3
How do most male children present at birth? When do they begin to have a wide-base, waddling gait and increasing leg weakness and falls?
appear normal at birth; these symptoms begin around age 2-6
What is the clinical sign that is characteristic of DMD?
Gower sign
Is weakness worse proximally or distally? In the lower limbs or upper limbs?
worse proximally; worse in lower limbs
By what age do children have difficulty climbing stairs?
By what age are they confined to a wheelchair?
8; 12
Development of kyphoscoliosis and joint contractures
The biceps brachii, triceps and quadriceps reflexes diminish and are absent in 50% of children by 10 years of age
Respiratory function gradually declines and leads to death in most patients in their early twenties
Cardiac dysrhythmias and congestive heart failure can occur late in the disease
Central nervous system involvement is involved in DMD.
DMD clinical features
What is markedly elevated in DMD (50-100X normal) at birth and peaks around 3 y/o
serum creatine kinase
These two liver enzymes are usually elevated in DMD
ALT
AST
What can an MRI reveal in DMD patients?
fat and connective tissue replacement in muscle
What can histology reveal in DMD patients?
reduced or absent dystrophin
What can muscle biopsies reveal in DMD patients?
scattered necrotic and regenerating myofibers, variability in myofiber size, increased CT, and small rounded regenerating myofibers
Histology of dystrophic tissue will show what three features?
increased connective tissue
central nuclei (instead of peripheral)
presence of regenerating and degenerating fibers
T/F: When comparing DMD and BMD, it is important to quantify the amount of protein in specific tissue and the size of protein.
True
Two ways to analyze protein expression in DMD patients
immunohistochemistry
Western blot
What is the ultimate diagnostic tool for muscular dystrophy?
gene sequencing
Milder form of dystroglycanopathy and can be distinguished from DMD clinically by the slower rate of progression and presence of dystrophin
Becker muscular dystrophy
Incidence of BMD?
5/100,000
Clinical features that help with diagnosis of BMD
family history compatible with X-linked recessive inheritance
ambulation past 15 years of age
Limb Girdle pattern of muscle weakness
Calf hypertrophy
T/F: In BDM, there are cardiac abnormalities similar to DMD, and a reduced life expectancy.
Truth be told!
What is observed for the following in BMD: Serum CK EMG MRI Histopathology
serum CK elevated
EMG abnormal
MRI can show fatty tissue replacement in affected muscles
Histopath similar to DMD, but less severe
Immunostaining reveals the presence of dystrophin with (blank) reactive antibodies but not (blank) reactive antibodies (truncated dystrophin protein) in most BMD cases
N-terminal; C-terminal
Immunoblot reveals (blank) quantity and (blank) size of dystrophin protein.
abnormal; reduced
What happens to women who are carriers of the DMD or BMD gene?
Women who are carriers are normally non-symptomatic, but a few develop muscle weakness- explained by the Lyon hypothesis: skewed X-inactivation of the normal X-chromosome and dystrophin gene
T/F: Females with translocations at the chromosomal Xp21 site or Turners may develop dystroglycanopathies
True
T/F: Manifesting carriers typically develop a mild limb-girdle phenotype similar to BMD. Laboratory and histologic features of manifesting carriers are similar to DMD and BMD.
That’s true..
What can be used to treat dystrophinopathies?
corticosteroids!
This has been shown to increase muscle strength and function since as early as 10 days and sustained for up to 3 years. Slows the rate of deterioration in children with DMD
Prednisone
What’s this: weight gain, excessive hair growth, irritability, stunted growth and hyperactivity, increased chance of infection, glucose intolerance, cataract formation, oestoporosis, osteonecrosis, problems with cardiac function
side effects of high doses of corticosteroid treatment
This is critical for DMD and BMD patients because of the contractures that develop early in the disease
physical therapy
This is a common complication of DMD resulting in pain, aesthetic damage and sometimes ventilator (respiratory) compromise.
scoliosis
This is considered with patients exceeding 35° 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 together as contiguous genes on Chr Xp21. Gene order is Xpter-DAX1-GKD-DMD-centromere. Why is this important?
Depending on the extent of the mutation patients may exhibit combined diseases e.g. children with DMD and GKD exhibit in addition to severe muscle weakness, severe pyschomoter delay, episodic nausea, vomiting and stupor associated with GKD deficiency
● Most common form is mutations in Emerin, a nuclear scaffolding protein localized to the inner nuclear membrane, involved in the attachment of heterochromatin
● X-linked recessive
● Wasting and weakness in upper arms, shoulders and legs
● Cardiac complications are frequent and include ventricular myocardial disease and conduction block leading to sudden death.
● Female carriers may develop cardiac dysfunction at older age that can lead to sudden death. There carriers should get regular ECG’s
● CK is elevated. Emerin is found in many tissues therefore skin biopsy can be used in diagnosis and confirmed by DNA testing
Emery-Driefuss muscular dystrophy
Emery-Driefuss muscular dystrophy caused by a mutation in (blank).
Emerin
Emerin is found in many tissues therefore what procedure can be used in diagnosis and confirmed by DNA testing?
skin biopsy
Autosomal dominant forms of Limb-girdle muscular dystrophy have what number in their name? Autosomal recessive forms of Limb-girdle muscular dystrophy have what number in their name?
1; 2
Which two forms of Limb-girdle muscular dystrophy are X-linked?
Dystrophin (DMD/BMD)
Emerin (EDMD)
Heterogeneous group of disorders that clinically resemble dystroglycanopathies except genes are autosomal
limb-girdle muscular dystrophies
Autosomal dominant LGMDs are classified as type (blank), while autosomal recessive are type (blank).
1; 2
What is the prevalence of LGMDs?
rare! 8 per million
caused by mutations in the myotilin gene
LGMD 1A
What does myotilin do?
it’s a sarcomeric protein that colocalizes with alpha actinin at the Z-disk
caused by mutations in lamin
LGMD 1B
What does lamin do?
it is required for nuclear cytoskeleton organization
caused by mutations in caveolin-3
LGMD 1C
Where is caveolin-3 located? What is it involved in?
located on the sarcolemma; involved in cell signaling and regulation of sodium channels
Histopathology of this disease reveals decreased caveoli.
LGMD 1C
caused by mutations in the calpain-3 gene
LGMD 2A
This LGMD has a normal life expectancy
LGMD 2A
What can be used to test for calpainopathies?
Western Blot
What is a classic clinical feature of LGMD 2A, or calpainopathy?
winged scapula
Caused by mutations in the dysferlin gene
LGMD 2B
Miyoshi Myopathy
Both LGMD2B and Miyoshi Myopathy are caused by mutations in dysferlin. They are both autosomal recessive. Adult-onset, slowly progressive. So what distinguished them from one another?
LGMD2B presents as muscle weakness in proximal lower girdle muscles
Miyoshi Myopathy presents as muscle weakness in calf muscles
How can you remember that Miyoshi Myopathy is just in the calf muscles?
Think of a weenie little Asian boy with no calves
● Onset 1st-3rd decade
● Loss of ambulation 2nd-4th decade
● CK markedly
● Cardiac involvement
sarcoglycanopathies
Mutations in any of the four sarcoglycan genes can cause LGMD2C, LGMD2D, LGMD2E and LGMD2F. All are autosomal recessive
sarcoglycanopathies
T/F: The sarcoglycans 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
True
Account for >10% of patients with a limb-girdle pattern and positive dystrophin
sarcoglycanopathies
T/F: In sarcoglycanopathies, disease severity is dependent on which protein is absent.
True
In this disease, the onset is variable. Wide range of phenotypes. Commonest form in UK/Germany. Calf/leg/tongue hypertrophy. Increased CK, risk of cardiomyopathy and respiratory failure.
LGMD 2I - FKRP
Calf hypertrophy is present in all forms of LGMD except which?
2B (dysferlin)
Which two LGMDs have cardiac involvement? In which is it rare?
sarcoglycan and FKRP
rare in calpain and dysferlin deficiency
Which LGMDs have DMD-like phenotype?
sarcoglycan, FKRP, and calpain
Which LGMD has a range of phenotypes?
FKRP
Clinical presentation of congenital muscular dystrophies? Pathology
hypotonia, weakness, onset at birth to 6 months, increased CK
pathology: dystrophic biopsy
What is a congenital muscular dystrophy which is merosin deficient and causes no or minor brain abnormalities?
MDC1A
Caused by mutations in the LAMA2 gene
MDC1A
What protein is completely or partially absent in MDC1A?
laminin 211 and 221 (merosin)
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
Selenoprotein N disorders are associated with two autosomal recessive conditions
multi-mini core disease
rigid spine syndrome
Two Collagen VI muscular dystrophies. Which is mild, which is severe?
Bethlem myopathy is mild, Ullrich Congenital MD is severe
Which collagen VI muscular dystrophy is associated with contractures and distal laxity?
Ullrich
Dystroglycanopathies are associated with major brain abnormalities. List three of em.
Fukuyama
Muscle Eye Brain Disease
Walker Warburg syndrome
This is a severe dystroglycanopathy, detected on early antenatal ultrasound, encephalocoeles frequent, type II lissencephaly
Walker Warburg Syndrome
Problem gene POMT1 which codes for O-mannosyltransferase and the glycosylation of alpha-dystroglycan
Walker Warburg Syndrome
Problem gene POMGnT1, seen in all populations, secondary merosin and alpha DG deficiency
Muscle eye brain disease
Severe phenotype clinically and histopathologically
generalised leg hypertrophy, macroglossia
Increased CK, (N) brain, (N) intellect, (N) NCS
LGMD2I - allelic variant - most common
LGMD in UK (>20%)
dilated cardiomyopathy very common
MDC1C - FKRP
Mutations in the Fukutin gene. Autosomal recessive.
Fukuyama congenital muscular dys
What is Fukutin involved in?
Fukutin is a glycosyl transferase and is involved in the glycosylation of alpha-dystroglycan
Patients are typically of Japanese origin
It is a homozygous founder mutation
Pts die by avg age 16
Heterozygous for a point mutation
Fukuyama CMD
Characterized by progressive muscle wasting and weakness and myotonia. Caused by mutations in myotonic dystrophy protein kinase gene. CTG repeats expand into the hundreds or thousands, and the mutation shows anticipation. Typical presentation is early teenage onset, weakness in hands and distal muscles and footdrop. Long face with mournful expression
myotonic dystrophy type 1
Characterized by progressive muscle wasting and weakness and myotonia. Allelic disorder. Caused by CCTG expansion. Most people manifest disease between 20-60 y/o. Starts with pain and stiffness in thigh muscles. Anticipation is milder.
myotonic dystrophy type 2 or PROMM
Autosomal dominant MD caused by a deletion in a repeating sequence D4Z4. When this region is hypomethylated it causes a myopathy. Expression of DUX4 gene is responsible. Severity of disease depends on size of deletion.
Facioscapulohumeral dystrophy
