2.5.2. PATH LAB - Muscle Tissue Pathology Flashcards
(179 cards)
1
Q
What is a sarcoma?
A
malignant mesenchymal tumor
2
Q
Disorders of neuromuscular junctions present as what?
A
painless weakness
3
Q
How do we recognize Myasthenia Gravis in patients?
A
Myasthenia gravis is often associated with thymic hyperplasia or thymoma, frequently involves ocular muscles, and is marked by fluctuating weakness that worsens with exertion
4
Q
How do we recognize Lambert-Eaton myasthenic syndrome?
A
Lambert-Eaton myasthenic presents with weakness in the extremities that improves with repetitive stimulation and is often a paraneoplastic disorder associated with lung cancer
5
Q
What gives rise to congential myasthenic syndromes?
A
Genetic defects in NMJ proteins
6
Q
How do bacterial toxins like Botox work?
A
Bacterial toxins such as botox can block NM transmission by blocking the release of ACh
Target SNARE proteins (review botulism lecture)
7
Q
What are the three main inflammatory myopathies of skeletal muscle?
A
The three main inflammatory myopathies are polymyositis, dermatomyositis, and inclusion body myositis
8
Q
What is Inclusion body myositis?
A
Inclusion body myositis is a chronic progressive disease of older patients associated with rimmed vacuoles
9
Q
What is Dermatomyositis?
A
Dermatomyositis occurs in children and adults, the latter frequently as a paraneoplastic disorder. Immune damage to small blood vessels and perifascicular atrophy are common features
10
Q
What is polymyositis?
A
Polymyositis is an adult onset myopathy caused by CD8+ T cells
11
Q
When we say "soft tissue" to what are we referring?
A
adipose tissue, blood vessels, lymph vessels, skeletal muscle, fibrous connective tissue & PNS (e.g., schwann cells)
12
Q
How often do soft tissue malignancies occur compare to benign tumors?
A
With the exception of skeletal muscle neoplasms, benign soft tissue tumors outnumber their malignant soft tissue tumors 100:1
13
Q
Most common area for soft tissue neoplasms?
A
Thigh, most common areas generally are the extremities
14
Q
What causes soft tissue sarcomas?
A
The majority of sarcomas are sporadic and have no known predisposing cause, but the best guess is that tumors arise from pluripotent mesenchymal stem cells, which acquire somatic “driver” mutations in oncogenes and tumor suppressor genes
15
Q
A small minority of soft tissue neoplasms are associated with germline mutations in tumor suppressor genes. What are the associated conditions?
A
Neurofibromatosis 1, Gardner syndrome, Li-Fraumeni syndrome, Osler-Weber Rendu syndrome
16
Q
When comparing a simple vs. a complex karyotype for adult sarcomas, what percentage of sarcomas are each one?
A
Simple Karyotype (15-20%) (typically younger) Complex karyotype (80-85%) (typically older)
17
Q
When comparing a simple vs. a complex karyotype for adult sarcomas, what ploidy pattern do we see with each?
A
Simple Karyotype Sarcomas are euploid [having an exact number of the haploid number of chromosomes] tumors Complex Karyotype Tumors are aneuploid [genes or chromosomal regions present in extra/fewer copies than normal] or polyploid
18
Q
What are the tumors we can see in adipose tissue?
A
Lipoma and liposarcoma
19
Q
What is the most common soft tissue tumor of adulthood?
A
Lipoma
20
Q
What is a lipoma?
A
A benign tumor of fat
21
Q
How do Lipomas present and how do we get rid of them?
A
Lipomas are soft, mobile, and painless (except angiolipoma) Cured by simple excision (mostly superficial)
22
Q
How does a lipoma appear on histology?
A
Different sizes and shapes of adipocytes, well-circumscribed Clear cytoplasm, small nuclei, very few vessels, and low mitoses - Not aggressively growing
23
Q
Who typically gets liposarcomas?
A
Folks in their 50s and 60s
24
Q
Where do liposarcomas typically occur?
A
in the deep soft tissues of the proximal extremities and in the retroperitoneum
25
Characterize a conventional lipoma (what it is, how common is it, where and when does it occur)
It is an encapsulated mass of mature adipocytes It is the most common subtype of lipomas It typically occurs in the proximal extremities and trunk in middle aged adults
26
What are the subtypes of liposarcoma?
1. Well-differentiated liposarcoma 2. Myxoid liposarcoma 3. Pleomorphic liposarcoma
27
What do we see with well differentiated liposarcomas?
Well-differentiated slow growing liposarcoma contains adipocytes with scattered atypical spindle cells
28
What do we see with Myxoid liposarcoma?
contains abundant basophilic extracellular matrix, arborizing capillaries and primitive cells at various stages of adipocyte differentiation reminiscent of fetal fat. Has malignant behavior; treatment at early stage is very important
29
What do we see with Pleomorphic liposarcoma?
Pleomorphic liposarcoma consists of sheets of anaplastic cells, bizarre nuclei and variable amounts of immature adipocytes (lipoblasts) Aggressive and frequently metastasizes
30
One of the key genes in the amplified region of chromosome 12q is what?
One of the key genes in the amplified region of chromosome 12q is MDM2 which encodes a potent inhibitor of p53
31
Treatment for liposarcomas?
Treatment: excision followed by post-op radiation (often recurs)
32
Types of fibrous tumors
Nodular Fasciitis Fibromatosis Fibrosarcoma
33
In what age group and with what kind of chromosomal changes do we see simple karyotype sarcomas?
Seen in younger patients Limited/Single chromosomal changes
34
In what age group and with what kind of chromosomal changes do we see complex karyotype sarcomas?
Seen in older patients Many severe chromosomal gains or losses, none of which are recurrent
35
Describe Nodular Fasciitis
A self-limited fibroblastic and myofibroblastic proliferation that typically occurs in young adults in the upper extremity
36
What medical history do we often see connected with the nodular fasciitis?
A history of trauma is present in ~25% of cases
37
Speed of growth for a nodular fasciitis?
the tumors grow rapidly over a period of several weeks or months
38
Treatment for nodular fasciitis?
Typically spontaneously regresses and if excised, it rarely recurs
39
Where do we see nodular fasciitis?
Arises in the deep dermis, subcutis, or muscle
40
Describe the Nodular Fasciitis on gross inspection
Grossly, the lesion is less than 5 cm, circumscribed, or slightly infiltrative
41
Describe the Nodular Fasciitis on histology
Richly cellular and contains plump, immature-appearing fibroblasts and myofibroblasts arranges randomly A gradient of maturation Lymphocytes and extravasated RBCs are common
42
Types of Fibromatosis
Superficial Deep
43
What are the histological features of a conventional lipoma?
Well encapsulated/circumscribed Different sizes and shapes of adipocytes Clear cytoplasm, small nuclei, very few vessels, and low mitoses (not aggressively growing)
44
What is one of the most common sarcomas of adulthood that occurs mainly in people in their 50s to 60s in the deep soft tissues of the proximal extremities and in the retroperitoneum
Liposarcoma
45
Amplification of _______ and ______ are characteristic of well-differentiated and myxoid liposarcomas, respectively
12q13-q15 and t(12;16)
46
One of the key genes in the amplified region of chromosome 12q is \_\_\_\_\_
MDM2
47
MDM2 encodes a potent inhibitor of \_\_\_\_\_
p53
48
Liposarcomas are histologically differentiated into 3 different subtypes; what are they?
1) Well-differentiated liposarcoma 2) Myxoid liposarcoma 3) Pleomorphic liposarcoma
49
Characterize a well-differentiated liposarcoma
Well-differentiated liposarcoma contains adipocytes with scattered atypical spindle cells Closest to normal; inactive Amplification of 12q13-q15; grows slowly
50
Describe the superficial fibromatosis
An infiltrative fibroblastic proliferation that can cause local deformity but has an innocuous clinical course
51
Describe the deep fibromatosis
Large, infiltrative masses that frequently recur but do not metastasize
52
Histology of superficial fibromatosis?
Nodular or poorly defined broad fascicles of fibroblasts in long, sweeping fascicles, surrounded by abundant dense collagen
53
What are the clinical subtypes of superficial fibromatoses?
Palmar Plantar Penile
54
Describe Palmar (Dupuytren contracture) superficial fibromatosis
Irregular or nodular thickening of the palmar fascia. Unilateral or bilateral. Attachment to the overlying skin causes puckering and dimpling Slowly progressive flexion contracture develops that mainly affects the fourth and fifth fingers of the hand
55
Describe plantar superficial fibromatosis
common in young patients, unilateral, and without contractures
56
Describe Penile superficial fibromatosis?
Palpable induration and plantar fibromatoses stabilize and do not progress, in some instances resolving spontaneously Some recur after excision, particularly the plantar variant Also known as Peyronie disease
57
Gross inspection yields what for a deep fibromatosis?
Gray-white, firm, poorly demarcated masses varying from 1 to 15 cm in greatest diameter Rubbery and tough, with marked infiltration of surrounding βmuscle, nerve and fat
58
Describe Pleomorphic Rhabdomyosarcoma
Characterized by numerous large, sometimes multinucleated, bizarre eosinophilic tumor cells and can resemble other pleomorphic sarcomas histologically
59
Gene mutation associated with deep fibromatosis?
Mutations in the APC or β-catenin genes. Both lead to increased Wnt signaling
60
Predisposition for deep fibromatosis?
The majority of tumors are sporadic, but individuals with familial adenomatous polyposis (Gardner syndrome) who have germline APC mutations are predisposed
61
How do deep fibromatoses feel?
In addition to possibly being disfiguring or disabling, deep-seated fibromatosis is occasionally painful
62
Treatment for deep fibromatoses?
Complete excision is difficult Medical therapy with cyclooxygenase 2 inhibitors, tyrosine kinase inhibitors, or hormonal blockade (tamoxifen)
63
Types of fibrosarcomas?
Infantile Adult
64
How do infantile fibrosarcomas look under histology?
Infantile (better prognosis): Mitotic rate with hemorrhage/necrosis
65
How do adult fibrosarcomas look under histology?
“Herringbone pattern”
66
How often are skeletal muscle tumors malignant?
Skeletal muscle neoplasms, in contrast to other mesenchymal histotypes, are almost all malignant
67
What is Rhabdomyoma?
Multiple benign neoplasms; (+) in cardiac tissue in points with tuberous sclerosis
68
Histology of Rhabdomyoma?
Eosinophilic spider-cells with low mitotic activity Strands of myofibrils = spider legs aka spider cells It looks bad, but is it not malignant because it has no mitotic activity
69
What is Rhabdomyosarcoma?
A malignant mesenchymal tumor with skeletal muscle differentiation
70
What kind of cellular damage is caused by Leiomyosarcoma?
Hemorrhagic and necrotic; metastasizes to lungs
71
Describe Alveolar Rhabdomyosarcoma
Traversed by a network of fibrous septae that divide the cells into clusters of aggregates, creating a crude resemblance to pulmonary alveoli
72
Describe Embryonal Rhabdomyosarcoma
Presents as soft gray infiltrative mass Tumor cells mimic skeletal muscle at various stages of embryogenesis
73
Describe Pleomorphic Rhabdomyosarcoma
Characterized by numerous large, sometimes multinucleated, bizarre eosinophilic tumor cells and can resemble other pleomorphic sarcomas histologically
74
What do we use Myogenin for?
Immunohistochemistry (e.g., myogenin) is usually necessary to confirm rhabdomyoblastic differentiation
75
What are sarcoma botryoides?
Variant of Embryonal Rhabdomyosarcoma. Develops in the walls of hollow, mucosal-lined structures They form a submucosal zone of hypercellularity called the cambium layer “A bunch of grapes”
76
Genetic abnormalities associated with the embryonal and pleomorphic subtypes of Rhabdomyosarcoma
Fusions of FOXO1 to either PAX3 or the PAX7 gene (alveolar) PAX3 initiates skeletal muscle differentiation Fusion interferes with the gene expression program that drives differentiation
77
Types of smooth muscle tumors
Leiomyoma Leiomyosarcoma
78
Describe Leiomyoma
A benign tumor of smooth muscle that often arises in the uterus (most common neoplasm in women) Lei = smooth; myo = muscle
79
Genetic connection to Leiomyomas
May be transmitted as an autosomal dominant trait that is also associated with uterine leiomyomas and renal cell carcinoma Germline loss-of-function mutation in the fumarate hydratase gene located on chromosome 1q42.3
80
Histology of leiomyomas?
1 to 2 cm and are composed of fascicles of densely eosinophilic spindle cells that tend to intersect each other at right angles Tapered nuclei (cigar shaped); low mitotic activity
81
Treatment for Leiomyomas
Solitary lesions are easily cured; however, multiple tumors may be so numerous that complete surgical removal is impractical
82
Describe Leiomyosarcomas
Account for 10-20% of soft tissue sarcomas; develop in the deep soft tissues of the extremities and retroperitoneum Present as painless firm masses
83
Histology for Leiomyosarcomas
Consist of eosinophilic spindle cells with blunt-ended, hyperchromatic nuclei arranged in interweaving fascicles Tumor cells contain bundles of thin filaments with dense bodies and pinocytic vesicles Nuclei ARE NOT cigar shaped; they are aggressive and able to grow faster Look for an abnormal mitotic figure
84
Immunohistochemistry for Leiomyosarcoma
Immunohistochemically, they stain with antibodies to smooth muscle actin and desmin
85
What kind of cellular damage is caused by Leiomyosarcoma?
Hemorrhagic and necrotic; metastasizes to lungs
86
Treatment for Leiomyosarcoma? Compare superficial and retroperitoneum.
Superficial or cutaneous leiomyosarcomas are usually small and have a good prognosis; those of the retroperitoneum are large, cannot be entirely excised, and cause death by both local extension and metastatic spread (especially to the lungs) Treatment = wide excision and radiation
87
Types of tumors of uncertain origins?
Synovial Sarcomas Undifferentiated Pleomorphic Sarcoma (UPS)
88
How do synovial sarcomas present?
Patients present with a deep-seated mass that has been present for several years
89
Most common genetic abnormalities associated with synovial sarcomas?
Most show a characteristic chromosomal translocation t(x;18)(p11;q11) producing SS18-SSX1, -SSX2, -SSX4 fusion genes that encode chimeric transcription factors
90
Monophasic synovial sarcomas
Monophasic synovial sarcoma consists of uniform spindle cells with scant cytoplasm and dense chromatin growing in short, tightly packed fascicles. Tumors may calcify.
91
Biphasic Synovial sarcomas
The biphasic type contains, in addition to the spindle cell component, gland-like structures composed of cuboidal to columnar epithelioid cells
92
Distinguishing types of synovial sarcomas?
Immunohistochemistry is helpful in identifying these tumors since the biphasic type is positive for epithelial markers (i.e., keratins)
93
Treatment for synovial sarcomas?
Treated aggressively with limb-sparing surgery and chemotherapy Common sites of metastases are the lung and regional lymph nodes
94
Describe Undifferentiated Pleomorphic Sarcoma (UPS)
Includes malignant mesenchymal tumors with high-grade, pleomorphic cells that cannot be classified into another category Can’t be molecularly, histologically or IHC categorized \*\*Represents the largest category of adult sarcomas
95
Genetic abnormalities associated with UPS?
Most tumors are aneuploid with multiple structural and numerical chromosomal changes
96
Histology for UPS?
Large, gray-white fleshy masses can can grow quite large (10-20 cm) Necrosis and hemorrhage are common Large, anaplastic spindled to polygonal cells with hyperchromatic irregular, sometimes bizarre nuclei
97
Treatment and prognosis for UPS?
Aggressive malignancies that are treated with surgery and adjuvant chemotherapy and/or radiation Prognosis is poor with metastases arising in 30-50% of cases
98
Presentation of diseases of the neuromuscular junction?
Regardless of cause, disorders that impair the function of NMJ tend to present with painless weakness
99
What is the most common cause of disrupted NM transmission
Autoantibodies that inhibit key NMJ proteins are the most common cause of disrupted NM transmission, as found in myasthenia gravis
100
What is myasthenia Gravis?
An autoimmune disease that is usually associated with autoantibodies directed against ACh receptors
101
Pathogenesis of Myasthenia Gravis?
AChR antibodies are thought to lead to the aggregation and degradation of the receptors
102
Association of Myasthenia Gravis with the thymus?
There is a strong association between pathogenic anti-AChR autoantibodies and thymic abnormalities ~10% of patients have a thymoma (tumor of thymic epithelial cells) Additional 30% have thymic hyperplasia
103
What are some clinical features of Myasthenia Gravis?
1. Fluctuating weakness that worsens with exertion 2. Diplopia and ptosis due to involvement of extraocular muscles 3. Determent in muscle response with repeated stimulation
104
Treatment for Myasthenia Gravis?
1. Acetylcholinesterase inhibitors 2. Plasmapheresis and immunosuppressive drugs 3. Decrease autoantibody titers 4. Thymectomy is often effective in patients with thymic hyperplasia or lacking thymic abnormalities
105
What is Lambert-Eaton Myasthenic Syndrome?
An autoimmune disorder caused by antibodies that block ACh release by inhibiting a presynaptic calcium channel
106
Clinical presentation of Lambert-Eaton Myasthenic Syndrome?
In contrast to myasthenia gravis, rapid repetitive stimulation increases muscle response Patients typically present with weakness of their extremities
107
Treatment for Lambert-Eaton Myasthenic Syndrome?
Treatment consists of drugs that increase ACh release by depolarizing synaptic membranes and immunosuppressive agents, such as those used to treat myasthenia gravis
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What are some clinical signs of other congenital myasthenic syndromes?
Many patients present with congential myasthenic syndromes in the perinatal period with poor muscle tone, external eye muscle weakness, and breathing difficulties
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What part of the AChR is typically at falt with congenital myasthenic syndromes?
Commonly loss-of-function mutations in the gene encoding the ε-subunit of the AChR
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What is Botulism?
Botulism is caused by exposure to a neurotoxin that is produced by the anaerobic Gram (+) organism Clostridium botulinum. It blocks the release of ACh from presynaptic neurons
111
What is curare?
Curare is a common name for related muscle relaxants that block AChR, resulting in flaccid paralysis
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What causes skeletal muscle atrophy?
Loss of innervation, disuse, cachexia, old age, and primary myopathies can all produce muscle atrophy
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What type of atrophy do we see with neurogenic disease?
clusters or groups of atrophic fibers
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What type of atrophy do we see with dermatomyositis?
perifascicular atrophy
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What type of atrophy do we see with prolonged corticosteroid therapy or disuse?
116
Compare myogenic and neurogenic injury
Disorders impacting skeletal muscle may do so by damaging myofibers directly (myopathic injury) or by disrupting muscle innervation (neurogenic injury)
117
What happens to muscle when it has been denervated? How about when it gets reinnervated?
Following denervation, myofibers undergo atrophy, often assuming a flattened, angulated shape; reinnervation restores fiber size and shape, but may make a denervated myofiber part of a different motor unit
This can lead to the enlargement of motor units which are susceptible to grouped atrophy
118
Myopathic processes are associated with a distinct set of morphologic changes that include the following
1. Segmental myofiber degeneration and regeneration
2. Myofiber hypertrophy
3. Cytoplasmic inclusions
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Myopathic processes are associated with a distinct set of morphologic changes that include segmental myofiber degeneration and regeneration. What four processes do we see within this set of changes?
Only part of the myofiber undergoes necrosis
Myophagocytosis of damaged myofiber segment
Fusion of activated satellite cells
Regenerating myofibers are rich in RNA and therefore basophilic
120
What cytoplasmic inclusions do we see with myopathic processes?
In the form of vacuoles, aggregates of proteins, or clustered organelles
121
What is Dermatomyositis?
Systemic autoimmune disease that typically presents with proximal muscle weakness (can’t comb hair or climb stairs) and skin changes
122
What cytology signs do we see with dermatomyositis?
Telangiectasias (dilated capillary loops) in the nail folds, eyelids, and gums
Deposition of the complement membrane attack complex (C5b-9)
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What is perifasicular atrophy?
Perifascicular atrophy (inflammation at the edge)
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Immunohistochemistry for Dermatomyositis?
Immunohistochemical studies may identify an infiltrate rich in CD4+ T cells and the deposition of C5b-9 in capillary vessels
125
What are Anti-Mi2 autoantibodies targeting and how do they present?
126
What are Anti-Jo1 autoantibodies targeting and how do they present?
Anti-Jo1 (directed against the enzyme histidyl t-RNA synthetase) are associated with interstitial lung disease, nonerosive arthritis, and a skin rash described as “mechanic’s hand”
127
What are Anti-P155/P140 autoantibodies targeting and how do they present?
Anti-P155/P140 (directed against several transcriptional regulators) are associated with paraneoplastic and juvenile cases of dermatomyositis
128
What is a heliotrope rash?
Lilac colored discoloration of the upper eyelids
129
What are Gottron papules?
Gottron papules: scaling erythematous eruption or dusky red patches over the knuckles, elbows, and knees
130
What is polymyositis?
131
What immune cells are prominent in the inflammatory phase of polymyositis?
CD8+ T cells are a prominent part of the inflammatory infiltrate in affected muscle
132
Distinguishing features of polymyositis?
Degeneration necrotic, regenerating, and atrophic myofibers are typically found in a random or patchy distribution
Perifascicular pattern of atrophy is absent
133
What is inclusion body myositis?
A disease of late adulthood that typically affects patients older than 50 years and is the most common inflammatory myopathy in patients older than age 65
134
What are some traits that are similar between inclusion body myositis and polymyositis?
Patchy often endomysial mononuclear inflammatory cell infiltrates rich in CD8+ T cells
Increased sarcolemmal expression of MHCI antigens
Focal invasion of normal appearing myofibers by inflammatory cells
Admixed degenerating and regenerating myofibers
135
What are some unique traits to only inclusion body myositis?
Abnormal cytoplasmic inclusions (“rimmed vacuoles”)
Tubolofilamentous inclusions in myofibers (seen on EM)
Cytoplasmic inclusions containing proteins typically associated with neurodegenerative diseases, like beta-amyloid, TDP-43, and ubiquitin
Endomysial fibrosis and fatty replacement
136
How does inclusion body myositis respond to routine inflamatory treatments?
Responds poorly to steroids or immunosuppressive therapies, another feature that argues against an inflammatory or immune origin
137
What are toxic myopathies caused by?
Caused by prescription or recreational drugs, or by certain hormonal imbalances
138
Most common complication of statins?
Statins (cholesterol lowering drugs) are the leading culprits of toxic myopathies.
139
Effect of chloroquine and hydroxychloroquine interfere with what aspect of cells?
Chloroquine and hydroxychloroquine (long-term therapy for autoimmune disease) interfere with normal lysosomal function.
Drug-induced lysosomal storage myopathy that presents with slowly progressive muscle weakness
140
Another name for Myosin deficiency myopathy and when do we see it?
ICU myopathy or myosin deficiency myopathy is a neuromuscular disorder seen in patients during the course of treatment for critical illness, especially with corticosteroid therapy
141
What are the 4 congenital myopathies?
142
Compare congenital muscular dystrophies to regular muscular dystrophies?
Adult muscular distrophies are characterized by progressive muscle damage that typically comes to attention after infancy
Exceptions to this rule are the congenital muscular dystrophies; these tend to present in infancy and are often associated with developmental abnormalities of the CNS as well as progressive muscle damage.
143
What are the two groups of congenital myopathies?
1. Conditions with defects in extracellular matrix surrounding myofibers
2. Conditions with abnormalities in receptors for extracellular matrix
144
Describe the histology, cause, and general traits of Ulrich Congenital Muscular Dystrophy:
Causative mutations involve one of three collagen VI alpha genes
Characterized by hypotonia, proximal contractures and distal hyperextensibility
Morphologic hallmark is mismatched expression of normally co-localized matrix proteins perlecan and collagen VI
145
Typical protein modification that causes abnormalities in receptors for extracellular matrix
disrupt the post-translational modification of alpha-dystroglycan by O-linked glycosylation. Mutations of alpha-dystroglycan itself result in fetal demise but defects in its post-translational modification result in milder forms of dystroglycan deficiency
146
What is alpha-dystroglycan expression important for?
Alpha-dystroglycan expression is important for CNS and eye-development.
147
Compare severe and milder cases of alpha-dystroglycan expression problems
Severe cases exhibit features of congenital muscular dystrophy as well as developmental defects of the CNS and eyes that cause seizures, mental retardation, and blindness. Milder forms may only cause skeletal muscle disease.
148
The most common muscular dystrophies are X-linked and stem from mutations that what? Because of this issue, what happens?
The most common muscular dystrophies are X-linked and stem from mutations that disrupt the function of a large structural protein called dystrophin, which causes replacement of skeletal muscle by adipose tissue
149
What is the general mutation that causes Duchenne and Becker muscular dystrophy?
Duchenne and Becker muscular dystrophy are caused by loss-of-function mutations in the dystrophin gene on the X chromosome.
150
Compare the onset and severity of Duchenne muscular dystrophy and Becker muscular dystrophy?
Duchenne muscular dystrophy is the most common early onset form and has a severe progressive phenotype.
Becker muscular dystrophy is a second relatively common dystrophinopathy that is characterized by later disease onset and a milder phenotype
151
What is dystrophin important for? In the cell, what can a defect in this protein cause?
Dystrophin is a key component of the dystrophin glycoprotein complex (DGC) that spans the plasma membrane and serves as a link between the cytoskeleton inside the myofiber and the basement membrane outside of the cell
Provides mechanical stability to the myofiber and its cell membrane during contraction.
Defects may lead to small membrane tears that permit influx of calcium, triggering events the result in myofiber degeneration
152
The gene mutation for Duchenne and Becker are slightly different. What mutations are associated with these two against dystrophin?
Duchenne muscular dystrophy is generally associated with mutations that cause deletion of dystrophin
153
In detail, describe the progression of muscular dystrophies as far as what biopsies of the muscles may look like.
1. At early stages of the disease, fascicular architecture is preserved and there is usually no inflammation except for the presence of myophagocytosis.
2. As the disease progresses, muscle tissue is replaced by collagen and fat cells (“fatty replacement/infiltration”). The remaining myofibers at this point in the course show prominent variation in size, from small atrophic fibers to large hypertrophied fibers.
This remodeling distorts the fascicular architecture of the muscle, which becomes markedly abnormal over time.
154
IHC patterns for Duchenne and Becker muscular dystrophies
Immunohistochemical studies for dystrophin show absence of the normal sarcolemmal staining pattern in Duchenne and reduced staining in Becker
155
In muscular dystrophy, we have ongoing muscular damage. What enzyme elevates because of this? What is the pattern for this enzyme over time?
Because of the ongoing muscle damage, serum creatine kinase is markedly elevated during the first decade of life (and then falls as muscle mass is lost)
156
For Duchenne's, what are the first indications clinically?
The first indications of muscle weakness are clumsiness and inability and inability to keep up with peers; weakness begins in the pelvic girdle
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What is pseudohypertrophy and what does it look like in those with Duchenne's?
Enlargement of the muscles of the lower leg associated with weakness (pseudohypertrophy) is often present
158
What are other hallmarks of Duchenne's besides the muscle weakness and pseudohypertrophy?
1. Scoliosis
2. Worsened respiratory reserve
3. Sleep hypoventilation
4. Cardiomyopathy with arrhythmias
5. Cognitive impairment
159
Causes of death with Duchenne's?
The mean age of death for patients with Duchenne is 25-30 and cause of death is usually respiratory insufficiency, pulmonary infection or heart failure
160
Compare the lethality of Becker's to Duchenne's
Becker presents in later childhood, adolescence or adult life. It is more slowly progressive and life expectancy is near normal.
161
Treatment options for Duchenne's and Becker's?
Treatment currently consists primarily of supportive care. Research is ongoing to establish therapy that restores dystrophin levels in skeletal and cardiac muscles.
162
Describe in general what myotonic dystrophy is as well as its inheritance pattern
An AD multisystem disorder associated with skeletal muscle weakness, cataracts, endocrinopathy, and cardiomyopathy
There is also sustained involuntary contraction of muscles
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What genetic abnormality causes myotonic dystrophy?
Expansions of CTG triplet repeats in the 3’-noncoding region of the myotonic dystrophy protein kinase (DMPK) gene
Toxic gain of function; sequester a protein called muscleblindlike-1 which has an important role in RNA splicing
164
What is Emery-Dreifuss Muscular Dystrophy?
Caused by mutations in genes that encode nuclear lamina proteins.
Clinically marked by a triad consisting of
1. slowly progressive humeroperoneal weakness
2. cardiomyopathy associated with conduction defects
3. early contractures of the Achilles tendon, spine, and elbows
165
What gene defects cause Emery-Dreifuss Muscular Dystrophy, what proteins are affected, and what do those proteins do?
X-linked = EMD1; autosomal = EMD2
Mutations in the genes encoding emerin and lamin, respectively
These proteins help maintain the shape and mechanical stability of the nucleus during muscle contraction
166
Describe Facioscapulohumeral Dystrophy
Associated with pattern of muscle involvement that includes prominent weakness of facial muscles and muscles of shoulder girdle
167
What genetic abnormality causes Facioscapulohumeral Dystrophy and what does this abnormality due biochemically?
Involves overexpression of DUX4 gene located in subtelomeric repeats on the long arm of chromosome 4. Disease is in those who also have single nucleotide polymorphisms (SNPs) immediately 3’ of DUX4 coding sequence.
DUX4 encodes a transcription factor, suggesting that the disease results from overexpression of DUX4 target genes
168
Describe Carnitine palmitoyltransferase II deficiency
169
McArdle disease's enzyme deficiency?
(myophosphorylase deficiency) and is one of the most common glycogen storage diseases affecting skeletal muscle
170
Pathology behind Pompe Disease?
Acid maltase deficiency results in impaired lysosomal conversion of glycogen to glucose
171
What is the most consistent pathologic change in skeletal muscle?
Most consistent pathologic change in skeletal muscle is abnormal aggregates of mitochondria that are seen preferentially in the subsarcolemmal area of affected myofibers, producing an appearance that is referred to as “ragged red fibers”
172
Why are ocular issues so common with skeletal muscle pathologies?
173
What is "floppy infant?"
Neuropathic disorder in which loss of motor neurons leads to muscle weakness and atrophy. AR disorder with an incidence of 1 in 6,000 births and is caused by a loss-of-function mutation in the SMN1 (survival of motor neuron-1) gene
174
What is the inheritance pattern for ion channel myopathies and what do they cause?
AD with variable penetrance
Epilepsy, migraine, movement disorders, peripheral nerve disease, and muscle disease
175
What is the KCNJ2 channel? Associated conditions?
potassium channel, causes Andersen-Twail syndrome (AD associated w/ periodic paralysis, heart arrhythmias, and skeletal abnormalities)
176
What is the SCN4A channel? Associated conditions?
sodium channel, causes several AD disorders for channelopathies
177
What is the CACNA1S channel? Associated conditions?
missense mutations in a subunit of a muscle calcium channel, causes hypokalemic paralysis
178
What is the CLC1 channel and associated conditions?
179
What is the RYR1 channel and associated conditions
RYR1: disrupts the function of the ryanodine receptor, which regulates calcium release from the SR , causes congenital myopathy and malignant hyperthermia
