skeletal muscle pathology (wk9) Flashcards
what are muscular dystrophies
Group of inherited muscle disorders leading to progressive weakness and muscle wastingc
characteristic of muscular dystrophy
Characteristic muscle fiber necrosis and regeneration
which protein is effected in Duchenne muscular dystrophy
dystrophin; loss of function (deletion or frame shift)
is Duchenne x or y linked
x linked
- Female carriers of the mutation can be mildly symptomatic due to unfavourable X- chromosome inactivation
what is the most common muscular dystrophy
Duchenne muscular dystrophy
what is the protein in Duchenne muscular dystrophy a key component of
- Dystrophin is a key component of the dystrophin glycoprotein complex
what does the dystrophin glycoprotein complex do normally
- This complex spans the plasma membrane, linking the cytoskeleton of the muscle fiber with the basement membrane.
- As a result provides mechanical stability to
the muscle fiber and it’s cell membrane (sarcolemma) during muscle contraction
what do defects in the dystrophin glycoprotein complex lead to
sarcolemma tears
§ Calcium influx from ECF àultimately triggering muscle fiber necrosis
what do sarcolemma tears allow for
Ca2+ influx –> necrosis
Duchenne pathogoloy
chronic muscle damage
muscle tissue replaced by collagen and fat cells
atrophy and hypertrophy of remaining muscle fibers
endomysial fibrosis
what is the sign/ test to do for duchenne
Gowers sign
- (+) Gower’s sign: patient often have to push off the thighs in order to stand from sitting
clinical features of duchenne
delayed walking in kids
clumsy and unable to keep up with peers
week pelvic girdle muscles
pseudo hypertrophy of lower leg
cognitive impair + learning disability
age of wheel chair and death in duchenne?
9= wheelchair
§ Patients develop joint contractures, scoliosis, worsening respiratory
reserve and sleep hypoventilation
§ Development of cardiomyopathies and arrhythmias can occur in older patients due to impact of dystrophin in cardiac muscle
25-30= death
- Commonlyfromrespiratoryinsufficiency,pulmonaryinfection, or heart failure
what is elevated in duchenne and then after decreases
creatine kinase
§ Initially high due to ongoing muscle damage
§ Levels decrease with loss of muscle mass
what protein is smaller and shorter in Becker muscular dystrophy
truncated dystrophin
so milder than duchennes
Becker vs duchenne
becker= truncated dystrophin
duchenne= absent dystrophin
is Becker x or y linked
x
onset and progression of Becker muscular dystrophy and life expectancy
- Onset later in later childhood, adolescence, or adulthood
- Generally similar but less severe than Duchenne Muscular dystrophy and has slower progression
- Patients are still at risk of developing dilated cardiomyopathy, but this is very rare compared to Duchenne Muscular dystrophy
- Prognosis:
§ Near-normal life expectancy
what is myotonia
sustained involuntary muscle contractions
what are the 2 types of triplet repeats in myotonic dystrophy
type 1: DMPK gene
type 2: CNBP gene
what type of genetic disorder is myotonic dystrophy
- Autosomal dominant disorder caused by expansion of triplet repeats
type 1 vs type 2 of myotonic dystrophy
- Type I: expansion of CGT trinucleotide repeat within the myotonic dystrophy protein kinase (DMPK) gene
- Type II: CCTG repeat expansion within the gene nucleic acid- binding protein (CNBP) gene
type 1 vs type 2 myotonic dystrophy which affects voluntary vs involuntary
Both types affect voluntary muscles, type I also affects involuntary muscles
type 1 myotonic dystrophy pathogenesis SPARKNOTES
CLC1 chloride channel
Type 1 myotonic dystrophy pathogenesis
Skeletal muscle phenotype may result of “toxic” gain-of- function effect by CGT triplet repeat expansion within the DMPK that disrupts splicing of mRNA transcripts of other proteins, including the transcript of a chloride channel (CLC1)
§ Lack of CLC1 may explain myotonia
Type 2 myotonic dystrophy pathogenesis SPARKNOTES
zinc fingers
type 2 myotonic dystrophy pathogenesis
- CNPB gene codes for a zinc-finger DNA binding protein
is type 1 or type 2 myotonic dystrophy more severe
type 1
peripheral and facial VS proximal (hip and thigh) muscles
which is type 1 and which is type 2 myotonic distrophy
type1- peripheral and face (also involuntary muscles like GI and uterus)
type 2- proximal muscles
type 2 myotonic dystrophy clinical features
- Generally less severe with fewer extra-muscular symptoms
- Tends to affect more proximal-located muscles (thigh and hip)
§ Often causing myalgic painm
type 1 myotonic dystrophy clinical features
- Myotonia, weakness, and wasting of peripheral muscles and
facial muscles
§ Weakness of the hands, ptosis - Can also include: cardiomyopathy, intellectual disability, cataracts and endocrine disorders (abnormal glucose tolerance, male hypogonadism)
- Patients with type I will also experience myotonia of involuntary muscles (eg. GI tract, uterus)
§ Dysphagia, constipation, uterine muscle abnormalities
myotonic dystrophy diagnose and prognosis
via history and genetic testing
reduce life expectancy (54 years) due to respiratory and cardiac disease
what is the most common drug related myopathy>
statin myopathy
what causes a statin myopathy?
decreases cholesterol and depletion of CoQ10
- Decreased cholesterol concentrations may impact sarcolemma
- Depletion of Coq10 (Ubiquinone)
clinical features of statin myopathy
weak muscles after exercise esp thighs
- Myalgias and muscle weakness after exercise are the prominent clinical features; often severe enough to discontinue or switch medication
§ typically affects the thigh muscles
§ CoQ10 seems to help, may improve exercise tolerance
which enzyme is blocked by statins in the cholesterol synthesis pathwya>
HMG CoA reductase (rate limiting step)
myasthenia gravis is an autoimmune condition has autoantibodies against what?
acetylcholine receptors
aka post synaptic (nicotinic) receptors
what is a thymoma (that can be seen in myasthenia gravis)
tumor of thyme epithelial cells
what organ can the anti-act receptor autoantibodies in myasthenia gravis have an effect on?
thyme abnormalities (thymoma or thymic hyperplasia)
who is myasthenia gravis most common in?
- In young adults, it is more commonly found in females, in older adults in males.
what causes the myofiber to not be able to response to Ach at the neuromuscular junction in Ab-Ach
§ Ab-Ach receptor complexes lead to a variety of problem ultimately limit the ability of the myofiber to respond to Ach at the neuromuscular junction:
- Impact turnover of Ach receptors leading decrease in overall number of receptors
- Blocks activation of the Ach receptors
- Can damage the neuromuscular junction due to complement fixation
2 initial findings of myasthenia gravis
ptosis and diplopia
features of myasthenia gravis
proximal muscle weakness, worse with exercise
- Fluctuating proximal muscle weakness
- Ptosis and diplopia are common initial findings
§ Levator palpebrae, extraocular muscles often initially
involved
§ In 15 – 25%, disease is exclusively extraocular - Proximal muscle involvement:
§ diaphragm, neck, facial muscles (snarling smile, difficulty
chewing foods)
§ Dysphagia may develop to both solids and liquids - Usually worse with activity/ exercise and improves with rest (fatiguability)
- Weakness seems to come and go initially (but eventually symptoms become more consistent)
diagnosis of myasthenia gravis
+ antibody screen… and history, physical exam etcp
what is myasthenic crisis RED FLAG
Respiratory weakness becomes severe enough to necessitate intubation
prognosis of myasthenia gravis
Prognosis has improved significantly with current therapies
* Complicationscanincludepneumonia,falls,andmyastheniccrisis § Myasthenic crisis – RED FLAG
* Respiratoryweaknessbecomessevereenoughto necessitate intubation
treat myasthenia gravis
Ach inhibitor drugs
§ Acetylcholinesterase inhibitors (first line of treatment) – increase half-life of Ach in the neuromuscular junction
§ Plasmapheresis & immunosuppressive drugs
§ Thymectomy for patients with a thymoma
2 skeletal muscle tumors
mostly malignant
- Rhabdomyosarcoma
- Synovial Cell sarcoma
Rhabdomyosarcoma; what are the 4 subtypes of this malignant mesenchymal tumor
4 subtypes: Alveolar, Embryonal, Pleomorphic, Spindle cell/sclerosis
what is the malignant cell rhabodomyoblast rich in
myosin and actin
where does Rhabdomyosarcoma occur most commonly
Alveolar and embryonal rhabdomyosarcoma are most common soft tissue sarcoma of childhood
cause of Rhabdomyosarcoma
chromosomal tranlocations
clinical features of Rhabdomyosarcoma
- Tumour is detected as a mass, sometimes painful – metastases tend
to cause respiratory difficulties, bone pain, and bone marrow failure * Tumours can occur anywhere in the body:
§ Head & neck, extremities, genitourinary tract - Embryonic type often tumours in mucosal cavities
(bladder, vagina, nasopharynx, middle ear) - Alveolar type often results in tumours in the extremities
prognosis of rhabdomyosarcoma
- Tumours are aggressive, with a poor survival rate in older
children/adults and those with metastatic disease - However, younger children with localized disease have a survival rate of about 80% 5 years after diagnosis
synovial cell sarcoma is most common in?
- Most common soft tissue tumour in adolescents and young adults
(represents 5-10% of all soft tissue sarcomas)
cause of synovial cell sarcoma
chromosomal translocation
clinical features of synovial cell sarcoma
long-standing nodule, mass is often painless and deep around appendixes
- Usuallyhistoryoflong-standingnodule
- Present for years → increases rapidly in size over few months
- Sometimes overlooked before growth
- Tumor spreads along fascial planes - much more widespread than apparent on initial evaluation
§ Mass often is painless and deep
* Usually situated around knee, hands and feet
* Malignancy can affect any part of appendicular skeleton
* Distal extremity tumors have a better prognosis than proximal or truncal tumors
what is fibromyalgia
Syndrome of persistent widespread pain, stiffness, fatigue, disrupted sleep, and cognitive difficulties. It is often accompanied by anxiety/depression and impairment of activities of daily living.
who is most effected by fibromyalgia
young-adult to middle age females
what is the classification of fibromyalgia
central sensitivity syndrome
neurosensory disorder characterized in abnormalities in pain processing by the CNS
what is the scale for fibromyalgia diagnosis
Diagnosis is based on widespread pain index (WPI) and self-administered patient questionnaire
what is the widespread pain index
for fibromyalgia –>pain or tender in 19 area
- Widespread pain index – score of 0-19
- Patients are asked if they have had pain or tenderness in 19 different body regions over the past week.
§ shoulder girdle, hip, jaw, upper arm, upper leg, lower arm, and lower leg on each side of the body, as well as upper back, lower back, chest, neck, and abdomen
§ Each region scores 1 point - Manual tender-points survey is also used during physical exam (though not required for diagnosis)
§ Self-administered patient questionnaire – score of 0-12 (section 2 & 3) * Section1:Assessdistributionofbodilypainasabove(scoreof0-
19; analogous to WPI)
* Section2:Assesesseverityofproblemswith:daytimefatigue, nonrestorative sleep, and cognitive dysfunction
§ Each is scored out from 0-3 (0=no problem, 3=severe problem)
* Section3:Assespainorcampsinlowerabdomen,depression,or headache in past 6 months
§ 1 point for each positive symptoms
* WPI/Section1iscombinedwithtotalpointsforsections2&3to
yield a score out of 0-31 (aka Polysymptomatic distress scale)
what score in needed for widespread pain index for fibromyalgia and for how long to be diagnosed
> 13 score for 3+ months
A score of 13 or greater, with symptoms being present at similar level or severity for at least 3 months, and not explained by another disorder is diagnostic of fibromyalgia.
what is chronic fatigue syndrome AKA
Myalgic encephalomyelitis (ME)
what is chronic fatigue syndrome
- Characterized by unexplained and profound fatigue that is
worsened by exertion - Accompanied by cognitive dysfunction and impairment of daily functioning that persists for at least 6 months
cause of chronic fatigue
viruses, envo triggers???
who is chronic fatigue most common in
middle aged females
what symptoms are needed to diagnose chronic fatigue syndrome
- Presence of 3 or more of the following symptoms for at least 6 months and symptoms severity must be moderate or severe at least 50% of the time
- Fatigue - unrelated to exertion and not relieved by rest
- Post-exertional malaise (PEM)
- Unrefreshing sleep – fatigue despite a night’s sleep
§ AND at least 1 of the following:
* Cognitive impairment
* Orthostatic intolerance
