53. SPINAL MUSCULAR ATROPHY
⢠Childhood diseases
⢠Chromosome #5 that harbors the
survival motor neuron gene
(SMN1)
⢠Anterior (ventral) Horn Cells
⢠Often PAN-fascicular
⢠Shoulder, hip muscles
54.
55. MYOPATHY, âDystrophicâ
⢠Jerryâs kids, no âDYSTROPHINâ
⢠DUCHENNE (DMD), x-linked
⢠BECKER (BMD) (less common, less
severe, same chromosome)
⢠Many others also, all of which have
complex genetic patterns which have
all been precisely defined
⢠MYOTONIA is a common feature
59. Limb Girdle Muscular Dystrophies
Inheritance
Locus
Gene
Clinicopathologic Features
1
A
Autosomal-dominant
5q31
Myotilin
Onset in adult life with slow progression of limb weakness, but
sparing of facial muscles; dysarthric speech
1
B
Autosomal-dominant
1q21
Lamin A/C
Onset before the age of 20 years in lower limbs, progression during
many years with cardiac involvement
1
C
Autosomal-dominant
3p25
Caveolin-3 (Mcaveolin)
Onset before the age of 20, clinically similar to type 1B
1
D
Autosomal-dominant
7p
Unknown
Limb girdle muscle weakness, adult onset
2
A
Autosomal-recessive
15q15.1-21.1
Calpain 3
Onset in late childhood to middle age; slow progression during 20â30
years
2
B
Autosomal-recessive
2p13.3-q13.1
Dysferlin
Mild clinical course with onset in early adulthood
2
C
Autosomal-recessive
13q12
Îł-Sarcoglycan
Severe weakness during childhood, rapid progression; dystrophic
myopathy on muscle biopsy
2
D
Autosomal-recessive
17q21
Îą-Sarcoglycan
(adhalin)
Severe weakness during childhood, rapid progression; dystrophic
myopathy on muscle biopsy
2
E
Autosomal-recessive
4q12
β-Sarcoglycan
Onset in early childhood, with Duchenne-like clinical course
2
F
Autosomal-recessive
5q33
δ-Sarcoglycan
Early onset and severe myopathy; dystrophic myopathy on muscle
biopsy
2
G
Autosomal-recessive
17q11-q12
Telethonin
Distal weakness with limb-girdle weakness in late childhood to
adulthood; rimmed vacuoles in muscle cells
2
H
Autosomal-recessive
9q31-q34.1
Tripartite motifcontaining protein
32 (TRIM32)
Limb-girdle and facial weakness with onset in childhood, mild, slowly
progressive course
60. MYOPATHY, Ion Channel
âChannelopathiesâ
⢠MYOTONIA/HYPOTONIC
PARALYSIS
⢠FAMILIAL, (genetic) DISEASES
⢠TRIGGERED BY:
â Exercise
â Cold
â Carb Intake
⢠Classified by K+, âK+, âK+
⢠MALIGNANT HYPERTHERMIA
can be triggered off by
anesthetic halogenated
inhalation agents in some of
these patients!!!
70. MYOPATHY,
NeuroMuscular Junction
⢠Myasthenia Gravis
â
â
â
â
â
â
Associated with thymomas
Thymectomies often useful Rx:
AUTOIMMUNE DISEASE, CLEARLY
Abâs to ANTI-CHOLINESTERASE RECEPTORS
Anticholinesterase test is very diagnostic (edrophonium)
YOUNG WOMEN WITH EYE MUSCLE SYMPTOMS:
⢠Ptosis ď
⢠Diplopiaď
⢠General Weakness
⢠Lambert-Eaton Syndrome (paraneoplastic), 60%
have malignancies, auto-antibodies against NMJx
Very simple format, 7 common neuropathies, 9 common myopathies.
Our original day 1 design of three types of diseases for everything is modified a bit! Notice the LARGE print.
Note how they, sorta, fit into the 3 disease types.
TRANSVERSE H&E section of a peripheral myelinated nerve. Is this the same âwavyâ thing now cut transversely? Ans: Yes
What are all the bullseyes? (axons) What are the clear areas around the bullseyes? (fatty myelin, washed out)
SILVER STAIN showing black axons surrounded by washed out fat (myelin)
MYELIN stain showing the REVERSE of the previous slide. If you flip back and forth between this pic and the previous one, it will be like overlaying the negative of a film over the positive.
Medium sized nerve, transverse section, showing a finite number of myelinated axons and schwann cells
How many axons are in this nerve section? Perhaps around 20? Ans: YES
Smaller neurovascular triad, or âbundleâ. How many axons are in this small nerve? Perhaps 5-8?
The more longitudinally a nerve happens to be sectioned, the more âwavyâ it appears.
Electron microscope section, peripheral nerve. How many axons are myelinated? Perhaps about 7?
Are the rest UN-myelinated? YES
Please differentiate between microtubules (small circles) and neurofilaments (dots). Find the schwann cell nucleus, find an UNmyelinated axon, find a mitochondrion.
Note that the myelin âlayeringâ has to start (INNER mesaxon) and end (OUTER mesaxon) somewhere!
It looks like one micrometer (micron) would span about 60 layers of myelin? True or false? Ans: TRUE
Slam dunk classical appearance of skeletal muscle. Why is skeletal muscle or voluntary striated muscle a better name for this than just striated muscle? Ans: Because cardiac muscle also has striations.
Logs on a fireplace may overlap with each other, even diagonally a bit, but they do NOT fuse.
Is the peripheral nature of skeletal muscle nuclei more apparent from cross or longitudinal sections? Ans: Cross Why? Ans: Simple geometry!
Are striations better seen on cross or longitudinal sections? Ans: Longitudinal Why? Ans: Simple geometry again!
EM, skeletal muscle, the sarcomere, like America, extends from âZâ to shining âZâ! Find glycogen. Find Mitochondria.
H gets smaller with contraction!
Find the sarcoplasmic reticulum, which is the endoplasmic reticulum of skeletal muscle. Find MYOSIN filaments, find ACTIN.
These are NON-SPECIFIC reactions of nerve and skeletal muscle to injury. NON-specific, NON-specific, NON-specific. Much of it is realated to the concepts we talked about in chapter 1.
Extremely important concepts of nerve demyelinization, axonal damage, and regeneration
Just about anything which stains FAT will be ABSENT in areas of DE-myelinization.
Muscle fiber necrosis
Muscle fiber vacuolization
Muscle fiber hypertrophy/atrophy. Certain fibers hypertrophy to make up for the loss of atrophic fibers
Can you still appreciate the âwavinessâ?
Why is auto-amputation common in severe leprosy? Ans: Nerve destructioon
Why a dermatomal distribution?
CMT is a very HETEROGENEOUS group of hereditary diseases involved with defective myelination, e.g., CMT1, CMT2, CMT3, CMT4, X-linked CMT.
Often, but not exactly correctly, the HMSNs are used interchangeably with the term CMT.
Duplication of a large region in chromosome 17p12 that includes the gene PMP22, is seen in 80% of CMT cases.
1) Peroneal muscle atrophy and 2) HIGH arching (pes cavum) is common in CMT, including 3) âclawâ toe.
BOTH demyelination/ischemia AND a direct TOXIC effect to peripheral nerves are seen in diabetes, which is the MOST COMMON cause of neuropathy, not to mention the severe ischemia.
Do you think the word âneuromaâ is in quotes because it is NOT a true clonal proliferative neoplasm? Ans: YES
Mortonâs Neuromas most commonly occur in the 3rd common digital branch of the MEDIAL plantar nerve, i.e., 3rd and 4th toe at the distal metatarsal level.
They were NOT discovered by Morton, and they are not truly âneuromasâ, in the true neoplastic sense of the word.
Schwannoma
But really, could this be ANY soft tissue tumor?
Antoni A: Palisading, âVerocayâ bodies
Antoni B: Edema, âmyxoidâ
Because SCHWANN cells are the ONLY nucleated cells found IN a nerve, dummy!
A myopathy is ANY primary disease of muscle, generally striated muscle.
The differential diagnoses of the various myopathies does not seem to follow the classical three divisions at all.
Hypertrophy/Atrophy scenario. Are some fibers thicker to make up for the thinning (atrophy) of other fibers? Yes!
What is myotonia? Ans: tonic muscle spasm or muscular rigidity
Dystrophin, an intracellular protein, forms an interface between the cytoskeletal proteins and a group of transmembrane proteins
Hypertrophy, atrophy, inflammation.
Note again the atrophy/hypertrophy scenario
MDA is not just DMD and BMD
http://en.wikipedia.org/wiki/Channelopathy
Floppy baby is not a disrespectful term.
Metabolic myopathies are related to MITOCHONDRIA
Do you thing the DARK lipid looks this way because it is stained with a lipophilic dye rather than having itâs usual washed out appearance?
Does an âunclearâ inflammatory etiology usually suggest autoimmuneâ Ans: YES
Half of dermatomyositis patients also have cancer, many are young adults and therefore there is a juvenile variant. Note the eyelid appearance and eyelid edema.
No skin changes, only in adults, no big association with cancer, and the inflammation is ENDOMYSEAL rather than PERIVASCULAR.
Very obscure disease, but said to be the most common acquired myopathy in people over the age of 50. Quads and wrist flexors, asymmetrically, is the rule.
Edrophonium is a acetylcholinesterase inhibitor, thereby relieving the symptoms temporarily.
Exceedingly RARE tumors, you may see, possibly ONE rhabdomyosarcoma in your life, perhaps. When you do, you will know 50X more about it than I am going to describe now. This was also discussed in the domain of âsoft tissueâ tumors.