Diphtheria Neuropathy
- from diphtheria exotoxin
- segmental demyelination
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presentation: paresthesias and weakness
Varicella-Zoster Virus Neuropathy
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latent infection of spinal cord and brain stem sensory ganglia.
- reactivation ⇒ shingles. trigeminal or thoracic nerve distribution.
- neuronal destruction with associated mononuclear cell infiltrates. peripheral nerves have axonal degeneration.
Hereditary and Sensory Autonomic Neuropathies
- HSANs. 5 types.
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presentation: numbness, pain, autonomic dysfunction.
HSAN Type I
- autosomal dominant.
- mutated SPTLC-1 gene.
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presentation: young adults. sensory neuropathy. axonal degeneration of myelinated fibers.
HSAN Type II
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autosomal recessive.
- mutated HSN2 gene.
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presentation: in childhood. sensory neuropathy. axonal degeneration of myelinated fibers.
HSAN Type III
- aka Riley-Day syndrome, familial dysautonomia.
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autosomal recessive.
- mutated IKAP gene.
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presentation: Jewish kids. autonomic neuropathy. axonal degeneration of unmyelinated fibers, atrophy and loss of sensory and autonomic ganglion cells.
HSAN Type IV
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autosomal recessive dysautonomia type II
- mutated NTRK1 gene.
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presentation: infants. insensitivity to pain and anhidrosis. almost complete loss of small myelinated and unmyelinated fibers.
HSAN Type V
- autosomal recessive
- mutated NGFB gene.
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presentation: infants. insensitivity to pain and temperature. nearly complete loss of small myelinated fibers.
Familial Amyloid Polyneuropathies
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autosomal dominant.
- deposition of amyloid in PNS.
- mutated transthyretin (transports thyroxine and retinol).
- amyloid fibrils made of transthyretin.
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morphology: amyloid deposits in vessel walls and CT with axonal degeneration.
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presentation: numbness, pain, autonomic dysfunction.
Adrenoleukodystrophy
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X-linked. 4% female carriers symptomatic.
- mutated ABCD1.
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morphology: segmental demyelination, onion bulbs, axonal degeneration (myelinated and unmyelinated).
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linear inclusions in Schwann cells.
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presentation: mixed motor and sensory neuropathy, adrenal insufficiency, spastic paraplegia.
- onset btw 10-20 yrs in men with leukodystrophy, 20-40 yrs in women with myeloneuropathy
- linear inclusions in Schwann cells.
- onset btw 10-20 yrs in men with leukodystrophy, 20-40 yrs in women with myeloneuropathy
Porphyria (AIP or Variegate Coproporphyria)
- autosomal dominant
- mutated enzymes in heme synthesis
- AIP = porphobilinogen
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morphology: acute and chronic axonal degeneration, regenerating clusters.
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presentation: acute episodes neuro dysfunction, psychiatric disturbances, abd pain, seizures, proximal weakness, autonomic dysfunction.
- may be precipitated from drugs.
- AIP = porphobilinogen
- may be precipitated from drugs.
Refsum Disease
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autosomal recessive.
- mutated PAHX gene.
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morphology: severe onion bulb formation.
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presentation: mixed motor and sensory neuropathy with palpable nerves, ataxia, night blindness, retinitis pigmentosa, ichthyosis.
- onset before age 20.
- onset before age 20.
Charcot-Marie-Tooth Disease
- aka hereditary motor and sensory neuropathy (HMSN) type I.
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autosomal dominant demyelinating disorder.
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pathogenesis: HMSN-1A has duplicated segment on chrom 17 ⇒ ↑ PMP-22 that compacts myelin as Schwann cells wrap around axons.
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HMSN-1B = mutated MPZ.
- mutations in connexin 32, protein degradation pathway, and myelination induction genes.
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morphology: segmental demyelination and onion bulb.
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presentation: young adults with distal muscle weakness and calf atrophy.
- HMSN-1B = mutated MPZ.
- mutations in connexin 32, protein degradation pathway, and myelination induction genes.
HMSN II
- autosomal dominant
- axonal loss without demyelination
- presents younger than HMSN type I.
- mutated kinesin.
Déjérine-Sottas Neuropathy
- aka HMSN III.
- autosomal recessive. infantile.
- progressive upper and lower extremity weakness and muscle atrophy, enlarged palpable nerves.
- mutated PMP-22 or MPZ.
- severe segmental demyelination, onion bulbs, axonal loss.
Peripheral Neuropathy in Adult-Onset DM
- present in about 50% DM.
- from nonenzymatic protein glycation and polyol-mediated damage.
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diabetic microvascular disease with secondary ischemic injury.
- types: distal symmetric sensory or sensorimotor neuropathy, autonomic neuropathy, focal or multifocal asymmetric neuropathy.
Distal Symmetric Sensory or Sensorimotor Neuropathy
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axonal neuropathy with loss of small fibers.
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sensory loss > motor loss.
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loss of pain ⇒ cutaneous ulcers, heal poorly from diabetic microvascular disease.
Autonomic Neuropathy
- 20-40% diabetics.
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presentation: postural hypotension, incomplete bladder emptying, sexual dysfunction.
Focal or Multifocal Asymmetric Neuropathy
- ex. unilateral ocular nerve palsy.
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secondary to vascular insufficiency of peripheral nerves.
Metabolic and Nutritional Peripheral Neuropathies
- from renal failure
- presents with distal symmetric sensory and motor neuropathy.
- from chronic liver disease, respiratory insufficiency, thyroid dysfunction.
- from deficiencies of thiamine, B6, B12, or E.
- from excessive alcohol consumption by ethanol toxicity and thiamine deficiency.
- presents with distal symmetric sensory and motor neuropathy.
Direct Infiltration or Nerve Compression
- by tumor ⇒ mononeuropathy, brachial plexopathy, cranial nerve palsy, or polyradiculopathy of lower extremities (meningeal carcinomatosis of cauda equina)
Paraneoplastic Syndrome of PNS
- progressive sensorimotor neuropathy (lower extremities) in 2-5% lung cancer.
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loss of dorsal root ganglia ⇒ sensory neuropathy
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circulating Ab against RNA-binding protein shared by neurons and tumor cells.
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deposition of light-chain amyloid in pts with plasma cell dyscrasias
- secondary to autoantibodies against myelin-associated glycoprotein
- circulating Ab against RNA-binding protein shared by neurons and tumor cells.
Toxic Neuropathies
- from exposure to industrial/environmental chemicals, biologic toxins, heavy metals (lead, arsenic), therapeutic drugs.
Traumatic Neuropathies
-
lacerations cutting a nerve
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avulsions when nerve under pressure
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traumatic neuromas from nerve transection or damage. painful nodules of tangled axons and CT from regenerating axonal sprouts.
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compression neuropathy = nerve compressed.
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Carpal Tunnel Syndrome: median nerve entrapped in wrist. see in edema, pregnancy, degenerative joint disease, hypothyroidism, amyloidosis, excessive wrist use.
- other nerves: ulnar nerve at elbow, peroneal nerve at knee, radial nerve in upper arm.
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compression neuropathy of foot in women.
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Morton neuroma: involves interdigital nerve at intermetatarsal sites ⇒ pain
- Carpal Tunnel Syndrome: median nerve entrapped in wrist. see in edema, pregnancy, degenerative joint disease, hypothyroidism, amyloidosis, excessive wrist use.
- other nerves: ulnar nerve at elbow, peroneal nerve at knee, radial nerve in upper arm.
- compression neuropathy of foot in women.
- Morton neuroma: involves interdigital nerve at intermetatarsal sites ⇒ pain
Spinal Muscular Atrophy
-
autosomal recessive motor neuron diseases, onset in childhood or adolescence.
- mutations of SMN1 gene on chromosome 5
-
# copies homologous SMN2 gene modifies gene severity.
- SMN for axonal transport, NMJ integrity.
- loss ⇒ neuronal cell death.
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morphology: large numbers of extremely atrophic muscle fibers, involve entire fascicle of muscle
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presentation: SMA type I = Werdnig-Hoffman disease: presents first 4 months of life with hypotonia and death by age 3 yr.
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SMA type 2: presents later, die as kid after age 4.
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SMA type 3: survive to adulthood.
- # copies homologous SMN2 gene modifies gene severity.
- SMN for axonal transport, NMJ integrity.
- loss ⇒ neuronal cell death.
- SMA type 2: presents later, die as kid after age 4.
- SMA type 3: survive to adulthood.
Duchenne Muscular Dystrophy
-
most severe and most common form muscular dystrophy.
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X-linked. 1/3500 males.
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DMD gene at Xp21 encodes dystrophin that transduces contractile forces from intracellular sarcomeres to ECM.
- 2/3 familial. 1/3 de novo
- no detectable dystrophin
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morphology: enlarged, rounded, hyaline fibers lacking normal cross striations.
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variation in myofiber diameter, ↑ internalized nuclei, degeneration/necrosis/phagocytosis of muscle fibers, regeneration of muscle fibers, proliferation of endomysial CT, muscles replaced by fat and CT, involves type I and type II fibers.
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presentation: by age 5, wheelchair by 10-12. death in early 20's.
- weakness in pelvic girdle muscles
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pseudohypertrophy: lower muscles hypertrophied with weakness.
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heart failure and arrhythmia, risk of cardiomyopathy
- cognitive impairment
- death from respiratory insufficiency, pulmonary infection, cardiac decompensation.
- 2/3 familial. 1/3 de novo
- no detectable dystrophin
- variation in myofiber diameter, ↑ internalized nuclei, degeneration/necrosis/phagocytosis of muscle fibers, regeneration of muscle fibers, proliferation of endomysial CT, muscles replaced by fat and CT, involves type I and type II fibers.
- weakness in pelvic girdle muscles
- pseudohypertrophy: lower muscles hypertrophied with weakness.
- heart failure and arrhythmia, risk of cardiomyopathy
- cognitive impairment
- death from respiratory insufficiency, pulmonary infection, cardiac decompensation.
Becker Muscular Dystrophy
-
X-linked muscular dystrophy.
- starts later than DMD, not as severe.
- mutated DMD gene at Xp21 encoding dystrophin
- 2/3 familial, 1/3 de novo.
-
↓ amounts dystrophin that has abnormal molecular weight.
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morphology: variations in myofiber diameter, ↑ internalized nuclei, degeneration/necrosis/phagocytosis of muscle fibers, regenerated muscle fibers, proliferation of endomysial CT, muscle replaced by fat and CT, type I and type II fibers involved.
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presentation: weakness in pelvic girdle muscles, pesudohypertrophy, heart failure and arrhythmia, cardiomyopathy, cognitive impairment.
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death by respiratory insufficiency, pulmonary infection, cardiac decompensation.
- 2/3 familial, 1/3 de novo.
-
↓ amounts dystrophin that has abnormal molecular weight.
morphology: variations in myofiber diameter, ↑ internalized nuclei, degeneration/necrosis/phagocytosis of muscle fibers, regenerated muscle fibers, proliferation of endomysial CT, muscle replaced by fat and CT, type I and type II fibers involved.
presentation: weakness in pelvic girdle muscles, pesudohypertrophy, heart failure and arrhythmia, cardiomyopathy, cognitive impairment.
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death by respiratory insufficiency, pulmonary infection, cardiac decompensation.
Limb Girdle Muscular Dystrophy
-
autosomal muscular dystrophy.
- affects proximal trunk and limb musculature.
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mutations of transmembrane sarcoglycan complex of proteins that link dystrophin with ECM.
Myotonic Dystrophy
- autosomal dominant
-
↑ in severity and appear at younger age in successive generations = anticipation.
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myotonia = sustained involuntary muscle contraction. cardinal neuromuscular symptom.
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pathogenesis: CTG trinucleotide repeat expansion on 19q13. affects mRNA for DMPK.
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morphology: fiber size heterogeneity, ↑ numbers internal nuclei and ring fibers (subsarcolemmal band of cytoplasm with rim of myofibrils that wrap around longitudinally oriented fibrils).
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changes in muscle spindles: fiber splitting, necrosis, regeneration.
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presentation: abnormalities in gait from foot dorsiflexor weakness, weakness in intrinsic hand muscles and wrist extensors, facial muscle atrophy, ptosis.
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cataracts, frontal balding, gonadal atrophy, cardiomyopathy, smooth muscle involvement, ↓ plasma IgG, abnormal glucose tolerance test.
↑ in severity and appear at younger age in successive generations = anticipation.
myotonia = sustained involuntary muscle contraction. cardinal neuromuscular symptom.
pathogenesis: CTG trinucleotide repeat expansion on 19q13. affects mRNA for DMPK.
morphology: fiber size heterogeneity, ↑ numbers internal nuclei and ring fibers (subsarcolemmal band of cytoplasm with rim of myofibrils that wrap around longitudinally oriented fibrils).
-
changes in muscle spindles: fiber splitting, necrosis, regeneration.
presentation: abnormalities in gait from foot dorsiflexor weakness, weakness in intrinsic hand muscles and wrist extensors, facial muscle atrophy, ptosis.
-
cataracts, frontal balding, gonadal atrophy, cardiomyopathy, smooth muscle involvement, ↓ plasma IgG, abnormal glucose tolerance test.
Channelopathies
-
familial disease with myotonia and/or hypotonic palsies
- hypotonic can be hyper, hypo, or normokalemic.
-
hyperkalemic periodic paralysis: mutated SCN4A sodium channel protein - regulates Na entry during muscle contraction.
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hypokalemic periodic paralysis: mutated gene for voltage gated L-type Ca channel.
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malignant hyperpyrexia (malignant hyperthermia): dramatic hypermetabolic state triggered by anesthesia. mutated gene for voltage gated L-type Ca channel (ryanodine receptor).
- anesthetic ⇒ uncontrolled sarcoplasmic Ca efflux ⇒ tetany, ↑ muscle metabolism, excess heat production.
- tachycardia, tachypnea, muscle spasms, hyperpyrexia later.
- hypotonic can be hyper, hypo, or normokalemic.
- anesthetic ⇒ uncontrolled sarcoplasmic Ca efflux ⇒ tetany, ↑ muscle metabolism, excess heat production.
- tachycardia, tachypnea, muscle spasms, hyperpyrexia later.
