amyloid neuropathy
TRANSCRIPT
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Amyloid NeuropathyAlexander LauderBoston University School of Medicine, Third YearJuly 29, 2010
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Pop Quiz: Question
What type of amyloid is the most common causeof amyloid neuropathy?
ATTR
AL
A
A2-microglobulin
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Pop Quiz: Answer
AL
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Outline Properties of Amyloid
Pathogenesis of Amyloidosis
Classification & Organ System Involvement
Amyloid Neuropathy Epidemiology
Etiology
Pathogenesis
Clinical Findings
Diagnostic Evaluation
Treatment
Prognosis
Summary
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Amyloid, what is it?
A pathologic protinaceous substance,deposited in the extracellular space of various
tissues and organs.
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Properties ofAmyloid
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Physical Nature
Continuous, nonbranching fibrils
7.5-10 nm diameter
ross- e a-p ea e s ee con orma on
~95% fibrils
~5% P component and other glycoproteins
Identical structure in all types of amyloidosis
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Types of Amyloid
AL (amyloid light chain)
Ig light chains
Produced by plasma cells: >
Fab
Fc
AA (amy o assoc a e ) Non-Ig protein derived from SAA
Acute phase reactant (IL-1, IL-6)
Synthesized in liver, choroid plexus, retinal epithelium
A amyloid amyloid precursor protein (APP)
Chromosome 21, Alzheimer disease
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Types of Amyloid, cont. Transthyretin (TTR) Serum protein Transports thyroxine and retinol Mutant forms cause familial amyloid polyneuropathy or
cardiomyopathy
Wild type form can lead to SSA, senile systemic (age-related) amyloidosis
2-microglobulin Component of MHC class I Long term hemodialysis
Prion Proteins local amyloidosis Misfolded proteins aggregate in extracellular space
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Pathogenesis
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Pathogenesis
Abnormal folding of proteins
Normal proteins fold improperly
Mutant proteins prone to misfolding
Deposited as fibrils in extracellular tissues Misfolded proteins are normally degraded
Intracellular: proteolysis
Extracellular: macrophage degradation
Amyloid proteins not degraded, accumulate
Disrupt normal function
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ClassificationSystemic
Localized
Hereditary
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Systemic AL: 1o Amyloidosis, associated with clonal B lymphoplasmacytic
diseases. All of these are AL, due to immunoglobulin light chains.
AL: plasma cell dyscrasia up to 30% with diagnostic features ofMM
MM: hi h rade lasma cell d scrasia with l tic bone lesions
hypercalcemia, anemia WM: Waldenstroms macroglobulinemia (lymphoplasmacytic
lymphoma) with IgM AL
Other B lymphomas
AA: 2o Amyloidosis, associated with chronic inflammation, infection.
Rheumatoid Arthritis Ankylosing Spondylitis
Inflammatory Bowel Disease
Hereditary Periodic Fever Syndromes like FMF
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Localized
Confined to a single organ
Alzheimers Disease
r on sease
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Hereditary
TTR
Familial Amyloid Polyneuropathy
ApoAI
Gelsolin
Lysozyme
Fibrinogen
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Affected Organ Systems Kidney: proteinuria, renal failure
Spleen: splenomegaly
Liver: hepatomegaly, elevated alkaline phosphatase
Heart: concentric ventricular hypertrophy, diastolicdysfunction, conduction system damage
Endocrine: adrenal, thyroid, pituitary, pancreas
GI: dysmotility, malabsorption, diarrhea or constipation
Nerve: carpal tunnel syndrome, peripheral and/orautonomic neuropathy
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Kidney
Amyloidosis of the kidney. The glomerular architecture is almost totallyobliterated by the massive accumulation of amyloid.
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Liver
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Heart
Cardiac Amyloidosis. A, Hematoxylin and eosin stain, showing amyloid appearing as amorphouspink material around myocytes. B, Congo red stain viewed under polarized light, in which amyloidshows characteristic apple-green birefringence (compared with collagen, which appears white).
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CNS: Cerebral amyloidangiopathy
A, Massive hypertensive hemorrhage rupturing into a lateral ventricle. B, Amyloid deposition in acortical arteriole in cerebral amyloid angiopathy; inset, Immunohistochemical staining for A showsthe deposited material in the vessel wall. C, Electron micrograph shows granular osmophilicmaterial in a case of CADASIL.
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AmyloidNeuropathy
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History
First described in families in Oporto, Portugal in1952
Andrade C. A peculiar form of peripheralneuro ath familiar at ical eneralized am loidosis
with special involvement of the peripheral nerves.Brain 75 (3): 40827
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Amyloidoses andNeuropathy
Associated with:
AL Amyloidosis (30%)
ATTR Amyloidosis: FAP familial amyloidotic
AF Amyloidosis: Other hereditary forms
ApoAI
Gelsolin: benign cranial and sensorypolyneuropathy
A2-microglobulin: carpal tunnel syndrome
Not associated with:
AA Amyloidosis
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TTR-FAP: Overview
Autosomal dominant
Only 1 mutant TTR allele required for disease
Transthyretin
Tetrameric plasma transport protein (T4, Retinol-BP/vitA)
Chromosome 18
Synthesis in liver, choroid plexus, retinal pigmentepithelium
Mutation changes 1o protein structure
Variant TTR present at birth
Mutation destabilizes tetramer
Does not form amyloid until adulthood
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TTR-FAP: >100 mutations
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TTR-FAP: System involvement
PNS: most common, peripheral neuropathy
ANS: orthostatic hypotension, alteration in GImotility
Heart: restrictive cardiomyopathy
Blood vessels:
CNS leptomeningeal amyloidosis
Cerebral infarcts & hemorrhage
Renal involvement not common
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TTR-FAP: Pathogenesis
Deposit aroundperforatingarterioles
Amyloiddisplaces nerve
fiber
Compression-induced
demyelinationand nerve fiber
loss withintraneural
amyloid
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Arteriolar deposit
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Nerve fiber displacement
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Demyelination with deposits
Cross Section of Sciatic N. bundles
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TTR-FAP:Location of Deposition
Peripheral nerves
Dorsal root ganglia
ep omen nges aroun an ra n
NO CNS parenchymal involvement
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Clinical Progression
Sensorimotor PolyneuropathySlow Progression over Years
ensory
Small fibersLower extremities
Feet ankles knees
Loss of Pain & Temp > LightTouch
Symmetric Paresthesias
Numbness
Burning pain
u onom c
ImpotenceGI motility alterations:
Diarrhea
Constipation
Bladder retention
Orthostatic hypotension
Dry mouth, dry eyes
Vocal hoarseness (rare)
o or
Vocal hoarsenessCarpal Tunnel
Distal limb weakness
Great toe extension
Foot drop
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Clinical Progression
Stage I Stage II Stage III~6yrs
Sensoryneuropathy
Lower limbs
Ambulatory
Steppagegait
Distal upperlimbs
Ambulatory
aid
Bedridden Confined to
wheelchair
No pain ortemp
sensation
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TTR-FAP: Other exam findings
Neuroarthropathies (Charcot joints)
Cranial neuropathies:
Progressive involvement of CN
V: facial sensation VIII: impaired hearing
XII: tongue movement
Sparing of oculomotor nerve
Carpal tunnel syndrome
Blindness from vitreous opacities
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ApoAI: Overview
12 mutations of ApoAI gene 1 mutation causes peripheral neuropathy
Autosomal Dominant
Gly26Arg: neuropathic variant protein
ApoA1: Lipid metabolism
Apolipoprotein
HDL
Activates LCAT
Peripheral tissues
Cholesterol Cholesterol Ester
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ApoAI: System involvement
Renal amyloid deposition, main feature
Liver
p een
Heart
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ApoAI: Pathogenesis
-helical protein
Incompletedegradation
-pleated sheet
Variant
ApoAI Gly26Arg
Increasedmetabolism
Remodeling Incorporation
into amyloidfibril
VariantGly26Arg only
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ApoAI: Pathogenesis
Deposit aroundperforatingarterioles
Amyloiddisplaces nerve
fiber
Compression-induced
demyelinationand nerve fiber
loss withintraneural
amyloid
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ApoAI:Location of Deposition
Peripheral nerves
Dorsal root ganglia
ep omen nges aroun an ra n
NO CNS parenchymal involvement
Similar to TTR-FAP
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Clinical Progression
Sensorimotor PolyneuropathySlow Progression over Years
ensory
Small fibersLower extremities
Feet ankles knees
Loss of Pain & Temp > LightTouch
Symmetric Paresthesias
Numbness
Burning pain
u onom c
ImpotenceGI motility alterations:
Diarrhea
Constipation
Bladder retention
o or
Vocal hoarsenessCarpal Tunnel
Distal limb weakness
Great toe extension
Foot drop
Ataxia
Tetraparesis
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ApoA1: Onset/Prognosis
Adult onset: 30-40s
Slowly progressive
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Gelsolin: Overview
Plasma gelsolin Actin modulating protein
Mutations result in abnormal proteolysis
Asp187Asn
Asp187Tyr
Systems Involved:
Nerve
Vascular
Renal
Onset: ~40 years of age
Involvement of CN VII leads to characteristic drooping offacial muscles, wrinkling, ptosis
Ptosis can be corrected surgically
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Gelsolin: Pathogenesis
Deposit aroundperforating
arterioles
Amyloiddisplaces nerve
fiber
Compression-induced
demyelinationand nerve fiber
loss withintraneural
amyloid
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Gelsolin: Clinical Progression
Lattice cornealdystrophy
Age 20-30
Cranialneuropathy
Age 40
Peripheralneuropathy
Limb involvement
Age >40
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AL: Overview
AL (amyloid light chain) Ig light chains
Produced by plasma cells: >
Fab
Fc
Sporadic Neuropathy:
30% have associated peripheral neuropathy
>25% have associated carpal tunnel syndrome
Renal involvement common (~80%)
Cardiac involvement (~45%)
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AL: Pathogenesis
Deposit aroundperforating
arterioles
Amyloiddisplaces nerve
fiber
Compression-induced
demyelinationand nerve fiber
loss withintraneural
amyloid
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Clinical Progression
Sensorimotor PolyneuropathySlow Progression over Years
ensory
Small fibers
Lower extremities
Feet ankles knees
Loss of Pain & Temp > LightTouch
Symmetric Paresthesias
Numbness
Burning pain
u onom c
Impotence
GI motility alterations:
Diarrhea
Constipation
Bladder retention
o or
Vocal hoarseness
Carpal Tunnel
Distal limb weakness
Great toe extension
Foot drop
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DiagnosticEvaluation
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Diagnostic Evaluation
Tissue biopsy to diagnose amyloid deposits Fat aspirate Involved organ
Gingival tissue or minor salivary gland
Sural nerve
Amyloid Typing AL
Bone marrow biopsy with immunohistochemistry for clonalplasma cells
Serum free light chain assay
Serum and urine immunofixation electropheresis
ATTR
DNA sequencing
AA
Immunohistochemistry
Identification of underlying infection, inflammatory disease
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Tissue biopsy
Light microscopy (H&E): amorphous, eosinophilic,hyaline, extracellular substance
Deposits induce pressure atrophy
Peripheral nerve Wallerian Degeneration Distal degeneration of axon & myelin sheath
Proximal axonal degeneration to next node
Cell body swells, nucleus is peripheralized
Congo red stain: apple-green birefringence
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Tissue Biopsy
Nerve involvement
Intraneural amyloid
amy o os s canno e
differentiated from TTRamyloidosis on basis of biopsy
Immunohistochemistry withspecific Abs
Helpful for differentiation
Not completely reliable
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Sural Nerve Biopsy
Vasculardeposits
o n raneura
deposits seen
Spotty natureof depositsdoes not
exclude nerveinvolvement
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Congo red staining
Cross links within fibrils
Polarized li ht
Apple greenbirefringence
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Commercial DNA Testing
Available for TTR Full TTR DNA testing if mutation unknown
Specific TTR sequence testing if mutation known
Not available for:
ApoAI
Gelsolin
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Treatment
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Treatment Goals
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Treatment
Nonspecific
Specific
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Nonspecific Treatment
Treat painful neuropathic symptoms
Agents:
Gabapentin
Amitryptyline
Pregabalin
Duloxetine
Tricyclic antidepressants, may exacerbate orthostasis
Opioid analgesics
Response to drug may change as diseaseprogresses
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Specific Treatment: TTR-FAP
Orthotopic liver transplantation Remove mutant TTR, synthesized in liver
Val30Met mutation best prognosis: 80% 5 year survival
er mu a ons: - year surv va
Some evidence of efficacy for ApoAI
Vitrectomy for corneal amyloid deposits
Small molecules to stabilize the normal TTR tetramer
Diflunisal (NSAID)
Tafamidis
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Specific Treatment: Gelsolin
Lattice corneal dystrophy Method: Corneal transplantation
Cutis laxis & blepharochalasis (resultant fromfacial palsy)
Method: Plastic surgery
Note: Gelsolin is essential protein of actin function Rx aimed to eliminate production will likely not be
tolerated
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Specific Treatment: AL
Anti-plasma cell chemotherapy Oral melphalan chemotherapy (relatively
ineffective)
transplantation
New agents
Bortezomib, proteasome inhibitor
Lenalidomide, immunomodulator
Others
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Summary
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Summary: OverviewTTR-FAP ApoA1 AL
Age at Onset 30s-70s 30s-40s Usually older pts
Gender M>F M=F M>FAssociatedSystems
SensorimotorWeight lossHeart failure
SensorimotorWeight loss
SensorimotorWeight lossHeart Failure
Increased ICP
CornealDystrophy
Renal Failure
Renal Failure
Family History Yes Yes No
Cause of Death Heart failure,
wastingsyndrome
Renal failure Heart failure,
arrhythmia,bleeding
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Summary: Clinical Findings
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Summary:Diagnosis & Treatment
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Take Home Points
Amyloidosis should not be considered a single disease All amyloid has a similar structure of -sheet fibrils
Am loid is either misfolded normal rotein or mutant rotein. Bothdeposit extracellularly and disrupt adjacent normal tissue function
Neuropathy occurs with AL and AF, particularly ATTR
Biopsy is required for diagnosis of systemic amyloidosis, following bygenetic, hematologic, immunochemical, and proteomics for typing
Treatment methods are both nonspecific and specific
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Thank you
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References & Images Benson M, Kincaid J. The molecular biology and clinical features of
amyloid neuropathy. Muscle & Nerve (2007) 36: 411-423.
Adams, D. Hereditary and acquired amyloid neuropathies. J Neurol(2001) 248: 647-657.
Kumar V, Abbas A, Fausto N. Robbins and Cotran Pathologic Basis ofsease. g on. aun ers se v er, .
Yazaki M et al. Rapidly progressive amyloid polyneuropathyassociated with a novel variant of transthyretin Ser 25. Muscle Nerve(2002) 25: 244-250.
Gillmore J et al. Organ transplantation in hereditary apolipoprotein AIamyloidosis. Am J Transplant (2006) 6: 2342-2347.
Benson M. The hereditary amyloidoses. Best Pract Res Clin Rheumatol(2003) 17: 909-927.
Images used with permission of Elsevier Publishing.
Goljan E. Rapid Review Pathology. Second Edition. Mosby Elsevier, 2007.
Kumar, V. Robins & Cotran Pathologic Basis of Disease. Eighth Edition. SaundersElselvier, 2010.