Amyloid

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AMYLOIDOSIS

Amyloid
General clinical features

Acquired
AL: PNS
ATTRwt
IgM
CNS Amyloidosis
Hereditary PNS amyloid
Transthyretin
Apolipoprotein A1
Gelsolin
β₂-microglobulin
Myopathy
Acquired
LGMD: 2B; 2I; 2L
Non-neurologic amyloid
Pathology images
Staining Methods

Neuropathy, Amyloid-like

Amyloid around vessel (Arrow)
Loss of smaller myelinated axons

GENERAL FEATURES ²²

History: "Amyloid"
- Virchow (1858): Starch-like "Amyloid" deposits react with iodine & sulfuric acid
- Bennhold (1922): Amyloid deposits stain with Congo red
- Divry & Florkin (1927): Congo red staining is birefringent with polarized light
Definition
- Protein misfolding diseases
- Pathologic characterization: Extracellular amyloid fibrils
- Detection: Congophilic
- Etiology: Heterogeneous
Cause
- Deposition of insoluble fibrillar proteins
  - Pattern: Antiparallel β-pleated sheet configuration
- General
  - Misfolding of precursor protein leads to
    - Aggregation of insoluble, possibly toxic, fibrils
    - Precipitation in tissues
  - Misfolded species can catalyze further misfolding
  - Mutations in precursor genes: May increase degree of amyloidogenicity
  - Amyloid fibril structure
    - Antiparallel β-strands of polypeptides
    - Lie perpendicular to long axis of fibril
    - Straight: Non-branching
    - Diameter: 7 to 10 nm
  - Serum amyloid P (SAP) component
    - Binds in calcium dependent, reversible manner to amylid fibrils
    - Stabilizes amyloid fibrils
  - Prion diseases are the only known transmissible form of amyloidosis
- Mechanisms
  - High levels of non-amyloidogenic protein
    - AA amyloidosis: Serum amyloid A protein (SAA) with chronic inflammation
  - Normal levels of mildly amyloidogenic protein
    - Senile amyloidosis: Normal transthyretin
  - Presence of amyloidogenic protein
    - Genetic
    - Infections
    - M-proteins
- Locations
  - Most disorders Extracellular regions of tissues
  - Inclusion body myositis: Intraccellar
Clinical
- Polyneuropathy ²³
  - Hereditary
  - Acquired
  - Clinical Patterns
    - Carpal tunnel syndrome: Especially bilateral
    - Weakness: Arms
    - Autonomic neuropathy
      - Orthostatic hypotension
      - GI: Constipation; Diarrhea; May be alternating
      - Erectile dysfunction
      - Sweating Δ
    - Small fiber sensory loss
    - Cranial neuropathy, multiple: AL amyloid
  - General course: Slow progression
- Myopathy ¹¹
  - General
    - Cranial involvement
      - Face: Bilateral; Especially AGel
      - Macroglossia: AL amyloid
      - Dysphagia: AL amyloid
    - Axial muscles (Bent spine): Some patients
  - Acquired: Monoclonal gammopathy
  - Hereditary
    - Causes of amyloid in muscle
      - Muscle only: CK very high
        
        LGMD 2B (R2): Dysferlin
        LGMD 2I (R9): FKRP
        LGMD 2L (R12): ANO5
      - With systemic features
        
        TTR
    - Clinical
      - Onset age vs Acquired: Younger; 41 vs 65 years
      - Weakness
        
        Proximal ± Distal
        
        Symmetric or Asymmetric
        
        Distal: Hereditary (LGMD 2B & 2I)
      - Fewer systemic features in hereditary: Less
        
        Dysphagia
        
        Weight loss
        
        Polyneuropathy (Sensory loss)
      - Muscle size
        
        Calf atrophy: More frequent in hereditary
      - Serum CK: High
      - Muscle biopsy
        
        More inflammatory cells
        
        LGMD 2B & 2I: Amyloid mainly in vessel walls
  - Amyloid in IM-VAMP (IBM) muscle: Intracellular pathology
    - Intracellular aggregates (β-amyloid protein), or
    - Near Vacuoles
- Systemic manifestations: Other
  - Myelopathy
  - Cardiomyopathy
    - Heart failure with
      - Preserved ejection fraction without hypertension
      - EKG: Low QRS voltage
      - Left ventricle wall thickness: Increased on echocardiography
    - Arrhythmia
  - Ophthalmologic
    - Cornea: Lattice dystrophy (Gelsolin)
    - Purpura: Periorbital (AL amyloid)
    - Vitreous opacities
    - Pupil Δ
  - Renal failure
    - Proteinuria without: Hypertension or diabetes
  - Weight loss
  - GI: Hepatomegaly (AL amyloid)
  - Skin
    - Ecchymoses & Purpura: AL amyloid
    - Cutis laxa: Gelsolin
  - Amyloidoma
  - Laboratory: M-protein in acquired disorders
- Treatments
  - Hereditary amyloid
    - Liver transplantation
    - TTR stabilizers
      - Tafamidis: Also useful for amyloid with cardiomyoparhy
      - Diflunisal
    - TTR synthesis inhibitor
      - Patisiran
    - TTR degradation
      - Inotersen
  - Acquired amyloid (AL)
    - Combined immunomodulation
    - Chemotherapy + Stem cell transplant
Laboratory
- Electrophysiology
  - Neuropathy: Axon loss or Small fiber neuropathy
  - Carpal tunnel syndrome: Especially bilateral
- Associated serum antibody
  - Serum M-Protein: Common in acquired disorders
- Laser captured microdissection & Mass spectrometry
  - Useful for Acquired & Hereditary-systemic amyloid
  - Not for: LGMD 2B & 2I
Pathology
- Amyloid Stains & Methods
  - Congo red
    - Visualization
      - Polarized light: Red-Green birefringent
      - Fluorescence: Over differentiate stain in alkaline alcohol
    - Technical: Tissue section thickness ≥ 10 μM
  - Thioflavin T
    - Mechanism
      - Dye is linked to cross-β structure in amyloid fibrils
    - Visualization: Fluorescence
    - Utility vs Congo red
      - More sensitive
      - Less specific: Binding to fibrin, keratin, intestinal muciphages, Paneth cells, Zymogen granules, Juxtaglomerular apparatus
      - Not permanent
  - Methyl violet & Methyl green
  - TTR amyloid
    - TTR aggregate-specific monoclonal antibody (clone 2T5C9)
  - Electron microscopy: Cylindrical fibrils
    - Composition: 75 Ậ in diameter: 2 25 Ậ rods separated by 25 Ậ interspace
    - Bundles: 2 to 8 in parallel orientation
- Amyloid Locations
  - Connective tissue
    - Nerve: Epineurium; Perineurium; Endoneurium; Vessel walls
    - Muscle: Perimysium; Endomysium; Vessel walls
  - Vessel walls: Intermediate-sized & Capillaries
  - Muscle fibers
    - Usual: Extracellular: Circumferential deposits around fiber periphery
    - IBM: Intracellular; Granular deposits, often associated with vacuoles

ACQUIRED AMYLOIDOSIS ¹⁶

AL Amyloid
ATTRwt
IgM
Amyloid
Deposition without amyloid

Epidemiology
- Incidence: 8 to 12 per 1,000,000
- Age
  - Most common in middle aged or older males
  - Median age at diagnosis: 76 years
- Median survival after diagnosis: 3 years
Amyloid Protein
- AL: Immunoglobulin light chains; κ or λ
- Light chain proteins
  - Amount: Increased serum levels of free light chains precede development of AL amyloidosis by many years
  - Folding
    - Normal: Often α-helical configuration
    - Amyloid: Misfolded & Forms β-pleated sheet
  - Disease
    - Insoluble protein: Deposits in tissues & interferes with organ function
    - Soluble light chains: May be directly toxic to tissues such as heart
Clinical: AL amyloid
- Associated disorders
  - Paraproteinemia (M-protein)
    - In 90% when serum & urine tested by immunofixation
    - Most common in nephrotic syndrome
    - Least common in polyneuropathy
    - Light chain in 1/3
    - Intact immunoglobulin in 2/3
    - λ light chains: AL type
    - κ light chains: Multiple myeloma; MGUS
  - Multiple myeloma : May present 10-81 months after diagnosis of AL
  - Immunoglobulin secreting B-cell neoplasms
    - CLL
    - Macroglobulinemia
    - Non lymphoplasmacytic lymphoma
- Polyneuropathy
  - Frequency: 20% of patients with light chain amyloid
  - Presenting feature: 20% of AL amyloid
  - Distal; Symmetric
  - Predominantly sensory
    - Pain & temperature loss most prominent
    - Distal weakness may develop later
  - Autonomic neuropathy
    - Orthostatic hypotension
    - Hypoactive pupils
    - Hypohidrosis
    - Bladder dysfunction
    - Impotence
    - Autonomic without general neuropathy: Rare patients
  - Carpal tunnel syndrome in 25%
  - Taste: Loss common; Symptomatic in some patients
- Mononeuritis multiplex
  - Associated with lymphoma
    - Hilar, mediastinal, axillary, and inguinal lymph nodes
    - IgG M-protein
  - Few systemic symptoms
  - Benign course common
- Myopathy
- Systemic features
  - Purpura: Periorbital
  - Submandibular swelling
  - Cardiac: Diastolic; Failure with preserved ejection fraction
  - Renal: Nephrotic syndrome
  - Muscle enlargement ± Weakness
  - Gastrointestinal: Diarrhea
  - Hepatic: Large; Alkaline phosphatase high with normal imaging
  - Anemia associated with multiple myeloma
  - Amyloidoma
- Prognosis
  - Gradual progression
  - Survival of 1 to 10 years depending on organ involvement
  - Shortest survival: Cardiac (< 1 year) & Renal dysfunction
  - Early deaths
    - ≥ 10% Plasma cells at diagnosis
    - Ig FLC level: High at diagnosis
    - Number of organs involved: High
    - Serum uric acid level: High
  - Measurements
    - N-terminal pro-brain natriuretic peptide (NT-proBNP) (normal < 8500 pg/L): Heart failure
    - Troponin T: High serum levels with early SCT mortality
    - Difference between involved & uninvolved Ig free light chain values
- Treatment: Combined immunomodulation; Chemotherapy + Stem cell transplant
  - High dose chemotherapy (HDC): Cyclophosphamide-Bortezomib-Dexamethasone or Daratumumab containing regimens
  - Peripheral blood stem cell transplant (PBSCT): After chemotherapy
  - Timing: 1st year of disease
  - Best prognosis: Limited disease
  - Worst prognosis: Multi-organ involvement
  - Translocation t(11;14)
    - 61% of amyloidosis patients
    - Progression-free survival: Reduced
    - Bortezomib-based therapies: Reduced response
Laboratory
- CSF: Protein mildly elevated
- Electrodiagnostic: Axonal neuropathy
- Nerve Biopsy
  - Axon loss
  - Amyloid: Contains
    - Light chain precursor protein, Monoclonal
    - Amyloid signature proteins: Apolipoprotein A-IV, Apolipoprotein E; Serum amyloid P component
- Urine: 24 hour immunofixation
- Immunoglobulins
  - Ig Free Light Chain (κ:λ) ratio (Normal = 0.26-1.65): Usually abnormal
  - M-protein: 40% to 50%
- Diagnosis: Mass spectroscopic analysis of amyloid
IgM�Related Light Chain Amyloidosis ⁷
- Epidemiology
  - 10% of patients with Waldenström
  - 6% to 10% of AL amyloidosis
- Clinical
  - Onset age: Median 66 years; 33 to 89 years
  - Renal (68%)
  - Neuropathy (3% to 28%): Sensory-Motor & Autonomic
  - Cardiac (45%)
  - Lymph node (20%)
  - Liver (35%)
  - Lymphoproliferative disease associations: non-Hodgkin lymphoma; Lymphoplasmacytic lymphoma (Waldenström)
  - Treatment
    - Autologous stem-cell transplantation
      - Good treatment response: 57%
    - Bortezomib, Cyclophosphamide, Dexamethasone, Daratumumab
  - Prognosis: Worse with nerve & liver involved, Older age & Abnormal Free light chain ratio; 16 to 90 months
- Laboratory
  - IgM levels: Median, 1g/dL; Range 29 to 9,130
  - IgM M-protein (100%)
  - λ light chain isotype: Less frequent
  - Biopsy: Amyloid

HEREDITARY PNS AMYLOIDOSIS
General

Mutations that occur in serum proteins allow them to form β-pleated sheets
Protein forming the amyloid is sometimes identifiable by immunocytochemistry
Liver transplantation: May be effective therapy for stabilizing disease in some tissues

Amyloidosis: Transthyretin-related (AMYLD1; ATTRv)

● Transthyretin (TTR)

; Chromosome 18q12.1; Dominant

TTR gene
TTR protein
Clinical: Genetic correlations
Clinical syndromes
FAP1
FAP2
Homozygotes
Treatments
Pathology
Variant: TTRwt

Nosology: Corino de Andrade disease
Epidemiology
- General frequency: 1:1,000,000
- ~50,000 patients worldwide: 10,000 with polyneuropathy
- Endemic foci: Portugal; Japan; Sweden; Brazil
TTR gene
- 4 exons: Exon 1 codes for signal peptide
- Mutations
  - > 140 identified
  - General locations
    - Exon 1: Only 1 mutation (Val20Ile); Not in signal peptide
    - Most in other 3 exons
  - Common
    - Val30Met
    - Thr60Ala
    - Ala97Ser: Taiwan
    - Val122Ile: African-American; Sicilian
    - Other
  - Mutation types
    - Most are missense point mutations
    - Deletion: 1 identified (V122δ)
  - Mutation locations: Usually in exons 2, 3, or 4
  - Mutation databases: HGMD
- Disease mechanism: "Gain-of-Function"
TTR Protein
- 127 amino acids
- Present in plasma
- Binds or Transports
  - Thyroxine (T4)
  - Retinol (Vitamin A)
- Normal configuration: Tetramer
- Amyloid formation by mutant transthyretin
  - Less stable tetramer
  - Monomers dissociate & may fold aberrantly
  - Aberrantly folded monomers aggregate to form amyloid
  - Protective mutations: Stabilize transthyretin tetramer
  - Potential treatment: Small molecules that stabilize transthyretin tetramer (Diflunisal) ³
- Amyloid deposition
  - Nerves: More in large than small
Genetic-Clinical correlations ¹³
- General
  - Specific mutations may have variable clinical presentation
  - Inheritance
    - 1/3 of patients have affected parent
    - 2/3 of patients have new mutation
  - Penetrance rate
    - Varies with mutation, geographical region, or ethnic group
    - Penetrance is higher in patients in endemic foci
  - Clinical associations
    - Cardiac onset: I68L; L111M; V122I
    - Neurological onset: C10R; V30M; F33L; S50R
- Specific mutations
  - Val30Met
    - Most common neurologic mutation: Especially in Portugal
    - Onset: 25 to 65 years
    - Neuropathy
      - Small fiber
      - Autonomic
        
        Greater frequency than with other mutations
        
        Short time from clinical onset (2.7 years)
    - Other: Carpal tunnel ; Ocular
    - Japanese: Late onset; Sensory without autonomic neuropathy; Male predominance
    - Protective mutations on other allele: Arg104His; Thr119Met
  - Val28Met: 7th decade onset neuropathy with impotence; No FH
  - Val40Ile
    - Cardiomyopathy: Late onset, Rapid progression
    - Amyloid in muscle
  - Gly47Ala: Autonomic common
  - Thr49Ser
    - Cardiomyopathy
    - Autonomic neuropathy: Present at onset in 50%; May be severe
  - Ser50Arg: Autonomic common
  - Ser52Pro: Autonomic common
  - Glu54Lys: Neuropathy, Vitreous opacity, Heart failure
  - Leu55Pro: Severe disease
  - Thr60Ala: Mixed phenotype
    - Epidemiology: United Kingdom
    - Clinical
      - Carpal tunnel
      - Neuropathic pain
      - Autonomic: Common
      - Cardiomyopathy: Restrictive
      - Gastrointestinal
      - Pathology
  - Phe64Leu ⁵
    - Common in Southern Italian families
    - Male:Female = 3:1
    - Onset: Later (7th & 8th decade); Paresthesias
    - Milder disease: Progression over 10 years
    - Neuropathy
      - Sensory: Distal
      - Autonomic (GI & BP): With disease progression; Moderate severity
      - Weakness: With disease progression
      - Axon loss
    - Cardiomyopathy
  - Ser77Tyr ¹⁸
    - Epidemiology
      - World wide: 2nd most frequent mutation
      - Yemenite Jews
    - Clinical
      - Onset age: Often > 50 years; Mean 57 years
      - Median nerve: Often involved
      - Polyneuropathy
        
        Sensory loss (65%)
        
        Weaknes: Distal (50%)
        
        Tendon reflexes: Ankle absent
      - Muscle pain
      - Autonomic: Common; Erectile, GI
      - Cardiomyopathy (84%)
      - Amyloid- carriers: May have neuropathy or carpal tunnel syndrome
    - Laboratory
      - Skin biopsy: Axon loss (> 90%)
  - Ile84Asn: Restrictive cardiomyopathy; Ocular
  - His90Asp ²¹
    - Epidemiology: 2 families
    - Clinical
      - Neuropathy: Sensory, Motor, Autonomic
      - Carpal tunnel syndrome
  - Ala97Ser (A117S) ¹⁸
    - Epidemiology: Taiwan; Thailand
    - Clinical
      - Later onset
      - Early features
        
        Polyneuropathy: Sensory > Motor; Autonomic
        Carpal tunnel syndrome
        
        Median distal latency: Long
        
        IENF reduced
      - Cardiac (70%)
      - Course: Progressive
      - Amyloid
        
        Sural nerve biopsy: 57% with amyloid
        
        Hepatocytes: Perinuclear TTR
      - Similar changes to presymptomatic diabetic neuropathy
  - Ile107Phe: Neuropathy, Sensory & Autonomic
  - Tyr114His: Carpal tunnel
  - Val122del: Rapid progression; Liver & Cardiac
  - Val122Ile ¹⁷
    - Epidemiology
      - World-wide: Most common
      - US Afro-Americans: 4% carry mutation
      - Sicilian
      - Hispanic: 0%
    - Genetics
      - Inheritance: Recessive or Dominant
      - Penetrance: Incomplete
      - Homozygous: Earlier onset
    - Clinical
      - Onset age: Late; Mean 62 years
      - Cardiomyopathy, Restrictive & Hypertrophic
        
        Most patients
        Often presenting feature
        
        Progression: Cardiac failure
      - Peripheral nerve: 40%
        
        Polyneuropathy
        
        May be asymptomatic
        
        Axon loss: Sensory-Motor
        
        Common on NCV
        
        Carpal tunnel syndrome
        
        Autonomic dysfunction: 20%
      - CNS: Infarction
      - Other associated features
        
        Hearing loss
        
        Spinal stenosis
        
        MGUS: Increased frequency
    - Carriers
      - Risk of heart failure: Higher than controls
      - Systolic & diastolic function: Worse
      - N-terminal pro�brain natriuretic peptide: Higher
      - Deaths: Similar to controls
  - CNS
    - General signs: Hearing loss; Migraine; Dementia; Cerebellar; Seizures; Stroke; Myelopathy
    - Asp18Gly: Meningocerebrovascular syndrome sparing eyes
    - Val30Gly: Oculoleptomeningeal syndrome
    - Ile107Val: Autonomic; Carpal tunnel; CNS; Multisystem (Cardiomyopathy; Lung; Joint; Angiopathy)
    - Leptomeningeal syndromes
      - Mutations: Leu12Pro; Asp18Gly; Ala25Thr; Val30Met; Gly53Glu
      - Clinical: Hemorrhage; Myelopathy; Hydrocephalus; Ataxia; Seizures; Dementia
  - Cardiomyopathy, Familial amyloid: V20I; P24S; A45T; Thr49Ser; Glu54Lys; I68L; L111M; V122I
- Protective mutation: Thr119 Met
Clinical syndromes
- Heterogeneous, with some relation to
  - Point mutation location
  - Ethnic background
- Onset 17-78 years
- Penetrance: Variable: 30% to 95%
- Signs
  - Peripheral nerve
    - Polyneuropathy
      - Sensory: Loss; Pain
      - Motor: Weakness in some patients
    - Carpal tunnel syndrome 1 (CTS1)
  - Autonomic (75%)
    - Varies in severity & type with different mutations
    - More with: Early onset disease
    - Common features: GI ¹⁵, Bladder, Orthostatic hypotension, Cardiac
    - Cardiac sympathetic denervation: Worse prognosis
    - GI
      - General: GI motility generally disturbed
      - Weight loss
      - Satiety, early
      - Diarrhea
      - Constipation
      - Nausea & Vomiting
      - Amyloid deposition: Submucosal predominant
    - Orthostatic hypotension ¹⁴
      - Diagnosis
        
        BP fall ≥ 20 mmHg systolic or 10 mmHg diastolic
        
        Neurogenic: Reduced heart rate increase
      - Causes
        
        Cardiomyopathy
        
        Volume depletion: Due to diarrhea or drug effects
        
        Neurogenic: Impaired norepinephrine release from sympathetic postganglionic neurons
      - Treatments: Symptomatic
        
        Discontinuation of aggravating medications or factors
        Droxydopa
  - Systemic: Cardiomyopathy, Vitreous opacities, Renal failure
  - Rare CNS: Hearing loss; Migraine; Dementia; Cerebellar; Seizures; Stroke; Myelopathy
- Laboratory
  - Neurofilament Light chain (Plasma/Serum)
    - High
    - May correlate with disease activity
FAP I: Clinical syndrome
- Genetics
  - Most common point mutation: Val30Met
  - Penetrance
    - High: Endemic Japanese foci
    - Low: Scattered, sporadic cases; Swedish endemic foci
  - Also > 23 other mutations
  - "Portuguese, Swedish & Japanese" types
- Clinical
  - Onset
    - Age
      - Range: 20 to 80 years
      - Later: Sporadic Japanese cases; Swedish endemic foci
      - Earlier: Japanese & Portugese endemic foci
    - Presentation: Polyneuropathy
      - Autonomic & Sensory
      - Onset: Legs
      - Painful dysesthesias
  - Male > Female: Especially in late onset sporadic cases
  - Weakness: Distal; Legs > Arms
  - Sensory loss
    - Early onset: Pain & Temperature loss most prominent
    - Late onset: Distal; Symmetric; All modalities; Paresthesias
  - Tendon reflexes: Reduced or Absent
  - Autonomic failure
    - Severe in early onset patients
    - Mild in late onset patients
  - Progression: Death in 7 to 10 years
- Laboratory
  - CSF protein: Moderately increased in 20%
  - Sural nerve
    - Axon loss
      - Myelinated axons: Especially in older onset patients
      - Unmyelinated axons
    - Amyloid
      - Most prominent in sympathetic ganglia, dorsal root ganglia & proximal nerve trunks
      - Deposition in connective tissue: Endoneurium, Perineurium, Epineurium
      - Primary damage may be to Schwann cells
  - Muscle: Chronic denervation with Reinnervation
    - Fiber type grouping: Large
    - Grouped atrophy: Large
    - Amyloid: Around perimysial vessels
FAP II: Clinical syndrome
- Genetics
  - Most common mutation: Ser77Tyr
- Clinical
  - Onset
    - 5th to 7th decades
    - Upper extremities
      - Carpal tunnel syndrome: May be only manifestation for 1 to 2 decades
  - Generalized polyneuropathy
    - Pain & Paresthesias
    - Weakness: Symmetric; May become severe
  - Restrictive cardiomyopathy: Arrhythmia; Cardiac insufficiency
  - Autonomic: Intestinal malabsorption; Hypotension
  - No renal or ocular involvement
  - Progression
    - Variable: Some stable; Others rapidly progressive
    - Survival high
    - Severe disability may develop
  - Treatment: Liver transplantation for disabled < 65 years
- Other point mutations: L58H, L58R, K70N, I84S, Y114H...
- "Indiana & Maryland " types
Other point mutations present with Cardiomyopathy or Renal disease
- Cardiomyopathy: Val122Ile
Treatments ¹²
- Liver transplantation
  - Prevents or slows further disease progression
  - No consistent recovery of function
  - Cognitive decline: May continue
  - Possible increased risk of cerebral amyloid angiopathy
- TTR stabilizers
  - Diflusinal ⁶
    - Dose: 250 mg 2x/day
    - Effect: Slower neuropathy & cardiopathy progression
  - Tafamidis (2-(3,5-dichloro-phenyl)-benzoxazole-6-carboxylic acid)
    - Dose: 20 mg/day
    - Delays progression of ATTRm-related polyneuropathy
- TTR gene silencing drugs
  - Patisiran
    - Small interfering (si) RNA, Silences mRNA
    - Outcome: Neuropathy scores Improved
    - Use supplemental Vitamin A
  - Vutrisiran
    - RNA interference (RNAi)
    - Double-stranded siRNAGalNAc conjugate
    - Binds & Silences TTR mRNA
    - Reduces serum TTR levels: Inhibits synthesis of variant & wild-type TTR
  - Inotersen
    - Antisense oligonucleotide
    - Reduces neuropathy progression & Improves QOL
  - Eplontersen
    - N-acetyl galactosamine (GalNAc)-conjugated antisense oligonucleotide (ASO)
    - Binds to TTR mRNA
    - Targets hepatic TTR mRNA: Inhibits TTR protein synthesis
    - Increased potency & receptor-mediated hepatocyte uptake vs Inotersen
- ? Iododeoxyrubicin (IDX)
Homozygotes: Val30Met ¹
- Similar clinical manifestations as heterozygotes: Illness not more severe
- Onset age: 45 to 68 years
- Some patients with
  - Late onset vitreous amyloidosis
  - Motor > Sensory neuropathy
    - Weakness: Distal
    - Fasciculations
    - Pathology: Focal edema; Subperineurial amyloid; Large & Small axon loss
  - Autonomic: Erectile dysfunction; Dysuria; Less orthostatic hypotension
TTR variant disorder: Amyloidosis Transthyretin wild type (ATTRwt)
- Epidemiology
  - Frequency
    - 10% to 44% of people > 80 years
    - 155 to 191/1,000,000
  - Associations
    - Increased age (> 75 years)
    - Males: Younger onset
- Inheritance: Sporadic
- Clinical
  - General: Frailty
  - Cardiac
    - Most common clinical feature of ATTRwt
    - Males > Females
    - TTRwt myocardial deposits in 25% of patients > 80 years
    - Cardiac failure: Patterns
      - Left ventricular ejection fraction low; ↑ NTproBNP
      - Heart failure with preserved ejection fraction
      - Aortic stenosis: Elderly patients
    - Laboratory: Myocardial retention of diphosphono-1,2-propanodicarboxylic acid
    - Treatment: Tafamadis
  - Other systemic
    - Pulmonary
    - Connective tissue
      - Biceps tendon rupture
      - Arthritis
      - Dupuytren's contracture
      - Rotator cuff tears
  - Amyloid common in GI tract & Subcutaneous tissue
  - Neurological
    - Carpal tunnel syndrome: 55% at onset
    - Lumbar Spine: Stenosis
    - Balance & Mobility disorders
    - No biopsy proven ATTRwt neuropathies
  - Hearing loss: All frequencies
  - Course: Slow progression over years to decades
  - Treatment: Tafamidis
- Laboratory
  - Pathology: Extracellular amyloid deposits
  - Fat aspirate: Low senstivity
  - Amyloid composition: Normal TTR
  - Other wild type amyloid deposition increased with age
    - Semenogelin 1
    - Apolipoprotein AIV
    - Cerebral: Aβ, ABri, ACys, APrP
    - Atrial
External link: GeneReviews

Amyloidosis, Familial Visceral (AMYLD3; ApoA1; FAP III; "Iowa" type)

²⁴
● Apolipoprotein A-1 (APOA1)

; Chromosome 11q23.3; Dominant

Gene
- Neuropathic amyloid: Missense mutation Gly26Arg in Iowa family
- Amyloid mutations, Other: Trp50Arg; Insertions & Deletions
- 18 mutations described: Missense & In-frame deletion
- Penetrance: Incomplete
- Gly26Arg: Renal amyloid common; Most common amyloidogenic mutation; Neuropathy in some patients
- Leu75Pro: Most eventually with amyloid; Onset 58 years
- Allelic disorders
  - Hypoalphalipoproteinemia, primary, 2, Recessive
  - Hypoalphalipoproteinemia, primary, 2, intermediate, Dominant
Protein
- Transports cholesterol from tissues to liver
- Major protein component of high density lipoprotein (HDL) in plasma
- Major plasma & chylomicron protein
- 50% synthesized in liver
Clinical (Iowa type): Similar to FAP I
- Onset age: Mean 43 to 58 years
- Polyneuropathy
  - Small fiber
  - Autonomic
  - Large fiber: Late
  - Slowly progressive
- Nephropathy (87%): Renal failure common (50%)
- Gastric Ulcer
- Hoarse Voice
Other non-neuropathic amyloid syndromes
- Hepatic disorders (67%)
- Cardiac ± Cutaneous: Leu90Pro; Arg173Pro; Leu174Ser
Course: Slow progression
Treatments
- Renal transplant for failue
- Liver transplant: May lead to amyloid regression
Cardiac amyloid: NT-proBNP high
Renal amyloid: eGFR low; Proteinuria mild or less common
Hepatic amyloid: ALP high

Amyloidosis, "Finnish" type (AMYLD4; FAP IV; Japanese)

²⁰
● Gelsolin (GSN)

; Chromosome 9q33.2; Dominant

Epidemiology
- "Finnish" type
- Also seen in USA, Portugal & Japan
Genetics
- Mutations
  - Common: Point mutations amino acid 187 (G654A, Asp187Asn; G654T, Asp187Tyr)
  - Other: Missense; N211K, c.640G>A, Met544Arg, Ala578Pro, Glu580Lys
- Allelic disorders
  - Bulbar paresis
  - Cerebral amyloid angiopathy
  - Itch: 1 patient without amyloid; Gly275Ser mutation ²⁵
Protein
- Binds to
  - Actin: barbed end of filaments; Prevents monomer exchange
  - Fibronectin
- Intracellular: Muscle; Phagocytes; Fibroblasts; Platelets
- Mutations: GSN protein
  - More sensitive to proteases
  - Cleaved into amyloidogenic peptides
Clinical features
- Onset age: 25 to 40 years
- PNS
  - Cranial Neuropathies
    - Face paresis: Bilateral; Upper early
    - Bulbar paresis
      - Dysphagia
      - Dysarthria
      - In older patients
      - Mutation association: D187Y
    - Also: V; XII; VIII
  - Sensory neuropathy: Often mild
    - Vibration loss
    - Paresthesias: Distal
    - Pain (30%)
    - Itch (30%)
    - Gait ataxia: Older patients
    - Corneal sensation: Reduced
    - ± Autonomic involvement
    - Severe
      - G654A mutation
      - Amyloid deposition in nerve connective tissue & near vessels
    - Some sensory loss may be related to proximal nerve involvement
  - Carpal tunnel syndrome: Often bilateral
  - Tendon reflexes: Reduced
  - Myokymia
- Systemic
  - Eye
    - Corneal lattice dystrophy; Also see Lattice corneal dystrophy IIIA
    - Dry eyes
    - Photophobia
    - Vision loss
  - Skin: Laxity (Cutis laxa), especially in face; Droopy eyelids; Dry mouth
  - Tongue: Atrophy
  - Cardiac (15%): Conduction abnormalities, occasional
  - Renal (15%): Proteinuria
- Course
  - Often benign
  - Some with episodic asperation
  - Usually normal lifespan
- Homozygotes: Rapidly progressive disease & Renal failure
Laboratory
- Electrodiagnostic
  - NCV: Axon loss; Some with Slowing; Carpal tunnel
  - EMG: Face denervation; Myokymia
- No cardiac involvement
- Amyloid in skin & nerve
- CSF: Protein mildly increased
- Nerve pathology ²
  - Amyloid
    - Deposition of gelsolin amyloid in vessel walls, deep skin layers, subcutaneous fat & perineurial sheaths
    - Nerve roots more severely affected than distal nerves
    - Other amyloid components: Apolipoprotein E, Amyloid P component, Cystatin C, α-Smooth muscle actin.
  - Axon loss
    - Age-related
    - Especially large myelinated axons
  - Myelin sheath: Reduction of cross-sectional area
  - Regenerating axon clusters
  - Perineurium: Hyaline thickening
  - Onion bulbs: Some (20%) patients
- Muscle pathology
  - Denervation in older (> 56) patients
  - Amyloid: Vessel walls; Perimysium
Gelsolin variant: Bulbar-onset Neuropathy ¹⁰
- Epidemiology: 1 American family, 5 patients
- Genetics
  - Inheritance: Dominant
  - Mutation: D187Y
- Clinical
  - Onset age: 37 to 64 years
  - Eyes: Dry; Photophobia; Corneal dystrophy; Ptosis
  - Face: Twitching; Weakness; Cutis laxa
  - Bulbar: Dysarthria; Dysphagia
  - Tongue: Atrophy
  - Limb strength: Normal
  - Sensory loss: Distal legs in 1 patient
- Laboratory
  - EMG
    - Myokymia: Face
    - Motor units: Large
    - Recruitment: Reduced

Amyloidosis (β2-Microglobulin) ⁴
● β₂-Microglobulin (B2M)

; Chromosome 15q21.1; Dominant

Epidemiology: 1 family
Genetics
- B2M mutation: Asp76Asn
- Allelic with: Hypoproteinemia, hypercatabolic
Clinical
- Onset age: 6th decade
- Gastrointestinal
  - Diarrhea
  - Constipation
  - Weight loss
- Autonomic neuropathy
  - Orthostatic hypotension
  - Sicca syndrome
- Course: Slow progression
Laboratory
- Renal function: Normal
- Circulating β2-microglobulin: Normal levels
- Pathology: Visceral amyloid
  - Composed of β₂-microglobulin
  - Locations: Spleen, Liver, Heart, Salivary glands, Nerves
  - Nerve pathology: Amyloid around endoneurial capillaries & in vessel walls
Variant syndrome
- Dialysis-related amyloidosis: Caused by sustained high plasma concentrations of wild-type β₂-microglobulin

OTHER AMYLOIDOSIS ⁹

NON-NEUROLOGIC
Classification	Associated features	Protein component
Secondary	Rheumatoid arthritis Inflammatory disorders Leprosy: Chronic	Serum Amyloid A (SAA) SAA1 & SAA2 ; SAA4
Familial Mediterranean fever (FMF)	Renal disease Abdominal pain	SAA 1° cause: Pyrin Treatment: Colchicine
AIAPP (Pancreatic amyloid)	Diabetes mellitus type 2 Insulinomas	Islet amyloid polypeptide
APro	Aging pituitary Prolactinoma	Prolactin
AKer	Skin	Keratins
AIns	Iatrogenic (Injection sites)	Insulin
AMed	Aortic media (Aging)	MFGE8 (Medin)
AANF	Cardiac atrial deposits	Atrial natriuretic factor
Senile Systemic	Cardiopathic; Carpal tunnel	Transthyretin (normal)
AL	Primary Organs: All except CNS Myeloma associated	Immunoglobulin light chain
AH	Primary Organs: All except CNS Myeloma associated	Immunoglobulin heavy chain
ACal	C cell thyroid tumors	(Pro)calcitonin
ALac	Cornea	Lactotransferrin
AKer	Corneal dystrophies	TGFBI
ALECT2	Renal	Leukocyte chemotaxin-2 (LECT2)
ASPC	Lungs	Lung surfactant protein
AGal7	Skin	Galectin 7 (GAL7; LGLAS7)
ACor	Cornified epithelia Hair follicles	Corneodesmosin (CDSN)
AOAAP	Odontogenic tumors	ODAM
ASem1	Vesicula seminalis	Semenogelin 1 (SEMG1
AEnf	Iatrogenic (Localized)	Enfurvitide
Hereditary component
AF	Cardiopathic	Transthyretin (mutation)
AGel: AMLYD4	Cornea Neuropathy	Gelsolin
Lattice corneal dystrophy Type IIIA	Corneal dystrophy & masses Cataracts	M1S1
Familial Visceral AFib: AMYLD2 AApoA1: AMYLD3 ALys: AMYLD5	Renal disease Organomegaly	Fibrinogen, α-chain (FGA) Apolipoprotein A-1 (APOA1) Lysozyme (LYZ) β₂-microglobulin (B2M)
Aβ₂M (Dialysis-associated)	Carpal tunnel syndrome Cysts: Bone; Tendon sheath Tendonitis: Hand; Shoulder Joint effusions& pain Myelopathy	β₂-microglobulin
Amyloidosis, renal (ALys)	Renal Visceral	Lysozyme (LYZ)
AApoAII	Renal	Apolipoprotein A II (APOA2)
AApoAIV	Renal medulla Systemic	Apolipoprotein A IV (APOA4)
AApoCII	Renal	Apolipoprotein C II (APOC2)
AApoCIII	Renal	Apolipoprotein C III (APOC3)
Muckle-Wells syndrome	Cold urticaria Deafness Renal amyloidosis	NLRP3 (CIAS1)
Multiple endocrine neoplasia Type 2A	Thyroid carcinoma Medullary, with amyloid Pheochromocytoma Parathyroid adenomas Cutaneous Notalgia paresthetica: T₂-T₆ posterior rami	RET oncogene
Endocrine (Localized)	Cardiac atria Thyroid Islets of Langerhans Pituitary	NPPA Calcitonin (CALCA) IAPP Prolactin
Primary Cutaneous (PLCA1)	Skin	Oncostatin M receptor-beta (OSMR)
Primary Cutaneous (PLCA2)	Skin	Interleukin 31 receptor A (IL31RA)

CNS
Classification	Disease Syndromes	Protein
ACys (Amyloidosis VI)	Cerebral amyloid angiopathy	Cystatin C
Aβ (Amyloid β A4)	Alzheimer's disease Cerebral amyloid angiopathy	Amyloid β A4 precursor protein (APP)
Amyloid β42	Alzheimer's disease	Presenilin 1 Presenilin 2
α-Synuclein (ASyn)	Parkinson disease 1 (PARK1) Parkinson disease 4 (PARK4) Dementia, Lewy body (DLB)	α-Synuclein (SNCA)
Amyloidoma		AL λ
APrP^sc	Spongiform encephalopathy	Prion protein
ATau	Dementia, frontotemporal ± Parkinsonism Pick disease Supranuclear palsy: PSNP1 Parkinson-Dementia	MAPT
Dysferlin	Alzheimer disease LGMD 2B	Dysferlin
ABri (Familial British) ADan (Familial Danish)	CNS ± Systemic	Integral membrane protein 2B (ITM2B)

Muscle
Classification	Disease Syndromes	Protein
Myopathy	LGMD 2B LGMD 2I LGMD 2L	Dysferlin FKRP ANO5

Amyloid myopathy: Acquired ⁸

Epidemiology
- Sex: Male > Female 4:1
Clinical
- Onset age: 43 to 82 years
- Weakness (> 90%)
  - Proximal (> 90%)
  - Distal (50%)
  - Legs > Arms
  - Respiratory
    - Failure: Occasional
    - Dyspnea (37%)
  - Dysphagia: 25% to 45%
  - Jaw: Claudication (25%)
  - Voice: Hoarseness
- Muscle pain (Myalgia): 33% to 40%
- Muscle size
  - Large
    - General: 20%
    - Macroglossia: 33%
  - Atrophy (25%)
- Tendon reflexes: Reduced in 60%
- Associated features
  - Neuropathy (30%): Sensory & Autonomic
  - Cardiac 70%
  - Renal 33%
  - Weight loss 57%
  - Fatigue 37%
  - Edema 22%
  - Skin: Alopecia; Finger nail loss or dystrophy
- Treatment
  - Melphalan: Response in minority
  - Stem cell transplant
- Course: Survival with light chain disease
  - Mean: 22 to 32 months
  - Cardiac disease: 15 months
Laboratory
- Serum CK
  - General: Normal in 50%; Occasional mild elevation; Rarely very high
  - Range: 46 to 5259
- Cardiac troponin T
  - May be high in asymptomatic patients
  - High: Suggests cardiac disease
- Hematologic disorders
  - Monoclonal gammopathy 60%
    - λ > κ Light chain disease: 50%
    - Progression to multisystem disease
    - M-protein type: IgG 33%; IgA 12%; IgM 4%; IgD 2%
    - Light chain only: 49%
  - Multiple myeloma
  - Waldenström macroglobulinemia
- EMG
  - Myopathy (88%)
  - Spontaneous activity 70%
    - Fibrillations or Positive sharp waves
    - Especiallly in gluteus & paraspinous muscles
- Nerve conductions: Small CMAP
- Muscle biopsy
  - Myopathy
    - Variation in muscle fiber size
    - Muscle fiber degeneration & Regeneration: 20%
    - Abnormal muscle fibers surrounded by granular basophilic material
  - Amyloid locations
    - Perimysium, Perivascular & Endomysium surrounding muscle fibers
  - Denervation: 40% to 80%
    - Atrophic fibers 75%
    - Fiber type groups 30%
Differential diagnosis
- LGMD: 2B (Dysferlin), 2L (Anoctamin-5)
- Also see: Acquired amyloidosis

Amyloidoma

Locations
- CNS: Choroid plexus & 2° extension into white matter
- PNS: Gasserian ganglion of the trigeminal nerve
Systemic: Little clinical evidence of lymphoplasmacytic neoplasm
Course: Slowly progressive
Amyloid type: AL λ light chain
Pathology
- Plasma cells: Along perivascular sheaths; No cytologic atypia
- Neoplasms of AL-producing B-cell clone capable of terminal differentiation.

Return to Immune-mediated axonal neuropathies
Return to Small fiber neuropathies
Return to Neuromuscular Home Page

References
1. Arch Neurol 2001;58:1914-1918
2. J Neuropath Exp Neurol 2002;61:565-571
3. Science 2003;299:713-716
4. N Engl J Med 2012;366:2276-2283
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13. Clin Auton Res 2019 Aug 31
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17. J Peripher Nerv Syst 2020 May 12
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19. Neurol Ther 2021 May 22
20. BMJ Case Rep 2022;15:e245764, Orphanet J Rare Dis 2020;15:19
21. Can J Neurol Sci 2023 Jan 10
22. Muscle Nerve 2021;64:23-36
23. Ann Neurol 2024 Jun 24
24. Amyloid 202;29:237-244
25. Journal of the Neurological Sciences 2024;463:123139

7/25/2024

AMYLOIDOSIS

Amyloid myopathy: Acquired 8

Amyloidoma

Amyloid myopathy: Acquired ⁸