Amyloid

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AMYLOIDOSIS

Amyloid
General clinical features

AL: Acquired PNS
CNS Amyloidosis
Hereditary PNS amyloid
Transthyretin
Apolipoprotein A1
Gelsolin
β₂-microglobulin
Myopathy
LGMD 2B
Non-neurologic amyloid
Pathology

Neuropathy, Amyloid-like

Amyloid around vessel (Arrow)
Loss of smaller myelinated axons

GENERAL FEATURES

Cause
- Deposition of insoluble fibrillar proteins in a β-pleated sheet configuration
- General
  - Misfolding of precursor protein leads to aggregation of insoluble, possibly toxic, fibrils that precipitate in tissues
  - Misfolded species can catalyze further misfolding
  - Mutations in precursor genes may increase degree of amyloidogenicity
  - Prion diseases are the only known transmissible form of amyloidosis
- Locations
  - Most disorders Extracellular spaces of tissues
  - Inclusion body myositis: Intraccellar
Polyneuropathy
Systemic manifestations
- Myopathy
- Myelopathy
- Cardiomyopathy
- Ophthalmologic
- Renal failure
- Amyloidoma
Electrophysiology
- Axonal, sensory, small fiber neuropathy
- Carpal tunnel syndrome
Associated serum antibody: ?
Serum M-Protein: Common in acquired disorders
Pathology
- Congo red positive deposits
  - Red-Green birefringent with polarized light
  - Fluorescent
- Locations
  - Connective tissue: Epineurial; Perimysial; Endomysial
  - Vessel walls: Intermediate-sized & Capillaries
  - Muscle fibers: Granular deposits in vacuoles in IBM
Treatment
- Hereditary forms: Liver transplantation
- Acquired forms (AL): Combined immunomodulation; Chemotherapy + Stem cell transplant

ACQUIRED AMYLOIDOSIS

Protein
- AL: Immunoglobulin light chains; κ or λ
Clinical
- Most common in middle aged males
- 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
- Polyneuropathy: Occurs in 20% of patients with light chain amyloid
  - Distal; Symmetric
  - Predominantly sensory
    - Pain & temperature loss most prominent
    - Distal weakness may develop later
  - Autonomic neuropathy
    - Orthostatic hypotension
    - Hypoactive pupils
    - Hypohydrosis
    - Bladder dysfunction
    - Impotence
  - Carpal tunnel syndrome in 25%
- 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
  - Renal: Nephrotic syndrome
  - Muscle enlargement ± weakness
  - Gastrointestinal: Diarrhea
  - Anemia associated with multiple myeloma
  - Amyloidoma
Laboratory
- CSF: Protein mildly elevated
- Electrodiagnostic: Axonal neuropathy
- Biopsy: Axonal loss; Amyloid
Prognosis
- Gradual progression
- Survival of 1 to 10 years depending on organ involvement
- Shortest survival with cardiac (< 1 year) & renal dysfunction
Treatment: Combined immunomodulation; Chemotherapy + Stem cell transplant
- High dose chemotherapy (HDC)
- Peripheral blood stem cell transplant (PBSCT): after chemotherapy
- Timing: 1st year of disease
- Best prognosis: Limited disease
- Worst prognosis: Multi-organ involvement

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

l Transthyretin (TTR)

; Chromosome 18q12.1; Dominant

TTR gene
- 4 exons: Exon 1 codes for signal peptide
- Mutations
  - General locations
    - Exon 1: Only 1 mutation (Val20Ile); Not in signal peptide
    - > 80 in other 3 exons
  - Mutation types
    - Most are missense point mutations
    - Deletion: 1 identified (V122δ)
  - Mutation databases: HGMD
TTR Protein
- 127 amino acids
- Present in plasma
- Binds: Thyroxine (20%); Retinol binding protein
- 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
Genetic-Clinical correlations
- 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
- Specific mutations
  - Val30Met
    - Most common neurologic mutation: Especially in Portugal
    - Onset: 25 to 65 years
    - Neuropathy: Small fiber & Autonomic
    - 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
  - Leu55Pro: Severe disease
  - Thr60Ala: Carpal tunnel; Restrictive cardiomyopathy
  - Phe64Leu ⁵
    - Common in Southern Italian families
    - Male:Female = 3:1
    - Onset: Later (7th & 8th decade); Paresthesias
    - Milder disease: Progression over 10 years
    - Neuropathy: Distal; Sensory; Autonomic (GI) & BP); Weakness with progression; Axonal
    - Cardiomyopathy
  - Ser77Tyr: Yemenite Jews; Sensory loss & Muscle pain
  - Ile84Asn: Restrictive cardiomyopathy; Ocular
  - Ile107Phe: Neuropathy, Sensory & Autonomic
  - Tyr114His: Carpal tunnel
  - Val122His: Restrictive cardiomyopathy, Recessive, Afro-Americans, Late onset
  - 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, other: Leu12Pro; Val30Met; Gly53Glu
  - Familial amyloid cardiomyopathy: V20I; P24S; A45T; I68L; L111M; V122I
- Protective mutation: Thr119 Met
Clinical syndromes
- Heterogeneous, with some relation to
  - Point mutation location
  - Ethnic background
- Signs include
  - Peripheral nerve
    - Polyneuropathy: Sensory, Autonomic, ± Motor
    - Carpal tunnel syndrome
  - Systemic: Cardiomyopathy, Vitreous opacities, Renal failure
  - Rare CNS: Hearing loss; Migraine; Dementia; Cerebellar; Seizures; Stroke; Myelopathy
- Onset 17-78 years
- Penetrance: Variable: 30% to 95%
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
  - Treatment
    - Liver transplantation: Prevents further disease progression; No consistent recovery of function
    - ? Iododeoxyrubicin (IDX)
- Laboratory
  - CSF protein: Moderately increased in 20%
  - Sural nerve biopsy
    - Axonal loss: Myelinated axons especially in older onset patients
    - Amyloid
      - Most prominent in sympathetic ganglia, dorsal root ganglia & proximal nerve trunks
      - Deposition in connective tissue: Endoneurium, Perineurium, Epineurium
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 mutation
  - Common in black population
  - Late onset: > 60 years
Homozygotes: Val30Met¹
- May have similar clinical manifestations as heterzygotes: Illness not more severe
- Onset: 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
External link: Gene clinics

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

l Apolipoprotein A-1 (APOA1)

; Chromosome 11q23.3; Dominant

Gene
- Neuropathic amyloid: Missense mutation Gly26Arg in Iowa family
- Other amyloid mutations: Trp50Arg; Insertions & deletions
Protein
- Transports cholesterol from tissues to liver
- Major plasma & chylomicron protein
Clinical features (Iowa type): Similar to FAP I
- Polyneuropathy
  - Small fiber
  - Autonomic
  - Large fiber: Late
  - Slowly progressive
- Nephropathy: Renal failure
- Gastric Ulcer
Other non-neuropathic amyloid syndromes
- Hepatic failure
- Cardiac ± Cutaneous: Leu90Pro; Arg173Pro; Leu174Ser

Amyloidosis (Gelsolin; FAP IV; "Finnish" (also Japanese) type

)
l Gelsolin (GSN)

; Chromosome 9q33.2; Dominant

Epidemiology
- "Finnish" type
- Also seen in USA & Japan
Genetics
- Mutations: Point mutations amino acid 187 (G654A or G654T)
Protein
- Binds to
  - Actin: barbed end of filaments; Prevents monomer exchange
  - Fibronectin
- Intracellular: Muscle; Phagocytes; Fibroblasts; Platelets
Clinical features
- Onset: 4th decade
- Cranial Neuropathies
  - Facial paresis (Upper)
  - Also: V; XII; VIII
  - Bulbar paresis in older patients
- Sensory neuropathy: Often mild
  - Vibration loss
  - Paresthesias: Distal
  - Gait ataxia: Older patients
  - Reduced corneal sensation
  - ± Autonomic involvement
  - Severe
    - G654A mutation
    - Amyloid deposition in nerve connective tissue & near vessels
- Carpal tunnel syndrome: Occasional
- Tendon reflexes: Reduced
- Corneal lattice dystrophy: Also see Lattice corneal dystrophy IIIA
- Skin: Laxity, especially over skin & face; Tongue
- Other organs: Rarely involved
- Course
  - Often benign
  - Some with episodic asperation
  - Usually normal lifespan
- Homozygotes: Rapidly progressive disease & Renal failure
Laboratory
- Electrodiagnostic: Axonal loss
- No cardiac involvement
- Amyloid in skin & nerve
- CSF: Protein mildly increased
Nerve pathology²
- Amyloid
  - Deposition of gelsolin amyloid in vessel walls & perineurial sheaths
  - Nerve roots more severely affected than distal nerves
  - Other amyloid components: Apolipoprotein E, Amyloid P component, Cystatin C, α-Smooth muscle actin.
- Axonal loss
  - Age-related
  - Especially large myelinated axons
  - Reduction of myelin sheath cross-sectional area
  - Regenerating clusters
- Perineurium: Hyaline thickening
- Onion bulbs: Some (20%) patients
Muscle pathology
- Denervation in older (> 56) patients
- Amyloid: Vessel walls; Perimysium

Amyloidosis (β2-Microglobulin) ⁴
l 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

NON-NEUROLOGIC
Classification	Associated features	Protein component
Secondary	Rheumatoid arthritis Inflammatory disorders Leprosy: Chronic	Serum Amyloid A (SAA) SAA1 & SAA2 ; SAA4
Aβ₂M (Dialysis-associated)	Carpal tunnel syndrome Cysts: Bone; Tendon sheath Tendonitis: Hand; Shoulder Joint effusions& pain Myelopathy	β₂-microglobulin
AIAPP (Pancreatic amyloid)	Diabetes mellitus type 2 Insulinomas	Islet amyloid polypeptide
APro	Aging pituitary Prolactinoma	Prolactin
AKer	Skin	Keratins
AIns	Iatrogenic	Insulin
AMed	Aortic media (Aging)	MFGE8 (Medin)
AANF	Cardiac atrial deposits	Atrial natriuretic factor
Senile Systemic	Cardiopathic; Carpal tunnel	Transthyretin (normal)
AF	Cardiopathic	Transthyretin (mutation)
AL	Primary Myeloma associated	Immunoglobulin light chain
AH	Primary Myeloma associated	Immunoglobulin heavy chain
ACal	C cell thyroid tumors	(Pro)calcitonin
? ALac	Cornea	Lactotransferrin
AKer	Corneal dystrophies	TGFBI
AGel	Cornea Neuropathy	Gelsolin
Lattice corneal dystrophy Type IIIA	Corneal dystrophy & masses Cataracts	M1S1
Familial Mediterranean fever	Renal disease Abdominal pain	SAA 1° cause: Pyrin Treatment: Colchicine
Familial Visceral (AFib; AApoAI; ALys)	Renal disease Organomegaly	Fibrinogen, α-chain Apolipoprotein A-1 Lysozyme
Muckle-Wells syndrome	Cold urticaria Deafness Renal amyloidosis	NLRP3 (CIAS1)
ALys	Renal Visceral	Lysozyme
Multiple endocrine neoplasia Type 2A	Thyroid carcinoma Medullary, with amyloid Pheochromocytoma Parathyroid adenomas Cutaneous Notalgia paresthetica: T₂-T₆ posterior rami	RET oncogene
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	Parkinson's disease	α-Synuclein
Amyloidoma		AL λ
APrP^sc	Spongiform encephalopathy	Prion protein
Dysferlin	Alzheimer disease LGMD 2B	Dysferlin

Amyloid myopathy

Epidemiology
- Onset: 50 to 80 years
- Sex: Male > Female 4:1
Clinical
- Weakness
  - Proximal; Legs > Arms
  - Respiratory failure: Occasional
  - Dysphagia: 25%
- Muscle pain: 40%
- Tendon reflexes: Reduced in 60%
- Large muscles: 20%; Macroglossia
- Course: Mean survival 22 months
Associated features
- Sensory & autonomic neuropathy
- Cardiac 70%
- Renal 33%
- Monoclonal gammopathy 60%
  - κ, or λ light chain disease: 50%
  - Progression to multisystem disease
Laboratory
- Serum CK: Usually normal; Occasional mild elevation; Rarely very high
- EMG
  - Myopathy
  - 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%
Treatment
- Melphalan: Response in minority
Differential diagnosis
- LGMD 2B
- 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.

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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
5. J Peripher Nerv Syst 2012;17:385-390

1/4/2013