Amyloid

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AMYLOIDOSIS

General clinical features

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

GENERAL FEATURES

Cause
- Deposition of insoluble fibrillar proteins in a &betaq;-pleated sheet configuration
- 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

ATTR: Transthyretin (Prealbumin)

l Chromosome 18q11.2-q12.1; Dominant

ATTR 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
ATTR 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 mutation: Especially in Portugal
    - Onset: 25 to 65 years
    - Neuropathy: Small fiber & autonomic
    - Protective mutations on other allele: Arg104His; Thr119Met
  - Val28Met: 7th decade onset neuropathy with impotence; No FH
  - Leu55Pro: Severe disease
  - 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: Gly53Glu; L12P; V30M
  - Familial amyloid cardiomyopathy: V20I; P24S; A45T; I68L; L111M; V122I
- Protective mutation: Thr119 Met
Clinical syndromes
- Heterogeneous, with some relation to:
  - Point mutation & 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
- Presentation: Generalized Autonomic & Sensory Polyneuropathy
  - Onset: Legs
  - Painful dysesthesias
- Most common point mutation: Val30Met
  - Onset: 20 to 80 years
    - Later: Sporadic Japanese cases; Swedish endemic foci
    - Earlier: Japanese & Portugese endemic foci
  - Penetrance
    - High: Endemic Japanese foci
    - Low: Scattered, sporadic cases; Swedish endemic foci
  - 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
  - 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
  - Treatment
    - Liver transplantation: Prevents further disease progression; No consistent recovery of function
    - ? Iododeoxyrubicin (IDX)
- Also > 23 other mutations
- "Portuguese, Swedish & Japanese" types
FAP II clinical syndrome
- Onset
  - Upper extremities, esp carpal tunnel syndrome
  - 5th decade
- Most common mutation: Ser77Tyr
  - Onset
    - 51 to 67 years
    - 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

ApoA1: Apolipoprotein A-1 (FAP III; "Iowa" type)

l Chromosome 11q23.3; Dominant

Gene
- Neuropathic amyloid: Point mutation Gly26Arg
- 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
- Nephropathy
- Gastric Ulcer
Other non-neuropathic amyloid syndromes
- Hepatic failure
- Cardiac ± Cutaneous: Leu90Pro; Arg173Pro; Leu174Ser

AGel: Gelsolin

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

)
l Gelsolin; Chromosome 9q32-q34; Dominant

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
- 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

OTHER AMYLOIDOSIS

NON-NEUROLOGIC
Classification	Associated features	Protein component
Secondary	Rheumatoid arthritis Inflammatory disorders Leprosy: Chronic	Protein A
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
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	Protein A 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	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	Skin	Oncostatin M receptor-beta (OSMR)

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.

Return to Immune-mediated axonal neuropathies
Return to Small fiber neuropathies
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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

12/11/2009