Amyloid neuropathies

Amyloidosis is a heterogeneous disease with many different clinical manifestations, occurring as a result of the deposition of insoluble protein fibrils which disrupt normal tissue structure. Over 25 proteins have been described that form amyloid, but only some are deposited in peripheral nerves. Progressive neuropathy is a common feature of familial amyloid polyneuropathy (FAP) and monoclonal immunoglobulin light-chain (AL) amyloidosis. Neuropathy is not a major feature of reactive AA amyloidosis, ß2-microglobulin amyloidosis or other types of amyloidosis. For classification of systemic amyloidosis, see Table.

Monoclonal immunoglobulin light-chain (AL) amyloidosis

This is the most common form of systemic amyloidosis. All patients have an underlying clonal B-cell dyscrasia; 10-20% meet criteria for multiple myeloma. Fibrils are derived from the variable region of lambda light chains in 75% and kappa chains in the remainder.

Clinical features

The mean age of onset is 65 years; AL amyloidosis rarely presents before 40 years. Two-thirds of patients are male [1]. Macroglossia and periorbital ecchymoses are pathognomonic but occur in a minority of patients. Other clinical features include carpal tunnel syndrome (CTS), sensory-motor axonal neuropathy with autonomic involvement, nephropathy and cardiomyopathy [2]. Symptoms of peripheral neuropathy typically start with small fibre symptoms such as unpleasant sensory symptoms including pain; progressive sensory loss and motor weakness occur later. Autonomic symptoms include nausea and vomiting, nocturnal diarrhoea, postural lightheadedness and erectile dysfunction [3]. Non-specific systemic features such as fatigue and weight loss are common.

Differential diagnosis

Small fibre neuropathies are a common reason for referral to neurologists; often idiopathic, the most frequent association is with abnormal glucose metabolism including diabetes and impaired glucose tolerance. These symptoms may be indistin- guishable from the early symptoms of amyloid neuropathy. The symptoms which should alert the neurologist to a possible diagnosis of amyloid include autonomic symptoms, new cardiac symptoms, the presence of a paraprotein or the rapid progression of the neuropathy to involve large fibres. If there is a family history of cardiomyopathy, pace-maker insertion or neuropathy, inherited amyloid neuropathy should be considered.

Diagnosis

Biopsy

A tissue diagnosis is essential in all forms of amyloidosis. Rectal or abdominal fat biopsy may be performed; however, in a patient presenting with neuropathy nerve biopsy is often performed directly. Because of the patchy nature of amyloid, a negative biopsy does not rule out amyloidosis. If clinical suspicion is high, repeat nerve biopsy or biopsy of another affected tissue should be undertaken. Histological examination after Congo red staining demonstrates green birefringence when viewed under polarised light. Immunohistochemical staining confirms the presence of λor κlight chains (Figure) but is not 100% sensitive.

Other investigations

Nerve conduction studies (NCS) typically show an axonal length-dependent peripheral neuropathy which is sensory more than motor. There is often superimposed CTS.2,3 Electromyography (EMG) may demonstrate acute and chronic denervation with reinnervation. In the early stages of disease, NCS may be normal but quantitative sensory testing may demonstrate a small fibre neuropathy [3].

All patients with suspected amyloidosis should have serum and urine protein electrophoresis, immunoglobulins, immunofixation and light chains checked. A monoclonal protein is detectable in the serum or urine in 90%, two-thirds have a light-chain present. However, because monoclonal gammopathies occur not uncommonly in the general population, the detection of a paraprotein in a patient with amyloidosis must be interpreted cautiously; one study found that 10% of patients with suspected AL amyloidosis had an inherited form [4]. Bone marrow biopsy typically contains a population of monoclonal plasma cells expressing λor κlight chains. N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin are useful to screen for cardiac involvement; a staging system using these biomarkers guides prognosis [5]. Skeletal survey is performed to investigate for myeloma lesions. Renal function is assessed, including measurement of proteinuria. SAP scintigraphy may be performed to demonstrate radiolabelled serum amyloid P. This is useful to monitor visceral amyloid load and response to treatment but does not differentiate between different forms of amyloid. Sensitivity is ~90% for AL amyloid; however, SAP scans do not reliably demonstrate peripheral nerve or cardiac involvement [6].

Cardiac dysfunction is a major cause of morbidity and mortality. Echocardiography in patients with cardiac amyloid deposition demonstrates thickened ventricular walls and interventricular septum and a granular myocardium. A characteristic finding is preserved wall motion at the left ventricular apex with hypokinesis in basal and midsections [7]. Electrocardiogram shows low voltage in limb leads and conduction block.

Management

Specific treatment

Several treatment regimens are available to suppress light chain production. High dose melphalan with autologous stem-cell trans plantation (HDM/SCT) is first line in selected patients. Monthly cycles of oral melphalan with dexamethasone may be considered for high risk patients [8]. Alternatives include borte-zomib- or lenalidomide-based options. For patients with single organ involvement solid organ transplantation may be used.

Supportive management

Management of patients with amyloidosis requires a multi-disciplinary approach. Wearing pressure stockings and judicious use of drugs like midodrine and fludrocortisone may help orthostasis. Eating small meals often helps nausea and anti-diarrhoeal medication may be required. Drugs for erectile dysfunction may be appropriate in some cases. Cardiac pacing may be required for arrhythmia. Medication for neuropathic pain is frequently required.

Prognosis

Survival is variable depending on organ involvement; the presence of congestive cardiac failure at diagnosis significantly reduces survival [5,10]. Survival has been significantly improved by the use of chemotherapy and SCT, with complete response rates ranging from 32-79% and responders surviving >4 years [9].

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Inherited amyloid neuropathies

Transthyretin (TTR)-related FAP

TTR-related FAP is the commonest form of inherited amyloid neuropathy. TTR is a protein which transports thyroxine and retinol; circulating as a tetramer of four identical non-covalently associated subunits. The liver is the major producer of TTR; however, small amounts are synthesised by the retina and choroid plexus.Genetics of TTR-related FAP

Over 100 mutations have been described in the TTR gene associated with TTR-related FAP . TTR-related FAP is dominantly inherited; however, variable penetrance means that patients may not have an obvious family history. The same mutation has different penetrance and age at onset in different populations. The most common mutation, Val30Met, presents in the second/third decade in Portuguese patients with a high penetrance [11], but presents later (sixth decade) in Swedish patients with lower penetrance [12]. In patients with Irish ancestry, the Thr60Ala mutation is the most prevalent; presenting in the sixth/seventh decade [13]. Recessive mutations have been described in TTR, without a more severe clinical phenotype.

Clinical features

CTS is often the initial symptom and may predate other symptoms by many years. Patients subsequently develop a small-fibre neuropathic syndrome with prominent pain which progresses relatively rapidly. As the disease progresses pain gives way to numbness, and large fibre involvement becomes apparent with a progressive sensory-motor neuropathy. Autonomic dysfunction including orthostatic hypotension, alternating diarrhoea and constipation, urinary incontinence and impotence are prominent later symptoms.

Diarrhoea also results from amyloid deposition in the gastrointestinal tract. Cardiac involvement is common. Other features include vitreous deposits and, less commonly, nephropathy and leptomeningeal involvement. Cachexia is a common late feature of the disease. Mean survival in untreated patients is approximately 10 years from symptom onset.

ApoA1-related FAP

ApoA1 is the main protein in high-density lipoprotein, secreted by the liver and intestine, and catabolised by the kidneys. The classical presentation of ApoA1-related FAP is with proteinuria and hypertension with slow progression of renal failure. Patients often have extensive visceral amyloid deposits with hepatosplenomegaly. A sensory-motor neuropathy with autonomic involvement may occur. There is a high incidence of nephropathy and gastric ulcers.

Gelsolin-related FAP

Gelsolin-related FAP occurs as a result of mutant gelsolin fragments being deposited as amyloid fibrils. Although originally and still most commonly described in Finland, it has subsequently been reported in European, American and Japanese families. The clinical features are of corneal lattice dystrophy producing corneal clouding (often the first sign of disease in the fourth decade), cutis laxa and cranial neuropathies. Facial weakness occurs, affecting the forehead first. Cranial nerves VIII, IX and XII are involved later with development of bulbar weakness. CTS is common; although peripheral neuropathy may occur it is not a prominent feature and is predominantly sensory. Autonomic dysfunction rarely occurs.

Diagnosis

Neurophysiology

TTR- and ApoA1-related FAP typically demonstrate a length-dependent sensory-motor axonal neuropathy although in TTR-related FAP , patchy slowing of motor conduction can be seen leading in some instances to an erroneous diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) [14]. In gelsolin-related FAP NCS may be normal other than showing evidence of CTS or mild reduction in sensory amplitudes; however, EMG may show denervation in facial and bulbar muscles.

Biopsy

Nerve biopsy is often used in patients presenting with a neuropathy to obtain a tissue diagnosis although, as for AL amyloidosis, other tissues including rectum, abdominal fat or heart can be biopsied. The histopathological features of FAP on nerve biopsy are similar to AL amyloidosis, with amyloid deposited in the endoneurium, epineurium and surrounding vessels. Immunolabelling with specific antibodies should be performed to confirm the amyloid type.

Genetic testing

Direct DNA sequencing of the relevant gene should be performed. Predictive testing of family members and prenatal or pre-implantation genetic diagnoses are possible.

Other findings

SAP scintigraphy has a much lower sensitivity (48%) for FAP than for AA or AL amyloid.6 Gadolinium-enhanced MRI of the brain and cord should be performed if leptomeningeal amyloidosis is suspected. Ophthalmological assessment should be performed to look for evidence of lattice corneal dystrophy in gelsolin-related FAP and for vitreous deposits in TTR-related FAP .

Treatment

General measures

Supportive management, including management of neuropathic pain and cardiac complications, with multi-disciplinary input as for AL amyloidosis is appropriate for patients with FAP . Carpal tunnel release may be appropriate for symptomatic CTS; if necessary, the flexor retinaculum may be biopsied perioperatively to confirm the presence of amyloid. Vitrectomy may be performed for vitreous deposits.

Specific treatment

The only specific treatment for TTR-related FAP is orthotopic liver transplantation to remove the source of abnormal TTR production. Severe peripheral neuropathy and significant autonomic neuropathy are relative contraindications and many patients (especially older patients) are too unwell to tolerate major surgery by the time of diagnosis. Patients with the Val30Met mutation benefit most from liver transplantation. With non-Val30Met TTR mutations, especially Thr60Ala, cardiomyopathy may progress rapidly after liver transplantation due to continued deposition of wild-type TTR on mutant TTR already laid down; patients with these mutations who have evidence of cardiomyopathy are generally not offered liver transplantation. Because the liver is otherwise healthy, the removed liver may be transplanted into a patient with end-stage liver disease (domino liver transplant).

Patients with ApoA1-related FAP may be offered kidney or combined heart and kidney transplant as end-stage renal failure is usually the predominant feature. Liver transplantation has been performed in occasional patients with some success [15]. There is no specific therapy for gelsolin-related FAP other than corneal transplant for lattice dystrophy, plastic surgery may be required for facial weakness.

Future directions

Advances have been made in understanding the pathogenesis and improving outcome for patients with amyloidoses. Trials are underway of medications that inhibit fibrillogenesis and enhance regression of SAP as well as that of a chimeric antibody which enhances clearance of amyloid fibrils. Several trials are ongoing comparing different chemotherapeutic/SCT regimens for treatment of AL amyloidosis. Diflunisal, a drug that stabilises amyloid precursor protein, is already used by patients with TTR-related FAP not suitable for liver transplant (evidence of efficacy awaited). Publication of reports on a similar drug, tafamidis, is awaited.

References

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2. Matsuda M, Gono T, Morita H, Katoh N, Kodaira M, Ikeda S. Peripheral nerve involvement in primary systemic AL amyloidosis: a clinical and electrophysiological study. European Journal of Neurology 2010. DOI: doi:10.1111/j.1468-1331.2010.03215.x

3. Kim DK, Zeldenrust SR, Low PA, Dyck PJ. Quantitative sensation and autonomic test abnormalities in transthyretin amyloidosis polyneuropathy. Muscle & Nerve 2009;40:363-70.

4. Lachmann HJ, Booth DR, Booth SE, et al. Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. The New England Journal of Medicine 2002;346:1786-91.

5. Dispenzieri A, Gertz MA, Kyle RA, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. Journal of Clinical Oncology 2004;22:3751-7.

6. Hazenberg BPC, van Rijswijk MH, Piers DA, et al. Diagnostic performance of 123I-labeled serum amyloid P component scintigraphy in patients with amyloidosis. The American Journal of Medicine 2006;119:355.e315-24.

7. Belkin RN, Kupersmith AC, Khalique O, et al. A novel two-dimensional echocardiographic finding in cardiac amyloidosis. Echocardiography 2010;27:1171-6.

8. Bember LM. Modern treatment of amyloidosis: unresolved questions. Journal of the American Society of Nephrology 2009;20:469-72.

9. Wechalekar AD, Hawkins PN, Gillmore JD. Perspectives in treatment of AL amyloidosis. British Journal of Haematology 2007;140:365-77.

10. Simmons Z, Specht CS. The neuromuscular manifestations of amyloidosis. Journal of Clinical Neuromuscular Disease 2010;11:145-57.

11. Saraiva MJM. Transthyretin mutartions in hyperthyroxinemia and amyloid disease. Human Mutation 2001;17:493-503.

12. Holmgren G, Holmberg E, Lindstrom A, et al. Diagnosis of familial amyloidotic polyneuropathy in Sweden by RFLP analysis. Clinical Genetics 1988;33:176-80.

13. Reilly MM, Staunton H, Harding AE. Familial amyloid polyneuropathy (TTR ala 60) in north west Ireland: a clinical, genetic, and epidemiological study. Journal of Neurology Neurosurgery and Psychiatry 1995;59:45-9.

14. Plante-Bordeneuve V, Ferreira A, Lalu T, et al. Diagnostic pitfalls in sporadic transthyretin familial amyloid polyneuropathy (TTR-FAP). Neurology 2007;69:693-8.

15. Testro AG, Brennan SO, Macdonell RAL, Hawkins PN, Angus PW. Hereditary amyloidosis with progressive peripheral neuropathy associated with Apolipoprotein AI Gly26Arg: outcome of hepatorenal transplantation. Liver Transplantation 2007;13:1028-31.