Amyloidosis is a heterogeneous group of diseases, either inherited or acquired, characterised by the deposition of insoluble protein fibrils in the extracellular space.¹ More than 35 distinct proteins have been identified to form amyloid in humans² but only some cause neuropathy (see Table 1). This review will focus on familial amyloid polyneuropathy (FAP), a subgroup of the inherited amyloidoses which cause neuropathy as one of the main symptoms.

Classification

The most common fibril protein deposited as amyloid in FAP is a variant form of transthyretin (TTR, formerly known as pre-albumin),³ but FAP can also occur secondary to apolipoprotein A-1⁴ and to gelsolin deposition.⁵ All FAP is inherited in an autosomal dominant manner, although penetrance may vary and clinical features differ significantly depending on subtype.

Before the emergence of molecular genetics, FAP was classified into four subtypes based on clinical constellation and ethnic origin: 

• Type I (lower limb onset)
• Type II (upper limb onset)
• Type III (lower limb neuropathy, nephropathy and gastric ulcers) 
• Type IV (cranial nerve involvement with corneal lattice dystrophy). 

However, characterisation of the constituent amyloidogenic protein has proven to be more useful:

• Transthyretin-related FAP (TTR-FAP), which encompasses types I and II of the original classification
• Apolipoprotein A1-related FAP (type III)
• Gelsolin-related FAP (type IV).

Transthyretin-related FAP

TTR is a small soluble protein composed of 127 amino acids. It transports thyroxine and retinol, circulating as a tetramer of four identical non-covalently associated sub-units. The main production site is the liver (> 90%), but small amounts are also synthesised by the retina and choroid plexus.

Genetics of TTR-related FAP

More than 150 TTR mutations have been identified in association with TTR-FAP. However, the penetrance for TTR amyloidosis varies even for patients with the same mutation and, thus, may present as apparently sporadic cases. The same mutation has different age at onset in different populations; TTR-FAP due to Val30Met (the first described and most common point mutation) presents in the second/third decade in Portuguese patients with a high penetrance,⁶ but presents later (sixth decade) in Swedish patients with a lower penetrance. In patients with Irish ancestry, the Thr60Ala mutation is the most prevalent. This particular mutation has been shown to originate from a single founder in northwest Ireland. These patients present in the sixth/seventh decade and reduced penetrance is reported.⁷

Clinical features

The cardinal clinical features in TTR-FAP are of sensorimotor peripheral neuropathy commonly associated with autonomic dysfunction, cardiomyopathy and, less frequently, vitreous, renal and leptomeningeal involvement. Carpal tunnel syndrome (CTS) is often the presenting symptom, especially in non-Val30Met patients and may precede the other symptoms by several years.

Polyneuropathy is length-dependent, usually starting in the lower limbs with initial symptoms of painful small fibre involvement. Typical examination findings of dissociated sensory loss are more pronounced for pain and temperature than for light touch and vibration.⁸ Patients may have prominent pain which progresses relatively rapidly. Eventually all sensory modalities are involved and complications secondary to painless injury to the feet may occur, eg. ulcers, cellulitis, osteomyelitis. Motor involvement typically occurs later in the disease course with wasting and weakness in the lower limbs, gradually progressing to the upper limbs.

Autonomic involvement usually manifests with orthostatic hypotension, troublesome gastrointestinal symptoms, such as diarrhoea triggered by meals, explosive and nocturnal diarrhoea, gastric distension, erectile dysfunction and urinary disturbance. Examination may demonstrate scalloped pupils, postural hypotension, an abnormal Valsalva response and a fixed pulse rate. The autonomic neuropathy can be debilitating and in the terminal stages of the disease patients are often bed bound due to a combination of severe peripheral and autonomic neuropathy.

Cardiac involvement is common, usually presenting with arrhythmia, heart block or heart failure. Mean survival in untreated patients is approximately 10 years from symptom onset, with patients usually succumbing to cachexia, intercurrent infection, cardiac or autonomic complications.⁸

Apolipoprotein A1-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, hypertension and slowly progressive renal failure. Most patients eventually require dialysis. Median time from presentation to end-stage renal failure is reported to be between eight and 20 years. There is a high incidence of gastric ulcers.⁹ Patients often have extensive visceral amyloid deposits with hepatosplenomegaly. A sensorimotor neuropathy with autonomic involvement may occur but is not the main feature of the disease.

Gelsolin-related FAP

Gelsolin is an actin-binding protein which regulates actin filament assembly and disassembly. Gelsolin-related FAP occurs as a result of mutant gelsolin fragments being deposited as amyloid fibrils. It is most commonly reported in Finland, but has also been described elsewhere. The clinical features are of corneal lattice dystrophy producing corneal clouding (often the first sign of disease in the fourth decade, may be asymptomatic), cutis laxa and progressive cranial neuropathy with the facial nerve most commonly involved, affecting the forehead first. Cranial nerves VIII, IX and XII may also be affected with development of bulbar weakness.¹⁰ Carpal tunnel syndrome is common. A mild sensory predominant neuropathy may occur but autonomic dysfunction is rarely present.¹⁰

Diagnosis

Biopsy

It is essential to demonstrate amyloid deposits by direct examination of biopsy material from the peripheral nerve, rectum, heart, subcutaneous fat or other tissue. A negative biopsy does not necessarily rule out amyloid since deposition can be patchy and biopsy of an alternate tissue may be required. Congo red and polarising filters demonstrate the characteristic apple green birefringence.¹⁰ Immunolabelling with specific antibodies may identify the type of amyloid. However, laser microdissection and mass spectroscopy is more sensitive and specific. The histopathological features of FAP on nerve biopsy demonstrate amyloid deposited in the endoneurium, epineurium and surrounding vessels.

Genetic testing

Direct DNA sequencing of the relevant gene should be performed. Predictive testing of family members should be considered, with appropriate genetic counselling, given the availability of treatment. Importantly, one study found that almost 10% of individuals diagnosed with AL amyloidosis without any family history actually had FAP which has significant implications for treatment.¹¹

Neurophysiology

TTR and ApoA1-related FAP typically demonstrate a length-dependent sensorimotor axonal neuropathy. In the early stages of TTR-FAP, the only abnormalities may be in small fibre function such as abnormal thermal thresholds. Later the sensory action potentials become progressively reduced, initially in the lower but eventually in the upper limbs. Motor responses become progressively reduced with disease progression, especially in the lower limbs. Occasionally FAP may mimic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Amyloid should be considered in any patient with apparent CIDP unresponsive to treatment. 

In gelsolin-related FAP, NCS may be normal other than showing mild reduction in sensory amplitudes or CTS, which has higher incidence than is suspected clinically. EMG may show denervation in facial and bulbar muscles. 

Other investigations

The extent of systemic amyloid deposition can be assessed using scintigraphic studies with serum amyloid P component (SAP), which is deposited in all types of amyloidosis. SAP scintigraphy is not useful for diagnosis of TTR-associated neuropathy or cardiomyopathy; 99m Tc-DPD scintigraphy is, however, very sensitive for cardiac TTR-amyloid. Troponin, NT-proBNP, ECG, echocardiogram and cardiac MRI are also useful for assessment of cardiac involvement. 

If leptomeningeal amyloidosis is suspected, a gadolinium-enhanced MRI and CSF analysis should be performed. Ophthalmological assessment is necessary to look for lattice corneal dystrophy in gelsolin-related FAP and for vitreous deposits in TTR-related FAP. Magnetic resonance neurography has been shown to identify early peripheral nerve lesions in asymptomatic mutation carriers.¹²

Diagnostic challenges

The rate of misdiagnosis in FAP is high (over 30%) with an average delay of nearly four years. The most frequent misdiagnosis is CIDP.¹³ Progression of neurological deficits or lack of response to treatment should prompt clinicians to consider an alternative diagnosis.

Treatment

General measures

Supportive management, including management of neuropathic pain and cardiac complications with multi-disciplinary input is important for all patients with FAP. Pacemakers may be required for arrhythmias. Carpal tunnel release may be appropriate for symptomatic CTS. Vitrectomy may be performed for vitreous deposits. Management of the autonomic neuropathy is particularly important for quality of life. Compression stockings, midodrine and fludrocortisone may help with ortostasis.⁸  Anti-diarrhoeal medication and codeine will help with gastrointestinal symptoms, as will eating small meals.

Specific treatments

Transplantation

Since the early 1990s, orthotopic liver transplant, which removes the primary source of abnormal TTR, has been used in the treatment of TTR amyloidosis. In patients with primarily the Val30Met mutation, early onset (< 50 years) and short duration of symptoms, who can endure the invasive surgical procedure and subsequent life-long immunosuppression, liver transplant is associated with a 15-year survival rate of nearly 80%.¹⁴ With non-Val30Met mutations, especially Thr60Ala, cardiomyopathy may progress rapidly after liver transplantation due to continued deposition of wild-type TTR on existing mutant TTR. Patients with these mutations and cardiomyopathy are generally not offered liver transplantation. 

Overall, cardiovascular mortality after liver transplant in amyloidosis is much higher than in patients undergoing transplantation for liver disease.¹⁴ In addition, ocular and leptomeningeal amyloid deposits continue to increase after transplantation, due to ongoing local mutant TTR synthesis. Since FAP livers are otherwise functionally normal, they may be used for a subsequent graft in patients with end-stage liver disease (domino liver transplant).¹⁵ However, recipients of the FAP liver may later develop amyloid neuropathy with a mean onset seven years after transplant.¹⁶

Although apolipoprotein A-1 is partially produced in the liver, liver transplantation to reduce the production of the abnormal precursor protein is only rarely used in ApoA1-related amyloid neuropathy. These patients may be offered a kidney or heart transplant¹⁷ as end-stage renal failure is usually the predominant feature. 

A corneal transplant may be required for lattice dystrophy in gelsolin-related FAP and plastic surgery may be required for facial weakness.

TTR stabilisers

In TTR amyloidosis, tetrameric structure is significantly destabilised leading to dissociation into monomers in a rate-limiting step which, in turn, aggregate as amyloid fibrils. Agents that stabilise TTR tetrameric structure can be expected to prevent amyloid deposition and slow disease progression. TTR stabilisers can be used in the early stage of the disease in anticipation of liver transplant or in patients not suitable for liver transplant. Diflunisal, a non-steroidal anti-inflammatory drug (NSAID), stabilises amyloid precursor protein and slows the progression of the neuropathy in Val30Met and non-Val30Met patients.¹⁸ Well known safety concerns with NSAIDs and their contraindication in severe congestive heart failure and renal insufficiency may limit its use in some TTR-FAP patients.

Tafamidis stabilises the TTR tetramer, slowing monomer formation, misfolding and amyloidogenesis. Initial studies did not reach statistical significance for the primary endpoints. It does, however, appear to reduce disease progression¹⁹ and is approved by the European Medicines Agency for use in stage one neuropathic patients (mobilising without support). It has a favourable long-term safety profile in Val30Met patients, maintaining their quality of life.²⁰ There is little data on patients with other mutations and the effect of the drug on TTR cardiomyopathy remains unclear.

Gene therapy

Gene therapy is a promising strategy for the treatment of TTR amyloidosis. Gene silencing therapies, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) have shown about 80% reduction in TTR plasma levels. Recently published trials of patisiran (siRNA)²¹ and inotersen (ASO)²² show promising clinical effects.

Drugs targeting amyloid fibrils

Experimental therapeutics, targeting the last phase of TTR amyloid formation, have tried to clear amyloid deposits already in the tissue to reduce the amyloid load and ultimately restore organ function. Anti-serum amyloid P (SAP) agents target the SAP component, a plasma protein found in all types of amyloidosis that reversibly binds to tissue amyloid fibrils.²³ TTR monoclonal antibodies inhibit fibrillogenesis and, to date, four monoclonal antibodies that strongly suppress TTR fibril formation have been identified.²⁴ Preliminary data has demonstrated removal of amyloid deposits by the synergistic combination of doxycycline and tauroursodeoxycholic acid. Clinical trials are seeking to replicate these findings in patients.

Conclusion

Recent advances have been made in diagnostic techniques. However, there is often a significant delay in diagnosis after the onset of symptoms. A better understanding of TTR amyloid formation has assisted several therapeutic developments which are less invasive than liver transplantation. Given the recent advances in treatments and promising new therapies, early and sometimes even pre-symptomatic diagnosis is increasingly important.

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