Familial Amyloid Polyneuropathy

In amyloidosis, extracellular deposition of amyloid occurs in a variety of organs such as the heart, intestinal tract, liver, and kidneys. In amyloid neuropathy, deposition of amyloid in peripheral nerves predominates. Amyloid neuropathy may be due to acquired, usually immunoglobulin-derived, amyloid, or it may be hereditary, as in familial amyloid polyneuropathy. Amyloid is a class of glycoproteins that have a fibrillar beta sheet structure and may be derived from a variety of precursor proteins. In familial amyloid polyneuropathy, the dominant form of amyloid is derived from transthyretin (TTR), but it may also be derived from apolipoprotein Al and gelosin. Initially, familial amyloid polyneuropathy (FAP) was described on a clinical basis, and four types were recognized. Despite overlap with the recent and increasing discoveries of specific gene mutations, this original classification is still useful ( .Takle.3.7.:4.).

Pathogenesis and Pathophysiology. To date, 36 mutations of the TTR gene have been described as well as mutations of the apolipoprotein A1 and gelosin protein genes. These are all autosomal dominant conditions with reduced penetrance, and most individuals are heterozygous for the given mutation. Some individuals who are homozygous for the Met 30 TTR mutation have been described, but there are no differences in their clinical phenotype compared to that of heterozygous individuals. The Met 30 mutation has arisen spontaneously in different parts of the world. y In contrast, the Ala 60 TTR mutation, which was first described in a family in the Appalachian region, has been found to be due to a founder effect, which originated in Ireland. '341

The deposition of amyloid may occur within the nerve rather than being derived from circulating amyloid. In the TTR-associated FAP with the Met 30 mutation, axonal loss that affects unmyelinated and small unmyelinated fibers and subsequently larger fibers is seen. Although axonal degeneration is the predominant pathological finding, segmental demyelination is also evident. The amyloid may have a diffuse or patchy distribution. On biopsy, amyloid deposition may be present only in proximal nerves and absent in distal nerves. Three patterns of amyloid deposition are seen: in the connective tissue of the peripheral nerves, in the endoneurial tissue, and in the vasa nervorum. The mechanism by which amyloid deposition leads to neuropathy is unclear. Some researchers have argued that the neuropathy results from a generalized metabolic disorder and that amyloid deposition is a secondary event. Deposition within the endoneurial vessels might result in ischemic nerve but would not fully explain the selectivity of small fiber involvement. Endoneurial blood vessel deposition of amyloid might alter vascular permeability, with consequent endoneurial edema contributing to the compressive damage of the nerves. Compressive damage may also result



FAP Type

Clinical Phenotype

Amyloid Precursor

Common Mutation

Type 1 (Portuguese)

Lower limb neuropathy


Met 30 (plus others)



Ala 60

Type 2 (Indiana)

Upper limb neuropathy


Ser 84, His 58 plus others

Type 3 (Iowa)

Lower limb neuropathy

Apolipoprotein A1

Arg 26


Gastric ulcers

Type 4 (Finnish)

Cranial neuropathy


Asp 187, Tyr 187

Corneal dystrophy

from the deposition of amyloid in the connective tissue surrounding the peripheral nerve. The presence of segmental demyelination favors a compressive etiology but is not the dominant pathology.

Epidemiology and Risk Factors. The most common FAP, the TTR-associated FAP with a Met 30 mutation, has been described in 500 Portuguese families, and the gelosin-derived FAP has been reported in 200 Finnish families. In contrast, some FAP mutations have been confined to a single family.

Clinical Features and Associated Disorders FAP Type 1 (Portuguese). This TTR-derived FAP was originally described in Portugal but has now been found in a wide variety of locations including Scandinavia and Mediterranean countries as well as North and South America and Japan. The age of onset varies with ethnic origin. The Portuguese develop symptoms in their twenties or thirties, whereas the Swedes and the French become symptomatic in their late fifties. The initial symptom is painful dysesthesia with attacks of stabbing pain in the lower limbs. With initial small fiber involvement, loss of pain and temperature sensation is reported. Patients are prone to foot ulcers, osteomyelitis, Charcot joints, and trophic skin changes. The neuropathy slowly progresses and eventually involves all nerve fiber types and all sensory modalities. Subsequent motor involvement results in muscle wasting and weakness with loss of reflexes. Months or years after the onset of disease in the lower limb, the upper limbs may become involved. Carpel tunnel syndrome may occur but is rarely a presenting feature. Autonomic neuropathy is frequent and is severe in some cases, with associated postural hypotension, impotence, gastrointestinal dysmotility, urinary difficulties, and dry skin. Cardiac amyloid deposition may be asymptomatic but can result in dysrhythmias and either a restrictive or hypertrophic cardiomyopathy. Renal involvement is occasionally severe.

The majority of patients with this clinical picture have the common TTR Met 30 mutation, but there are a large number of other point mutations in the TTR gene that give rise to a similar clinical picture. The Ala 60 Thr TTR point mutation gives rise to an Irish-Appalachian variant of FAP, which has the distinguishing features of a later onset (the sixth and seventh decades), prominent motor and large fiber sensory involvement, and more severe and symptomatic cardiac involvement.

FAP Type 2 (Indiana). This form was originally described in families of Swiss origin in Indiana and of German origin in Maryland. Patients present in middle life, commonly with bilateral carpal tunnel syndrome and vitreous opacities. Some patients, particularly males, have a more generalized neuropathy, with motor features in the upper limbs that then spread to the lower limbs. Autonomic neuropathy can occur, but both this and the generalized neuropathy are rarely disabling. Hepatosplenomegaly may occur. The vitreous abnormalities can cause severe visual impairment. The original cases had a Ser 84 or His 58 TTR point mutation, but a variety of other mutations have been described.y , y

FAP Type 3 (Iowa). This disorder has many features in common with FAP type l. Upper and lower extremities are affected, but usually there is no associated carpal tunnel syndrome. Peripheral neuropathy can be severe, but the autonomic neuropathy is less prominent. Peptic ulceration may occur, and renal involvement results in hypertension and uremia. Amyloid deposition also occurs in the liver, adrenal glands, and testes. This type of FAP is associated with apolipoprotein Al-derived amyloid, and a substitution of arginine for glycine has been found in nucleotide 26 of the gene.

FAP Type 4 (Finnish). This form of FAP was first described in a Finnish family but has since been reported in Dutch, Japanese, and Irish-American families. Corneal dystrophy begins in the thirties but is usually asymptomatic. A progressive cranial neuropathy then occurs that involves principally the facial nerve, although the trigeminal, hyperglossal, and vestibular nerves may also be involved. The facial skin becomes initially thickened and then atrophic. A mild generalized sensory and autonomic neuropathy then ensues. Although cardiac deposition of amyloid has been reported, this is rarely symptomatic. In these cases, the amyloid precursor protein is gelosin, and two mutations have been described in this gene thus far. y , y

Differential Diagnosis. The differential diagnosis of FAP varies with the presentation and is wider when there is no family history. Presentation with a painful, distal, and mainly sensory neuropathy of small-fiber type poses a differential diagnosis of leprosy, diabetes, vasculitis, or paraneoplastic associated neuropathies. Familial small-fiber neuropathies include type 1 hereditary sensory neuropathy and the neuropathy associated with Tangier's disease. Presentation with carpal tunnel syndrome requires differentiation from hypothyroidism, diabetes, osteoarthritis, and acromegaly. Carpal tunnel syndrome may also occur in patients undergoing hemodialysis, in whom there is deposition of beta-microglobulin derived amyloid. Presentation with prominent autonomic symptoms may require differentiation from other hereditary diseases such as familial dysautonomia (Riley-Day syndrome), dopamine beta-hydroxylase deficiency, and Fabry's disease.

Evaluation. Hematological and biochemical tests may reflect hepatic, renal, or gastrointestinal infiltration with amyloid. In isolated cases of amyloid neuropathy a careful search for monoclonal antibodies is required to exclude acquired amyloidosis. Urine and serum should be screened; they may be found positive in up to 85 percent of cases, gamma chains being the predominant monoclonal species. ECG may show evidence of cardiac involvement with conduction disturbances including heart block or abnormalities such as widespread Q-wave and T-wave repolarization changes. Echocardiography can show either a restrictive or hypertrophic cardiomyopathy. Autonomic function tests typically reveal abnormal responses of blood pressure and heart rate to postural change and other provocative measures. Neurophysiological studies show an axonal neuropathy, but in the early stages when only small-diameter fibers are involved, the sensory nerve action potentials may be preserved. Sensory and motor conduction velocities are usually normal or only slightly reduced. EMG demonstrates evidence of chronic partial denervation in longstanding cases. In FAP type 4, electrophysiological studies show evidence of both axonal degeneration and demyelination. The histological diagnosis of amyloid requires pathological demonstration of amyloid deposition, detected by staining with Congo red, and the characteristic green bire

fringence with polarizing filters. Electromicroscopy can also reveal the characteristic fibrillar appearance of the protein. Rectal tissue is most accessible to sample. Immunohistochemistry can characterize the nature of the amyloid, although there may be technical difficulties in doing this when only small amounts of amyloid are present. TTR antibody immunohistochemistry is negative in some cases if TTR is not the precursor for the amyloid. It is also possible to detect variant TTR in the blood using autoimmune assay and enzyme-linked immunosorbent assay techniques. Screening tests for the common TTR mutations are available. When there is a high index of suspicion and evidence of a variant TTR is present, sequencing of the entire TTR gene may be justified in the absence of one of the common mutations.

Management. The mainstay of treatment is supportive in patients with autonomic, renal, gastrointestinal, and vitreous complications. Plasma exchange, in the hope of removing the circulating amyloid protein, has not been successful. Since over 90 percent of TTR is synthesized in the liver, some patients have undergone liver transplantation, resulting in a significant decline in the circulating TTR levels and reported stabilization of some symptoms, including the neuropathy. However, liver transplantation remains a hazardous procedure, particularly in those patients with autonomic involvement, y , y and the optimal timing of such a procedure is unclear.

Prognosis and Future Perspectives. The prognosis of the different forms of FAP varies. In patients with FAP type 1, death from sepsis and systemic disease occurs about 15 years from the onset, but in late-onset cases, disease progression may be slower. In FAP type 2, peripheral neuropathy and autonomic involvement are not severe, and individuals may survive as long as 35 years with some disability. However, the vitreous disposition may lead to severe visual loss. In FAP type 3, peripheral neuropathy becomes disabling over the course of 10 years, and death is the result of renal failure over a 20-year period.

Undoubtedly, further mutations will be added to the 36 known mutations of the TTR gene, and further mutations for the other amyloid variants will be found as well. Already some knowledge of how these precursor variants become amyloidogenic is available, which may lead to ways of intervening in this process. A future suggested treatment is extracorporeal immune absorption onto TTR antibodies, which may be the subject of future clinical trials. y

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