familial amyloid polyneuropathy

Familial amyloid polyneuropathy

Familial amyloid polyneuropathy (FAP) also called familial transthyretin amyloidosis, transthyretin familial amyloid polyneuropathy or hereditary transthyretin amyloidosis, is a rare inherited condition characterized by progressive, disabling and life-threatening polyneuropathy affecting the peripheral and autonomic nervous system as well as non-neuropathic changes of cardiomyopathy, nephropathy, vitreous opacities, and central nervous system amyloidosis 1). Familial amyloid polyneuropathy (FAP) is characterized by abnormal build-up of a protein called amyloid in the body’s organs and tissues resulting in progressive length-dependent axonal, sensorimotor and autonomic polyneuropathy, first described by Andrade 2). The substitution of methionine for valine at position 30 (Val30Met) on the transthyretin (TTR) gene was later identified as the cause of the original description of familial amyloid polyneuropathy 3). Currently, >150 mutations of the TTR gene are known; most of them are amyloidogenic, producing a broad range of phenotypes associated with familial amyloid polyneuropathy 4). The original mutation described Val30Met (alternatively named pVal50Met) is the most common worldwide and is primarily associated with neuropathy 5). Disease onset can be described as bimodal, with one peak in the third to fourth decades of life (early-onset patients: <50 years old) and another peak in the sixth decade of life (late-onset patients with familial amyloid polyneuropathy; ≥50 years old) 6).

Familial amyloid polyneuropathy is a multi-organ and life-threatening disease resulting in multiple disabilities. Familial amyloid polyneuropathy symptoms start in adulthood and get worse over time. Familial amyloid polyneuropathy (FAP) signs and symptoms depend on where the amyloid protein is building up 7). Amyloid build-up in the nerves of the peripheral nervous system causes a loss of sensation in the lower limbs, feet, and hands (peripheral neuropathy). Amyloid build-up can also affect the involuntary body functions, such as blood pressure, heart rate, and digestion 8). Other areas of the body that may be affected are the heart, kidneys, eyes, and gastrointestinal tract 9).

Familial amyloid polyneuropathy usually begins in the third to fifth decade in persons from endemic foci in Portugal and Japan; onset is later in persons from other areas. Typically, sensory neuropathy starts in the lower extremities with paresthesias and hypesthesias of the feet, followed within a few years by motor neuropathy. In some persons, particularly those with early-onset disease, autonomic neuropathy is the first manifestation of the condition; findings can include: orthostatic hypotension, constipation alternating with diarrhea, attacks of nausea and vomiting, delayed gastric emptying, sexual impotence, anhidrosis, and urinary retention or incontinence. Cardiac amyloidosis is mainly characterized by progressive cardiomyopathy. Individuals with leptomeningeal amyloidosis may have the following central nervous system findings: dementia, psychosis, visual impairment, headache, seizures, motor paresis, ataxia, myelopathy, hydrocephalus, or intracranial hemorrhage 10).

The exact incidence of familial transthyretin amyloidosis is unknown. It is more common in certain parts of Portugal, Sweden, and Japan. The common TTR gene mutation, known as valine at position 30 (Val30Met), associated with familial transthyretin amyloidosis occurs in about 1 in 583 people in some parts of Portugal, compared to about 1 in 100,000 people in the U.S. A different TTR gene mutation associated with familial amyloid polyneuropathy, Val122Ile, is more common in parts of West Africa 11). While familial amyloid polyneuropathy is more common in certain parts of the world, it has been found across all ethnic groups and occurs equally in males and females.

Because the penetrance for familial amyloid polyneuropathy is not 100%, an individual with a TTR genetic variant may be symptom free until late adulthood. The penetrance may vary by variant, geographic region, or ethnic group. The penetrance appears to be much higher in individuals in endemic foci than outside of endemic foci 12). In Portugal, cumulative disease risk in individuals with the p.Val50Met variant is estimated at 80% by age 50 and 91% by age 70 years, whereas the risk in French heterozygotes is 14% by age 50 and 50% by age 70 years 13). In Sweden, the penetrance is much lower: 1.7% by age 30, 5% by age 40, 11% by age 50, 22% by age 60, 36% by age 70, 52% by age 80, and 69% by age 90, respectively 14). Some p.Val50Met homozygotes remain asymptomatic 15).

The natural history of familial amyloid polyneuropathy was described 30 years ago in patients of Portuguese origin with early onset (<50 years) 16) and more recently in patients with late onset in Japan (≥50 years) 17). Study and follow up of a cohort of 483 Portuguese patients with FAP in Porto enabled the disease course to be described in three stages 18). Another staging system concerned the progression of walking disability in familial amyloid polyneuropathy (see Table 1) 19). The course of late onset met30 transthyretin familial amyloid polyneuropathy has recently shown major functional severity, faster progression of sensorimotor polyneuropathy and reduced survival 20).

Table 1. Stages of familial amyloid polyneuropathy for locomotion

Coutinho et al. 21)Duration of stageYamamoto et al. 22)
Stage 1The disease is limited to the lower limbs Walking without any help. Slight weakness of the extensors of the big toes.5.6 ± 2.8 yearsPND ISensory disturbances in extremities Preserved walking capacity
Stage 2Motor signs progress in lower limbs with steppage and distal amyotrophies, the muscles of the hands begin to be wasted and weak. The patient is by then obviously handicapped but can still move around, although needing help.4.8 ± 3.6 yearsPND II PND IIIa PND IIIbDifficulties walking but without the need for a walking stick One stick or one crutch required for walking. Two sticks or two crutches required for walking
Stage 3The patient is bedridden or confined to a wheelchair, generalized weakness and areflexia.2.3 ± 3.1 yearsPND IVPatient confined to a wheelchair or a bed

Footnote: PND = a modified polyneuropathy disability score.

[Source 23) ]

The treatment of familial amyloid polyneuropathy (FAP) is complex and requires a multidisciplinary approach, mainly neurological and cardiological. It includes specific treatments to stop the progression of systemic amyloidogenesis, the symptomatic treatment of the peripheral and autonomic neuropathy and the treatment of organs severely involved by amyloidosis (heart, eyes, kidneys). First-line specific treatment of familial amyloid polyneuropathy is liver transplantation, which allows suppression of the main source of mutant transthyretin, to stop the progression of the neuropathy in 70% of cases in the long term and to double the median survival. In cases of severe renal or cardiac insufficiency, a combined kidney–liver or heart–liver transplantation can be discussed. Tafamidis (Vyndaqel) is a novel specific stabilizer of transthyretin which, in the very early stages of familial amyloid polyneuropathy, slows the progress of peripheral neuropathy. This drug should be proposed in cases of stage 1 symptomatic polyneuropathy. Other innovative medicines have been developed by biopharmaceutical companies to block the hepatic production of mutant and wild type transthyretin which are harmful in late-onset familial amyloid polyneuropathy (> 50 years old), including RNA interference therapeutics and antisense oligonucleotides, and to remove the amyloid deposits (monoclonal antibody antiserum amyloid P). Clinical trials should first assess patients with late onset familial amyloid polyneuropathy or non-met30 transthyretin familial amyloid polyneuropathy who are less responsive to liver transplantation or in case of significant progression of the neuropathy with Vyndaqel. Initial cardiac assessment and periodic cardiac investigations are important for patients with familial amyloid polyneuropathy because of the frequency of cardiac impairment, which is responsible for the high rate of mortality. Prophylactic pacemaker treatment should be discussed. Symptomatic treatments are required to improve patients’ quality of life. Familial screening of people with transthyretin mutation and regular follow up are essential. Appropriate clinical examination and complementary investigations are vital for the early detection of disease onset and to start specific therapy as soon as possible.

Familial amyloid polyneuropathy prognosis is poor, leading to patients’ death within an average period ranging from 7 to 10 years after diagnosis, in late- and early-onset cases 24).

Familial amyloid polyneuropathy causes

Familial transthyretin amyloidosis is caused by changes (mutations) in the TTR gene. The TTR gene is responsible for making a protein called transthyretin (TTR) which transports vitamin A (retinol) and a hormone called thyroxine to many parts of the body. To transport thyroxine, four transthyretin proteins must be attached (bound) to each other to form a four-protein unit (tetramer). To transport retinol, transthyretin must form a tetramer and also bind to retinol binding protein. Transthyretin is produced primarily in the liver. A small amount of this protein is produced in an area of the brain called the choroid plexus and in the light-sensitive tissue that lines the back of the eye (the retina). Mutations in TTR lead to a transthyretin protein that is not made correctly. The faulty protein then folds up to form amyloid. Amyloid builds up in various parts of the body causing nerve and tissue damage 25). Currently, >150 mutations of the TTR gene are known; most of them are amyloidogenic, producing a broad range of phenotypes associated with familial amyloid polyneuropathy 26). The original mutation described Val30Met (alternatively named pVal50Met) is the most common worldwide and is primarily associated with neuropathy 27).

Most people who have familial amyloid polyneuropathy have inherited the TTR mutation from a family member. However, a few people with familial amyloid polyneuropathy will have no family history of the disease and have a new (de novo) mutation in the TTR gene 28). Not all people who have a TTR gene mutation will develop transthyretin amyloidosis.

Familial amyloid polyneuropathy inheritance pattern

Familial amyloid polyneuropathy (FAP) or hereditary transthyretin amyloidosis is inherited in an autosomal dominant manner. This means only one copy of a mutated TTR gene is needed for a person to have the condition. The mutation can be inherited from a parent or can happen by chance for the first time (de novo) in an individual 29).

Each child of a person with familial amyloid polyneuropathy has a 50% chance of inheriting the mutation. Most children who inherit a TTR mutation will develop familial amyloid polyneuropathy, although they could be more or less severely affected than their parent. For reasons that are unclear, some people have mutations in the TTR gene and never develop familial amyloid polyneuropathy 30).

Often autosomal dominant conditions can be seen in multiple generations within the family. If one looks back through their family history they notice their mother, grandfather, aunt/uncle, etc., all had the same condition. In cases where the autosomal dominant condition does run in the family, the chance for an affected person to have a child with the same condition is 50% regardless of whether it is a boy or a girl. These possible outcomes occur randomly. The chance remains the same in every pregnancy and is the same for boys and girls.

  • When one parent has the abnormal gene, they will pass on either their normal gene or their abnormal gene to their child. Each of their children therefore has a 50% (1 in 2) chance of inheriting the changed gene and being affected by the condition.
  • There is also a 50% (1 in 2) chance that a child will inherit the normal copy of the gene. If this happens the child will not be affected by the disorder and cannot pass it on to any of his or her children.

There are cases of autosomal dominant gene changes, or mutations, where no one in the family has it before and it appears to be a new thing in the family. This is called a de novo mutation. For the individual with the condition, the chance of their children inheriting it will be 50%. However, other family members are generally not likely to be at increased risk.

Figure 1 illustrates autosomal dominant inheritance. The example below shows what happens when dad has the condition, but the chances of having a child with the condition would be the same if mom had the condition.

Figure 1. Familial amyloid polyneuropathy autosomal dominant inheritance pattern

Familial amyloid polyneuropathy autosomal dominant inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

Familial amyloid polyneuropathy symptoms

Familial transthyretin amyloidosis is a slowly progressing, adult-onset inherited condition that is characterized by the buildup of abnormal deposits of a protein called amyloid (amyloidosis) in the body’s organs and tissues. These protein deposits most frequently occur in the peripheral nervous system, which is made up of nerves connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound. Protein deposits in these nerves result in a loss of sensation in the extremities (peripheral neuropathy). The autonomic nervous system, which controls involuntary body functions such as blood pressure, heart rate, and digestion, may also be affected by amyloidosis. In some cases, the brain and spinal cord (central nervous system) are affected. Other areas of amyloidosis include the heart, kidneys, eyes, and gastrointestinal tract. The age at which symptoms begin to develop varies widely among individuals with familial amyloid polyneuropathy and is typically between ages 20 and 70.

Symptoms depend on which body parts are most affected. The age symptoms begin may also vary by country. In Portugal and Japan, people with familial amyloid polyneuropathy usually start developing symptoms in their late 20s to 40s. In other parts of the world, people with familial amyloid polyneuropathy may not have symptoms until after age 50 31).

The following findings indicate that age at onset varies greatly even within ethnically identical populations with the same TTR genetic variant:

  • For persons of Japanese ancestry with the p.Val50Met variant who are related to two large endemic foci (Ogawa village and Arao city), the mean age at onset is 40.1±12.8 years (range 22-74 years) 32).
  • For persons of Japanese ancestry with p.Val50Met who are unrelated to the two large endemic foci, the mean age at onset is much later (62.7±6.6 years) (range 52-80 years) 33).
  • For persons of Portuguese ancestry with the p.Val50Met variant, the mean age at onset is 33.5±9.4 years (range 17-78 years).
  • For persons of Swedish, French, or British ancestry, the mean age at onset is much later than that in individuals of Japanese or Portuguese ancestry 34).

The most common form of familial amyloid polyneuropathy affects the peripheral nervous system. The peripheral nerves send messages from the brain and spinal cord to the rest of the body. Other forms of familial amyloid polyneuropathy can affect the brain, spinal cord, heart, and eyes 35).

Familial amyloid polyneuropathy symptoms include 36):

  • Weakness, numbness or pain in the lower legs and feet
  • Carpal tunnel syndrome in both wrists
  • Sexual impotence
  • Urinary problems, protein in the urine
  • Diarrhea or constipation
  • Unexplained weight loss
  • Dry eyes, increased pressure in the eyes (glaucoma), seeing ‘floaters’
  • Abnormal heart beat, enlarged heart
  • Getting dizzy when moving from sitting to standing (orthostatic hypotension)
  • Dry eyes and mouth

Sensorimotor neuropathy and autonomic neuropathy progress over ten to 20 years. Various types of cardiac conduction block frequently appear. Cachexia is a common feature at the late stage of the disease. Later symptoms may include muscle weakness and stiffness, difficulty with coordination, stroke, seizures, dementia, and congestive heart failure 37). Affected individuals usually die of cardiac failure, renal failure, or infection.

Sensorimotor neuropathy and autonomic neuropathy are accompanied by visceral involvement. Cardiomyopathy (e.g., cardiac failure, arrhythmia, conduction block), ophthalmopathy (e.g., vitreous opacities, glaucoma), nephropathy, and/or CNS manifestations (e.g., transient focal neurologic episodes, intracerebral and/or subarachnoid hemorrhages) are frequently seen in the advanced stage of the disease.

Individuals with specific TTR variants (e.g., p.Leu78His, p.Leu78Arg, p.Lys90Asn, p.Ile104Ser, p.Ile127Val, p.Tyr134His) tend to develop carpal tunnel syndrome as an initial symptom 38).

Less common symptoms include skin changes, hearing loss, shortness of breath, and anemia 39).

Cardiovascular involvement

Patients with cardiac amyloidosis often present with signs and symptoms suggesting chronic heart failure (ie, dyspnea on exertion, peripheral edema) and/or arrhythmias (ie, palpitations, lightheadedness, syncope) 40).

Cardiac amyloidosis is usually late onset. Most individuals develop cardiac symptoms after age 50 years; cardiac amyloidosis generally presents with restrictive cardiomyopathy. The typical electrocardiogram shows a pseudoinfarction pattern with prominent Q wave in leads II, III, aVF, and V1-V3, presumably resulting from dense amyloid deposition in the anterobasal or anteroseptal wall of the left ventricle. The echocardiogram reveals left ventricular hypertrophy with preserved systolic function. The thickened walls present “a granular sparkling appearance.”

Among the variants responsible for cardiac amyloidosis, p.Val142Ile is notable for its prevalence in African Americans. Approximately 3.0%-3.9% of African Americans are heterozygous for p.Val142Ile 41). The high frequency of p.Val142Ile partly explains the observation that in individuals in the US older than age 60 years, cardiac amyloidosis is four times more common among blacks than whites 42).

Neuropathic involvement

Peripheral nerve problems are the presenting complaints in most cases of familial amyloid polyneuropathy and can be reliably differentiated from other types of peripheral nervous system disease by the fact that they are most often symmetric, distal polyneuropathies that typically begin in the lower limbs, progress to the upper limbs, and then affect more proximal aspects of the limbs and the trunk. A family history of a similar polyneuropathy is usually present and hence warrants a rigorous family history discussion as part of the history.

Patients with peripheral nerve deposits note sensorimotor impairment. While the majority present with bilateral, lower-to-upper extremity symptoms, as described above, some TTR variants present as lower-limb neuropathy (eg, TTR V30M), while other variants present as primarily upper-limb neuropathy (eg, TTR I84S, TTR L58H) 43).

Neuropathy in patients with ATTR V30M often presents as lower extremity weakness, pain, and/or impaired sensation. Autonomic dysfunction, often manifested as sexual or urinary dysfunction, is common 44).

Other manifestations

Amyloid deposition on the gastrointestinal tract wall, especially with involvement of the gastrointestinal autonomic nerves, is common 45). Patients with gastrointestinal deposits present with alternating diarrhea and constipation. Nausea and vomiting also occur.

Nodular cutaneous amyloidosis has been reported in an individual with the p.Tyr134His variant 46). Shortness of breath induced by diffuse pulmonary amyloid deposition has been reported in two individuals with the p.Asp58Ala variant 47). Anemia with low erythropoietin has been reported in 25% of individuals 48).

Weakness and paresthesias of one or both hands, suggesting carpal ligament involvement, is often the presenting symptom in patients with the variant TTR L58H. It can also be observed in patients with other variants, including normal-sequence TTR. Carpal tunnel syndrome may precede other clinical manifestations, sometimes by as much as 20 years.

Ocular involvement, including vitreous opacity, glaucoma, dry eye, and ocular amyloid angiopathy, is common and occurs in most individuals with TTR pathogenic variant p.Val50Met 49). Vitreous opacification has been reported in approximately 20% of families with various TTR pathogenic variants, including p.Val50Met 50). Four of 43 individuals with the p.Val50Met variant developed vitreous amyloidosis as the first manifestation of familial amyloid polyneuropathy 51). In one case report, vitreous opacification was the only evidence of amyloid deposit caused by the p.Trp61Leu variant 52).

Eye involvement may present as follows:

  • Dry eye, red eye, painful eye, conjunctivitis
  • Floaters in eyes, decreased visual acuity

Familial amyloid polyneuropathy diagnosis

The diagnosis of familial transthyretin amyloidosis can be difficult because the signs and symptoms of familial amyloid polyneuropathy often look like other, more common conditions.

The diagnosis of familial amyloid polyneuropathy is established in an individual with characteristic clinical features, family history, and histopathology showing amyloid deposits identified on biopsy that bind to anti-transthyretin antibodies, and identification of a heterozygous pathogenic variant in TTR gene by molecular genetic testing.

Clinical features

Slowly progressive sensorimotor and/or autonomic neuropathy that is frequently accompanied by one or more of the following:

  • Cardiac conduction blocks
  • Cardiomyopathy
  • Nephropathy
  • Vitreous opacities
  • Glaucoma

Family history

Consistent with autosomal dominant inheritance (see Figure 1 above)

Note: While family history supports the diagnosis, absence of other affected individuals in the family does not preclude the diagnosis of familial amyloid polyneuropathy, especially in persons older than age 50 years.

Histopathology

  • Tissue biopsy to identify amyloid deposits. Tissues suitable for biopsy include: subcutaneous fatty tissue of the abdominal wall, skin, gastric or rectal mucosa, sural nerve, and peritendinous fat from specimens obtained at carpal tunnel surgery. With Congo red staining, amyloid deposits show a characteristic yellow-green birefringence under polarized light.
  • Note: Sensitivity of endoscopic biopsy of gastrointestinal mucosa is approximately 85%; biopsy of the sural nerve is less sensitive because amyloid deposition is often patchy 53).
  • Immunohistochemistry of tissue biopsies with anti-transthyretin antibodies to identify amyloid deposits associated with transthyretin amyloidosis

Establishing the diagnosis

The diagnosis of familial amyloid polyneuropathy is established in an individual with the above clinical features, biopsy showing amyloid deposits that bind to anti-transthyretin antibodies, and identification of a heterozygous pathogenic variant in transthyretin gene (TTR gene) by molecular genetic testing.

Familial amyloid polyneuropathy treatment

There is no treatment available for familial transthyretin amyloidosis (transthyretin familial amyloid polyneuropathy) that reverses damage caused by amyloid deposits, but there are treatments that may prevent or delay progression. Treatment depends on which tissues are affected and how far the disease has progressed.

Liver transplantation is the “gold standard” for treatment for familial amyloid polyneuropathy, because it replaces the main source of amyloid. It may slow or halt progression of peripheral neuropathy, but the disease often still progresses in the eyes and brain. Liver transplantation ideally should be done as early as possible before there are severe neurological problems 54). Orthotopic liver transplantation (in which the native liver is removed and replaced by the donor organ in the same anatomic position as the original liver) halts the progression of peripheral and/or autonomic neuropathy; orthotopic liver transplantation is recommended in individuals younger than age 60 years with: (1) disease duration less than five years, (2) polyneuropathy restricted to the lower extremities or with autonomic neuropathy alone, and (3) no significant cardiac or renal dysfunction.

Several medications that include transthyretin tetramer stabilizers and gene-silencing therapies have been developed that slow the build-up of amyloid along nerves and in other parts of the body. These include tafamidis, diflunsial, and more recently inotersen and patisiran. There are other drugs that are currently under investigation for this condition 55).

Additional treatments may include heart and/or kidney transplantation, replacement of the liquid part of the eye (vitrectomy) for eye involvement, surgical treatment for glaucoma and carpal tunnel surgery 56). In those with sick sinus syndrome or second-degree or third-degree AV block, a cardiac pacemaker may be indicated.

Diuretics, medications that remove excess water and salt from the body, are often used to manage congestive heart failure associated with the disease. Other symptoms of familial amyloid polyneuropathy are treated as they arise 57).

Surveillance

Serial nerve conduction studies to monitor polyneuropathy; serial electrocardiogram, echocardiography, and serum B-type natriuretic peptide levels to monitor cardiomyopathy and conduction block; follow modified body mass index to monitor nutritional status.

Agents and circumstances to avoid

Local heating appliances, such as hot-water bottles, which can cause low-temperature burn injury in those with decreased temperature and pain perception.

Liver transplantation

Recommended clinical criteria for liver transplantation in individuals with familial amyloid polyneuropathy include the following 58):

  • Age younger than 60 years
  • Disease duration less than five years
  • Either polyneuropathy that is restricted to the lower extremities or autonomic neuropathy alone
  • No significant cardiac or renal dysfunction

As of the end of December 2017, 2,236 individuals with familial amyloid polyneuropathy, approximately 90% of whom were heterozygous for the p.Val50Met variant, had undergone liver transplantation (http://www.fapwtr.org/ram_fap.htm). The five-year survival rate was significantly higher in individuals with the p.Val50Met variant than in those with other pathogenic variants (80% vs 57%) 59). The most common causes of postoperative death were cardiovascular events (29%) and septicemia (26%) 60).

Predictors of poor outcomes in transplanted individuals include 61):

  • Poor nutritional condition (modified body mass index <600)
  • Severe polyneuropathy (Norris score <55/81)
  • Permanent urinary incontinence
  • Marked postural hypotension
  • A fixed pulse rate
  • Age ≥50 years (especially in males)
  • Pathogenic variants other than Val30Met (pVal50Met)
  • Presence of cardiomyopathy

Liver transplantation is not effective in the non-neuropathic forms of familial amyloid polyneuropathy (i.e., cardiac amyloidosis, leptomeningeal amyloidosis, and familial oculoleptomeningeal amyloidosis [FOLMA]).

Cardiomyopathy was reported to progress after liver transplantation in some individuals with specific pathogenic variants other than p.Val50Met (e.g., p.Ala56Pro, p.Glu62Gly, and p.Ser97Tyr) 62). It is presumed that amyloid cardiomyopathy may accelerate after liver transplantation by progressive deposition of wild type TTR on a template of amyloid derived from variant TTR 63). Therefore, it is critical to assess the severity of cardiac amyloidosis when considering liver transplantation 64).

Individuals with leptomeningeal involvement may not be candidates for liver transplantation because amyloidogenic TTR variants that cause intracranial amyloid deposits are considered to be derived from the choroid plexus. Leptomeningeal amyloidosis / cerebral amyloid angiopathy may develop after liver transplantation as the choroid plexus continues to produce variant TTR 65).

Amyloid ophthalmopathy (e.g., vitreous opacities and glaucoma) may also progress after liver transplantation, possibly as the result of de novo production of variant TTR in the retinal epithelium.

Note: Because liver involvement in familial amyloid polyneuropathy is minimal, the liver of an individual with familial amyloid polyneuropathy can be grafted into an individual with liver cancer or end-stage liver disease (so-called “domino” liver transplantation). Since 1995, 1,254 domino liver transplantations have been performed. Several individuals who received a liver graft from heterozygotes with familial amyloid polyneuropathy developed symptomatic systemic transthyretin amyloidosis 66).

Familial amyloid polyneuropathy prognosis

The prognosis and life expectancy for each person with familial transthyretin amyloidosis (hereditary transthyretin amyloidosis) varies and depends on the TTR gene mutation present, organ(s) involved, and how early a person is diagnosed and treated. Some people whose symptoms begin at a younger age may live for only a few years after diagnosis, while older patients with slowly progressive disease can live for many years 67). Life expectancy on average of people with familial amyloid polyneuropathy typically live for 7-12 years after they are first diagnosed 68). Death is most often due to cardiac dysfunction, infection, or cachexia 69).

The long-term outlook after liver transplant is also influenced by many factors, including the type of amyloid present, nutritional status, age, and how much the brain and heart are involved 70). Newer medications are now available that help slow the build-up of amyloid and delay symptoms and it is not yet clear how these medications will affect the long-term outlook for people with familial amyloid polyneuropathy. People with questions about their personal outlook should speak with their healthcare providers.

Familial amyloid polyneuropathy prognosis

The natural course of familial amyloid polyneuropathy can be classified into the following three stages 71):

  • Stage 1 – Sensory polyneuropathy
  • Stage 2 – Progressive walking disability
  • Stage 3 – Wheelchair bound or bedridden

The prognosis depends on the presence and identity of a TTR variant and the organ(s) involved. Patients with early-onset of variant-sequence TTR may die within a few years of diagnosis. Older patients with slowly progressive disease can live for decades after the onset of symptoms and may never develop life-threatening disease 72).

Penetrance of the individual TTR mutations vary. The penetrance of the same mutation in different geographic areas can also vary, for example, the Portuguese population showing much higher penetrance of the Val30Met mutation during middle age (80% at 50 years) compared with the French population (18% at 50 years) 73).

In contrast to light chain amyloidosis (AL), symptomatic cardiac involvement in familial amyloid polyneuropathy does not necessarily portend a poor prognosis. Median survival in cardiac light chain amyloidosis is about 6 months, but is several years in older patients with cardiac familial amyloid polyneuropathy, even in those with a TTR variant. Familial amyloid polyneuropathy usually proves fatal within 7–12 years from the onset of symptoms, most often due to cardiac dysfunction, infection, or cachexia 74).

Within most of the regions in which it is endemic, clinical onset of familial amyloid polyneuropathy often occurs before age 40 years with progressive sensory-motor and autonomic neuropathy, leading to cachexia and eventually death. Length-dependent small-fiber sensory and motor polyneuropathy with life-threatening autonomic dysfunction is a distinguishing feature of familial amyloid polyneuropathy in these areas. In addition, cardiac, renal, and ocular involvement are also common 75).

In nonendemic areas, and in endemic regions of Sweden, the onset of disease-related symptoms tends to be later in life, from age 50 years onward and with a male predominance for the late-onset familial amyloid polyneuropathy. Neuropathy tends to affect all fibers and may closely resemble chronic inflammatory demyelinating polyneuropathy (CIDP). Typically, sensory and motor neuropathy symptoms of upper and lower extremities occur, associated with mild autonomic symptoms 76).

Familial amyloid polyneuropathy life expectancy

The prognosis and life expectancy for each person with familial transthyretin amyloidosis (hereditary transthyretin amyloidosis) varies and depends on the TTR gene mutation present, organ(s) involved, and how early a person is diagnosed and treated. Some people whose symptoms begin at a younger age may live for only a few years after diagnosis, while older patients with slowly progressive disease can live for many years 77). Life expectancy on average of people with familial amyloid polyneuropathy typically live for 7-12 years after they are first diagnosed 78). Death is most often due to cardiac dysfunction, infection, or cachexia 79).

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