Clinical characteristics.

Hereditary transthyretin (ATTR) amyloidosis is characterized by a slowly progressive peripheral sensorimotor and/or autonomic neuropathy as well as non-neuropathic changes of cardiomyopathy, nephropathy, vitreous opacities, and CNS amyloidosis. The disease 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 CNS findings: dementia, psychosis, visual impairment, headache, seizures, motor paresis, ataxia, myelopathy, hydrocephalus, or intracranial hemorrhage.

Diagnosis/testing.

The diagnosis of hereditary ATTR amyloidosis is established in a proband with characteristic clinical features, amyloid deposits identified on biopsy that bind to anti-TTR antibodies, and identification of a heterozygous pathogenic variant in TTR by molecular genetic testing.

Management.

Treatment of manifestations: Orthotopic liver transplantation (OTLX) halts the progression of peripheral and/or autonomic neuropathy; OTLX 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. Additional treatment options include TTR tetramer stabilizers and gene-silencing therapies. Surgery is indicated for carpal tunnel syndrome, vitrectomy for vitreous involvement, and surgical treatment for glaucoma. In those with sick sinus syndrome or second-degree or third-degree AV block, a cardiac pacemaker may be indicated.

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/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.

Evaluation of relatives at risk: If the family-specific pathogenic variant is known, molecular genetic testing ensures early diagnosis and treatment. If the familial variant is not known, clinical evaluations ensure early diagnosis and treatment.

Genetic counseling.

Hereditary ATTR amyloidosis is inherited in an autosomal dominant manner. Each child of an affected individual (who is heterozygous for one TTR pathogenic variant) has a 50% chance of inheriting the TTR variant. For affected individuals homozygous for TTR pathogenic variants:

• Each sib is at a 50% risk of inheriting one TTR pathogenic variant and a 25% risk of inheriting two TTR pathogenic variants;
• All offspring will inherit a pathogenic variant.

Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in the family. Requests for prenatal testing for adult-onset conditions that (like hereditary ATTR amyloidosis) do not affect intellect and have some treatment available are not common.

Suggestive Findings

Hereditary transthyretin (ATTR) amyloidosis should be suspected in adults with the following clinical features, family history, and histopathology.

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

Note: While family history supports the diagnosis, absence of other affected individuals in the family does not preclude the diagnosis of hereditary ATTR amyloidosis, 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 [Hund et al 2001, Koike et al 2004, Vital et al 2004].
• Immunohistochemistry of tissue biopsies with anti-TTR antibodies to identify amyloid deposits associated with ATTR amyloidosis

Establishing the Diagnosis

The diagnosis of hereditary ATTR amyloidosis is established in a proband with the above clinical features, biopsy showing amyloid deposits that bind to anti-TTR antibodies, and identification of a heterozygous pathogenic variant in TTR by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include single-gene testing and use of a multigene panel:

• Single-gene testing. Sequence analysis of TTR detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.
  Note: (1)Targeted analysis for pathogenic variants can be performed first for the most common pathogenic variant, c.148G>A (p.Val50Met). (2) Since hereditary ATTR amyloidosis occurs through a gain-of-function mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
• A multigene panel that includes TTR and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Clinical features of hereditary transthyretin (ATTR) amyloidosis can include peripheral sensorimotor neuropathy and autonomic neuropathy, as well as non-neuropathic changes (cardiomyopathy, nephropathy, vitreous opacities, and CNS amyloidosis) (see Table 2).

Neuropathy. The cardinal feature of ATTR-amyloid neuropathy is slowly progressive sensorimotor and autonomic neuropathy [Ando et al 2005]. Typically, sensory neuropathy starts in the lower extremities and is followed by motor neuropathy within a few years. The initial signs of this sensory neuropathy are paresthesias (sense of burning, shooting pain) and hypesthesias of the feet. Temperature and pain sensation are impaired earlier than vibration and position sensation. By the time sensory neuropathy progresses to the level of the knees, the hands have usually become affected. In the full-blown stage of the disease, sensory loss, muscle atrophy, and weakness of the extremities show a glove and stocking distribution. Foot drop, wrist drop, and disability of the hands and fingers are common symptoms of motor neuropathy.

Autonomic neuropathy may occur as the first clinical symptom of the disease. The symptoms of autonomic dysfunction include: orthostatic hypotension [Vita et al 2005], constipation alternating with diarrhea, attacks of nausea and vomiting, delayed gastric emptying, sexual impotence, anhidrosis, and urinary retention or incontinence. Because of sensory loss and autonomic dysfunction, trophic ulcers on the lower extremities are common. Frequently, the autonomic neuropathy produces the most significant morbidity of the disorder.

The disease usually begins in the third, fourth, or fifth decade in persons from endemic foci in Portugal and Japan; onset is later in persons from other areas. The following findings indicate that age at onset varies greatly even within ethnically identical populations with the same TTR pathogenic 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) [Nakazato 1998].
• 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) [Misu et al 1999, Ikeda et al 2002].
• 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 [Planté-Bordeneuve et al 1998].

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. Affected individuals usually die of cardiac failure, renal failure, or infection.

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 [Nakazato 1998, Connors et al 2000, Benson 2001, Hund et al 2001, Connors et al 2003].

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.

Non-neuropathic amyloidosis. Individuals with hereditary ATTR amyloidosis do not necessarily present with polyneuropathy. Cardiac amyloidosis and leptomeningeal amyloidosis are well-known non-neuropathic forms of hereditary ATTR amyloidosis that are associated with specific TTR variants. In these types of hereditary ATTR amyloidosis, polyneuropathy is absent or, if present, less evident. Approximately one third of the TTR protein variants are accompanied by vitreous opacities.

Cardiac amyloidosis, mainly characterized by progressive cardiomyopathy, has been associated with more than two thirds of TTR pathogenic variants (see Table 6) [Nakazato 1998, Benson 2001, Saraiva 2001, Connors et al 2003, Hattori et al 2003, Benson & Kincaid 2007]. In some families with specific TTR variants, such as p.Asp38Asn, p.Val40Ile, p.Pro44Ser, p.Ala65Thr, p.Ala65Ser, p.His76Arg, p.Gly77Arg, p.Ile88Leu, p.Ala101Thr, p.Ala101Val, p.His108Arg, p.Glu112Lys, p.Arg123Ser, p.Leu131Met, or p.Val142Ile, cardiomyopathy without peripheral neuropathy is a main feature of the disease.

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, _aV_F, 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 [Yamashita et al 2005]. 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 [Jacobson et al 1997].

Leptomeningeal (oculoleptomeningeal) amyloidosis / cerebral amyloid angiopathy. Amyloid deposition is seen in the pial and arachnoid membrane, as well as in the walls of vessels in the subarachnoid space associated with TTR pathogenic variants including p.Leu32Pro, p.Asp38Gly, p.Ala45Thr, p.Val50Gly, p.Ala56Pro, p.Gly73Glu, p.Gly73Ala, p.Phe84Ser, p.Tyr89His, or p.Tyr134Cys (see Table 6) [Petersen et al 1997, Nakazato 1998, Brett et al 1999, Mascalchi et al 1999, Uemichi et al 1999, Connors et al 2000, Benson 2001, Ellie et al 2001, Saraiva 2001, Ikeda et al 2002, Blevins et al 2003, Connors et al 2003, Hammarström et al 2003, Sekijima et al 2003]. Amyloid in the blood vessels disappears as the vessels penetrate the brain parenchyma.

Individuals with leptomeningeal amyloidosis show CNS signs and symptoms including: transient focal neurologic episodes, dementia, psychosis, visual impairment, headache, seizures, motor paresis, ataxia, myelopathy, hydrocephalus, or intracranial hemorrhage.

When associated with vitreous amyloid deposits, leptomeningeal amyloidosis is known as familial oculoleptomeningeal amyloidosis (FOLMA) [Petersen et al 1997, Jin et al 2004].

In leptomeningeal amyloidosis protein concentration in the cerebrospinal fluid is usually high, and gadolinium-enhanced MRI typically shows extensive enhancement of the surface of the brain, ventricles, and spinal cord [Brett et al 1999].

Although meningeal biopsy is necessary to confirm amyloid deposition in the meninges, characteristic MRI findings and the presence of a pathogenic variant in TTR strongly suggest this pathology [Mitsuhashi et al 2004]. CNS ATTR amyloid deposition can also be detected by amyloid PET, using Pittsburgh compound B (PiB) [Sekijima et al 2016].

Ocular amyloidosis. 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 [Ando et al 1997]. Vitreous opacification has been reported in approximately 20% of families with various TTR pathogenic variants, including p.Val50Met [Benson 2001, Connors et al 2003, Kawaji et al 2004, Benson & Kincaid 2007]. Four of 43 individuals with the p.Val50Met variant developed vitreous amyloidosis as the first manifestation of hereditary ATTR amyloidosis [Kawaji et al 2004]. In one case report, vitreous opacification was the only evidence of amyloid deposit caused by the p.Trp61Leu variant [Yazaki et al 2002].

Nephropathy. The kidney is consistently involved with marked deposition of amyloid demonstrated at postmortem examination. Mild to severe renal involvement is usually seen in the advanced stage [Haagsma et al 2004, Lobato et al 2004]. Renal involvement, including nephritic syndrome and progressive renal failure, occurs in about one third of individuals of Portuguese descent with early-onset hereditary ATTR amyloidosis caused by TTR pathogenic variant p.Val50Met [Lobato et al 2004]; however, severe renal dysfunction rarely occurs in individuals with late-onset disease.

Other. Amyloid deposition on the gastrointestinal tract wall, especially with involvement of the gastrointestinal autonomic nerves, is common [Ikeda et al 1982, Ikeda et al 1983]. Nodular cutaneous amyloidosis has been reported in an individual with the p.Tyr134His variant [Mochizuki et al 2001]. Shortness of breath induced by diffuse pulmonary amyloid deposition has been reported in two individuals with the p.Asp58Ala variant [Yazaki et al 2000a]. Anemia with low erythropoietin has been reported in 25% of individuals [Beirão et al 2004].

Genotype-Phenotype Correlations

Heterozygotes. Despite intensive investigation, few genotype-phenotype correlations have been detected.

The benign variant c.416C>T (p.Thr139Met) has a protective effect on amyloidogenesis in individuals who have the p.Val50Met variant [Hammarström et al 2001, Sebastião et al 2001].

Most TTR pathogenic variants result in peripheral and autonomic neuropathy; but some pathogenic variants have been associated with phenotypes in which peripheral or autonomic neuropathy is clinically absent or less prominent:

• Cardiac amyloidosis is caused by p.Asp38Asn, p.Val40Ile, p.Pro44Ser, p.Ala65Thr, Ala65Ser, p.His76Arg, p.Gly77Arg, p.Ile88Leu, p.Ala101Thr, p.Ala101Val, p.His108Arg, p.Glu112Lys, p.Arg123Ser, p.Leu131Met, or p.Val142Ile [Nakazato 1998, Benson 2001, Saraiva 2001, Connors et al 2003, Benson & Kincaid 2007]. Peripheral and autonomic neuropathy are absent or less evident in persons with these variants.
• Leptomeningeal amyloidosis is associated with p.Leu32Pro, p.Asp38Gly, p.Ala45Thr, p.Val50Gly, p.Ala56Pro, p.Gly73Glu, p.Gly73Ala, p.Phe84Ser, p.Tyr89His, or p.Tyr134Cys [Petersen et al 1997, Nakazato 1998, Brett et al 1999, Mascalchi et al 1999, Uemichi et al 1999, Connors et al 2000, Benson 2001, Ellie et al 2001, Saraiva 2001, Ikeda et al 2002, Blevins et al 2003, Connors et al 2003, Hammarström et al 2003, Sekijima et al 2003].
  It has been demonstrated that highly destabilized TTR variants induce leptomeningeal amyloidosis [Hammarström et al 2001, Sekijima et al 2003, Sekijima et al 2005].

Homozygosity for the p.Val50Met variant has been reported in at least 19 individuals from 14 families [Munar-Qués et al 2001, Tojo et al 2008]. Eight homozygotes for variants p.Val142Ile (5), p.Leu78His (1), p.Phe84Leu (1), and p.Ile88Leu (1) have been reported [Jacobson et al 1990, Nichols et al 1991, Ferlini et al 1996, Askanas et al 2000, Jacob et al 2007, Perfetto et al 2011].

Homozygotes present with a slightly more severe clinical course (higher incidence rate and earlier onset) than heterozygotes within the same family [Tojo et al 2008]; amyloid deposition is more widespread in homozygotes than in heterozygotes [Yoshinaga et al 2004]. Most homozygotes are members of families characterized by incomplete penetrance of hereditary ATTR amyloidosis.

Penetrance

Because the penetrance for hereditary ATTR amyloidosis is not 100%, an individual with a TTR pathogenic 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 [Misu et al 1999]. 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 [Planté-Bordeneuve et al 2003]. 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 [Hellman et al 2008].

Some p.Val50Met homozygotes remain asymptomatic.

Nomenclature

Historic protein numbering was based on the mature protein after cleavage of a 20-amino-acid signal sequence (e.g., p.Val50Met would be referred to as Val30Met). Standard nomenclature uses numbering beginning at the Met initiation codon. Variants reported in older literature may use historic nomenclature.

The neuropathy associated with TTR pathogenic variants, now called hereditary ATTR amyloidosis, was formerly referred to as one of the following:

• Familial amyloid polyneuropathy type I (or the Portuguese-Swedish-Japanese type)
• Familial amyloid polyneuropathy type II (or the Indiana/Swiss or Maryland/German type)

Prevalence

The p.Val50Met pathogenic variant, found worldwide, is the most widely studied TTR variant and is responsible for the well-known large foci of individuals with TTR amyloid polyneuropathy in Portugal, Sweden, and Japan. Numerous families with various pathogenic variants other than p.Val50Met have also been identified worldwide.

The frequency of hereditary ATTR amyloidosis caused by the variant p.Val50Met is estimated at 1:538 in northern Portugal (Povoa do Varzim and Vila do Conde), the largest cluster worldwide of individuals with hereditary ATTR amyloidosis.

In individuals of northern European origin in the US, the frequency of p.Val50Met-related hereditary ATTR amyloidosis is estimated at 1:100,000 [Benson 2001].

The frequency of p.Val50Met heterozygotes is 1.5% in the northern part of Sweden [Holmgren et al 1994]; however, the penetrance is very low in this area [Hellman et al 2008] (see Penetrance).

The frequency of p.Val142Ile in the African American population is 3.0%-3.9%; most heterozygous individuals develop late-onset cardiac amyloidosis. More than 5% of the population in some areas of West Africa is heterozygous for this variant. In the US, the frequency of p.Val142Ile in the white and Hispanic populations is 0.44% and 0.0%, respectively [Jacobson et al 1997, Yamashita et al 2005].

Genetically Related (Allelic) Disorders

Familial euthyroid hyperthyroxinemia is caused by benign variants in TTR, including p.Gly26Ser, p.Ala129Thr, p.Ala129Val, and p.Thr139Met [Nakazato 1998, Benson 2001, Saraiva 2001]. The TTR protein binds approximately 15% of serum thyroxine. These variants increase total serum thyroxine concentration because of their increased affinity for thyroxine; however, they increase neither free thyroxine nor free triiodothyronine. Therefore, individuals with these sequence variants develop no clinical symptoms (i.e., they are euthyroid).

Wild type ATTR amyloidosis (previously called senile systemic amyloidosis, or senile cardiac amyloidosis) results from the pathologic deposition of wild type TTR, predominantly in the heart. Pathologic deposits are also seen in the lungs, blood vessels, and the renal medulla of the kidneys [Westermark et al 2003]. Wild type ATTR amyloidosis affects mainly the elderly but is rarely diagnosed during life [Sekijima et al 2018]. Thus, the precise prevalence of wild type ATTR amyloidosis is still unknown, but the examination of autopsy samples revealed a prevalence of 10%-25% in the elderly (age >80 years) [Cornwell et al 1988, Ueda et al 2011].

Wild type ATTR amyloidosis typically does not cause symptoms or can result in cardiac symptoms. The majority of individuals with wild type ATTR amyloidosis present with carpal tunnel syndrome [Nakagawa et al 2016]. Wild type ATTR amyloidosis should be distinguished from hereditary ATTR amyloidosis with variant TTR or other forms of amyloidosis such as primary (AL) amyloidosis. In contrast to the rapid progression of heart failure in AL amyloidosis, wild type ATTR amyloidosis results in slowly progressive heart failure [Ng et al 2005]. Westermark et al [2003] have indicated that the lung may be a more reliable tissue for amyloid detection than the heart.