Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

ATTR amyloidosis

Transthyretin-related hereditary amyloidosis is an autosomal dominant disorder with variable penetrance. It is caused by mutations of the TTR gene.

Classification

Three types of ATTR amyloidosis can be distinguished based on dominating symptoms.

FAP, neuropathic amyloidosis, is dominated by peripheral neuropathy.

In FAC, cardiac amyloidosis, heart failure is the most obvious clinical finding.

A third type, senile systemic amyloidosis, which is also characterized by transthyretin deposits is not related to TTR mutations and therefore not hereditary.

Clinical Findings

Organs involved in transthyretin-related hereditary amyloidosis include heart and peripheral nerves. More rarely, gastrointestinal and renal involvement is observed.

Heart

The affected heart shows enlargement and progressive failure. If cardiac involvement dominates the clinical picture we call the disease familial amyloid cardiomyopathy (FAC).

Nerves

The peripheral polyneuropathy predominantly affects autonomous and somatic fibers. This disease is rapidly progressive. It is accompanied by carpal tunnel syndrome and muscle loss. If the involvement of the peripheral nervous system dominates the clinical picture we call the disorder familial amyloid polyneuropathy (FAP).

Gastrointestinal tract

Some of the gastrointestinal sumptoms such as diarrhea and obstipation are also related to peripheral autonomous neuropathy. Often the symptoms resemble food intolerance.

Kidney

Renal symptoms include proteinuria and renal insufficiency. Both are rather mild and therefore often ignored.

Management

Since 1991 therapy includes liver transplatation which eleminates the main source of misfolded transthyretin. With significant cardiomyopathy a combined heart and liver transplantation can be considered. Since 2011 a drug to prevent misfolded transthyretin is approved for the treatment of FAP and the approval for FAC is on its way.

Symptoms

Polyneuropathy
Polyneuropathy preferentially autonomous and somatic is the dominating symptom of FAP.
Cardiomyopathy
Cardiomyopathy in FAC is predominantly characterized by cardiomegaly and reduced physical capacity.
Muscle atrophy
Muscle loss in FAP is the result of polyneuropathy. It presents with gait abnormality.
Diarrhea
Diarrhea and obstipation can alternate. They are the result of autonomous polyneuropathy.
Proteinuria
Proteinuria might be only mild but signals renal involvement.
Renal insufficiency
Though renal insufficiency may develop due to renal involvement, this condition will rarely dominate the clinical picture.

Systematic

Hereditary amyloidosis
ATTR amyloidosis
TTR
Amyloidosis, cerebroarterial
Cryopyrin-associated periodic syndrome
Familial mediterranean fever
Finnish type Amyloidosis
Hereditary renal amyloidosis

References:

1.

Glenner GG et al. (1984) Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein.

[^]
2.

Uemichi T et al. (1999) Oculoleptomeningeal amyloidosis associated with a new transthyretin variant Ser64.

[^]
3.

Hund E et al. (2001) Transthyretin-associated neuropathic amyloidosis. Pathogenesis and treatment.

[^]
4.

None (2001) Transthyretin mutations in hyperthyroxinemia and amyloid diseases.

[^]
5.

Ikeda S et al. (2002) Familial transthyretin-type amyloid polyneuropathy in Japan: clinical and genetic heterogeneity.

[^]
6.

Blevins G et al. (2003) Oculoleptomeningeal amyloidosis in a large kindred with a new transthyretin variant Tyr69His.

[^]
7.

None (1952) A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves.

[^]
8.

Jacobson DR et al. (1992) Transthyretin Pro55, a variant associated with early-onset, aggressive, diffuse amyloidosis with cardiac and neurologic involvement.

[^]
9.

KAUFMAN HE et al. (1959) Vitreous opacities diagnostic of familial primary amyloidosis.

[^]
10.

Ray SS et al. (2004) A possible therapeutic target for Lou Gehrig's disease.

[^]
11.

Sekijima Y et al. (2005) The biological and chemical basis for tissue-selective amyloid disease.

[^]
12.

Liu YT et al. (2008) Transthyretin Ala97Ser in Chinese-Taiwanese patients with familial amyloid polyneuropathy: genetic studies and phenotype expression.

[^]
13.

None (1991) Inherited amyloidosis.

[^]
14.

Benson MD et al. (1977) Generalized amyloid in a family of Swedish origin. A study of 426 family members in seven generations of a new kinship with neuropathy, nephropathy, and central nervous system involvement.

[^]
15.

Hagiwara K et al. (2009) Highly selective leptomeningeal amyloidosis with transthyretin variant Ala25Thr.

[^]
16.

Yang NC et al. (2010) Clinical presentations and skin denervation in amyloid neuropathy due to transthyretin Ala97Ser.

[^]
17.

Westermark P et al. (1990) Fibril in senile systemic amyloidosis is derived from normal transthyretin.

[^]
18.

Ikeda S et al. (1987) Hereditary generalized amyloidosis with polyneuropathy. Clinicopathological study of 65 Japanese patients.

[^]
19.

Sequeiros J et al. (1987) Onset in the seventh decade and lack of symptoms in heterozygotes for the TTRMet30 mutation in hereditary amyloid neuropathy-type I (Portuguese, Andrade).

[^]
20.

Uitti RJ et al. (1988) Familial oculoleptomeningeal amyloidosis. Report of a new family with unusual features.

[^]
21.

Holmgren G et al. (1988) Homozygosity for the transthyretin-met30-gene in two Swedish sibs with familial amyloidotic polyneuropathy.

[^]
22.

Furuya H et al. (1987) Molecular analysis of a variant type of familial amyloidotic polyneuropathy showing cerebellar ataxia and pyramidal tract signs.

[^]
23.

Mahloudji M et al. (1969) The genetic amyloidoses with particular reference to hereditary neuropathic amyloidosis, type II (Indiana or Rukavina type).

[^]
24.

Wong VG et al. (1967) Primary familial amyloidosis.

[^]
25.

Saraiva MJ et al. (1984) Amyloid fibril protein in familial amyloidotic polyneuropathy, Portuguese type. Definition of molecular abnormality in transthyretin (prealbumin).

[^]
26.

None (1981) Partial amino acid sequence homology between an heredofamilial amyloid protein and human plasma prealbumin.

[^]
27.

Dalakas MC et al. (1981) Amyloid in hereditary amyloid polyneuropathy is related to prealbumin.

[^]
28.

Goren H et al. (1980) Familial oculoleptomeningeal amyloidosis.

[^]
29.

Ducla-Soares J et al. (1994) Correlation between clinical, electromyographic and dysautonomic evolution of familial amyloidotic polyneuropathy of the Portuguese type.

[^]
30.

Holmgren G et al. (1994) Geographical distribution of TTR met30 carriers in northern Sweden: discrepancy between carrier frequency and prevalence rate.

[^]
31.

Coelho T et al. (1994) A study of 159 Portuguese patients with familial amyloidotic polyneuropathy (FAP) whose parents were both unaffected.

[^]
32.

Drugge U et al. (1993) Familial amyloidotic polyneuropathy in Sweden: a pedigree analysis.

[^]
33.

Vidal R et al. (1996) Meningocerebrovascular amyloidosis associated with a novel transthyretin mis-sense mutation at codon 18 (TTRD 18G)

[^]
34.

Herrick MK et al. (1996) Massive leptomeningeal amyloidosis associated with a Val30Met transthyretin gene.

[^]
35.

Garzuly F et al. (1996) Familial meningocerebrovascular amyloidosis, Hungarian type, with mutant transthyretin (TTR Asp18Gly)

[^]
36.

Jacobson DR et al. (1997) Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans.

[^]
37.

Petersen RB et al. (1997) Transthyretin amyloidosis: a new mutation associated with dementia.

[^]
38.

Koo EH et al. (1999) Amyloid diseases: abnormal protein aggregation in neurodegeneration.

[^]
39.

Altland K et al. (1999) Potential treatment of transthyretin-type amyloidoses by sulfite.

[^]
40.

None (2001) Amyloidosis: a convoluted story.

[^]
41.

MUNSAT TL et al. (1962) Clinical manifestations and diagnosis of amyloid polyneuropathy. Report of three cases.

[^]
42.

Reixach N et al. (2004) Tissue damage in the amyloidoses: Transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture.

[^]
43.

Koike H et al. (2004) Pathology of early- vs late-onset TTR Met30 familial amyloid polyneuropathy.

[^]
44.

Ando Y et al. (2005) Transthyretin-related familial amyloidotic polyneuropathy.

[^]
45.

Holmgren G et al. (1991) Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30).

[^]
46.

Sandgren O et al. (1991) Vitreous involvement in familial amyloidotic neuropathy: a genealogical and genetic study.

[^]
47.

Dowell JD et al. (2007) Familial oculoleptomeningeal amyloidosis associated with primary angiitis of the CNS.

[^]
48.

Yi S et al. (1991) Systemic amyloidosis in transgenic mice carrying the human mutant transthyretin (Met30) gene. Pathologic similarity to human familial amyloidotic polyneuropathy, type I.

[^]
49.

Okayama M et al. (1978) Primary amyloidosis with familial vitreous opacities: an unusual case and family.

[^]
50.

Coelho T et al. (2013) Safety and efficacy of RNAi therapy for transthyretin amyloidosis.

[^]
51.

Costa PP et al. (1978) Amyloid fibril protein related to prealbumin in familial amyloidotic polyneuropathy.

[^]
52.

Yamada M et al. (1987) "Sporadic" prealbumin-related amyloid polyneuropathy: report of two cases.

[^]
53.

Ueno S et al. (1988) 'Nonprealbumin-related' familial amyloid polyneuropathy.

[^]
54.

Tanaka M et al. (1988) Familial amyloidotic polyneuropathy without familial occurrence: carrier detection by the radioimmunoassay of variant transthyretin.

[^]
55.

Glenner GG et al. (1971) Amyloid fibril proteins: proof of homology with immunoglobulin light chains by sequence analyses.

[^]
56.

Coimbra A et al. (1971) Familial amyloid polyneuropathy: an electron microscope study of the peripheral nerve in five cases. I. Interstitial changes.

[^]
57.

Coimbra A et al. (1971) Familial amyloid polyneuropathy: an electron microscope study of the peripheral nerve in five cases. II. Nerve fibre changes.

[^]
58.

Glenner GG et al. (1974) Beta-pleated sheet fibrils. A comparison of native amyloid with synthetic protein fibrils.

[^]
59.

None (1971) Unusual cause of vitreous opacities. Primary familial amyloidosis.

[^]
60.

Libbey CA et al. (1984) Familial amyloid polyneuropathy. Demonstration of prealbumin in a kinship of German/English ancestry with onset in the seventh decade.

[^]
61.

Cornwell GG et al. (1981) Senile cardiac amyloid: evidence that fibrils contain a protein immunologically related to prealbumin.

[^]
62.

Ando Y et al. (1995) Change in variant transthyretin levels in patients with familial amyloidotic polyneuropathy type I following liver transplantation.

[^]
63.

Ando Y et al. (1994) Role of nitric oxide in the peripheral vessels of patients with familial amyloidotic polyneuropathy (FAP) type I.

[^]
64.

Holmgren G et al. (1993) Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis.

[^]
65.

Rocha A et al. (2016) Liver transplantation in transthyretin amyloidosis: Characteristics and management related to kidney disease.

[^]
66.

OMIM.ORG article

Omim 105210 [^]
67.

Wikipedia article

Wikipedia EN (Familial_amyloid_polyneuropathy) [^]
Update: April 29, 2019