Attrv30m Amyloidosis

Watchlist

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Retrieved

2021-01-23

Source

Orphanet

Trials

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Genes

TTR, FAP, GSN, APP, B2M, APOA1, CRP, MMP9, SERPINA1, PRNP, RBP4, SAA1, SAA2, ATXN2, SST

Drugs

3-(3-(3,5-Dimethyl-1H-pyrazol-4-yl)propoxy)-4-fluorobenzoic acid, Doxycycline hyclate, Eprodisate

3-(3-(3,5-Dimethyl-1H-pyrazol-4-yl)propoxy)-4-fluorobenzoic acid, Doxycycline hyclate, Eprodisate, Patisiran ( Onpattro ), Phosphorothioate oligonucleotide targeted to transthyretin ( TEGSEDI ), Revusiran, Tafamidis ( VYNDAQEL ), synthetic double-stranded siRNA oligonucleotide targeted against transthyretin mRNA, with six phosphorothioate linkages in the backbone, and nine 2'-fluoro and thirty-five 2'-O-methyl nucleoside residues in the sequence, which is covalently linked via a phosphodiester group to a ligand containing three N-acetylgalactosamine residues

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Familial amyloid polyneuropathy (FAP) or transthyretin (TTR) amyloid polyneuropathy is a progressive sensorimotor and autonomic neuropathy of adulthood onset. Weight loss and cardiac involvement are frequent; ocular or renal complications may also occur.

Epidemiology

The prevalence worldwide is unknown, but the prevalence in the general population in Japan has recently been estimated at around 1 per million.

Clinical description

FAP is clinically heterogeneous, with the clinical presentation depending on the genotype and geographic origin. FAP usually presents as a length-dependent sensory polyneuropathy with autonomic disturbances. Inaugural manifestations are paresthesiae, pain or trophic lesions of the feet, gastrointestinal disorders or weight loss. The most pronounced sensory loss involves pain and temperature sensation. Motor loss occurs later. Autonomic features include postural hypotension, and gastrointestinal and genitourinary disorders.

Etiology

FAP is transmitted as an autosomal dominant trait and is caused by mutations in the TTR gene (18q12.1). More than 40 TTR mutations have been identified so far and are associated with varying patterns of organ involvement, age of onset and disease progression. The most common variant is the TTR Val30Met substitution for which several endemic foci have been identified most notably from Portugal, Japan and Sweden. However, the Val30Met phenotype varies between these countries.

Diagnostic methods

Detection of amyloid-associated TTR mutations is required for diagnosis. However, identification of a disease-causing mutation is not considered as diagnostic because penetrance is variable. Clinical observation and tissue biopsy (from the nerve or kidney, labial salivary glands, subcutaneous fat tissue or rectal mucosa) are required for a definitive diagnosis: amyloid deposits are characterized by Congo red staining on light microscopy and green birefringence on polarized light microscopy.

Differential diagnosis

The differential diagnosis should include diabetic neuropathy, chronic inflammatory demyelinating polyneuropathy (see this term), and light chain (AL), gelsolin and apolipoprotein A1 amyloidosis (see these terms).

Antenatal diagnosis

Antenatal diagnosis through chorionic villus sampling should be proposed to patients with early-onset (< 40 years) forms of FAP.

Genetic counseling

Genetic counseling should be offered to affected families and presymptomatic detection of relatives of an index case is important to allow early diagnosis.

Management and treatment

Management of FAP should be multidisciplinary, involving a neurologist, geneticist, cardiologist and liver surgeon. Liver transplantation (LT) is currently the only treatment for preventing synthesis of the amyloidogenic variants of TTR. LT can stop progression of the disease during its early stages. Symptomatic treatments are essential for sensorimotor and autonomic neuropathy and visceral complications.

Prognosis

FAP is a severe and disabling disease. Severe cardiac, renal and ocular manifestations may develop. Death occurs within a mean interval of 10.8 years after onset of the inaugural symptoms and may occur suddenly or may be secondary to infections or cachexia.