ATTRV30M amyloidosis (ORPHA:85447)
A rare hereditary ATTR amyloidosis (hATTR) characterized by a progressive, length-dependent sensorimotor axonal polyneuropathy and/or autonomic neuropathy in adulthood. Renal, ocular and cardiac involvement also frequently occurs. Two different phenotypes are associated with this mutation, namely early-onset V30M and late-onset V30M, that differ in terms of age on onset (<50 years or >50 years, respectively), presenting features, histopathological characteristics, rate of disease progression and response to therapy.
Epidemiology
ATTRV30M is the most common hATTR. The worldwide prevalence is unknown, although data is available for countries like Portugal, Japan and Sweden where the disease is relatively frequent. In Portugal the estimated incidence is 1/115,000 people a year, and the estimated prevalence is 1/4,360 adults.
Clinical description
Early-onset V30M manifests usually from the fourth decade of life. Inaugural symptoms are consistent with a small fibre neuropathy and typically include pain and temperature sensation loss in lower limbs. Motor neuropathy occurs later. Autonomic features include postural hypotension, gastrointestinal and genitourinary disorders. Rhythm disturbances, including atrioventricular nodal block requiring pacemaker implantation, are also frequent at disease onset. Proteinuria progressing to nephrotic syndrome may be an early clinical finding as well. In late-onset V30M, small and large nerve fibres are usually affected since the early stages of the disease, manifesting with a rapidly progressing sensory and motor polyneuropathy. Carpal tunnel syndrome may anticipate peripheral neuropathy in lower limbs. Infiltrative cardiomyopathy frequently develops, leading to heart failure.
Etiology
The disease is caused by a methionine for valine substitution at residue 30 of the mature TTR protein, which is encoded by the TTR gene located on chromosome18q12.1. It leads to misfolding and dissociation of the TTR tetramer and monomer aggregation as amyloid in tissues and organs.
Diagnostic methods
Detection of V30M TTR variant by genetic testing and tissue biopsy (preferably a non-invasive biopsy like minor labial salivary gland, subcutaneous fat tissue or rectal mucosa) are required for a complete diagnosis. Green birefringence on polarized light microscopy after Congo red staining reveal amyloid deposits. Amyloid deposits are typed by immunohistochemistry or mass spectrometry for definite diagnosis when a patient also presents with a serum and/or urinary monoclonal gammopathy.
Differential diagnosis
The differential diagnosis includes diabetic neuropathy, chronic inflammatory demyelinating polyneuropathy, AL, AGel and AApoAI amyloidosis.
Antenatal diagnosis
Prenatal/pre-implantation diagnosis is possible and should be discussed in the context of genetic counseling. It is more relevant in families with early-onset V30M, depending also on local regulations. The emerging availability of effective disease-modifying therapies is reducing the request for pre-implantation diagnosis. Antenatal diagnosis is usually not an option in late-onset V30M, due to advanced age of onset and reduced penetrance.
Genetic counseling
The pattern of inheritance is autosomal dominant. Genetic counselling should be offered to affected individuals and their at-risk relatives, informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
Management of the disease should be multidisciplinary, involving neurologist, geneticist, cardiologist, nephrologist, ophthalmologist and gastroenterologist. Liver transplantation is no longer a first-line treatment. Presently, patients that are able to walk unassisted (FAP stage 1) can be treated with a gene-silencing agent (RNAi patisiran, vutrisiran or ASO inotersen) or with the TTR stabilizer tafamidis 20 mg/day. Patients that require support for walking (FAP stage 2) can be treated with a gene-silencing agent only.
Prognosis
This neurological disease is progressive and highly disabling if untreated. Severe cardiac, renal and ocular manifestations may develop. Before disease-modifying treatment availability, death occurred within a mean interval of 10.8 years after onset of the inaugural symptoms.

                            Last update: 
                            May 2023


                            - Expert reviewer(s): 
                            Dr Laura OBICI | RITA*


                                * European Reference Network