Hereditary ATTR amyloidosis (ORPHA:271861)
A rare genetic systemic disease characterized by adult onset, progressive sensorimotor and autonomic neuropathy and infiltrative cardiomyopathy. Neurological involvement usually starts with sensory loss in the extremities and progresses with motor neuropathy. Cardiomyopathy presents with rhythm abnormalities and heart failure. The disease also frequently manifests with a range of additional clinical signs and symptoms due to associated ocular, renal, central nervous system and gastrointestinal involvement.
Epidemiology
Hereditary ATTR amyloidosis (hATTR) is estimated to affect >10,000 individuals globally.
Clinical description
Disease onset typically occurs in adult life, with age and presenting symptoms largely depending on genotype. Initial signs usually include pain, temperature sensation loss, numbness or tingling in lower limbs extremities. Motor neuropathy progressively ensues causing walking instability, inability to walk unassisted and ultimately need for a wheelchair. Autonomic symptoms, including bowel abnormalities, early satiety, orthostatic hypotension and erectile dysfunction may appear in the initial stages of the disease, particularly in patients with an early onset phenotype. Heart involvement, with signs of infiltrative cardiomyopathy leading to heart failure, develops in the majority of patients. Most patients are therefore classified as mixed phenotype (both neurological and cardiac). With respect to drug prescription, impairment due to polyneuropathy is scored with the familial amyloidotic polyneuropathy (FAP) staging system which has three stages : stage 1 is defined by unassisted walking; stage 2 is defined by need for assisted walking and stage 3 is defined by wheelchair-bound or bedridden patient.
Etiology
Over 140 mutations in the TTR gene are presently associated with hATTR. Mutations cause TTR tetramer instability, proteolytic remodeling and dissociation into monomers, leading to misfolding, aggregation and deposition as amyloid in tissues and organs.
Diagnostic methods
Genetic testing revealing a heterozygous pathogenic TTR and tissue biopsy (preferably non-invasive 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. In the absence of a serum and/or urinary monoclonal gammopathy, bone tracer scintigraphy with a Perugini score ≥2 represents indirect evidence of TTR amyloid deposition. Amyloid deposits must be 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, and AL, AGel and AApoAI amyloidosis. Increased left ventricular wall thickness should be differentiated from hypertensive heart disease, concentric hypertrophy from aortic stenosis, hypertrophic cardiomyopathy or other infiltrative cardiomyopathies, such as Fabry disease.
Antenatal diagnosis
Prenatal and preimplantation diagnosis is possible when the pathogenic variant has previously been identified in a family member. However for TTR variants associated with a late-onset phenotype antenatal diagnosis is very rarely requested, particularly in light of emerging disease-modifying therapies.
Genetic counseling
hATTR is dominantly transmitted. Genetic counseling is highly recommended to at-risk patients' relatives, informing them there is a 50% risk of inheritance in siblings and offspring. Pre-symptomatic testing is increasingly offered in hATTR due to emerging disease-modifying therapies.
Management and treatment
There are two different classes of disease-modifying therapies for hereditary transthyretin amyloidosis: TTR stabilizers and gene-silencing agents. Tafamidis is the first-in-class transthyretin stabilizer that prevents misfolding and aggregation by stabilizing the native protein structure. It is approved for hATTR with FAP stage 1 polyneuropathy at the dose of 20 mg/daily and for hATTR with cardiomyopathy at the dose of 61 mg/daily. Gene-silencing agents approved by EMA for hATTR with polyneuropathy (FAP stages 1 and 2) include RNAi agents patisiran and vutrisiran and the antisense oligonucleotide (ASO) inotersen.
Prognosis
Prognosis depends on disease stage at treatment start. Advanced heart involvement is associated with worse prognosis.

                            Last update: 
                            May 2023


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


                                * European Reference Network