ATTRv

ATTRv, short for hereditary transthyretin amyloidosis with polyneuropathy, is a systemic amyloidosis caused by pathogenic variants in the TTR gene that lead to deposition of misfolded transthyretin as amyloid in multiple tissues. It is inherited in an autosomal dominant pattern with considerable variability in age of onset and disease severity.

Clinical features are dominated by progressive, length-dependent sensorimotor polyneuropathy and autonomic dysfunction. Patients may experience numbness, weakness, burning pain, orthostatic hypotension, constipation or diarrhea, erectile dysfunction, and bladder dysfunction. Cardiac involvement may develop later, contributing to cardiomyopathy and arrhythmias; ocular, renal, and gastrointestinal tract involvement can also occur.

Genetics and epidemiology: more than a hundred TTR variants have been described; Val30Met (Val50Met in some nomenclatures) is among the most common worldwide. The disease shows regional patterns: early-onset forms are common in endemic areas such as Portugal and parts of Sweden; late-onset disease is more typical in other populations. Penetrance varies by variant and family background.

Diagnosis: suspicion arises from compatible clinical features and family history. Definitive diagnosis requires genetic testing to identify a pathogenic TTR variant, often supported by tissue confirmation of amyloid deposits stained with Congo red and typed for TTR. Cardiac involvement is evaluated with echocardiography, MRI, and nuclear imaging such as technetium-99m pyrophosphate to distinguish ATTR from other amyloidoses.

Management and prognosis: treatment focuses on disease-modifying therapies that reduce TTR production or stabilize the TTR tetramer. Tafamidis and diflunisal act as stabilizers; patisiran (siRNA) and inotersen (antisense oligonucleotide) are approved to treat polyneuropathy due to ATTRv. Supportive care includes pain control, physical therapy, autonomic symptom management, and monitoring for cardiac complications; liver transplantation is now rarely used. Prognosis varies with genotype and age of onset.