PracticeUpdate

Inherited Transthyretin-Mediated Amyloidosis: Though Diagnosis and Monitoring Are a Challenge, Treatment is Being Revolutionized

This progressive autosomal-dominant disorder is becoming a treatable genetic neuropathy

I nherited transthyretin-mediated amyloidosis (hATTR) is becoming a treatable genetic neurop- athy, concluded two presentations at ICNMD 2018. Diagnosis and monitoring of hATTR are challenging Davide Pareyson, MD, of the Institute for Research and Health Care, C. Besta Neurological Institute in Milan, Italy, explained that hATTR has become a treat- able disorder since effective therapies have become available. Early diagnosis is therefore fundamental to prevent progression of this disease, which is lethal, if left untreated. Diagnosis is easier in familial cases in endemic regions, where Val30Met is the most frequent muta- tion, awareness is high, and typical presentation is a predominantly small-fiber, length-dependent sensory neuropathy with dysautonomia, involving motor fib- ers only later. On the other hand, diagnosis is often delayed in non-endemic regions where neuropathy occurs late in life, the spectrum of mutations is much wider, family history is often negative or misleading, signs of dysautonomia are subtle, and presentation is atyp- ical with a sensorimotor polyneuropathy involving all fiber types, and progression is faster. A high degree of clinical suspicion and careful inves- tigation of neuropathy features, of early autonomic manifestations, of carpal tunnel syndrome, and of cardiac, ocular, or renal involvement allow prompt identification of the disease and early treatment. Careful monitoring of pre-symptomatic mutation car- riers permits early detection of the first symptomatic phases of the disease. Systematic and homogenous follow-up of treated individuals, with common core protocols, will allow the collection of data useful to optimize treatment and select the best therapeutic options according to disease type and stage.

Improvement in clinical and paraclinical outcome measures is challenging. Neuropathy Impairment Scores should be unified and simplified. Linear scales should be designed. Glomerular filtration rate seems a reliable biomarker for disease staging and possibly for monitoring dis- ease evolution, as well as brain natriuretic peptide as a marker of cardiac disease. Modified body mass index is another easy-to-calcu- late, important parameter. Standardized nerve conduction studies, nerve ech- ography, nerve MRI, skin biopsy, echocardiography, cardiac scintigraphy, cardiac MRI, and autonomic function tests are all important tools for diagnosis and monitoring of the disease course during treatment. Though a diagnostic challenge, treatment for hATTR is being revolutionized Dr. Pareyson explained that hATTR is an autoso- mal-dominant disorder caused by mutations of the transthyretin gene. Transthyretin is synthesized mainly by the liver and released in plasma as a tetrameric transport protein. Mutations in transthyretin, of which Val30Met is the most common worldwide, cause transthyretin tetramer dissociation, monomer misfolding, and aggregation into insoluble fibrillar proteins in different tissues. Orthotopic liver transplantation, in which the main site of mutated transthyretin production is removed, proved able to halt or slow neurological progression and was, until a few years ago, standard of care in individuals at later disease stages. The non-steroidal anti-inflammatory drug diflunisal has also been reported to be as effective as a transthyretin tetramer stabilizer. Diflunisal has produced significant slowing of disease progression in treated individuals. The antibiotic doxycycline and the taurine conjugate form of ursodeoxycholic acid exert a synergistic effect on fibril disruption. These agents are under

Dr. Davide Pareyson

PRACTICEUPDATE CONFERENCE SERIES • ICNMD 2018 12