Transthyretin familial amyloid polyneuropathy (TTR-FAP) in Mallorca: a comparison between late- and early-onset disease.

The age of onset (AO) of hereditary ATTR amyloidosis (hATTR) is known to vary between populations, with differing characteristics reported according to AO in endemic/non-endemic foci. This was a retrospective study of patients with early AO (<50 years) and late AO (≥50 years) hATTR at our center in Mallorca. Data were collected on patient demographics, clinical disease manifestation, and physical symptoms. A total of 95 patients were analyzed, with mean follow-up of 9 years from diagnosis. The early AO group included 53 patients (33 male) and the late AO group included 42 patients (21 male). Neurologic involvement was the most common initial symptom, although it was significantly more frequent in the late AO vs. early AO group (p = 0.015). Autonomic involvement was observed in 26% of patients in the early AO group, but was rarely observed in the late AO group (5%). During follow up, cardiologic symptoms, renal involvement, and ophthalmologic symptoms were significantly more common in the late AO group (p < 0.05). This retrospective study demonstrates the variation in disease presentation and progression according to AO of hATTR at our Mallorcan center.

Ophthalmological manifestations in hereditary transthyretin (ATTR V30M) carriers: a review of 513 cases.

PURPOSE: Assessment of ocular involvement in transthyretin-related familial amyloidosis with polyneuropathy (FAP) in a large cohort of Portuguese patients. METHODS: We reviewed the medical records of 513 Portuguese FAP mutation carriers, at the Ophthalmology Service, Centro Hospitalar do Porto, between 1 January 2008 and 31 January 2013. Abnormal conjunctiva vessels (ACV), Schirmer test, tear break-up time (TBUT), amyloid deposition on the iris (DAI), scalloped iris, amyloid deposition on the anterior capsule of the lens (DAL), vitreous amyloidosis, retinal amyloid angiopathy and glaucoma were evaluated and registered. RESULTS: Of the 513 carriers, 477 (93%) had clinical systemic disease with a median duration of 9.3 (5.1-13.7) years and 247 were men. Of these, 343 (72%) had been liver transplanted, on median of 6.6 (3.3-10.8) years before inclusion in this study. No ocular abnormalities were identified in the asymptomatic carriers (7%). The abnormalities observed with decreasing frequency were abnormal TBUT (379 patients, 79.5%, 751 eyes), abnormal Schirmer test (320 patients, 67%, 635 eyes), DAI (183 patients, 38.4%, 350 eyes), DAL (157 patients, 32.9%, 308 eyes), scalloped iris (133 patients, 27.9%, 238 eyes), glaucoma (97 patients, 20%, 165 eyes), vitreous amyloidosis (83 patients, 17.4%, 139 eyes), ACV (68 patients, 14%, 136 eyes) and amyloidotic retinal angiopathy (21 patients, 4%, 32 eyes). Patients with abnormal Schirmer test (p < 0.001), scalloped iris (p = 0.006) and vitreous amyloidosis (p = 0.007) were significantly older than the others. According to their age of onset of systemic disease, the patients have been split into early-onset (<40 years old), intermediate-onset (40-50 years old), late onset (>50 years old) and asymptomatic carriers. We observed a statistically significant difference in the prevalence of ACV (p = 0.045) and of an abnormal Schirmer test (p = 0.004) between groups. Transplanted patients have a significantly higher prevalence of DAI (p = 0.001), DAL (p = 0.009) and vitreous amyloidosis (p = 0.025) than non-transplanted patients. Of the 165 eyes with glaucoma, 92.1% had scalloped iris (p < 0.001) and of 32 eyes with retinal amyloidotic angiopathy, 68.8% had vitreous amyloidosis (p < 0.001). All prevalences increased with time of disease. The earliest ocular manifestations were abnormal Schirmer test and abnormal TBUT (12% and 17% at 5 years of clinical disease) and the least prevalent was retinal amyloid angiopathy (8% at 15 years of clinical disease). CONCLUSION: Ocular disorders in FAP patients are common, and their prevalence increases with disease duration. Prevalence is influenced by several factors, such as the age at onset of FAP and liver transplantation.

Recent advances in the treatment of familial amyloid polyneuropathy.

The treatment of familial amyloid polyneuropathy (FAP) requires a multidisciplinary approach, mainly neurological and cardiological. It includes specific treatments to stop the progression of systemic amyloidogenesis, the symptomatic treatment of the peripheral and autonomic neuropathy and the treatment of organs severely involved by amyloidosis (heart, eyes, kidneys). First-line specific treatment of met30 transthyretin (TTR) FAP is liver transplantation, which allows suppression of the main source of mutant TTR, to stop the progression of the neuropathy in 70% of cases in the long term and to double the median survival. In cases of severe renal or cardiac insufficiency, a combined kidney-liver or heart-liver transplantation can be discussed. Tafamidis (Vyndaqel) is a novel specific stabilizer of TTR which, in the very early stages of met30 TTR FAP, slows the progress of peripheral neuropathy. This drug should be proposed in cases of stage 1 symptomatic polyneuropathy. Other innovative medicines have been developed by biopharmaceutical companies to block the hepatic production of mutant and wild type TTR which are harmful in late-onset FAP (> 50 years old), including RNA interference therapeutics and antisense oligonucleotides, and to remove the amyloid deposits (monoclonal antibody antiserum amyloid P). Clinical trials should first assess patients with late onset FAP or non-met30 TTR FAP who are less responsive to liver transplantation or in case of significant progression of the neuropathy with Vyndaqel. Initial cardiac assessment and periodic cardiac investigations are important for patients with FAP because of the frequency of cardiac impairment, which is responsible for the high rate of mortality. Prophylactic pacemaker treatment should be discussed. Symptomatic treatments are required to improve patients' quality of life. Familial screening of people with TTR mutation and regular follow up are essential. Appropriate clinical examination and complementary investigations are vital for the early detection of disease onset and to start specific therapy as soon as possible.