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

Abstract

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.

Corneal confocal microscopy and familial amyloidotic polyneuropathy

“…Then, secondary to ocular production of TTR by the ciliary pigment epithelium, deposits on the iris, the pupillary margin and the anterior crystalloid appear; also, scalloped iris and glaucoma develop. Finally, abnormalities due to the production of TTR by the retinal pigment epithelium are observed, including vitreous amyloidosis and amyloid retinal angiopathy [2]. Other ophthalmological manifestations have been reported: corneal hypoesthesia, pupillary light-near dissociation and more rarely bilateral optic neuropathy [3].…”

Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis

“…The ocular involvement in patients with TTR amyloidosis is generally a rare manifestation 33 because it depends on numerous factors (eg, liver transplantation, disease age of onset, and disease duration), but it is well described in several studies of Val30Met TTR amyloidosis in Portuguese families. 34,35 The Val122Ile mutation is widely described in the literature as the leading cause of cardiac amyloidosis in patients with African ancestry. 36 This correlation was also confirmed in patients of European descent.…”

Population diversity of the genetically determined TTR expression in human tissues and its implications in TTR amyloidosis

“…In the two European Val30Met endemic areas (i.e., Portugal and Sweden), Val30Met patients show two distinct phenotypic presentations. In Val30Met Portuguese families, the disease shows early-onset, strong severity, and high penetrance [8, 9], whereas Val30Met Swedish patients have late-onset, intermediate severity, and low penetrance [10]. This complex genotype-phenotype correlation indicates that the clinical presentation is not only regulated by the disease-causing mutation.…”