Tenosynovial complications identify TTR cardiac amyloidosis among patients with hypertrophic cardiomyopathy phenotype.

Recent evidence suggests that carpal tunnel syndrome (CTS) and brachial biceps tendon rupture (BBTR) represent red flags for ATTR cardiac amyloidosis (ATTR-CA). The prevalence of upper limb tenosynovial complications in conditions entering differential diagnosis with CA, such as HCM or Anderson-Fabry disease (AFD), and hence their predictive accuracy in this setting, still remains unresolved. OBJECTIVE: To investigate the prevalence of CTS and BBTR in a consecutive cohort of ATTR-CA patients, compared with patients with HCM or AFD and with individuals without cardiac disease history. PARTICIPANTS: Consecutive patients with a diagnosis of ATTR-CA, HCM and AFD were evaluated. A control group of consecutive patients was recruited among subjects hospitalized for noncardiac reasons and no cardiac disease history. The presence of BBTR, CTS or prior surgery related to these conditions was ascertained. RESULTS: 342 patients were prospectively enrolled, including 168 ATTR-CA (141 ATTRwt, 27 ATTRm), 81 with HCM/AFD (N = 72 and 9, respectively) and 93 controls. CTS was present in 75% ATTR-CA patients, compared with 13% and 10% of HCM/AFD and controls (P = 0.0001 for both comparisons). Bilateral CTS was present in 60% of ATTR-CA patients, while it was rare (2%) in the other groups. BBTR was present in 44% of ATTR-CA patients, 8% of controls and 1% in HCM/AFD. CONCLUSIONS: CTS and BBTR are fivefold more prevalent in ATTR-CA patients compared with cardiac patients with other hypertrophic phenotypes. Positive predictive accuracy for ATTR-CA is highest when involvement is bilateral. Upper limb assessment of patients with HCM phenotypes is a simple and effective way to raise suspicion of ATTR-CA.

Differential expression of the insulin-like growth factor II and transthyretin genes in the developing rat choroid plexus.

Choroid plexus (CP) development may depend on an inductive interaction between primordial CP epithelium and the overlying mesenchyme. Expression of the two CP epithelial-expressed genes, transthyretin (TTR) and insulin-like growth factor II (IGF-II), were studied by in situ hybridization in the developing rat. Transthyretin mRNA is expressed in abundance in the primordial CP epithelium prior to CP morphogenesis (e10-11) but IGF-II mRNA expression begins later (e13) and increases gradually as morphogenesis proceeds. In the CP stroma (mesenchyme), IGF-II mRNA is abundant prior to CP morphogenesis but decreases as embryogenesis proceeds and is absent in the adult. Our findings suggest that IGF-II may play an early paracrine and later autocrine role in CP development. A model is proposed in which IGF-II synthesized by mesenchyme serves as an inducing principle for CP epithelial differentiation.

Familial amyloidotic polyneuropathy presenting with carpal tunnel syndrome and a new transthyretin mutation, asparagine 70.

We report familial amyloidotic polyneuropathy in a pedigree of German ancestry residing in New Jersey. Eight affected subjects presented in the third to seventh decade with carpal tunnel syndrome (CTS) and one subject presented with vitreous opacification. Transmission was autosomal dominant and survival was prolonged. Affected subjects were heterozygous for a novel mutation in serum transthyretin (TTR), resulting in an asparagine for lysine substitution at residue 70 of the TTR monomer. We report two methods for rapid identification of the mutation based on the polymerase chain reaction. This pedigree further emphasizes the evolving phenotypic and genotypic heterogeneity of the transthyretinopathies. Familial or sporadic CTS or unexplained vitreous opacification suggest the possibility of TTR amyloidosis and should prompt a search for TTR mutations.

The distribution of retinol-binding protein and its mRNA in the rat eye.

Although a constant supply of retinol is a critical requirement for the visual cycle, the molecular mechanisms underlying retinol delivery, uptake, storage, and transport in the eye are not well understood. Previously the synthesis of serum retinol-binding protein (RBP) in the mammalian eye was reported. Now the distribution of RBP and RBP mRNA in the rat eye has been studied by immunohistochemical and in situ hybridization techniques has been studied. The RBP mRNA was present only in the cytoplasm of retinal pigment epithelial (RPE) cells, terminating abruptly at the pars plana. On the other hand, RBP immunoreactivity was more widespread. The most intense immunostaining was present in retinal ganglion cells, the corneal endothelium, and under certain conditions of tissue fixation, the corneal epithelium. Consistent but less intense immunoreactivity was detected in the photoreceptors, Müller cells, inner plexiform layer, ciliary epithelium and stroma, iris epithelium, retinal pigment epithelium, lacrimal glandular epithelium, and periorbital soft tissues. These findings suggest that RBP synthesized by the RPE may be secreted to various ocular locations. However, at present, uptake from plasma cannot be excluded as another possible source of ocular RBP. In the plasma, holo-RBP (the retinol-RBP complex) is transported in complex with another plasma protein, transthyretin (TTR). This substance is also synthesized by the RPE and its distribution in the eye is similar to that described for RBP. Taken together, these findings support the proposal that ocular RBP and TTR may function cooperatively in the intraocular translocation of retinol.

The retinal pigment epithelium is the unique site of transthyretin synthesis in the rat eye.

Transthyretin (TTR), or prealbumin, is a 55-kD tetrameric protein which plays an important role in the plasma transport of thyroxine, and through its interaction with retinol-binding protein, of retinol. Four major sources of TTR synthesis have been identified in the mammal: liver hepatocytes, visceral yolk sac endoderm, choroid plexus epithelium, and the eye. We now report in situ hybridization studies demonstrating that in the rat eye, the retinal pigment epithelium is the unique source of TTR synthesis. This finding underscores the developmental, structural, and functional homology between the choroid plexus epithelium and the retinal pigment epithelium. Although the functional significance of ocular TTR synthesis is unclear, it is likely that it serves to transport thyroxine or retinol across the blood-retina barrier, thereby facilitating their effects on differentiation and morphogenesis. Considering the importance of retinol in the biochemistry of the visual process, we propose that TTR may play a role in the intraocular cycling of retinol.

Distribution of transthyretin in the rat eye.

We reported previously synthesis of transthyretin (TTR), or prealbumin, a transport protein for thyroxine and retinol, in the eyes of rats and cows and showed that in the rat eye, TTR mRNA is localized exclusively in the retinal pigment epithelium (RPE). We now demonstrate by immunohistochemistry that TTR has a more widespread distribution in the rat eye than does its mRNA. Intense immunoreactivity for TTR was found in the RPE, ciliary epithelium, iris epithelium, corneal endothelium, optic nerve fiber layer of the retina, and lens capsule. Depending on the method of processing, immunoreactivity of varying intensity was found also in other ocular structures. In particular, the retinal ganglion cells were strongly immunoreactive on frozen sections but not on paraffin sections. Although vitreous humor was not included in the sections of adult rat eye, sections of a 25-mm rat embryo showed intense immunoreactivity in the vitreous humor. Since plasma TTR does not cross Bruch's membrane into the retina, our findings suggest that ocular TTR is synthesized, at least in part, in the RPE and is transported to specific locations within the eye. Although the physiologic role of ocular TTR is unknown, it is possible that it participates in retinol cycling within the eye. The widespread ocular distribution of TTR may account for the occurrence of various forms of ocular amyloidosis in the familial amyloidotic polyneuropathies, a group of dominantly inherited disorders caused by point mutations in the TTR gene.

Retinol-binding protein is synthesized in the mammalian eye.

As the chromophoric component of the visual pigment, retinol plays an essential role in vision. In the plasma, retinol is transported by retinol-binding protein (RBP) in complex with transthyretin (TTR, prealbumin). In previous work we demonstrated intraocular synthesis of TTR. To determine whether RBP is also synthesized in the eye, we performed Northern and Western blot analysis of rat eye, and detected both RBP mRNA and immunoreactive RBP. Regional Northern analysis of bovine eye localized RBP mRNA to ciliary body/iris and retina/RPE. Preliminary immunohistochemical studies revealed a widespread but heterogeneous distribution of RBP in rat eye. We postulate that ocular RBP and TTR are involved in the intraocular translocation of retinol.

Transthyretin is synthesized in the mammalian eye.

Transthyretin (TTR, prealbumin) is a 55 kDa protein which plays an important role in the plasma transport of thyroxine and retinol. Although the liver and choroid plexus are the two major known sites of TTR synthesis, several lines of evidence suggest the possibility of a separate ocular source of TTR. We report the presence of TTR mRNA in rat and bovine eye and of TTR in rat eye. Preliminary immunohistochemical data indicate that the retinal pigment epithelium is a major site of TTR immunoreactivity in the rat. While the functional significance of ocular TTR synthesis is unclear, TTR may be involved in the ocular translocation and processing of retinol. The finding of TTR synthesis in the eye may explain ocular involvement in the familial amyloidotic polyneuropathies.