Familial amyloid polyneuropathy with substitution of methionine for valine at position 30 in the TTR gene is the most common type of hereditary transthyretin amyloidosis. Although several authors have previously reported a size-dependent fiber loss, predominantly involving unmyelinated and small diameter myelinated fibers, the mechanisms of nerve fiber loss have not been fully understood. In this study we establish the morphometric pattern of peripheral neuropathy in familial amyloid polyneuropathy patients and asymptomatic mutation carriers in the biopsies from our archive and correlated the pathological findings with clinical features. Ninety-eight patients with familial amyloid polyneuropathy and thirty-seven asymptomatic mutation carriers (TTR Val30Met mutation), aged between 17 and 84 years, that underwent sural nerve biopsy between 1981 and 2017 at Centro Hospitalar Universitário do Porto were studied. Thirty-one controls were included for comparison. The median age at nerve biopsy was 26.0 [(interquartile range = 23.5-39.5] years for asymptomatic mutation carriers, 45.0 [35.0-60.0] years for familial amyloid polyneuropathy patients and 44.0 [30.0-63.0] years for controls. The median duration between nerve biopsy and symptoms onset was 7.0 [3.3-11.8] years (range: 1 to 27 years) in the asymptomatic carriers. Most patients were in an earlier disease stage (93% with a polyneuropathy disability scale ≤ 2). Patients had loss of small and myelinated fibers compared to both asymptomatic carriers and controls (p<0.001), whereas asymptomatic carriers showed loss of small myelinated fibers when compared to controls (p<0.05). The loss of myelinated fibers increased with disease progression (p<0.001), and patients in more advanced clinical stage showed more frequent amyloid deposition in the nerve (p=0.001). There was a positive correlation between large myelinated fiber density and time to symptoms onset in the asymptomatic carriers that developed early-onset form of the disease (r = 0.52, p<0.01). Additionally, asymptomatic carriers with amyloid deposition already present in sural nerve biopsies developed symptoms earlier than those with no amyloid (p<0.01). In conclusion, this study confirms that small fiber size loss is an initial event in familial amyloid polyneuropathy, already present in asymptomatic gene carriers, starting several years before symptoms onset. We show for the first time that large myelinated fibers loss and amyloid deposition are pathological features that correlate independently with short period to symptoms onset for asymptomatic carriers that developed early-onset form of the disease. These findings are therapeutically relevant, as it would allow for a better interpretation of the role of disease-modifying agents in transthyretin familial amyloid polyneuropathy.

Hereditary transthyretin amyloidosis (ATTRv) is a systemic disease caused by the accumulation of misfolded transthyretin (TTR). It usually presents with an adult-onset progressive axonal peripheral neuropathy and cardiomyopathy. In the central nervous system (CNS), variant TTR is produced by the choroid plexus and accumulates in the leptomeninges. CNS symptoms have been increasingly recognized in this population, including transient focal neurological episodes and stroke, particularly in patients with the V30M mutation and longstanding disease. The prevalence, pathophysiology, and progression of CNS involvement remain to be clarified. The present work explores if there is a recognizable sequence of CNS TTR deposition in ATTRv. We studied the topographical and severity distribution of TTR deposition in 16 patients with ATTRv, aged 27–69 years and with a mean disease duration of 10.9 years (range: 3–29). Our results suggest that CNS pathological involvement in V30M ATTRv occurs early in the disease course, probably starting in pre-symptomatic phases, and follows a distinct sequence. Leptomeninges and subarachnoid meningeal vessels are affected earlier, then followed by perforating cortical vessels and subpial deposition, and finally by deposition in the subependymal and basal ganglia vessels near the ependymal lining. Brainstem and spinal cord show early and severe involvement, with amyloid subpial deposition already seen in initial stages. Despite massive superficial amyloid deposition, no parenchymal deposition outside subpial or subependymal regions was found. Additionally, vascular lesions or superficial cortical siderosis were not frequent. Future studies with more patients from different populations and TTR mutations will be important to confirm these findings. Defining stages of TTR pathology in the CNS may be useful to better understand pathogenic mechanisms leading to symptoms and to interpret neuroimaging biomarkers.

Teratomas of the middle ear are rare neoplasms. Only a few examples have been reported. As a rule, they are cured by resection and do not require adjuvant therapy.

Uncombable hair syndrome is a rare disorder of the hair shaft that leads to silvery and unruly hair. The hair shaft anomaly is characterized by a longitudinal groove that is detected by scanning electronic microscopy-considered to be the gold standard for diagnosis. Recently, hair cross-sectioning has been reported as a viable alternative, but currently available methods still have some flaws, especially because of hair samples' processing specificities. Here, we present two cases of uncombable hair syndrome and a new embedding technique using epoxy to perform the diagnosis.

The gill of Aplysia depilans consists of several wedge-shaped pinnules with a highly folded structure, differing from the typical ctenidial gills of mollusks. Light microscopy and transmission electron microscopy were used to investigate this organ in juveniles and adults. In this species, the gill epithelium comprised ciliated, unciliated, and secretory cells. The ultrastructural analysis suggests other functions for the gill besides respiration. The deep cell membrane invaginations associated with mitochondria in the basal region of epithelium point to a role in ion regulation.Endocytosis and intracellular digestion were other activities detected in epithelial cells. In juveniles, an intranuclear crystalline structure was seen in some ciliated cells.The presence of an intranuclear crystalline structure was frequently associated with chromatin decondensation, swelling of the nuclear envelope and endoplasmic reticulum cisternae, and abundance of Golgi stacks. As these intranuclear inclusions were not found in the gill of the adult specimens, their occurrence in the two juveniles seems likely to be an anomalous condition whose cause cannot be established at the moment. Mucous cells were the most abundant secretory cells in the epithelium, but a few epithelial serous cells were also found. In addition, large protein-secreting subepithelial cells had the main cell body inserted in the connective tissue and a long thin neck crossing the epithelium. Mucous cells can be considered responsible for the production of the mucus layer that protects the epithelium, but the specific functions of the epithelial and subepithelial proteinsecreting cells remain elusive. Below the epithelium, a layer of connective tissue with muscle cells lined the narrow hemolymph space. The connective tissue included cells with a large amount of rough endoplasmic reticulum cisternae. Bacteria were found on the surface of the gill, and the most abundant had a thin stalk for attachment to the epithelial cells.