The hidden face of Wilson's disease.

In brief, the classic form of Wilson's disease (WD) is an autosomal-recessive condition with hepatic, neurologic, psychiatric and systemic manifestations. However, the diagnosis should not be excluded because of a family history consistent with autosomal-dominant transmission. The latest next-generation sequencing (NGS) studies have demonstrated a gap between phenotype and genetic prevalences, and also suggest that WD may still be underdiagnosed. In a majority of WD patients, early recognition and appropriate treatment can result in resolution of symptoms and/or improved quality of life. Thus, finding WD in patients aged>40 years or with thrombocytopenia, hemolytic anemia, unexplained bone pain, amenorrhea, repeated spontaneous abortion or renal lithiasis is of major importance. These symptoms can all be found on their own or in association with mild-to-incapacitating neurological and/or neuropsychiatric manifestations. While brain lesions of the lenticular, midbrain and dentate nuclei are classic, white-matter changes and cortical lesions may also be observed: these are often asymmetrical with frontal lobe predilection and, when extensive, associated with a poor prognosis. These lesions are due mainly to copper deposition, but may also be related to focal accumulation of other metals, such as iron and manganese. A new biological marker called 'relative exchangeable copper' (REC) facilitates diagnosis and familial screening. Patient monitoring is important to ensure treatment adherence, efficacy and tolerability, and to detect rare complications such as copper deficiency induced by chronic copper chelation and hepatocarcinoma in patients with cirrhosis. Currently used treatments are copper chelators and zinc salts. Therapeutic perspectives are liver transplantation, new copper chelators as tetrathiomolybdate, hepatocyte/tissue transfer and gene therapy.

Accumulation of flotillin-1 in tangle-bearing neurones of Alzheimer's disease.

The protein flotillin-1 is associated with the 'lipid rafts', that is, membrane microdomains that are enriched in cholesterol and sphingolipids. We compared flotillin-1 immunoreactivity in the hippocampus, amygdala and isocortex (Brodmann area 22) of six controls and 13 Alzheimer's disease (AD) cases (10 sporadic and three familial). A diffuse labelling of the neuropil was observed in most of the samples. The intensity of this labelling was not correlated with the density of neurofibrillary tangles (NFT) or of senile plaques. Some neuronal cell bodies were diffusely labelled in patients as in controls. Immunostained granular bodies were found in the cell body of a few neurones. The density of neuronal profiles containing large granular bodies (diameter > or =2 microm) was significantly higher in AD cases and was correlated with the density of NFTs in the three regions that were studied. Sections stained by double immunofluorescence methods and examined with confocal microscopy suggested that flotillin-1 accumulated most often in tangle-bearing neurones (76% of flotillin-1-positive neurones contained a NFT). Flotillin-1 immunoreactivity, even when found in a tangle-bearing neurone, was not colocalized with tau protein indicating that the two proteins were not in close contact and probably in different subcellular compartments. Flotillin-1-positive granular bodies were also found in neurones containing Pin1-positive vesicles but were not colocalized with them. Flotillin-1 immunoreactivity was colocalized with cathepsin D, a lysosomal marker. These data indicate that flotillin-1, a marker of rafts, accumulates in lysosomes of tangle-bearing neurones in the course of AD.