Clinical and genetic studies of families with the tau N279K mutation (FTDP-17).

The tau N279K mutation was identified in four separately ascertained families in the United States, Japan, and France and in another recently discovered affected individual in Japan. The authors analyzed genealogical and clinical records and DNA samples. Average age at onset was 43 years; survival time was 7 years. All families exhibited similar clinical features, with parkinsonism, dementia, and supranuclear palsy uniformly seen. A founder effect indicated by a shared disease haplotype was seen only in two Japanese families. The N279K mutation can develop independently in different parts of the world.

[Migraine and the idiopathic Raynaud phenomenon]. / Migraine et phénomène de Raynaud idiopathique.

The successive onset of spasms of distal arteries of the limbs and complicated migraine in a young migrainous woman raised the possibility of a common mechanism for both disorders. Three similar cases have been reported and two recent epidemiological studies have shown the frequent association of migraine attacks and Raynaud's phenomenon or variant angina in a individual patient. The possible role of vasospasm in triggering the migrainous aura is discussed.

[Recurrent cerebral ischaemic attacks in young subjects. Arteriolar dysplasia or early atheroma?]. / Accidents ischémiques cérébraux successifs chez le sujet jeune. Dysplasie artériolaire, athérome précoce?

The case of a 33-year old woman with recurrent cerebral and peripheral ischaemic attacks is reported and the difficult nosological problem of juvenile ischaemia is discussed. Thromboangiitis obliterans (Buerger's disease) was excluded by morphological studies of finger tips, temporal artery and dermis, which demonstrated arteriolar dysplasia and premature aging of the connective tissue. A diagnosis of "juvenile atheroma" may be considered in view of the dyslipidaemia and increase in skin cholesterol and apoprotein B concentrations observed. A review of the literature, together with the biochemical and histological findings in this patient, suggests that ischaemic attacks, dysplasia of small vessels and serum dyslipidaemia reflected in the dermis are all manifestations of early atheroma.

A mutation at codon 279 (N279K) in exon 10 of the Tau gene causes a tauopathy with dementia and supranuclear palsy.

Recently intronic and exonic mutations in the Tau gene have been found to be associated with familial neurodegenerative syndromes characterized not only by a predominantly frontotemporal dementia but also by the presence of neurological signs consistent with the dysfunction of multiple subcortical neuronal circuitries. Among families, the symptomatology appears to vary in quality and severity in relation to the specific Tau gene mutation and often may include parkinsonism, supranuclear palsies, and/or myoclonus, in addition to dementia. We carried out molecular genetic and neuropathological studies on two patients from a French family presenting, early in their fifth decade, a cognitive impairment and supranuclear palsy followed by an akinetic rigid syndrome and dementia. The proband died severely demented 7 years after the onset of the symptoms; currently, his brother is still alive although his disease is progressing. In both patients, we found a Tau gene mutation in exon 10 at codon 279, resulting in an asparagine to lysine substitution (N279K). Neuropathologically, widespread neuronal and glial tau accumulation in the cortex, basal ganglia, brain stem nuclei as well as in the white matter were the hallmark of the disease. These deposits were shown by immunohistochemistry and immunoelectron microscopy, using a battery of antibodies to phosphorylation-dependent and phosphorylation-independent epitopes present in multiple tau regions. In the neocortex, tau-immunopositive glial cells were more numerous than immunopositive neurons; the deeper cortical layers as well as the white matter adjacent to the cortex contained the largest amount of immunolabeled glial cells. In contrast, some brain stem nuclei contained more neurons with tau deposits than immunolabeled glial cells. The correlation of clinical, neuropathological and molecular genetic findings emphasize the phenotypic heterogeneity of diseases caused by Tau gene mutations. Furthermore, to test the effect of the N279K mutation and compare it with the effect of the P301L exon 10 mutation on alternative splicing of Tau exon 10, we used an exon amplification assay. Our results suggest that the N279K mutation affects splicing similar to the intronic mutations, allowing exon 10 to be incorporated more frequently in the Tau transcript.