Démence fronto-temporale familiale avec inclusions marquées par l’anti-ubiquitine dans le tronc cérébral

Abstract

Les démences fronto-temporales (DFT) forment un groupe hétérogène. Nous avons étudié une famille dont la mère et quatre enfants étaient atteints de DFT d’expression clinique typique, avec début précoce, avant 40 ans, par des troubles de la personnalité, et évolution prolongée, environ 30 ans, avec longue conservation de l’orientation spatiale, sans signe d’atteinte du motoneurone ni signes extrapyramidaux. L’étude neuropathologique d’un cas montra une atrophie massive prédominant au niveau des lobes frontaux. Dans les zones atrophiques, il existait une perte neuronale et un aspect spongieux des couches superficielles. Il n’y avait pas d’inclusion argentophile « de Pick », mais des inclusions marquées par l’anti-ubiquitine, mais non par l’anti-Tau, dans le fascia dentata. Dans le cytoplasme de certains neurones, dans les couches profondes du cortex mais surtout dans le tronc cérébral (réticulée magnocellulaire, noyaux du pont, noyaux moteurs, particulièrement noyau masticateur), de grandes inclusions argentophiles ovoïdes ou réniformes, peu denses, marquées seulement par l’anti-ubiquitine étaient observées. L’étude génétique mettait en évidence un Lod score positif non significatif avec des marqueurs flanquant le gène MAPτ, en l’absence de mutation décelable de ce gène. L’étude biochimique de la protéine Tau ne montrait pas d’anomalie qualitative. L’affection transmise dans la famille que nous avons étudiée paraît distincte aussi bien des DFT associées à une sclérose latérale amyotrophique (SLA) que des « taupathies ». Fronto-temporal dementias (FTD) were described a century ago on the macroscopic basis of frontal and/or temporal lobe atrophy. Progress in neuropathology, immunohistochemistry, biochemistry and genetics has since shown that they are heterogeneous entities, encompassing many different diseases with similar clinical presentations. A few, such as tauopathies due to mutations of the gene coding for tau protein (MAPτ form a well-defined group. Definition and grouping of other types of FTD is still problematic. We studied a family where the mother and 4/8 children were affected with FTD. Clinical presentation was typical of FTD. Onset was ill-defined with early (at age 40 years or less) personality changes. The clinical course was protracted (about 30 years). For a long period, the patients were able to live in the community in spite of obvious signs such as hyperorality and loss of verbal initiative; operative orientation as to place was preserved for a long time: a mute patient was still able to drive. Signs of extrapyramidal or motoneuron involvement were not observed. The genetic study failed to detect any mutation in MAPτ; the lod score for flanking markers was positive but not significant. Biochemical study showed no qualitative abnormality in tau protein. Neuropathological study of one affected subject showed brain atrophy (962g), with elective frontal lobe involvement. Cortical nerve cell loss was more marked in superficial layers and in frontal areas; glia was inconspicuous; pseudolaminar spongiosis was present in the more severely affected zones. No argentophilic “Pick bodies“ were seen; ubiquitin-positive, tau-negative round inclusions were present in the cytoplasm of fascia dentata neurones. “Tangles“ were mostly restricted to the entorhinal cortex, partly correlated with tau immunoreactivity, but better with ubiquitin immunoreactivity. Large, ovoid or reniform, moderately dense, spongy, granular or filamentous argentophilic cytoplasmic nerve cell inclusions were observed. They were ubiquitin-positive, but did not react with other antibodies, particularly anti-tau. They were present in swollen nerve cells in the deeper cortical layers but were most conspicuous in the brain stem: in the magnocellular reticular nuclei (e.g. nucleus centralis pontis ), in the pes pontis , in the inferior olive and in motor nuclei, especially in the trigeminal motor nucleus. They were not associated with nerve cell loss, atrophy nor pycnosis. Cerebellar relay nuclei neurones were swollen, and their cytoplasm contained argentophilic filaments. In our opinion, “ubiquitinopathy” would be non-specific and “Motor Neuron Disease-Inclusion Dementia” (MNDID) would not be satisfactory as a diagnosis for the present cases of FTD. Hopefully, progress in genetics may allow a causal, and thence definitive, classification.