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Evidence for Cholinergic Dysfunction in Autosomal Dominant Kufs Disease

  • Pamela Jarrett (a1), Alexander Easton (a2), Kenneth Rockwood (a3), Sarah Dyack (a4), Alexander McCollum (a1), Victoria Siu (a5), Seyed M. Mirsattari (a6) (a7) (a8) (a9), Andreu Massot-Tarrús (a5), M. Jill Beis (a4), Nolan D’Souza (a5) and Sultan Darvesh (a3) (a10)...

Abstract

Objective: Neuronal ceroid-lipofuscinoses are a heterogeneous group of inherited disorders in which abnormal lipopigments form lysosomal inclusion bodies in neurons. Kufs disease is rare, and clinical symptoms include seizures, progressive cognitive impairment, and myoclonus. Most cases of Kufs disease are autosomal recessive; however, there have been a few case reports of an autosomal dominant form linked to mutations within the DNAJC5 gene. Methods: We describe a family with Kufs disease in which the proband and three of her four children presented with cognitive impairment, seizures, and myoclonus. Results: Genetic testing of all four children was positive for a c.346_348delCTC(p.L116del) mutation in the DNAJC5 gene. The proband brain had an abundance of neuronal lipofuscin in the cerebral cortex, striatum, amygdala, hippocampus, substantia nigra, and cerebellum. There were no amyloid plaques or neurofibrillary tangles. Immunohistochemistry demonstrated that the cholinergic neurons and cholinergic projection fibers were spared, but there was a profound loss of choline acetyltransferase within the caudate, putamen, and basal forebrain. This suggests a loss of choline acetyltransferase as opposed to a loss of the neurons. Conclusions: This report describes the clinical history of autosomal dominant Kufs disease, the genetic mutation within the DNAJC5 gene, and the neuropathological findings demonstrating depletion of choline acetyltransferase in the brain.

Manifestation d’un dysfonctionnement cholinergique dans la forme autosomique dominante de la maladie de Kufs. Objectif: Les céroïdes-lipofuscinoses neuronales constituent un groupe hétérogène de maladies héréditaires en vertu desquelles des lipofuscines anormales forment des inclusions lysosomales dans les neurones. La maladie de Kufs, elle, demeure inhabituelle. Ses signes cliniques incluent des convulsions, une détérioration cognitive progressive et la myoclonie. La plupart des cas de maladie de Kufs sont autosomiques récessifs. Cela dit, quelques études de cas ont rapporté l’existence d’une forme dominante autosomique liée à des mutations sur le gène DNAJC5. Méthodes: Nous voulons décrire ici une famille atteinte de la maladie de Kufs, famille au sein de laquelle le proposant et trois de ses quatre enfants ont donné à voir une détérioration cognitive, des convulsions et des signes de myoclonie. Résultats: Le dépistage génétique des quatre enfants s’est révélé positif en ce qui regarde la mutation suivante sur le gène DNAJC5 : c.346_348delCTC (p.L116del). Le cerveau du proposant montrait aussi une abondance de lipofuscines neuronales anormales dans le cortex cérébral, le striatum, l’amygdale, l’hippocampe, la substance noire (substantia nigra) et le cervelet. Aucune neuro-dégénérescence neuro-fibrillaire, aucune plaque amyloïde n’a par ailleurs été détectée. Des analyses d’immunocytochimie ont démontré que des neurones cholinergiques, de même que leurs projections, avaient été épargnés ; cela dit, on a pu observer une grande perte de choline acétyltransférase (ChAT) au sein du noyau caudé, du putamen et de la base du prosencéphale. Tout cela suggère donc une perte de ChAT et non une perte de neurones. Conclusions: Cette étude a décrit les antécédents cliniques liés à un cas de forme autosomique dominante de la maladie de Kufs. Elle s’est penchée sur des mutations génétiques affectant le gène DNAJC5 et sur des résultats neuro-pathologiques attestant la diminution de la ChAT dans le cerveau.

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Copyright

Corresponding author

Correspondence to: Pamela Jarrett, Department of Geriatric Medicine, St. Joseph’s Hospital, Horizon Health Network, 130 Bayard Drive, Saint John, NB E2L 3L6, Canada. E-mail: Pam.Jarrett@HorizonNB.ca

References

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