Kufs disease due to mutation of<i>CLN6</i>: clinical, pathological and molecular genetic features

Berkovic, Samuel F.; Oliver, Karen; Canafoglia, Laura; Krieger, Penina; Damiano, John A.; Hildebrand, Michael S.; Morbin, Michela; Vears, Danya F.; Sofia, Vito; Giuliano, Loretta; Garavaglia, Barbara; Simonati, Alessandro; Santorelli, Filippo M.; Gambardella, Antonio; Labate, Angelo; Belcastro, Vincenzo; Castellotti, Barbara; Özkara, Çiğdem; Zeman, Adam; Rankin, Julia; Mole, Sara; Aguglia, Umberto; Farrell, Michael; Rajagopalan, Sulekha; McDougall, Alan; Brammah, Susan; Andermann, Frédérick; Andermann, Eva; Dahl, Hans Henrik M.; Franceschetti, Silvana; Carpenter, Stirling

doi:10.1093/brain/awy297

Cited by 34 publications

(28 citation statements)

References 42 publications

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“…Psychosis is extremely rare in conditions that feature myoclonus as a predominant, or long‐standing, clinical manifestation (myoclonus related to multisystemic general medical conditions, such as anti–N‐methyl‐D‐aspartate receptor encephalitis, has been excluded from this review). Psychosis has been reported in myoclonus‐dystonia attributed to heterozygous mutations or deletions in the epsilon‐sarcoglycan gene (MYC/DYT‐SGCE), in patients with myoclonic epilepsy of Lafora (MYC/ATX‐EPM2A and MYC/ATX‐NHLRC1), in which prolonged complex visual hallucinations are mostly of epileptic origin and may respond to antiepileptic drugs, rather than antipsychotics, and in some types of neuronal ceroid‐lipofuscinoses (NCLs) with myoclonus as a prominent and consistent associated movement disorder (MYC‐CLN6, MYC‐DNAJC5, MYC‐CLN3, and MYC/ATX‐KCTD7) . NCLs presents with psychosis in up to 20% of patients, although some of them combine psychosis with myoclonus or myoclonic epilepsy .…”

Section: Resultsmentioning

confidence: 99%

“…148 Delusions, as well as visual and auditory hallucinations, have been reported. [149][150][151] The association of psychosis with dementia is common, 147,149,152 and a propensity toward neuroleptic malignant syndrome has been reported. 153,154 Tremor Psychosis is absent in disorders that include tremor as a predominant or frequent clinical manifestation in the absence of other signs of parkinsonism.…”

Section: Myoclonusmentioning

confidence: 99%

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Nosology and Phenomenology of Psychosis in Movement Disorders

Rossi

Farcy

Starkstein

et al. 2020

Movement Disord Clin Pract

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Background Background: Psychotic symptoms, such as delusions and hallucinations, are part of the clinical picture of several conditions presenting movement disorders. Phenomenology and epidemiology of psychosis in Parkinson's disease have received wide attention; however, the presence of psychosis in other movement disorders is, comparatively, less well known. Objectives Objectives: To review psychotic symptoms present in different movement disorders. Methods Methods: A comprehensive and structured literature search was performed to identify and analyze data on patients with movement disorders and comorbid psychosis.

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Section: Resultsmentioning

confidence: 99%

Section: Myoclonusmentioning

confidence: 99%

Nosology and Phenomenology of Psychosis in Movement Disorders

Rossi

Farcy

Starkstein

et al. 2020

Movement Disord Clin Pract

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“…Kufs disease secondary to CLN6 mutation typically manifests with myoclonic and, to a lesser extent, tonic–clonic seizures in the third decade, with bimodal peaks in teenage and early adult life. Motor function and cognition progressively deteriorate, with patients becoming wheelchair-bound approximately 12 years after symptom onset [ 6 ]. Cortical myoclonus is a universal feature, manifesting early in the course of disease and progressing to become the prominent disabling feature and causing severe motor impairment.…”

Section: Discussionmentioning

confidence: 99%

“…Dementia is widely considered to be a universal feature of Kufs disease, however, exceptions do exist in the literature. One case series of 20 patients with CLN6 -related Kufs disease included 2 patients without evidence of cognitive impairment 7 and 20 years after disease onset [ 6 ]. These were Turkish siblings of consanguineous heritage, who developed generalised seizures at 18 and 26 years of age, respectively, and carried homozygous mutations of CLN6 (c.509A > G, p.Tyr170Cys) [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

Moyamoya and progressive myoclonic epilepsy secondary to CLN6 bi-allelic mutations – A previously unreported association

Talbot

Singh

Puvirajasinghe

et al. 2020

Epilepsy & Behavior Reports

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The neuronal ceroid lipofuscinoses (NCL) are a collection of lysosomal storage diseases characterised by the accumulation of characteristic inclusions containing lipofuscin in various tissues of the body and are one of the causes of progressive myoclonic epilepsy. Mutations in at least thirteen genes have been identified as causes of NCL, which can present as infantile, late-infantile, juvenile or adult forms. CLN6 codes for an endoplasmic reticulum transmembrane protein of unknown function. Homozygous and compound heterozygous mutations of the gene are associated with both late-infantile (LINCL) and adult onset (ANCL) forms of NCL, including Kufs disease, comprising ANCL without associated visual loss. Moyamoya, a rare vasculopathy of the circle of Willis, has been reported in conjunction with a number of inflammatory and other diseases, as well as a handful of lysosomal storage diseases. To our knowledge, this is the first reported case of Moyamoya in the context of the neuronal ceroid lipofuscinoses or a CLN6 -related disease.

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“…Patients with CLN6 generally begin to exhibit symptoms before the age of 40 (mean age 28). Clinical manifestations of disease first present as myoclonus epilepsy, followed by ataxia and dementia due to cerebral and cerebellar atrophy (Berkovic et al, 2019). A neuronal ceroid lipofuscinosis (Nclf ) murine model was established by a one base pair insertion in the orthologous mouse Cln6 gene resulting in a frame shift defect that recapitulates many aspects of the disease such as Wallerian degeneration and paralysis (Bronson et al, 1998).…”

Section: Neuronal Ceroid-lipofuscinosesmentioning

confidence: 99%

Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases

Favret

Weinstock

Feltri

et al. 2020

Front. Mol. Biosci.

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There are over 50 lysosomal hydrolase deficiencies, many of which cause neurodegeneration, cognitive decline and death. In recent years, a number of broad innovative therapies have been proposed and investigated for lysosomal storage diseases (LSDs), such as enzyme replacement, substrate reduction, pharmacologic chaperones, stem cell transplantation, and various forms of gene therapy. Murine models that accurately reflect the phenotypes observed in human LSDs are critical for the development, assessment and implementation of novel translational therapies. The goal of this review is to summarize the neurodegenerative murine LSD models available that recapitulate human disease, and the pre-clinical studies previously conducted. We also describe some limitations and difficulties in working with mouse models of neurodegenerative LSDs.

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Kufs disease due to mutation ofCLN6: clinical, pathological and molecular genetic features

Cited by 34 publications

References 42 publications

Nosology and Phenomenology of Psychosis in Movement Disorders

Nosology and Phenomenology of Psychosis in Movement Disorders

Moyamoya and progressive myoclonic epilepsy secondary to CLN6 bi-allelic mutations – A previously unreported association

Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases

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