Kufs disease due to mutation of CLN6

clinical, pathological and molecular genetic features

Samuel F. Berkovic, Karen L. Oliver, Laura Canafoglia, Penina Krieger, John A. Damiano, Michael S. Hildebrand, Michela Morbin, Danya F. Vears, Vito Sofia, Loretta Giuliano, Barbara Garavaglia, Alessandro Simonati, Filippo M. Santorelli, Antonio Gambardella, Angelo Labate, Vincenzo Belcastro, Barbara Castellotti, Cigdem Ozkara, Adam Zeman, Julia Rankin & 11 others Sara E. Mole, Umberto Aguglia, Michael Farrell, Sulekha Rajagopalan, Alan McDougall, Susan Brammah, Frederick Andermann, Eva Andermann, Hans Henrik M. Dahl, Silvana Franceschetti, Stirling Carpenter

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Kufs disease is the major adult form of neuronal ceroid lipofuscinosis, but is rare and difficult to diagnose. Diagnosis was traditionally dependent on the demonstration of characteristic storage material, but distinction from normal age-related accumulation of lipofuscin can be challenging. Mutation of CLN6 has emerged as the most important cause of recessive Kufs disease but, remarkably, is also responsible for variant late infantile ceroid lipofuscinosis. Here we provide a detailed description of Kufs disease due to CLN6 pathogenic variants. We studied 20 cases of Kufs disease with CLN6 pathogenic variants from 13 unrelated families. Mean age of onset was 28 years (range 12-51) with bimodal peaks in teenage and early adult life. The typical presentation was of progressive myoclonus epilepsy with debilitating myoclonic seizures and relatively infrequent tonic-clonic seizures. Patients became wheelchair-bound with a mean 12 years post-onset. Ataxia was the most prominent motor feature. Dementia appeared to be an invariable accompaniment, although it could take a number of years to manifest and occasionally cognitive impairment preceded myoclonic seizures. Patients were usually highly photosensitive on EEG. MRI showed progressive cerebral and cerebellar atrophy. The median survival time was 26 years from disease onset. Ultrastructural examination of the pathology revealed fingerprint profiles as the characteristic inclusions, but they were not reliably seen in tissues other than brain. Curvilinear profiles, which are seen in the late infantile form, were not a feature. Of the 13 unrelated families we observed homozygous CLN6 pathogenic variants in four and compound heterozygous variants in nine. Compared to the variant late infantile form, there was a lower proportion of variants that predicted protein truncation. Certain heterozygous missense variants in the same amino acid position were found in both variant late infantile and Kufs disease. There was a predominance of cases from Italy and surrounding regions; this was partially explained by the discovery of three founder pathogenic variants. Clinical distinction of type A (progressive myoclonus epilepsy) and type B (dementia with motor disturbance) Kufs disease was supported by molecular diagnoses. Type A is usually caused by recessive pathogenic variants in CLN6 or dominant variants in DNAJC5. Type B Kufs is usually associated with recessive CTSF pathogenic variants. The diagnosis of Kufs remains challenging but, with the availability of genetic diagnosis, this will largely supersede the use of diagnostic biopsies, particularly as biopsies of peripheral tissues has unsatisfactory sensitivity and specificity.

Original languageEnglish
Pages (from-to)59-69
Number of pages11
JournalBrain : a journal of neurology
Volume142
Issue number1
DOIs
Publication statusPublished - Dec 15 2018

Fingerprint

Neuronal Ceroid-Lipofuscinoses
Molecular Biology
Mutation
Progressive Myoclonic Epilepsy
Seizures
Dementia
Ceroid
Biopsy
Lipofuscin
Wheelchairs
Dermatoglyphics
Ataxia
Age of Onset
Italy
Atrophy
Electroencephalography
Pathology
Amino Acids
Sensitivity and Specificity
Survival

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Berkovic, S. F., Oliver, K. L., Canafoglia, L., Krieger, P., Damiano, J. A., Hildebrand, M. S., ... Carpenter, S. (2018). Kufs disease due to mutation of CLN6: clinical, pathological and molecular genetic features. Brain : a journal of neurology, 142(1), 59-69. https://doi.org/10.1093/brain/awy297

Kufs disease due to mutation of CLN6 : clinical, pathological and molecular genetic features. / Berkovic, Samuel F.; Oliver, Karen L.; 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; Ozkara, Cigdem; Zeman, Adam; Rankin, Julia; Mole, Sara E.; Aguglia, Umberto; Farrell, Michael; Rajagopalan, Sulekha; McDougall, Alan; Brammah, Susan; Andermann, Frederick; Andermann, Eva; Dahl, Hans Henrik M.; Franceschetti, Silvana; Carpenter, Stirling.

In: Brain : a journal of neurology, Vol. 142, No. 1, 15.12.2018, p. 59-69.

Research output: Contribution to journalArticle

Berkovic, SF, Oliver, KL, Canafoglia, L, Krieger, P, Damiano, JA, Hildebrand, MS, Morbin, M, Vears, DF, Sofia, V, Giuliano, L, Garavaglia, B, Simonati, A, Santorelli, FM, Gambardella, A, Labate, A, Belcastro, V, Castellotti, B, Ozkara, C, Zeman, A, Rankin, J, Mole, SE, Aguglia, U, Farrell, M, Rajagopalan, S, McDougall, A, Brammah, S, Andermann, F, Andermann, E, Dahl, HHM, Franceschetti, S & Carpenter, S 2018, 'Kufs disease due to mutation of CLN6: clinical, pathological and molecular genetic features', Brain : a journal of neurology, vol. 142, no. 1, pp. 59-69. https://doi.org/10.1093/brain/awy297
Berkovic SF, Oliver KL, Canafoglia L, Krieger P, Damiano JA, Hildebrand MS et al. Kufs disease due to mutation of CLN6: clinical, pathological and molecular genetic features. Brain : a journal of neurology. 2018 Dec 15;142(1):59-69. https://doi.org/10.1093/brain/awy297
Berkovic, Samuel F. ; Oliver, Karen L. ; 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 ; Ozkara, Cigdem ; Zeman, Adam ; Rankin, Julia ; Mole, Sara E. ; Aguglia, Umberto ; Farrell, Michael ; Rajagopalan, Sulekha ; McDougall, Alan ; Brammah, Susan ; Andermann, Frederick ; Andermann, Eva ; Dahl, Hans Henrik M. ; Franceschetti, Silvana ; Carpenter, Stirling. / Kufs disease due to mutation of CLN6 : clinical, pathological and molecular genetic features. In: Brain : a journal of neurology. 2018 ; Vol. 142, No. 1. pp. 59-69.
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T2 - clinical, pathological and molecular genetic features

AU - Berkovic, Samuel F.

AU - Oliver, Karen L.

AU - Canafoglia, Laura

AU - Krieger, Penina

AU - Damiano, John A.

AU - Hildebrand, Michael S.

AU - Morbin, Michela

AU - Vears, Danya F.

AU - Sofia, Vito

AU - Giuliano, Loretta

AU - Garavaglia, Barbara

AU - Simonati, Alessandro

AU - Santorelli, Filippo M.

AU - Gambardella, Antonio

AU - Labate, Angelo

AU - Belcastro, Vincenzo

AU - Castellotti, Barbara

AU - Ozkara, Cigdem

AU - Zeman, Adam

AU - Rankin, Julia

AU - Mole, Sara E.

AU - Aguglia, Umberto

AU - Farrell, Michael

AU - Rajagopalan, Sulekha

AU - McDougall, Alan

AU - Brammah, Susan

AU - Andermann, Frederick

AU - Andermann, Eva

AU - Dahl, Hans Henrik M.

AU - Franceschetti, Silvana

AU - Carpenter, Stirling

PY - 2018/12/15

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N2 - Kufs disease is the major adult form of neuronal ceroid lipofuscinosis, but is rare and difficult to diagnose. Diagnosis was traditionally dependent on the demonstration of characteristic storage material, but distinction from normal age-related accumulation of lipofuscin can be challenging. Mutation of CLN6 has emerged as the most important cause of recessive Kufs disease but, remarkably, is also responsible for variant late infantile ceroid lipofuscinosis. Here we provide a detailed description of Kufs disease due to CLN6 pathogenic variants. We studied 20 cases of Kufs disease with CLN6 pathogenic variants from 13 unrelated families. Mean age of onset was 28 years (range 12-51) with bimodal peaks in teenage and early adult life. The typical presentation was of progressive myoclonus epilepsy with debilitating myoclonic seizures and relatively infrequent tonic-clonic seizures. Patients became wheelchair-bound with a mean 12 years post-onset. Ataxia was the most prominent motor feature. Dementia appeared to be an invariable accompaniment, although it could take a number of years to manifest and occasionally cognitive impairment preceded myoclonic seizures. Patients were usually highly photosensitive on EEG. MRI showed progressive cerebral and cerebellar atrophy. The median survival time was 26 years from disease onset. Ultrastructural examination of the pathology revealed fingerprint profiles as the characteristic inclusions, but they were not reliably seen in tissues other than brain. Curvilinear profiles, which are seen in the late infantile form, were not a feature. Of the 13 unrelated families we observed homozygous CLN6 pathogenic variants in four and compound heterozygous variants in nine. Compared to the variant late infantile form, there was a lower proportion of variants that predicted protein truncation. Certain heterozygous missense variants in the same amino acid position were found in both variant late infantile and Kufs disease. There was a predominance of cases from Italy and surrounding regions; this was partially explained by the discovery of three founder pathogenic variants. Clinical distinction of type A (progressive myoclonus epilepsy) and type B (dementia with motor disturbance) Kufs disease was supported by molecular diagnoses. Type A is usually caused by recessive pathogenic variants in CLN6 or dominant variants in DNAJC5. Type B Kufs is usually associated with recessive CTSF pathogenic variants. The diagnosis of Kufs remains challenging but, with the availability of genetic diagnosis, this will largely supersede the use of diagnostic biopsies, particularly as biopsies of peripheral tissues has unsatisfactory sensitivity and specificity.

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