Mutated CTSF in adult-onset neuronal ceroid lipofuscinosis and FTD.
OBJECTIVE
To investigate the molecular basis of a Belgian family with autosomal recessive adult-onset neuronal ceroid lipofuscinosis (ANCL or Kufs disease [KD]) with pronounced frontal lobe involvement and to expand the findings to a cohort of unrelated Belgian patients with frontotemporal dementia (FTD).


METHODS
Genetic screening in the ANCL family and FTD cohort (n = 461) was performed using exome sequencing and targeted massive parallel resequencing.


RESULTS
We identified a homozygous mutation (p.Ile404Thr) in the Cathepsin F (CTSF) gene cosegregating in the ANCL family. No other mutations were found that could explain the disease in this family. All 4 affected sibs developed motor symptoms and early-onset dementia with prominent frontal features. Two of them evolved to akinetic mutism. Disease presentation showed marked phenotypic variation with the onset ranging from 26 to 50 years. Myoclonic epilepsy in one of the sibs was suggestive for KD type A, while epilepsy was not present in the other sibs who presented with clinical features of KD type B. In a Belgian cohort of unrelated patients with FTD, the same heterozygous p.Arg245His mutation was identified in 2 patients who shared a common haplotype.


CONCLUSIONS
A homozygous CTSF mutation was identified in a recessive ANCL pedigree. In contrast to the previous associations of CTSF with KD type B, our findings suggest that CTSF genetic testing should also be considered in patients with KD type A as well as in early-onset dementia with prominent frontal lobe and motor symptoms.
Neurodegenerative Brain Diseases Group (J.v.d.Z., S.V.M., L.D., F.P., A.S., C.V.B.), Department of Molecular Genetics, VIB, Antwerp; Institute Born-Bunge (J.v.d.Z., S.V.M., L.D., F.P., S.E., C.C.-D.G., A.S., P.C., J.-J.M., C.V.B.), CLIPS, Computational Linguistics and Psycholinguistics (J. Verhoeven), University of Antwerp; Department of Neurology and Memory Clinic (P.M., R.C., S.V.M., S.E.), ZNA Middelheim and Hoge Beuken, Antwerp; Clinical and Experimental Neurolinguistics (P.M., T.D.), Vrije Universiteit Brussel, Belgium; Department of Language and Communication Science (J. Verhoeven), City University, London, UK; Department of Neurology (A.S.), University Hospital Ghent and University of Ghent; Department of Neurology (S.V.M., P.C.), Antwerp University Hospital; and Department of Neurology (J. Versijpt), University Hospital Brussels, Belgium.
Julie
J
van der Zee
Neurodegenerative Brain Diseases Group (J.v.d.Z., S.V.M., L.D., F.P., A.S., C.V.B.), Department of Molecular Genetics, VIB, Antwerp; Institute Born-Bunge (J.v.d.Z., S.V.M., L.D., F.P., S.E., C.C.-D.G., A.S., P.C., J.-J.M., C.V.B.), CLIPS, Computational Linguistics and Psycholinguistics (J. Verhoeven), University of Antwerp; Department of Neurology and Memory Clinic (P.M., R.C., S.V.M., S.E.), ZNA Middelheim and Hoge Beuken, Antwerp; Clinical and Experimental Neurolinguistics (P.M., T.D.), Vrije Universiteit Brussel, Belgium; Department of Language and Communication Science (J. Verhoeven), City University, London, UK; Department of Neurology (A.S.), University Hospital Ghent and University of Ghent; Department of Neurology (S.V.M., P.C.), Antwerp University Hospital; and Department of Neurology (J. Versijpt), University Hospital Brussels, Belgium.
Peter
P
Mariën
Neurodegenerative Brain Diseases Group (J.v.d.Z., S.V.M., L.D., F.P., A.S., C.V.B.), Department of Molecular Genetics, VIB, Antwerp; Institute Born-Bunge (J.v.d.Z., S.V.M., L.D., F.P., S.E., C.C.-D.G., A.S., P.C., J.-J.M., C.V.B.), CLIPS, Computational Linguistics and Psycholinguistics (J. Verhoeven), University of Antwerp; Department of Neurology and Memory Clinic (P.M., R.C., S.V.M., S.E.), ZNA Middelheim and Hoge Beuken, Antwerp; Clinical and Experimental Neurolinguistics (P.M., T.D.), Vrije Universiteit Brussel, Belgium; Department of Language and Communication Science (J. Verhoeven), City University, London, UK; Department of Neurology (A.S.), University Hospital Ghent and University of Ghent; Department of Neurology (S.V.M., P.C.), Antwerp University Hospital; and Department of Neurology (J. Versijpt), University Hospital Brussels, Belgium.
Roeland
R
Crols
Neurodegenerative Brain Diseases Group (J.v.d.Z., S.V.M., L.D., F.P., A.S., C.V.B.), Department of Molecular Genetics, VIB, Antwerp; Institute Born-Bunge (J.v.d.Z., S.V.M., L.D., F.P., S.E., C.C.-D.G., A.S., P.C., J.-J.M., C.V.B.), CLIPS, Computational Linguistics and Psycholinguistics (J. Verhoeven), University of Antwerp; Department of Neurology and Memory Clinic (P.M., R.C., S.V.M., S.E.), ZNA Middelheim and Hoge Beuken, Antwerp; Clinical and Experimental Neurolinguistics (P.M., T.D.), Vrije Universiteit Brussel, Belgium; Department of Language and Communication Science (J. Verhoeven), City University, London, UK; Department of Neurology (A.S.), University Hospital Ghent and University of Ghent; Department of Neurology (S.V.M., P.C.), Antwerp University Hospital; and Department of Neurology (J. Versijpt), University Hospital Brussels, Belgium.
Sara
S
Van Mossevelde
Neurodegenerative Brain Diseases Group (J.v.d.Z., S.V.M., L.D., F.P., A.S., C.V.B.), Department of Molecular Genetics, VIB, Antwerp; Institute Born-Bunge (J.v.d.Z., S.V.M., L.D., F.P., S.E., C.C.-D.G., A.S., P.C., J.-J.M., C.V.B.), CLIPS, Computational Linguistics and Psycholinguistics (J. Verhoeven), University of Antwerp; Department of Neurology and Memory Clinic (P.M., R.C., S.V.M., S.E.), ZNA Middelheim and Hoge Beuken, Antwerp; Clinical and Experimental Neurolinguistics (P.M., T.D.), Vrije Universiteit Brussel, Belgium; Department of Language and Communication Science (J. Verhoeven), City University, London, UK; Department of Neurology (A.S.), University Hospital Ghent and University of Ghent; Department of Neurology (S.V.M., P.C.), Antwerp University Hospital; and Department of Neurology (J. Versijpt), University Hospital Brussels, Belgium.
Lubina
L
Dillen
Neurodegenerative Brain Diseases Group (J.v.d.Z., S.V.M., L.D., F.P., A.S., C.V.B.), Department of Molecular Genetics, VIB, Antwerp; Institute Born-Bunge (J.v.d.Z., S.V.M., L.D., F.P., S.E., C.C.-D.G., A.S., P.C., J.-J.M., C.V.B.), CLIPS, Computational Linguistics and Psycholinguistics (J. Verhoeven), University of Antwerp; Department of Neurology and Memory Clinic (P.M., R.C., S.V.M., S.E.), ZNA Middelheim and Hoge Beuken, Antwerp; Clinical and Experimental Neurolinguistics (P.M., T.D.), Vrije Universiteit Brussel, Belgium; Department of Language and Communication Science (J. Verhoeven), City University, London, UK; Department of Neurology (A.S.), University Hospital Ghent and University of Ghent; Department of Neurology (S.V.M., P.C.), Antwerp University Hospital; and Department of Neurology (J. Versijpt), University Hospital Brussels, Belgium.
Federica
F
Perrone
Neurodegenerative Brain Diseases Group (J.v.d.Z., S.V.M., L.D., F.P., A.S., C.V.B.), Department of Molecular Genetics, VIB, Antwerp; Institute Born-Bunge (J.v.d.Z., S.V.M., L.D., F.P., S.E., C.C.-D.G., A.S., P.C., J.-J.M., C.V.B.), CLIPS, Computational Linguistics and Psycholinguistics (J. Verhoeven), University of Antwerp; Department of Neurology and Memory Clinic (P.M., R.C., S.V.M., S.E.), ZNA Middelheim and Hoge Beuken, Antwerp; Clinical and Experimental Neurolinguistics (P.M., T.D.), Vrije Universiteit Brussel, Belgium; Department of Language and Communication Science (J. Verhoeven), City University, London, UK; Department of Neurology (A.S.), University Hospital Ghent and University of Ghent; Department of Neurology (S.V.M., P.C.), Antwerp University Hospital; and Department of Neurology (J. Versijpt), University Hospital Brussels, Belgium.
Sebastiaan
S
Engelborghs
Neurodegenerative Brain Diseases Group (J.v.d.Z., S.V.M., L.D., F.P., A.S., C.V.B.), Department of Molecular Genetics, VIB, Antwerp; Institute Born-Bunge (J.v.d.Z., S.V.M., L.D., F.P., S.E., C.C.-D.G., A.S., P.C., J.-J.M., C.V.B.), CLIPS, Computational Linguistics and Psycholinguistics (J. Verhoeven), University of Antwerp; Department of Neurology and Memory Clinic (P.M., R.C., S.V.M., S.E.), ZNA Middelheim and Hoge Beuken, Antwerp; Clinical and Experimental Neurolinguistics (P.M., T.D.), Vrije Universiteit Brussel, Belgium; Department of Language and Communication Science (J. Verhoeven), City University, London, UK; Department of Neurology (A.S.), University Hospital Ghent and University of Ghent; Department of Neurology (S.V.M., P.C.), Antwerp University Hospital; and Department of Neurology (J. Versijpt), University Hospital Brussels, Belgium.
Jo
J
Verhoeven
Neurodegenerative Brain Diseases Group (J.v.d.Z., S.V.M., L.D., F.P., A.S., C.V.B.), Department of Molecular Genetics, VIB, Antwerp; Institute Born-Bunge (J.v.d.Z., S.V.M., L.D., F.P., S.E., C.C.-D.G., A.S., P.C., J.-J.M., C.V.B.), CLIPS, Computational Linguistics and Psycholinguistics (J. Verhoeven), University of Antwerp; Department of Neurology and Memory Clinic (P.M., R.C., S.V.M., S.E.), ZNA Middelheim and Hoge Beuken, Antwerp; Clinical and Experimental Neurolinguistics (P.M., T.D.), Vrije Universiteit Brussel, Belgium; Department of Language and Communication Science (J. Verhoeven), City University, London, UK; Department of Neurology (A.S.), University Hospital Ghent and University of Ghent; Department of Neurology (S.V.M., P.C.), Antwerp University Hospital; and Department of Neurology (J. Versijpt), University Hospital Brussels, Belgium.
Tine
T
D'aes
Neurodegenerative Brain Diseases Group (J.v.d.Z., S.V.M., L.D., F.P., A.S., C.V.B.), Department of Molecular Genetics, VIB, Antwerp; Institute Born-Bunge (J.v.d.Z., S.V.M., L.D., F.P., S.E., C.C.-D.G., A.S., P.C., J.-J.M., C.V.B.), CLIPS, Computational Linguistics and Psycholinguistics (J. Verhoeven), University of Antwerp; Department of Neurology and Memory Clinic (P.M., R.C., S.V.M., S.E.), ZNA Middelheim and Hoge Beuken, Antwerp; Clinical and Experimental Neurolinguistics (P.M., T.D.), Vrije Universiteit Brussel, Belgium; Department of Language and Communication Science (J. Verhoeven), City University, London, UK; Department of Neurology (A.S.), University Hospital Ghent and University of Ghent; Department of Neurology (S.V.M., P.C.), Antwerp University Hospital; and Department of Neurology (J. Versijpt), University Hospital Brussels, Belgium.
Chantal
C
Ceuterick-De Groote
Neurodegenerative Brain Diseases Group (J.v.d.Z., S.V.M., L.D., F.P., A.S., C.V.B.), Department of Molecular Genetics, VIB, Antwerp; Institute Born-Bunge (J.v.d.Z., S.V.M., L.D., F.P., S.E., C.C.-D.G., A.S., P.C., J.-J.M., C.V.B.), CLIPS, Computational Linguistics and Psycholinguistics (J. Verhoeven), University of Antwerp; Department of Neurology and Memory Clinic (P.M., R.C., S.V.M., S.E.), ZNA Middelheim and Hoge Beuken, Antwerp; Clinical and Experimental Neurolinguistics (P.M., T.D.), Vrije Universiteit Brussel, Belgium; Department of Language and Communication Science (J. Verhoeven), City University, London, UK; Department of Neurology (A.S.), University Hospital Ghent and University of Ghent; Department of Neurology (S.V.M., P.C.), Antwerp University Hospital; and Department of Neurology (J. Versijpt), University Hospital Brussels, Belgium.
Anne
A
Sieben
Neurodegenerative Brain Diseases Group (J.v.d.Z., S.V.M., L.D., F.P., A.S., C.V.B.), Department of Molecular Genetics, VIB, Antwerp; Institute Born-Bunge (J.v.d.Z., S.V.M., L.D., F.P., S.E., C.C.-D.G., A.S., P.C., J.-J.M., C.V.B.), CLIPS, Computational Linguistics and Psycholinguistics (J. Verhoeven), University of Antwerp; Department of Neurology and Memory Clinic (P.M., R.C., S.V.M., S.E.), ZNA Middelheim and Hoge Beuken, Antwerp; Clinical and Experimental Neurolinguistics (P.M., T.D.), Vrije Universiteit Brussel, Belgium; Department of Language and Communication Science (J. Verhoeven), City University, London, UK; Department of Neurology (A.S.), University Hospital Ghent and University of Ghent; Department of Neurology (S.V.M., P.C.), Antwerp University Hospital; and Department of Neurology (J. Versijpt), University Hospital Brussels, Belgium.
Jan
J
Versijpt
Neurodegenerative Brain Diseases Group (J.v.d.Z., S.V.M., L.D., F.P., A.S., C.V.B.), Department of Molecular Genetics, VIB, Antwerp; Institute Born-Bunge (J.v.d.Z., S.V.M., L.D., F.P., S.E., C.C.-D.G., A.S., P.C., J.-J.M., C.V.B.), CLIPS, Computational Linguistics and Psycholinguistics (J. Verhoeven), University of Antwerp; Department of Neurology and Memory Clinic (P.M., R.C., S.V.M., S.E.), ZNA Middelheim and Hoge Beuken, Antwerp; Clinical and Experimental Neurolinguistics (P.M., T.D.), Vrije Universiteit Brussel, Belgium; Department of Language and Communication Science (J. Verhoeven), City University, London, UK; Department of Neurology (A.S.), University Hospital Ghent and University of Ghent; Department of Neurology (S.V.M., P.C.), Antwerp University Hospital; and Department of Neurology (J. Versijpt), University Hospital Brussels, Belgium.
Patrick
P
Cras
Neurodegenerative Brain Diseases Group (J.v.d.Z., S.V.M., L.D., F.P., A.S., C.V.B.), Department of Molecular Genetics, VIB, Antwerp; Institute Born-Bunge (J.v.d.Z., S.V.M., L.D., F.P., S.E., C.C.-D.G., A.S., P.C., J.-J.M., C.V.B.), CLIPS, Computational Linguistics and Psycholinguistics (J. Verhoeven), University of Antwerp; Department of Neurology and Memory Clinic (P.M., R.C., S.V.M., S.E.), ZNA Middelheim and Hoge Beuken, Antwerp; Clinical and Experimental Neurolinguistics (P.M., T.D.), Vrije Universiteit Brussel, Belgium; Department of Language and Communication Science (J. Verhoeven), City University, London, UK; Department of Neurology (A.S.), University Hospital Ghent and University of Ghent; Department of Neurology (S.V.M., P.C.), Antwerp University Hospital; and Department of Neurology (J. Versijpt), University Hospital Brussels, Belgium.
Jean-Jacques
JJ
Martin
Neurodegenerative Brain Diseases Group (J.v.d.Z., S.V.M., L.D., F.P., A.S., C.V.B.), Department of Molecular Genetics, VIB, Antwerp; Institute Born-Bunge (J.v.d.Z., S.V.M., L.D., F.P., S.E., C.C.-D.G., A.S., P.C., J.-J.M., C.V.B.), CLIPS, Computational Linguistics and Psycholinguistics (J. Verhoeven), University of Antwerp; Department of Neurology and Memory Clinic (P.M., R.C., S.V.M., S.E.), ZNA Middelheim and Hoge Beuken, Antwerp; Clinical and Experimental Neurolinguistics (P.M., T.D.), Vrije Universiteit Brussel, Belgium; Department of Language and Communication Science (J. Verhoeven), City University, London, UK; Department of Neurology (A.S.), University Hospital Ghent and University of Ghent; Department of Neurology (S.V.M., P.C.), Antwerp University Hospital; and Department of Neurology (J. Versijpt), University Hospital Brussels, Belgium.
Christine
C
Van Broeckhoven
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