title: C9ORF72 expansion does not affect the phenotype in Nasu-Hakola disease with the DAP12 mutation.
abstract: Nasu-Hakola disease (NHD) is a rare autosomal recessive disease that is characterized by cyst-like bone lesions and pathologic fractures combined with an early-onset frontal type of dementia. Mutations in DNAX-activation protein 12 (DAP12) and triggering receptor expressed on myeloid cells 2 (TREM2) are the known genetic causes of NHD. However, the role of both these genes in the neurodegenerative process is still partly unclear, and the input of other modifying factors has been postulated. Frontotemporal lobar degeneration (FTLD) is a neuropathologically and genetically heterogeneous neurodegenerative disease. A hexanucleotide repeat expansion in the chromosome 9-associated open reading frame 72 (C9ORF72) gene is the most common cause of familial FTLD in Finland. Here, we describe a family with 3 siblings with a clinical diagnosis of NHD. All patients had an equivalent age of onset of the behavioral/cognitive symptoms, and brain imaging revealed a similar pattern of brain atrophy and calcification in putamen and caudate nucleus. Case II-3 had the most severe phenotype with epilepsy and a rapid cognitive decline. Genetic analyses were performed in 2 patients (cases II-2 and II-3), and both had a homozygous DAP12 deletion. Because the role of DAP12 and TREM2 in neurodegeneration in NHD is partly unclear, our aim was to evaluate the role of other genetic variations as modifiers. The C9ORF72 expansion was found in case II-2. Exome sequencing did not reveal any other mutations that could be involved in FTLD. Case II-3 had a novel predictably deleterious mutation in the progressive myoclonic epilepsy type 2 (EPM2), which may have influenced his epilepsy as the EPM2 has been implicated in Lafora progressive myoclonic epilepsy. We conclude that the C9ORF72 expansion is probably an incidental finding because it did not have any apparent influence on the phenotype. Exome sequencing identified several rare missense variants and indels. Additional analyses in other NHD patients will be needed to elucidate their clinical relevance.
authors.affiliation: Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Eino
authors.initials: E
authors.lastname: Solje
authors.affiliation: Department of Neurology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Hartikainen
authors.affiliation: Biomedicum Research Programs Unit, Molecular Neurology, Department of Neurology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Miko
authors.initials: M
authors.lastname: Valori
authors.affiliation: Institute of Clinical Medicine-Radiology, University of Eastern Finland, Kuopio, Finland; Department of Clinical Radiology, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Ritva
authors.initials: R
authors.lastname: Vanninen
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland; Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Tiihonen
authors.affiliation: Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland.
authors.forename: Panu
authors.initials: P
authors.lastname: Hakola
authors.affiliation: Biomedicum Research Programs Unit, Molecular Neurology, Department of Neurology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
authors.forename: Pentti J
authors.initials: PJ
authors.lastname: Tienari
authors.affiliation: Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland; Department of Neurology, Kuopio University Hospital, Kuopio, Finland. Electronic address: anne.remes@uef.fi.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Remes
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000369:Aged, 80 and over; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D008060:Lipodystrophy / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000235:genetics*; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D035781:Siblings; D013344:Subacute Sclerosing Panencephalitis / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D008565:Membrane Proteins; D011506:Proteins; C110546:TYROBP protein, human
keywords: C9ORF72; DAP12; Epilepsy; Frontotemporal dementia; Polycystic lipomembranous osteodysplasia and sclerosing leukoencephalopathy; TREM2; TYROBP