Objective: To describe clinical and pathological features of a patient affected by inclusion body miopathy (IBM) and frontotemporal dementia (FTD). Hereditary IBM associated with Paget disease of the bone (PDB) and FTD (IBMPFD) is a rare autosomal dominant disease caused by mutations in the valosin-containing protein (VCP) gene, mapped on chromosome 9p13–p12. VCP is an ubiquitously expressed member of ATPase family, involved in different cellular pathways including ubiquitin-proteasome–dependent protein degradation, apoptosis and cell-cycle control. All the pathogenic mutations of VCP gene described so far are located within the region coding of N-terminal domain, which is the binding region for partner proteins suggesting that genetic variants could interfere in protein interaction with components of ubiquitin proteasome and endoplasmic reticulum associated degradation. Methods: A 69-year-old Italian male patient presented by the age of 50 years a progressive weakness distally in arms and proximally in legs and developed frontotemporal dementia at the age of 66 years. Family history was negative A CT scan disclosed a selective fronto-temporal atrophy. Muscle biopsies were analysed by standard histological, histochemical and ultrastructural methods. VCP, ubiquitin, desmin and myotilin immunoreactivities were investigated by immunohistochemistry. VCP gene was analysed by sequence analysis. Results: Two muscle biopsies disclosed pathological features consistent with IBM characterized by progressive degenerative changes and rimmed vacuoles in association with the presence of VCP- and ubiquitin-positive cytoplasmic and nuclear muscle protein aggregates. These deposits were present, although in a lower quantity, also in patients with sporadic inclusion body myositis. A novel heterozygous mutation C687T was found within exon 5 (R159C) of the VCP gene. The C687T mutation was absent in 200 age-matched control individuals. It is located only four amino acids away from the mutational hotspot previously described in IBMPFD and represents the same type of mutation (R>H). Conclusions: A novel VCP gene mutation was found in an apparently sporadic IBM with later appearance of frontotemporal dementia. The histopathologic features, such as VCP sarcoplasmic over-expression and nuclear inclusion, may suggest this molecular aetiology. However only the combined clinical features of IBM and FTD seems to be helpful to address the correct genetic investigation.

Clinical and pathological aspects of an Italian patient with inclusion body myopathy and frontotemporal dementia carrying a novel mutation in valosin-containing protein gene / A. Bersano, R. Del Bo, C. Lamperti, S. Ghezzi, N. Bresolin, L. Napoli, E. Ballabio, M. Moggio, L. Candelise, G.P. Comi, S. Corti. ((Intervento presentato al 17. convegno Meeting of the European Neurological Society tenutosi a null nel null.

Clinical and pathological aspects of an Italian patient with inclusion body myopathy and frontotemporal dementia carrying a novel mutation in valosin-containing protein gene

R. Del Bo
Secondo
;
C. Lamperti;N. Bresolin;E. Ballabio;L. Candelise;G.P. Comi
Penultimo
;
S. Corti
Ultimo
2007

Abstract

Objective: To describe clinical and pathological features of a patient affected by inclusion body miopathy (IBM) and frontotemporal dementia (FTD). Hereditary IBM associated with Paget disease of the bone (PDB) and FTD (IBMPFD) is a rare autosomal dominant disease caused by mutations in the valosin-containing protein (VCP) gene, mapped on chromosome 9p13–p12. VCP is an ubiquitously expressed member of ATPase family, involved in different cellular pathways including ubiquitin-proteasome–dependent protein degradation, apoptosis and cell-cycle control. All the pathogenic mutations of VCP gene described so far are located within the region coding of N-terminal domain, which is the binding region for partner proteins suggesting that genetic variants could interfere in protein interaction with components of ubiquitin proteasome and endoplasmic reticulum associated degradation. Methods: A 69-year-old Italian male patient presented by the age of 50 years a progressive weakness distally in arms and proximally in legs and developed frontotemporal dementia at the age of 66 years. Family history was negative A CT scan disclosed a selective fronto-temporal atrophy. Muscle biopsies were analysed by standard histological, histochemical and ultrastructural methods. VCP, ubiquitin, desmin and myotilin immunoreactivities were investigated by immunohistochemistry. VCP gene was analysed by sequence analysis. Results: Two muscle biopsies disclosed pathological features consistent with IBM characterized by progressive degenerative changes and rimmed vacuoles in association with the presence of VCP- and ubiquitin-positive cytoplasmic and nuclear muscle protein aggregates. These deposits were present, although in a lower quantity, also in patients with sporadic inclusion body myositis. A novel heterozygous mutation C687T was found within exon 5 (R159C) of the VCP gene. The C687T mutation was absent in 200 age-matched control individuals. It is located only four amino acids away from the mutational hotspot previously described in IBMPFD and represents the same type of mutation (R>H). Conclusions: A novel VCP gene mutation was found in an apparently sporadic IBM with later appearance of frontotemporal dementia. The histopathologic features, such as VCP sarcoplasmic over-expression and nuclear inclusion, may suggest this molecular aetiology. However only the combined clinical features of IBM and FTD seems to be helpful to address the correct genetic investigation.
giu-2007
Settore MED/26 - Neurologia
Clinical and pathological aspects of an Italian patient with inclusion body myopathy and frontotemporal dementia carrying a novel mutation in valosin-containing protein gene / A. Bersano, R. Del Bo, C. Lamperti, S. Ghezzi, N. Bresolin, L. Napoli, E. Ballabio, M. Moggio, L. Candelise, G.P. Comi, S. Corti. ((Intervento presentato al 17. convegno Meeting of the European Neurological Society tenutosi a null nel null.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/44520
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