Einschlusskörpermyopathie, Paget-Krankheit und frontotemporale Demenz: eine VCP-bedingte, multisystemische Proteinopathie

Zusammenfassung

Mutationen des humanen VCP-Gens, welches für das Valosin-enthaltende Protein (engl. Valosin Containing Protein; Synonyme: p97, TER ATPase) kodiert, sind mit verschiedenen multisystemischen Proteinaggregationserkrankungen assoziiert. Wir stellen einen Patienten vor, der an einer progressiven Myopathie und beginnenden kognitiven Defiziten leidet. In der diagnostischen Muskelbiospie zeigte sich das Bild einer Einschlusskörpermyopathie mit Proteinaggregaten. Die kraniale MRT- und F18-FDG-PET/CT Bildgebung erbrachte den Nachweis einer deutlichen fronto-temporalen Atrophie sowie einer fronto-temporalen Hypoperfusion. Basierend auf der klinischen Symptomatik des Patienten erfolgte eine molekulargenetische Diagnostik, die eine heterozygote c.277C>T (p.Arg93Cys) Mutation des VCP-Gens detektierte, so dass abschließend die Diagnose einer IBMPFD (engl. Inclusion Body Myopathie with Paget Disease of the Bones and Fronto-temporal Dementia) gestellt werden konnte.

Abstract

Mutations of the human VCP gene, which encodes the Valosin Containing Protein (synonyms: p97, TER ATPase), are associated with various multi-systemic protein aggregation diseases. We report on a patient with progressive myopathy and incipient cognitive deficits. A diagnostic muscle biopsy revealed an inclusion body myopathy with protein aggregates. Magnetic resonance imaging and F18-positron-emission-tomography disclosed a fronto-temporal atrophy and glucose hypometabolism of the frontal and temporal lobes, respectively. Based on the clinical findings, a genetic analysis was performed which revealed a heterozygous c.277C>T (p.Arg93Cys) mutation of the VCP gene, thus confirming the diagnosis of IBMPFD (Inclusion Body Myopathie with Paget Disease of the Bones and Fronto-temporal Dementia).

Schlüsselwörter

VCP - IBM-PFD - Myopathie - Fronto-temporale Demenz

Key words

VCP - myopathy - IBMPFD - frontotemporal dementia

• Literatur

• 1 Schröder R. Protein aggregate myopathies: the many faces of an expanding disease group. Acta Neuropathol 2013; 125: 1-2
• 2 Watts GD, Wymer J, Kovach MJ. et al., Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 2004; 36: 377-381
• 3 Baek GH, Cheng H, Choe V. et al., Cdc48: a swiss army knife of cell biology. J Amino Acids 2013; 2013: 183421
• 4 Clemen CS, Marko M, Strucksberg KH. et al., VCP and PSMF1: Antagonistic regulators of proteasome activity. Biochem Biophys Res Commun 2015; 463: 1210-1217
• 5 Hübbers CU, Clemen CS, Kesper K. et al., Pathological consequences of VCP mutations on human striated muscle. Brain 2007; 130: 381-393
• 6 Meyer H, Weihl CC. The VCP/p97 system at a glance: connecting cellular function to disease pathogenesis. J Cell Sci 2014; 127: 3877-3883
• 7 Johnson JO, Mandrioli J, Benatar M. et al., Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 2010; 68: 857-864
• 8 Chan N, Le C, Shieh P. et al., Valosin-containing protein mutation and Parkinson’s disease. Parkinsonism Relat Disord 2012; 18: 107-109
• 9 Gonzalez MA, Feely SM, Speziani F. et al., A novel mutation in VCP causes Charcot-Marie-Tooth Type 2 disease. Brain 2014; 137: 2897-2902
• 10 de Bot ST, Schelhaas HJ, Kamsteeg EJ. et al., Hereditary spastic paraplegia caused by a mutation in the VCP gene. Brain 2012; 135: e223 ; author reply e224
• 11 Evangelista T, Weihl CC, Kimonis V. et al., 215th ENMC International Workshop VCP-related multi-system proteinopathy (IBMPFD) 13-15 November 2015, Heemskerk, The Netherlands. Neuromuscul Disord 2016; 26: 535-547
• 12 Kimonis VE, Mehta SG, Fulchiero EC. et al., Clinical studies in familial VCP myopathy associated with Paget disease of bone and frontotemporal dementia. Am J Med Genet A 2008; 146A: 745-757
• 13 Abrahao A, Abath Neto O, Kok F. et al., One family, one gene and three phenotypes: A novel VCP (valosin-containing protein) mutation associated with myopathy with rimmed vacuoles, amyotrophic lateral sclerosis and frontotemporal dementia. J Neurol Sci 2016; 368: 352-358
• 14 Rijal R, Arhzaouy K, Strucksberg KH. et al., Mutant p97 exhibits species-specific changes of its ATPase activity and compromises the UBXD9-mediated monomerisation of p97 hexamers. Eur J Cell Biol 2016; 95: 195-207
• 15 Al-Obeidi E, Al-Tahan S, Surampalli A. et al., Genotype-phenotype study in patients with VCP valosin-containing protein mutations associated with multisystem proteinopathy. Clin Genet 2017
• 16 Kim HJ, Kim NC, Wang YD. et al., Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 2013; 495: 467-473
• 17 Le Ber I, Van Bortel I, Nicolas G. et al., hnRNPA2B1 and hnRNPA1 mutations are rare in patients with “multisystem proteinopathy” and frontotemporal lobar degeneration phenotypes. Neurobiology of Aging 2014; 35 (934) e935-936
• 18 Regensburger M, Turk M, Pagenstecher A. et al., VCP-related multisystem proteinopathy presenting as early-onset Parkinson disease. Neurology 2017
• 19 Spina S, Van Laar AD, Murrell JR. et al., Phenotypic variability in three families with valosin-containing protein mutation. Eur J Neurol 2013; 20: 251-258