inclusion body myopathy with paget 's disease of the bone and frontotemporal dementia ( ibmpfd ) is a rare late - onset autosomal dominant disorder due to a mutation of the valosin - containing protein ( vcp ) gene . we report the case of a patient who developed progressive weakness of the limbs in his fifties , until he was confined to a wheelchair . at that time , he developed acute behavioural changes including irritability , severe anxiety and major depression , which led to him being hospitalised in a psychiatric hospital . he also suffered from aphasia and executive function impairment , which helped us to diagnose a behavioural form of frontotemporal dementia ( ftd ) . the diagnosis of ibmpfd due to a mutation in the vcp gene was confirmed by a genetic study of the vcp gene ( r155h mutation ) . the clinical diagnosis of ibmpfd is suggested by the presence of at least one of three major manifestations as follows : inclusion body myopathy ( mean onset at 42 years of age ) , paget 's disease of the bone and ftd ( mean onset at 55 years of age ) . it is mostly the behavioural form of ftd ( behavioural changes , executive dysfunction and aphasia ) . one interesting finding in our report is the predominance of the psychiatric symptoms at the beginning of the behavioural changes , which led to the diagnosis of ftd . the diagnosis of ibmpfd was confirmed by the genetic study : the r155h mutation found on exon 5 domain cdc48 is the most frequent of the 18 known mutations in the vcp gene . inclusion body myopathy with paget 's disease of the bone and frontotemporal dementia ( ibmpfd ) is a rare late - onset autosomal dominant multi - system disorder , with variable penetrance of three typical clinical components : inclusion body myopathy , paget 's disease and frontotemporal dementia ( behavioural form ) . this disorder is due to mutations of the valosin - containing protein ( vcp ) gene on chromosome 9p21-p12 [ 1 , 2 ] . eighteen mutations in 12 loci of the vcp gene have been identified , originally in north american families . the proband was diagnosed with inclusion body myopathy and then frontotemporal dementia with a psychiatric onset . the proband was a 54-year - old french male patient with a personal history of dyslipidaemia and tuberculosis in childhood . from the age of 41 years , he slowly developed progressive weakness and atrophy of proximal upper - limb muscles and later ( at 46 years of age ) involvement of the lower limbs , associated with axial weakness . at that time , the walking test was unlimited , whereas at 50 years of age , he was only able to walk 50 m using a cane for support . then , the proband developed acute behavioural changes including irritability , severe anxiety and major depression , which led to him being hospitalised in a psychiatric hospital at 53 years of age . his cognitive dysfunctions consisted of impaired frontal lobe functions , dominated by major behavioural changes ( such as changes in affects , decline in social interpersonal conduct and perseveration ) and aphasia ( phonemic and semantic paraphasia ) . his score on the frontotemporal behavioural scale was abnormal ( 3 items out of 4 were pathological ) . however , his memory was not impaired : the mini - mental state examination ( mmse ) was normal ( 29 out of 30 points ) . 1 ) showed fibrillation potentials and positive sharp waves at rest , and myopathic or neurogenic features according to the muscles examined : polyphasic small - amplitude short - duration motor unit potentials and polyphasic long - duration with slow - frequency motor unit potentials were found together in the emg study . these results suggested inclusion body myopathy , which was confirmed by a muscle biopsy revealing histopathological changes consisting of rimmed vacuoles . plasma creatine kinase levels were mildly increased ( 262 iu / l , normal values 20220 iu / l ) . cerebral magnetic resonance imaging ( mri ) was performed at 54 years of age and revealed frontal and internal temporal atrophy ( fig . 2 ) . fluorodeoxyglucose ( fdg ) positron emission tomography ( pet ) scan showed severe bilateral hypometabolism , involving especially the frontal and temporal lobes ( fig . behavioural - type frontotemporal dementia was therefore diagnosed based on the clinical frontal lobe dysfunction and the results of the cerebral mri and pet scan . moreover , the mother and the grandfather of the index patient had died with an unknown myopathy ( confined to a wheelchair at the end of their lives ) . the diagnosis of ibmpfd due to a mutation in the vcp gene was suggested given the personal and familial history of the patient . this diagnosis was confirmed by the genetic study of the vcp gene which revealed the vcp r155h mutation ( exon 5 , domain cdc48 , 464 g > a ) . the genetic study was not performed in the mother and the grandfather of the index patient . the absence of bone pain , hearing problems or spontaneous fractures , the normality of the serum concentration of alkaline phosphatase and the normality of a 99mtc total - body bone scan ruled out paget 's disease of the bone . ibmpfd is a rare disorder originally described in north american families . unlike hereditary inclusion body myopathy , which is autosomal recessive the clinical diagnosis of ibmpfd is suggested by the presence of at least one of three major manifestations as follows [ 1 , 2 ] : inclusion body myopathy , paget 's disease of the bone and frontotemporal dementia . inclusion body myopathy is characterised by a mean onset at 42 years of age with progressive proximal and then distal muscle weakness and atrophy . emg of affected muscles reveals fibrillations and positive sharp waves at rest , and an association with myopathic and neuropathic potentials with movement . frontotemporal dementia begins at 55 years of age on average and is characterised by the predominance of behavioural changes ( disinhibition , irritability and anxiety ) , executive dysfunction and aphasia ; the memory is preserved for a long time . one interesting finding in our case report is the onset of frontotemporal dementia in the form of psychiatric symptoms , which has rarely been described in previous studies [ 3 , 4 ] . the diagnosis of frontotemporal dementia is confirmed , on the one hand , by frontal and temporal atrophy on cerebral mri and , on the other hand , by frontal and temporal hypometabolism on the fdg pet scan . in our case , frontotemporal hypometabolism on the pet scan seemed to be more severe than expected with atrophy in these areas on mri . in fact , the higher severity of hypometabolism compared to atrophy in the same areas of the brain suggests some functional alteration such as disruption of connected areas . bone involvement is typical of paget 's disease , which also appears at 42 years of age on average , with raised serum concentrations of alkaline phosphatase and abnormalities on bone scintigraphy . however , the penetrance of ibmpfd is variable according to the type of mutation of the vcp gene and is age - related . only 12% of the patients with ibmpfd described in the literature had all the three major manifestations of the disease previously described ; 50% had only two major manifestations in any combination ( 20% had inclusion body myopathy associated with frontotemporal dementia as did our proband ) . other phenotypic features have been reported , including dilated cardiomyopathy , hepatic fibrosis , cataracts and sensory - motor axonal neuropathy . at muscle biopsy , the paucity of abnormalities suggesting hereditary inclusion body myopathy associated with a mutation of the vcp gene is frequent , even when this is performed on an affected muscle : in our case , only rimmed vacuoles , which are non - specific neuropathological disorders , suggestive of both sporadic and hereditary inclusion body myopathy , were found at biopsy . in fact , whereas ibmpfd muscle biopsies have variable myopathic features , immunohistochemical analyses mostly find inclusions of mutant vcp , which co - localise with accumulations of ubiquitinated proteins and tdp-43 ( tar dna - binding protein 43 ) inclusions and are more specific to the hereditary association between inclusion body myopathy and frontotemporal dementia [ 2 , 7 ] . concerning the genetic study of our proband , the r155h mutation found on exon 5 , domain cdc48 , in the vcp gene corresponds to one of the mutations originally described in north american families . eighteen mutations in 12 loci of the vcp gene in the chromosome 9p21-p12 have been identified and are listed in table 1 . the phenotypes are inconsistent with the different vcp mutations : in most cases , the onset of paget 's disease of the bone in patients with the r155h mutation , as carried by our index patient , occurs later than is the case with other vcp mutations . as a consequence , we can not exclude the possibility that he will develop paget 's disease of the bone later . to conclude , even though ibmpfd is a rare clinical entity , the diagnosis should be considered when a patient suffers from inclusion body myopathy or paget 's disease of the bone or frontotemporal dementia and has a similar family history . frontotemporal dementia occurs more often in a behavioural form and can begin with psychiatric symptoms alone . known or new mutations of the vcp gene should be screened for in order to confirm the suspected clinical diagnosis .
introductioninclusion body myopathy with paget 's disease of the bone and frontotemporal dementia ( ibmpfd ) is a rare late - onset autosomal dominant disorder due to a mutation of the valosin - containing protein ( vcp ) gene.case reportwe report the case of a patient who developed progressive weakness of the limbs in his fifties , until he was confined to a wheelchair . at that time 
 , he developed acute behavioural changes including irritability , severe anxiety and major depression , which led to him being hospitalised in a psychiatric hospital . 
 he also suffered from aphasia and executive function impairment , which helped us to diagnose a behavioural form of frontotemporal dementia ( ftd ) . 
 the diagnosis of ibmpfd due to a mutation in the vcp gene was confirmed by a genetic study of the vcp gene ( r155h mutation).discussionthe clinical diagnosis of ibmpfd is suggested by the presence of at least one of three major manifestations as follows : inclusion body myopathy ( mean onset at 42 years of age ) , paget 's disease of the bone and ftd ( mean onset at 55 years of age ) . it is mostly the behavioural form of ftd ( behavioural changes , executive dysfunction and aphasia ) . 
 one interesting finding in our report is the predominance of the psychiatric symptoms at the beginning of the behavioural changes , which led to the diagnosis of ftd . 
 the diagnosis of ibmpfd was confirmed by the genetic study : the r155h mutation found on exon 5 domain cdc48 is the most frequent of the 18 known mutations in the vcp gene .