Valosin-containing protein Asp395Gly mutation in a patient with frontotemporal dementia: a case report

Following Alzheimer’s disease (AD), frontotemporal dementia (FTD) is the second most common neurodegenerative disorder in patients with onset of dementia before 65 years of age [1]. FTD is a clinically, pathologically, and genetically heterogeneous syndrome that presents with personality and behavioral changes reflecting dysfunction of the frontal and temporal lobes [2]. So far, several causative genes for FTD have been identified, with hexanucleotide repeat expansion in C9ORF72 being the most common genetic cause of both familial (~ 25%) and sporadic (~ 5%) FTD [1, 3]. Familial FTD accounts for approximately 30–50% of all FTD cases in Euro-American countries; however, the frequency of familial FTD is reportedly relatively rare in Asian regions, including India, Indonesia, Japan, Taiwan, and Philippines, where family history of FTD spectrum disorders was reported in 5.5% of FTD patients [1, 4]. This might be due to the genetic differences of the frequency of FTD patients carrying expanded repeats in C9ORF72, which is substantially lower in the Japanese series than in Euro-American series [3].

Variants in the valosin-containing protein (VCP) gene were identified as one of the causes for inclusion body myopathy (IBM) associated with Paget disease of the bone (PDB) and FTD (IBMPFD) [5]. Subsequently, pathogenic variants in VCP have been shown to contribute various neurodegenerative disorders, such as amyotrophic lateral sclerosis, Parkinson’s disease, and Charcot–Marie–Tooth disease [5‐7]. The phenotypes of patients with VCP pathogenic variants are highly diverse; approximately 90% of the patients have IBM, 30–40% have PDB, and 15–30% have FTD, with overlapping symptoms. On the other hand, only 2–3% of the patients with VCP pathogenic variants had FTD alone phenotype [5, 8]. Thus, a small number of the previously reported patients with pathogenic variants in VCP had only FTD symptoms without IBM and PDB [1, 5, 8‐12]. In the present study, we report a case of likely sporadic FTD in a Japanese patient carrying the pathogenic variant in VCP (p.Asp395Gly), without evidence of IBM or PDB, more than 15 years after the onset of FTD symptoms.

The patient was a 62-year-old, right-handed Japanese man. His pedigree chart is depicted in Fig. 1a. Written informed consent for genetic analysis and publication of this report was obtained from the patient’s wife. His past medical history was unremarkable and no similar disease was noted in his family. He graduated from university at the age of 22 years and worked as a civil servant employed by prefectural governments thereafter. He presented with depressive mood due to a heavy burden of work and visited a psychiatric clinic at 37 years of age. He was diagnosed with depression and was administered antidepressant medication. Since then, he repeatedly requested temporary leaves of absence and lacked the motivation to work and to perform household chores, however, his motivation for entertainment and hobbies did not diminish. This led to the consideration of atypical depression rather than typical depression, which is characterized by a persistent decrease in motivation. At the age of 45 years, he tended to indulge in self-centered behaviors, such as visiting a movie theater or playing a Japanese gambling machine without permission, while pretending to go to work. From around the age of 50 years, self-centered behaviors such as absenteeism and returning home from work without permission worsened, followed by executive dysfunction associated with planning and doing work. He was absent from work due to these behaviors and was referred to our hospital at the age of 52 years.

At the initial visit, the patient maintained good manners, although he was not lively and lacked seriousness for his situation and improvement of his condition. His Mini-Mental State Examination score was 25, failing in the domains of orientation to place, attention/ calculations, recall, and repetition. Moreover, his frontal lobe dysfunction was revealed by Frontal Assessment Battery [13, 14], a short bedside cognitive and behavioral battery to assess frontal lobe functions (score was 12/18). The results of other neurological examinations were normal. Magnetic resonance imaging (MRI) revealed bilateral frontal lobe atrophy (Fig. 2a). Technetium-99 m ethyl cysteinate dimer ([^99mTc]ECD) single-photon emission computed tomography (SPECT) revealed bilateral frontal lobe hypoperfusion (Fig. 2b). The patient was diagnosed with a behavioral variant of FTD based on Rascovsky et al.’s diagnostic criteria [2] and had to leave work. He was admitted to a psychiatric hospital at the age of 54 due to prominent self-centered behavior, overeating, irritability, and disinhibition.

The FTD progressed over the years, and by the age of 62 years, he had almost no speech and had a remarkable decrease in spontaneity. He needed help to perform activities of daily living but was able to eat and walk by himself. Muscle weakness and atrophy of the extremities were not observed. MRI revealed substantial atrophy in the frontal and temporal lobes and periventricular leukoaraiosis (Fig. 2c). [^99mTc]ECD SPECT revealed bilateral frontal and parietal lobe hypoperfusion (Fig. 2d). [¹¹C]Pittsburgh compound B-positron emission tomography was negative for the presence of amyloid. His laboratory data, including the creatine kinase level, were normal. The concentrations of cerebrospinal fluid (CSF) total tau and phosphorylated tau proteins were 389 pg/mL and 53.2 pg/mL (cut-off: 50 pg/mL), respectively.

There were no signs of bone involvement (e.g., elevated serum alkaline phosphatase levels). Computed tomography of the trunk and limbs did not reveal muscle atrophy. Bone scintigraphy did not identify prominent bone lesions. There were no myopathic features or inclusion bodies on the right rectus femoris muscle biopsy (Supplementary Fig).

In the present study, we report a Japanese patient carrying p.Asp395Gly VCP, which manifested as likely sporadic FTD devoid of associated muscle or bone involvement. Relatedly, a recent study reported that four patients in two pedigrees with familial FTD carrying p.Asp395Gly VCP had typical FTD symptoms but did not display IBM or PDB [12]. Unfortunately, in the current study, genetic tests for the other relatives, including the patient’s parents, could not be performed. The patient’s father died due to myocardial infarction at 87 years of age and his mother of stomach cancer at age 40. Neither had a history of FTD, muscle weakness, or bone-related symptoms. Moreover, none of his three siblings (aged above 70 years), or their children, developed the disease. As such, there may be a possibility that the parents, especially his mother, carried the VCP pathogenic variant. Alternatively, the FTD in this case may have been caused by a de novo mutation, although we could not arrive at a definite conclusion. Despite these limitations, this study contributes to further establish the genotype-phenotype correlation of p.Asp395Gly VCP with pure FTD in addition to the previous report [12].

Some cases of pure FTD without IBM or PDB have been reported in FTD patients carrying pathogenic variants linked to FTLD-VCP. Of these, most are familial, whereas very few sporadic cases have been reported [1, 5, 8‐12]. Our patient’s age of 62 years was above the mean age of onset for VCP-related IBM and PDB (40.4 ± 10.0 and 48.2 ± 10.9 years, respectively) [5], and the patient was therefore likely to have pure FTD. Furthermore, our patient carrying p.Asp395Gly VCP was afflicted by likely sporadic FTD, which may suggest the need for screening for pathogenic VCP variants in the Japanese FTD patients, regardless of the family history or the absence of the features of IBM or PDB.

In general, previously identified pathogenic variants in VCP other than p.Asp395Gly are associated with frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) pathologically [8] and cause a hereditary disease called multisystem proteinopathy that affects various organs including the nervous system, skeletal muscle, and bone [5]. On the contrary, p.Asp395Gly VCP was recently reported to cause FTD with tauopathy characterized by the accumulation of neuronal vacuoles and neurofibrillary tau tangles (NFT) and not FTLD-TDP [12]. Notably, in this case, the CSF phosphorylated tau level was mildly increased unlike in typical FTD patients. Therefore, our patient may also have FTD due to NFT accumulation similar to the FTD patients with p.Asp395Gly VCP, although detailed CSF analysis including phosphorylated tau level was not described in the previous report [12].

Interestingly, this patient presented with symptoms of atypical depression before the development of behavioral abnormalities, unlike the previous studies where patients with p.Asp395Gly VCP had only typical FTD symptoms. The symptoms of atypical depression, in this case, may have been connected with very mild frontal lobe dysfunction, such as apathy and disinhibition. Other studies have reported that patients with progressive muscular atrophy and psychiatric symptoms, such as depression and anxiety, who subsequently developed FTD after 12 years from the onset, had the VCP pathogenic variant (p.Arg155His) [17]. Thus, the atypical depression preceding FTD in this case may have been associated with p.Asp395Gly VCP. The clinical phenotypes of cases with the VCP pathogenic variant (p.Asp395Gly) need to be further investigated in a wide variety of populations.

In conclusion, p.Asp395Gly VCP was identified in a patient with likely sporadic FTD without muscle and bone involvement. Our findings suggest that FTD with p.Asp395Gly VCP, akin to other hereditary FTDs, may present with psychiatric disorders preceding the development of FTD. In addition, VCP variants should be considered in patients diagnosed with sporadic pure FTD, even in the absence of IBM or PDB. Further studies are needed to clarify the clinical phenotype of patients with p.Asp395Gly VCP.