A novel exon 2 I27V valosin-containing protein variant is associated with dissimilar clinical syndromes

Abstract

Mutations in valosin-containing protein (VCP) are associated with a syndromic constellation of inclusion body myositis, Paget’s disease of bone and frontotemporal dementia. Here we describe the case reports of two patients with a novel variation (p.I27V) in the VCP gene that was not identified in a healthy control population. One patient presented with a frontotemporal dementia syndrome associated with raised serum alkaline phosphatase and a family history of progressive muscle disease and behavioural decline, while the second patient presented with isolated progressive dysarthria. Together these cases suggest a potential for the same VCP mutation to produce distinct patterns of brain damage, underlining the clinical heterogeneity of VCP-associated disease.

INTRODUCTION

Mutations in valosin-containing protein (VCP) have been shown to be associated with a constellation of disorders which frequently co-occur: inclusion body myositis, Paget’s disease of the bone and frontotemporal dementia (IBMPFD) [1,2,3]. More recently it has been suggested that they are also a cause of familial motor neurone disease (MND)/amyotrophic lateral sclerosis (ALS) [4]. Currently seventeen mutations in VCP are described [http://www.molgen.ua.ac.be/FTDMutations]. Mutations were originally described in exons 3, 5, 6 and 10 of the VCP gene, and more recently also in exons 4, 7 and 11. Both IBMPFD and MND/ALS overlap pathologically with frontotemporal lobar degeneration (FTLD) being associated with ubiquitin-positive, TDP-43-positive neuronal inclusions on pathological examination [5,6,7]. VCP mutations are rare in large series of patients with FTLD (or MND/ALS) and the phenotypic spectrum continues to be delineated [4,8,9]. Here we describe two patients in association with a novel VCP variant in exon 2.

CASE DESCRIPTIONS

Case 1

This man developed progressive cognitive difficulties from the age of 55 years. He took early retirement from his job as a telephone operator as he was unable to learn the new skills required with computerised procedures and subsequently complained of an insidious deterioration in episodic memory. At the same time he developed progressive behavioural disturbance, gradually withdrawing from social activity and developing paranoid ideas (he became convinced, erroneously, that thieves were trying to break into his car). From the age of 63 he became slower physically with decreased mobility, difficulty using his hands and the development of a mild tremor which did not respond to levodopa therapy. His father had died at the age of 67 with a neurodegenerative disorder characterised by progressive muscle weakness accompanied by personality change and aggression, and had received a diagnosis of “progressive muscular atrophy”.

When initially assessed at the age of 65, he had a symmetrical akinetic rigid syndrome with myoclonus in the upper limbs and bilateral limb apraxia. Neuropsychological assessment revealed a verbal IQ of 84 and performance IQ of 73. Verbal subtest scores were defective for arithmetic, low average for similarities and digit span and average for vocabulary whilst performance subtest scores were all low average apart from block design which was defective. He scored at an impaired level on tests of both verbal and visual episodic memory (Warrington Short Recognition Memory Test for Words and Faces) and had decreased verbal fluency. However, he had intact naming (at the 90^th percentile on the Graded Naming Test) and reading (high average performance on the National Adult Reading Test). Blood screens were normal apart from a raised serum ALP (193 IU/L; normal range 40-100IU/L). Brain MRI showed marked symmetrical cerebral atrophy involving the frontal and parietal lobes. Brain SPECT revealed bilateral parietal lobe hypometabolism. He was subsequently lost to follow-up.

Case 2

This woman developed progressive speech disturbance beginning at the age of 72 years with a tendency to stumble over polysyllabic words. Her first language was English but she spoke fluent French and noticed that her French accent had deteriorated. Over the following three years her speech became increasingly hesitant and effortful but without speech errors or word-finding difficulty, nor other cognitive complaints. There was no known family history of neurological illness although her father had committed suicide in his mid 50’s and she had lost touch with her father’s family. Her mother’s sister and four maternal cousins had a developmental stutter.

When initially assessed at the age of 75 her speech was dysarthric, effortful and dysprosodic but there was no language impairment. The neurological examination was otherwise normal (in particular, there were no extrapyramidal or cerebellar signs). On neuropsychological assessment, episodic memory, naming, reading, visuospatial skills and executive function were normal. Blood screens including serum ALP and brain MRI at this time were normal. Over the following three years she exhibited a slowly progressive dysarthria without the development of any linguistic impairment or other cognitive or neurological features. Repeat blood screens three years after the initial assessment revealed raised serum ALP (139 IU/L) and inflammatory markers (CRP 90, ESR 47); serum CPK was normal (119). Electromyography was normal; in particular, there was no evidence of myopathy.

Genetic analysis

Both patients were screened for mutations in progranulin, MAPT, and VCP genes as part of a previously published study of 225 patients with a degenerative disorder within the FTLD spectrum [8]. This study was approved by the National Hospital for Neurology and Neurosurgery Local Research Ethics Committee. Both patients were found to have the same variant in exon 2 of the VCP gene (p.I27V, c.79A>G, CCDS ID 6573). This mutation was not found in 451 healthy UK blood donor samples obtained from the European Collection of Cell Cultures (ECACC) matched for ethnicity.

DISCUSSION

VCP mutations have been described in exon 3 (R93C, R95G, R95C), exon 4 (P137L), exon 5 (R155C, R155H, R155S, R155P, G157R, R159C, R159H, R191Q), exon 6 (L198W, A232E), exon 7 (T262A), exon 10 (N387H) and exon 11 (A439S) [http://www.molgen.ua.ac.be/FTDMutations]. In the absence of samples from other family members to show segregation, we cannot be certain of the pathogenicity of I27V. The absence of the I27V variant in the healthy control population screened here does not exclude the possibility that this is a rare neutral polymorphism in the British population. Suggestive evidence can be provided by algorithms which predict pathogenicity based on the similarity of amino acids changed in the context of the predicted protein structure and evolutionary conservation. However these algorithms, such as PolyPhen, are inaccurate [10]. From mutation series listed above, only R155C and R159C are regarded as probably pathogenic by PolyPhen, and G157R possibly pathogenic, therefore in silico prediction of pathogenicity at this gene is not likely to be reliable. Hence, although the family histories in our cases coupled with ancillary laboratory findings (in particular, raised serum ALP) are consistent with a pathogenic role for the I27V variant, further corroboration will be necessary to confirm this.

If VCP mutations cause IBMPFD mean age of clinical onset is in the fifth decade most commonly with a myopathy. However, the age of onset ranges widely from the third to the eighth decades and the disease may present with Paget’s disease of bone or frontotemporal dementia as the first syndrome [1,2,3]. Disease duration is also variable with some patients living over 30 years from onset. The characteristic triad of myopathy, Paget’s disease and dementia occurs in a minority of cases: whereas over 90% of patients have a myopathy, Paget’s disease has been reported in around half the cases and dementia in only around a third of cases (though cognitive decline may occur late in the course) [3]. Laboratory features are similarly of variable diagnostic utility: while serum ALP is usually raised in association with Paget’s disease of the bone, serum CPK may be normal even in cases with myopathy. The clinical spectrum has recently been extended by the association of VCP mutations with MND/ALS [4]. Although data are relatively limited currently, it appears that patients with VCP-related MND/ALS may present with either limb or bulbar onset of symptoms indistinct from the features of sporadic MND/ALS [4].

CONCLUSIONS

The present cases together underline the potential phenotypic variability of VCP mutations. Case 1 presented with a frontotemporal dementia syndrome with raised serum ALP and a family history of progressive muscle disease and behavioural decline, while Case 2 exhibited an isolated progressive dysarthria also associated with raised serum ALP. If indeed the pathogenetic role of the p.I27V variant is substantiated in future work, these cases suggest that the same VCP mutation can produce strikingly divergent patterns of brain damage. This phenotypic variation may in turn depend on additional unidentified genetic or environmental factors, in keeping with the heterogeneity of tissue types affected by VCP-associated disease.