Elsevier

Journal of the Neurological Sciences

Volume 368, 15 September 2016, Pages 352-358
Journal of the Neurological Sciences

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

https://doi.org/10.1016/j.jns.2016.07.048Get rights and content

Highlights

  • VCP missense variants have been associated with variable phenotypes.

  • Reported phenotypes include IBM, ALS and FTD.

  • We report a novel VCP variant with intrafamilial phenotypic variability.

  • This study expands the genotypic spectrum of VCP missense variants.

Abstract

Background

VCP (valosin-containing protein gene) variants have been associated with peripheral and central neurodegenerative processes, including inclusion body myopathy (IBM), Paget disease of bone (PDB), frontotemporal dementia (FTD), and familial amyotrophic lateral sclerosis (ALS) type 14. The combination of IBM, PDB (IBMPFD1) can presented in one individual. However, the association of IBMPFD1 and ALS in the same family is rare.

Methods

We reported three individuals from a Brazilian kindred with intrafamilial phenotype variability. Whole exome sequencing (WES) of the proband was performed and revealed a novel VCP variant. VCP Sanger sequencing was performed in the proband and his family members to confirm WES finding and segregation. We performed a systematic review of the literature regarding the genotypic-phenotypic VCP correlations.

Results

Each individual presented with either myopathy with rimmed vacuoles, ALS, or FTD. There was no PDB. WES of the proband identified the heterozygous variant c.271A > T (p.Asn91Tyr) in the exon 3 of VCP. Sanger sequencing confirmed the segregation of this variant in an autosomal-dominant pattern.

Conclusion

This study expands the genotypic spectrum of the missense mutations of the VCP gene with a novel p.Asn91Tyr variant found in a Brazilian family presenting with the unusual intrafamiliar association of myopathy with rimmed vacuoles, ALS and FTD.

Introduction

Valosin-containing protein (VCP, also known as CDC48 or homolog of p97) is an ubiquitously expressed, multifunctional member of AAA (ATPase Associated with diverse cellular Activities) superfamily and has been involved with multiple ubiquitin-dependent intracellular processes [1], [2], [3], [4]. Autosomal dominant, heterozygous missense variants in VCP are linked to a spectrum of phenotypes (also known as Multisystem Proteinopathy) which includes myopathy with rimmed vacuoles or inclusion body myopathy (IBM), early-onset Paget disease of the bone (PDB), frontotemporal dementia (FTD) or familial amyotrophic lateral sclerosis (ALS type 14, OMIM #613954) [1], [5], [6].

VCP-related myopathy with rimmed vacuoles, PDB or FTD in any combination is known as IBMPFD1 (OMIM #167320), an autosomal dominant inherited spectrum of disorders with incomplete penetrance and adult onset [7]. Myopathy is the most common feature, characterized by progressive proximal-predominant muscle weakness resembling a limb-girdle muscular dystrophy pattern, along with normal or mildly elevated serum creatine kinase (CK) levels [8]. A distal myopathy phenotype has also been reported [9]. The most common findings in the muscle biopsy are rimmed vacuoles and ubiquitin-positive, VCP-positive and TDP-43-positive inclusions [8], [10]. PDB is seen in approximately 50% of cases and presents with osteolytic bone lesions or polyostotic skeletal disorganization, pathological fractures, and high serum alkaline phosphatase (ALP) [3], [8], [10]. FTD is recognized in almost one third of patients harboring VCP pathogenic variants. Neuroimaging studies have shown frontal and anterior temporal lobe cortical atrophy [8], [10], [11]. The first Brazilian family with IBMPFD1 harboring p.Arg93Cys variant at VCP was described in 2011 [11].

Other neurological features have also been described, such as parkinsonism, dystonia, myotonia, sensorimotor axonal neuropathy and sensorineural hearing loss [3], [10], [12]. Systemic features have been rarely reported, such as cardiomyopathy, cataracts and hepatic steatosis, but the association of these systemic manifestations with VCP mutations remains uncertain [3].

Herein, we describe three Brazilian patients from the same family presenting with isolated IBM-like myopathy (proband), sporadic ALS (his brother) and isolated late-onset FTD (his father) harboring a novel VCP variant. No PDB was seen. To our knowledge, this is first description of intrafamilial association of ALS, myopathy and FTD in a Brazilian kindred.

Section snippets

Patients

This study was approved by UNIFESP Research Ethics Board. An informed consent was obtained from all subjects or their legal representatives. The proband, his brother and his father (Fig. 1A) were clinically assessed and medical records were reviewed, including results of neuroimaging, serum CK and ALP levels, nerve conduction studies (NCS)/needle electromyography (EMG), and muscle biopsy whenever available.

Muscle biopsy

Open muscle biopsy was performed in the left vastus lateralis of the proband under local

Case reports

Proband (Fig. 1A, arrow): A 48-year-old Brazilian man presented with a 7-year history of mild, symmetric weakness and reduced muscle bulk in the proximal arms (deltoid, biceps and triceps) and legs (quadriceps), with normal flexor digitorum profundus muscle strength (Fig. 1B). No cognitive changes were noted and the Portuguese version of MOCA [14] testing was 28 out of 30. Screening for PDB included normal serum ALP levels (46–51 U/L) and normal plain X-ray of the hips, long bones and head.

Discussion

VCP is a highly conserved gene in a vast range of species and homozygous knockout Vcp mice do not survive to the early embryological development [52]. VCP is an ubiquitously-expressed hexameric protein containing a polyubiquitin binding CDC48 N-domain, two ATPase domains (D1 and D2), and C-terminal domains [44]. To date, the majority of the described missense variants (Table 1) are located in exons 3 and 5, which encode the CDC48 domain, resulting in VCP conformational changes and ultimately

Financial disclosure

The authors report no disclosures.

Conflict of interest

The authors report no conflicts of interest.

Acknowledgement

We are thankful to the patients involved in this study. We also thankful to Dr. Hanika Pinto for insightful suggestions to this manuscript.

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