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
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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