Resolving a Multi-Generational Neuromuscular Mystery in a Family Presenting with a Variable Scapuloperoneal Syndrome in a c.464G&gt;A, p.Arg155His <i>VCP</i> Mutation

Jerath, Nivedita U.

doi:10.1155/2019/2403024

Cited by 4 publications

(3 citation statements)

References 15 publications

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“…Subsequent cohorts confirmed this triad as common in patients with mutations in the VCP gene but also extended the phenotype to involvement of the CNS, motor neurones, sensory and/or motor peripheral nerves and the skeletal muscle 1 7 10 13 16–21 33–36. Our study confirms that muscle weakness, affecting both proximal or distal muscles of the lower and/or upper limbs, is the main symptom at onset, turning MSP into a challenging diagnosis whereas patients can be classified as having limb girdle muscle weakness, distal myopathy or scapuloperoneal syndrome 37…”

Section: Discussionsupporting

confidence: 78%

Genotype–phenotype correlations in valosin-containing protein disease: a retrospective muticentre study

Schiava

Ikenaga

Villar-Quiles

et al. 2022

J Neurol Neurosurg Psychiatry

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BackgroundValosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget’s disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype–phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype–phenotype correlations.MethodsDescriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene.ResultsTwo hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death.ConclusionThis study expands the knowledge on the phenotypic presentation, natural history, genotype–phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.

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Section: Discussionsupporting

confidence: 78%

Genotype–phenotype correlations in valosin-containing protein disease: a retrospective muticentre study

Schiava

Ikenaga

Villar-Quiles

et al. 2022

J Neurol Neurosurg Psychiatry

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“…We performed a literature review on the clinical and genetic characteristics of previously reported ALS‐VCP cases (Table S1), 2,4–7,16,23–33 and illustrated mutation sites in VCP associated with ALS, IBMPFD, and other phenotypes (Figure S1). 2–5,7,16,20–86 A total of 59 cases have been reported, with the disease typically developing in patients in their 40s–50s, and 14 of the 33 cases survived without artificial respiration for more than five years. Given that the epidemiological studies of general ALS suggest that the peak prevalence is observed in patients in their 70s–80s, and that the median survival time is two to four years, 87–91 the ALS‐VCP cases might be characterized by relatively early disease onset and slow disease progression.…”

Section: Discussionmentioning

confidence: 99%

An autopsy report of a familial amyotrophic lateral sclerosis case carrying VCP Arg487His mutation with a unique TDP‐43 proteinopathy

Matsubara

Izumi

Oda³

et al. 2021

Neuropathology

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We here report an autopsy case of familial amyotrophic lateral sclerosis (ALS) with p.Arg487His mutation in the valosin-containing protein (VCP) gene (VCP), in which upper motor neurons (UMNs) were predominantly involved. Moreover, our patient developed symptoms of frontotemporal dementia later in life and pathologically exhibited numerous phosphorylated transactivation response DNAbinding protein of 43 kDa (p-TDP-43)-positive neuronal cytoplasmic inclusions and short dystrophic neurites with a few lentiform neuronal intranuclear inclusions, sharing the features of frontotemporal lobar degeneration with TDP-43 pathology type A pattern. A review of previous reports of ALS with VCP mutations suggests that our case is unique in terms of its UMN-predominant lesion pattern and distribution of p-TDP-43 pathology. Thus, this case report effectively expands the clinical and pathological phenotype of ALS in patients with a VCP mutation.

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“…The most common VCP /p97 mutations include R155H, R155C, R159H, and R93C [ 4 ]. To date, additional VCP variants have been reported, a few of which were classified as variants of unknown significance that were not previously associated with human disease [ 3 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. Here, we report multiple previously undescribed likely pathogenic variants in the VCP gene that were identified in five patients, three from the same family.…”

Section: Introductionmentioning

confidence: 99%

Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1

Columbres

Chin

Pratti

et al. 2023

Genes

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Valosin-containing protein (VCP) gene mutations have been associated with a rare autosomal dominant, adult-onset progressive disease known as multisystem proteinopathy 1 (MSP1), or inclusion body myopathy (IBM), Paget’s disease of bone (PDB), frontotemporal dementia (FTD), (IBMPFD), and amyotrophic lateral sclerosis (ALS). We report the clinical and genetic analysis findings in five patients, three from the same family, with novel VCP gene variants: NM_007126.5 c.1106T>C (p.I369T), c.478G>A (p.A160T), and c.760A>T (p.I254F), associated with cardinal MSP1 manifestations including myopathy, PDB, and FTD. Our report adds to the spectrum of heterozygous pathogenic variants found in the VCP gene and the high degree of clinical heterogeneity. This case series prompts increased awareness and early consideration of MSP1 in the differential diagnosis of myopathies and/or PDB, dementia, or ALS to improve the diagnosis and early management of clinical symptoms.

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Resolving a Multi-Generational Neuromuscular Mystery in a Family Presenting with a Variable Scapuloperoneal Syndrome in a c.464G>A, p.Arg155His VCP Mutation

Cited by 4 publications

References 15 publications

Genotype–phenotype correlations in valosin-containing protein disease: a retrospective muticentre study

Genotype–phenotype correlations in valosin-containing protein disease: a retrospective muticentre study

An autopsy report of a familial amyotrophic lateral sclerosis case carrying VCP Arg487His mutation with a unique TDP‐43 proteinopathy

Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1

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