A Clinicopathologic Case Report of a Female with Valosin-Containing Protein (VCP) Gene Mutation Related Disease

Surampalli Abhilasha,Khare Manaswitha,Wang Annabel,Donkervoort Sandra,Nalbandian Angèle,Kimonis Virginia E,Yin Hong,Weiss John,Mozaffar Tahseen,Castellani Rudolph,Rubio García Ana ,Patel Payal

doi:10.23937/ijnd-2017/1710006

Surampalli Abhilasha, Khare Manaswitha + Show 10 more

Open Access

https://doi.org/10.23937/ijnd-2017/1710006

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Abstract

Valosin Containing Protein (VCP) gene mutations have been reported in ~1-2% of familial amyotrophic lateral sclerosis (ALS). We report a case of clinically defined and neuropathologically confirmed ALS in a 48-year-old, emaciated female with a p.R155C (c.463 C > T) mutation in VCP gene. She presented with progressive generalized muscular weakness, weight loss, dyspnea on exertion, combined nasal and spastic dysarthria, positive jaw jerk and exaggerated gag reflex.

Highlights

Inclusion Body Myopathy associated with Paget’s disease of bone and Frontotemporal Dementia (IBMPFD OMIM#167320) [1]) or more recently described as multisystem proteinopathy [2] is an autosomal dominant disorder caused by mutations in the Valosin Containing Protein (VCP) gene first identified by Watts, et al [3,4]
90% of the mutation positive individuals develop myopathy in their 30s-40s manifesting as shoulder and pelvic girdle muscle weakness and atrophy; later progressively involving other muscle groups; 50% develop Paget disease of bone (PDB) typically in their 30s and 30% develop frontotemporal dementia (FTD) in their mid-50s [3,5] in which the characteristic changes in personality and progressive loss of language precede memory loss
Immunostains for tau were universally negative. This case is illustrative of a rare aspect of VCP disease- fulminant classic amyotrophic lateral sclerosis (ALS) associated with upper and lower motor neuron signs, progressive generalized muscular weakness, spasticity, weight loss, dyspnea, spastic dysarthria, positive jaw jerk, exaggerated gag reflex, and neuropathological findings of extensive spinal motor neuron degeneration with loss of spinal anterior horn cells, gliosis and mislocalization of TDP-43 positive inclusions

Summary

Introduction

Inclusion Body Myopathy associated with Paget’s disease of bone and Frontotemporal Dementia (IBMPFD OMIM#167320) [1]) or more recently described as multisystem proteinopathy [2] is an autosomal dominant disorder caused by mutations in the Valosin Containing Protein (VCP) gene first identified by Watts, et al [3,4]. ALS: Amyotrophic Lateral Sclerosis; AchR: Acetylcholine Receptor; EMG: Electromyography; FUS: Fused in Sarcoma/Translated in Liposarcoma; FTD: Frontotemporal Dementia; IBMPFD: Inclusion Body Myopathy, Paget’s Disease of Bone and Frontotemporal Dementia; IBMFRS: Inclusion Body Myopathy Functional Rating Scale; MRI: Magnetic Resonance Imaging; MuSK: Muscle Specific Kinase; PDB: Paget’s Disease of Bone; SNIP: Spontaneous Nasal Inspiratory Pressure; SOD1: Cu/Zn-Superoxide Dismutase; TDP 43: TAR DNA-Binding Protein 43; VCP: Valosin Containing Protein

Results

Conclusion