Annals of Indian Academy of Neurology
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Year : 2023  |  Volume : 26  |  Issue : 1  |  Page : 85-86

Rapidly progressive ALS with atypical parkinsonism: An unusual case of multisystem proteinopathy from India

1 Department of Neurology, Bombay Hospital and Medical Research Center, Mumbai, Maharashtra, India
2 Department of Neurology, J.L.N. Medical College, Ajmer, Rajasthan, India
3 Department of Clinical Neurophysiology (ENMG &EP), Bombay Hospital and Medical Research Center, Mumbai, Maharashtra, India

Date of Submission06-Oct-2022
Date of Decision03-Nov-2022
Date of Acceptance18-Nov-2022
Date of Web Publication26-Dec-2022

Correspondence Address:
Satish V Khadilkar
110, New Wing, Bombay Hospital, 12, New Marine Lines, Mumbai - 400 020, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aian.aian_819_22

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How to cite this article:
Halani HA, Saini PK, Chavan P, Mansukhani KA, Khadilkar SV. Rapidly progressive ALS with atypical parkinsonism: An unusual case of multisystem proteinopathy from India. Ann Indian Acad Neurol 2023;26:85-6

How to cite this URL:
Halani HA, Saini PK, Chavan P, Mansukhani KA, Khadilkar SV. Rapidly progressive ALS with atypical parkinsonism: An unusual case of multisystem proteinopathy from India. Ann Indian Acad Neurol [serial online] 2023 [cited 2023 Feb 1];26:85-6. Available from:

Dear Editor,

We report the first case of multisystem proteinopathy (MSP) from India and document an uncommon phenotypic expression. Our patient had pathogenic variants in the valosin-containing protein (VCP) gene. Clinically, there was a peculiar combination of rapidly progressive amyotrophic lateral sclerosis and atypical parkinsonism along with Paget's disease of the bone. There was no evidence of myopathy. The disease seems uncommon in Asia and has been documented sparsely. The term “multisystem proteinopathy (MSP)” applies to a composite of rare inherited disorders affecting muscle, bone, and nervous systems in different combinations. The usual inheritance pattern is autosomal dominant and rarely sporadic. The earliest descriptions of VCP-related diseases were given by Kimonis et al.[1] and Watts et al.[2] They first reported the peculiar combination of hereditary inclusion body myopathy (h-IBM), Paget's disease of bone (PDB), and dementia (FTD), which then came to be recognized as the classical phenotype of the disease known as IBMPFD. Thereafter, the disease has been increasingly reported, largely in Western countries. The term MSP currently incorporates various phenotypic aspects.[3] The major phenotypes known within the spectrum are myopathy, PDB, FTD-ALS, Parkinson's disease, and peripheral neuropathy. Apart from the VCP, other genes now included in the spectrum are heterogeneous nuclear ribonucleoprotein A2B1 and A1 (hnRNPA2B1 and hnRNPA1) genes, Sequestosome 1 (SQSTM1), Matrin-3 (MATR3), T-cell restricted intracellular antigen 1 (TIA1), and optineurin (OPTN).[4],[5] The common underlying molecular mechanism is that of disruption of the cellular protein degradation pathways resulting in protein misfolding and aggregation.[4]

A 47-year female presented with limb-girdle weakness along with neck flexor weakness and dysphagia progressive for six months. She simultaneously developed mask-like facies, hypophonia, bradykinesia, and neck dystonia (mild torticollis). In addition, there were postural tremors and bilateral pyramidal signs in form of hyperreflexia, spasticity, and pseudobulbar features. Extraocular movements showed vertical gaze restriction, slow saccades, and impaired vertical optokinetic nystagmus. A mixture of bulbar dysfunction including tongue fasciculations as well as pseudobulbar dysfunction was evident. She was given a trial of levodopa with adequate dose titration in view of the parkinsonian features, to which she failed to respond. The disease course was rapidly progressive over six months, leading to fully established ALS with a near anarthric state. The cognitive evaluation did not reveal any significant abnormalities, though the examination was limited because of the anarthric state. Electromyography showed anterior horn cell involvement evidenced by denervation and fibrillation potentials in proximal and distal muscles of all four limbs [Figure 1]. Serum CK was normal, and alkaline phosphatase was elevated. Skull X-rays and MRI brain showed abnormal widening and signal within the diploic spaces of the calvarial bones and narrowing of the skull foramen, strongly suggestive of Paget's disease of bone. The clinical exome sequencing showed a heterozygous likely pathogenic variant at exon 5, c.475C>A (p.Arg159Ser) in domain 2 (CDC48) of VCP protein. There was no such family history present, and none of the family members have been tested for genetic mutation.
Figure 1: Electromyography traces from trapezius showing fibrillations and positive sharp waves and FDI muscles showing active denervation

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MSP has been infrequently documented in the Asian continent with only a few case reports[5] available. There is no documentation of MSP from India to date. Further, this patient had an unusual set of clinical findings.

Firstly, our patient did not have a myopathy which is common in MSP. The previously studied cohorts[6],[7] of VCP mutations have reported myopathy (~90%) as the most common manifestation of MSP, which was strikingly absent in this patient. Though the pattern of weakness (symmetrical limb-girdle and axial) raised the possibility of a myopathy, upper and lower motor neuron involvement was clearly evident clinically and electrophysiologically. There was no clinical or electrophysiological evidence of a myopathy; hence, a biopsy of the muscle was not ordered. Secondly, the course and tempo of progression of ALS were quite rapid with severe bulbar involvement, rarely seen in MSP.[6] It appears from the literature that VCP mutations account for 1%–2% of familial ALS, but their occurrence in sporadic cases is unknown.[8] Our patient represents one such rare instance of sporadic ALS with VCP mutation. Thirdly, another distinct feature was the presence of atypical parkinsonism in the patient, along with supranuclear gaze palsy, which makes this phenotypic combination as part of MSP rarer. Overall, VCP mutations are uncommon causes of PD.[9] Thus, the patient exhibited two uncommon features, namely ALS and atypical parkinsonism, and did not have a myopathy.

To date, about 50 different VCP gene mutations have been reported, the majority of them being heterozygous missense mutations.[4] The general lack of genotype–phenotype correlation is observed across various studies. The mutation in the present case, i.e., c.475C>A (p.Arg159Ser), is previously reported with phenotypes of IBMPFD, FTD/ALS, and hereditary spastic paraparesis (HSP)-PDB, LGMD, and neuropathy.[10] Our patient further adds to this list. One intriguing observation can be made as to the affection of the same codons with different mutations (R155H, R155C, R159C, R159G) has led to varying phenotypes on different occasions.[2] This may point to the presence of mutational hotspots in VCP gene, with possible vulnerability to modifier genes and/or environmental or yet unknown factors leading to heterogeneous phenotypes.

We wish to, through our report, bring to attention the existence of this rare condition in the Indian population and document the further expansion of the phenotypic spectrum of multisystem proteinopathy. The documentation is relevant as new insights into the molecular mechanisms are expected to help the therapeutic advancements.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Kimonis VE, Kovach MJ, Waggoner B, Leal S, Salam A, Rimer L, et al. Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone. Genet Med 2000;2:232-41.  Back to cited text no. 1
Watts GD, Wymer J, Kovach MJ, Mehta SG, Mumm S, Darvish D, et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 2004;36:377-81.  Back to cited text no. 2
Evangelista T, Weihl CC, Kimonis V, Lochmüller H, Clemen C, Deshaies R, et al. 215th ENMC international workshop VCP-related multi-system proteinopathy (IBMPFD) 13–15 November 2015, Heemskerk, The Netherlands. Neuromuscul Disord 2016;26:535-47.  Back to cited text no. 3
Korb MK, Kimonis VE, Mozaffar T. Multisystem proteinopathy: Where myopathy and motor neuron disease converge. Muscle Nerve 2021;63:442-54.  Back to cited text no. 4
Inoue M, Iida A, Hayashi S, Mori-Yoshimura M, Nagaoka A, Yoshimura S, et al. Two novel VCP missense variants identified in Japanese patients with multisystem proteinopathy. Hum Genome Var 2018;5:1-5.  Back to cited text no. 5
Al-Obeidi E, Al-Tahan S, Surampalli A, Goyal N, Wang AK, Hermann A, et al. Genotype-phenotype study in patients with valosin-containing protein mutations associated with multisystem proteinopathy. Clin Genet 2018;93:119-25.  Back to cited text no. 6
Figueroa-Bonaparte S, Hudson J, Barresi R, Polvikoski T, Williams T, Töpf A, et al. Mutational spectrum and phenotypic variability of VCP-related neurological disease in the UK. J Neurol Neurosurg Psychiatry 2016;87:680-1.  Back to cited text no. 7
Koppers M, van Blitterswijk MM, Vlam L, Rowicka PA, van Vught PW, Groen EJ, et al. VCP mutations in familial and sporadic amyotrophic lateral sclerosis. Neurobiol Aging 2012;33:837-e7.  Back to cited text no. 8
Baizabal-Carvallo JF, Jankovic J. Parkinsonism, movement disorders and genetics in frontotemporal dementia. Nat Rev Neurol 2016;12:175-85.  Back to cited text no. 9
Wong TH, Pottier C, Hondius DC, Meeter LH, Van Rooij JG, Melhem S, et al. Three VCP mutations in patients with frontotemporal dementia. J Alzheimer's Dis 2018;65:1139-46.  Back to cited text no. 10


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