Multisystem proteinopathy: Where myopathy and motor neuron disease converge

Korb, Manisha Kak; Kimonis, Virginia; Mozaffar, Tahseen

doi:10.1002/mus.27097

Cited by 44 publications

(53 citation statements)

References 128 publications

(203 reference statements)

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“…The term multisystem proteinopathy (MSP) was introduced to define a group of hereditary diseases characterized by deleterious protein accumulation in brain and spinal cord neurons, skeletal muscle, and other organs (27). Initially encompassing the inclusion body myopathy, Paget disease, frontotemporal dementia (IBMPFD) motor neuron disease spectrum, which includes VCP, HNRNPA2B1, and HNRNPA1 genes (MSP1, MSP2, and MSP3, respectively), MSP classification now incorporates the pathologies associated to SQSTM1 (MSP4), MATR3 (MSP5), TIA1, and eventually OPTN genes (28).…”

Section: Discussionmentioning

confidence: 99%

First Family of MATR3-Related Distal Myopathy From Italy: The Role of Muscle Biopsy in the Diagnosis and Characterization of a Still Poorly Understood Disease

et al. 2021

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Mutations in the MATR3 gene are associated to distal myopathy with vocal cord and pharyngeal weakness (VCPDM), as well as familiar and sporadic motor neuron disease. To date, 12 VCPDM families from the United States, Germany, Japan, Bulgary, and France have been described in the literature. Here we report an Italian family with a propositus of a 40-year-old woman presenting progressive bilateral foot drop, rhinolalia, and distal muscular atrophy, without clinical signs of motor neuron affection. Her father, deceased some years before, presented a similar distal myopathy phenotype, while her 20-year-old son is asymptomatic. Myopathic changes with vacuolization were observed in muscle biopsy from the propositus. These results, together with the peculiar clinical picture, lead to MATR3 gene sequencing, which revealed a heterozygous p.S85C mutation in the propositus. The same mutation was found in her son. Over a 5-year follow-up, progression is mild in the propositus, while her son remains asymptomatic. Clinical, radiological, and pathological data of our propositus are presented and compared to previously reported cases of VCPDM. VCPDM turns out to be a quite homogenous phenotype of late-onset myopathy associated to p.S85C mutation in MATR3 gene. MATR3-related pathology, encompassing myopathy and motor neuron disease, represents an illustrative example of multisystem proteinopathy (MSP), such as other diseases associated to mutations in VCP, HNRNPA2B1, HNRNPA1, and SQSTM1 genes. The present report contributes to a further characterization of this still poorly understood pathology and points out the diagnostic utility of muscle biopsy in challenging cases.

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Section: Discussionmentioning

confidence: 99%

First Family of MATR3-Related Distal Myopathy From Italy: The Role of Muscle Biopsy in the Diagnosis and Characterization of a Still Poorly Understood Disease

et al. 2021

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“…Over 50 heterozygous missense mutations in VCP, mapped to chromosome 9p13.3-12, cause autosomal dominant VCP MSP [4,7,8]. VCP mutations are the most common in genetically diagnosed families with MSP and are designated MSP1 [1]. Other genes associated with MSP may cause a clinically indistinguishable phenotype.…”

Section: Geneticsmentioning

confidence: 99%

“…The previously used term, inclusion body myopathy associated with Paget’s disease of bone (and frontotemporal dementia (IBMPFD), is no longer favored given the other phenotypes that may occur. Other genes that are associated with a similarly presenting MSP syndrome include heterogeneous nuclear ribonucleoprotein A2B1 and A1 ( hnRNPA2B1, hnRNPA1 ), sequestosome 1 ( SQSTM1 ), matrin 3 ( MATR3 ), T-cell restricted intracellular antigen 1 ( TIA1 ), optineurin ( OPTN ), annexin 11 ( ANXA11 ), and profilin 1 ( PFN1I ), many of which share common pathophysiology of disruption of RNA stress granule function or autophagic degradation, and patients presenting with these MSP syndromes may benefit from similar diagnostic and treatment strategies [ 1 , 2 ].…”

Section: Introductionmentioning

confidence: 99%

Development of a standard of care for patients with valosin-containing protein associated multisystem proteinopathy

Korb

Peck²,

Alfano

et al. 2022

Orphanet J Rare Dis

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Valosin-containing protein (VCP) associated multisystem proteinopathy (MSP) is a rare inherited disorder that may result in multisystem involvement of varying phenotypes including inclusion body myopathy, Paget’s disease of bone (PDB), frontotemporal dementia (FTD), parkinsonism, and amyotrophic lateral sclerosis (ALS), among others. An international multidisciplinary consortium of 40+ experts in neuromuscular disease, dementia, movement disorders, psychology, cardiology, pulmonology, physical therapy, occupational therapy, speech and language pathology, nutrition, genetics, integrative medicine, and endocrinology were convened by the patient advocacy organization, Cure VCP Disease, in December 2020 to develop a standard of care for this heterogeneous and under-diagnosed disease. To achieve this goal, working groups collaborated to generate expert consensus recommendations in 10 key areas: genetic diagnosis, myopathy, FTD, PDB, ALS, Charcot Marie Tooth disease (CMT), parkinsonism, cardiomyopathy, pulmonology, supportive therapies, nutrition and supplements, and mental health. In April 2021, facilitated discussion of each working group’s conclusions with consensus building techniques enabled final agreement on the proposed standard of care for VCP patients. Timely referral to a specialty neuromuscular center is recommended to aid in efficient diagnosis of VCP MSP via single-gene testing in the case of a known familial VCP variant, or multi-gene panel sequencing in undifferentiated cases. Additionally, regular and ongoing multidisciplinary team follow up is essential for proactive screening and management of secondary complications. The goal of our consortium is to raise awareness of VCP MSP, expedite the time to accurate diagnosis, define gaps and inequities in patient care, initiate appropriate pharmacotherapies and supportive therapies for optimal management, and elevate the recommended best practices guidelines for multidisciplinary care internationally.

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“…As VCP -related phenotype has been expanding, IBMPFD term is currently misused in favor of the most inclusive and recently coined multisystem proteinopathy (MSP) ( 118 ). MSP is not restricted to VCP mutations, but other genes with similar functions have been shown to cause this severe disease ( 119 ).…”

Section: Phenotypic Pleiotropy: the Case Of Vcpmentioning

confidence: 99%

The Role of VCP Mutations in the Spectrum of Amyotrophic Lateral Sclerosis—Frontotemporal Dementia

et al. 2022

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Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurological diseases which, respectively, and primarily affect motor neurons and frontotemporal lobes. Although they can lead to different signs and symptoms, it is now evident that these two pathologies form a continuum and that hallmarks of both diseases can be present within the same person in the so-called ALS-FTD spectrum. Many studies have focused on the genetic overlap of these pathologies and it is now clear that different genes, such as C9orf72, TARDBP, SQSTM1, FUS, and p97/VCP can be mutated in both the diseases. VCP was one of the first genes associated with both FTD and ALS representing an early example of gene overlapping. VCP belongs to the type II AAA (ATPases Associated with diverse cellular activities) family and is involved in ubiquitinated proteins degradation, autophagy, lysosomal clearance and mitochondrial quality control. Since its numerous roles, mutations in this gene lead to different pathological features, first and foremost TDP-43 mislocalization. This review aims to outline recent findings on VCP roles and on how its mutations are linked to the neuropathology of ALS and FTD.

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Multisystem proteinopathy: Where myopathy and motor neuron disease converge

Cited by 44 publications

References 128 publications

First Family of MATR3-Related Distal Myopathy From Italy: The Role of Muscle Biopsy in the Diagnosis and Characterization of a Still Poorly Understood Disease

First Family of MATR3-Related Distal Myopathy From Italy: The Role of Muscle Biopsy in the Diagnosis and Characterization of a Still Poorly Understood Disease

Development of a standard of care for patients with valosin-containing protein associated multisystem proteinopathy

The Role of VCP Mutations in the Spectrum of Amyotrophic Lateral Sclerosis—Frontotemporal Dementia

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