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Article ; Online: Genetic-Based Treatment Strategies for Muscular Dystrophy and Congenital Myopathies.

Findlay, Andrew R / Weihl, Conrad C

Continuum (Minneapolis, Minn.)

2022 Volume 28, Issue 6, Page(s) 1800–1816

Abstract: Purpose of review: This article discusses the foundational concepts of genetic treatment strategies employed in neuromuscular medicine, as well as the importance of genetic testing as a requirement for applying gene-based therapy.: Recent findings: ... ...

Abstract	Purpose of review: This article discusses the foundational concepts of genetic treatment strategies employed in neuromuscular medicine, as well as the importance of genetic testing as a requirement for applying gene-based therapy. Recent findings: Gene therapies have become a reality for several neuromuscular disorders. Exon-skipping and (in Europe) ribosomal read-through approaches are currently available to a subset of patients with Duchenne muscular dystrophy. Microdystrophin gene replacement has shown promise and is nearing the final stages of clinical trials. Numerous gene-based therapies for other muscular dystrophies and congenital myopathies are progressing toward approval as well. Summary: Muscular dystrophies and congenital myopathies are a heterogenous group of hereditary muscle disorders. Confirming a diagnosis with genetic testing is not only critical for guiding management, but also an actual prerequisite for current and future gene therapies. Recessive loss-of-function or dominant haploinsufficiency disorders may be treated with gene replacement strategies, whereas dominant negative and toxic gain-of-function disorders are best addressed with a variety of knockdown approaches. It is important to recognize that many therapeutics are mutation specific and will only benefit a subset of individuals with a specific disease.
MeSH term(s)	Humans ; Muscular Dystrophy, Duchenne/genetics ; Genetic Testing ; Exons ; Genetic Therapy
Language	English
Publishing date	2022-12-26
Publishing country	United States
Document type	Review ; Journal Article
ISSN	1538-6899
ISSN (online)	1538-6899
DOI	10.1212/CON.0000000000001203
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Article ; Online: Sporadic Inclusion Body Myositis and Other Rimmed Vacuolar Myopathies.

Weihl, Conrad C

Continuum (Minneapolis, Minn.)

2019 Volume 25, Issue 6, Page(s) 1586–1598

Abstract: Purpose of review: This article reviews the clinical, laboratory, and histopathologic features of sporadic inclusion body myositis (IBM) and explores its pathogenic overlap with inherited myopathies that have IBM-like pathology.: Recent findings: ... ...

Abstract	Purpose of review: This article reviews the clinical, laboratory, and histopathologic features of sporadic inclusion body myositis (IBM) and explores its pathogenic overlap with inherited myopathies that have IBM-like pathology. Recent findings: Sporadic IBM is the most common acquired muscle disease in patients older than 50 years of age and is becoming more prevalent because of the increasing age of the population, the emerging development of more inclusive diagnostic criteria, and the advent of a diagnostic autoantibody. No effective therapy is known, and the pathogenic mechanism remains unclear. Some pathogenic insight can be gleaned from other myopathies with pathologic similarities or hereditary inclusion body myopathies. Although clinically distinct from sporadic IBM, preclinical models of hereditary inclusion body myopathy have offered an opportunity to move some therapies toward clinical development. Summary: Patients with sporadic IBM experience significant morbidity, and the disease is associated with a large unmet medical need. As therapies are developed, improved diagnosis will be essential. Early diagnosis relies on awareness, clinical history, physical examination, laboratory features, and appropriate muscle biopsy processing. Future research is needed to understand the natural history, identify genetic risk factors, and validate biomarkers to track disease progression. These steps are essential as we move toward therapeutic interventions.
MeSH term(s)	Aged ; Distal Myopathies/diagnosis ; Distal Myopathies/genetics ; Distal Myopathies/therapy ; Humans ; Male ; Middle Aged ; Myositis, Inclusion Body/diagnosis ; Myositis, Inclusion Body/genetics ; Myositis, Inclusion Body/therapy
Language	English
Publishing date	2019-12-11
Publishing country	United States
Document type	Case Reports ; Journal Article ; Review
ISSN	1538-6899
ISSN (online)	1538-6899
DOI	10.1212/CON.0000000000000790
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Article ; Online: VCP Inhibition Augments NLRP3 Inflammasome Activation.

Sharma, Ankita / Dhavale, Dhruva D / Kotzbauer, Paul T / Weihl, Conrad C

Inflammation

2024

Abstract: Lysosomal membrane permeabilization caused either via phagocytosis of particulates or the uptake of protein aggregates can trigger the activation of NLRP3 inflammasome- an intense inflammatory response that drives the release of the pro-inflammatory ... ...

Abstract	Lysosomal membrane permeabilization caused either via phagocytosis of particulates or the uptake of protein aggregates can trigger the activation of NLRP3 inflammasome- an intense inflammatory response that drives the release of the pro-inflammatory cytokine IL-1β by regulating the activity of CASPASE 1. The maintenance of lysosomal homeostasis and lysosomal membrane integrity is facilitated by the AAA+ ATPase, VCP/p97 (VCP). However, the relationship between VCP and NLRP3 inflammasome activity remains unexplored. Here, we demonstrate that the VCP inhibitors, DBeQ and ML240 elicit the activation of NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs) when used as activation stimuli. Moreover, genetic inhibition of VCP or VCP chemical inhibition enhances lysosomal membrane damage and augments LLoME-associated NLRP3 inflammasome activation in BMDMs. Similarly, VCP inactivation also augments NLRP3 inflammasome activation mediated by aggregated alpha-synuclein fibrils and lysosomal damage. These data suggest that VCP is a participant in the complex regulation of NLRP3 inflammasome activation.
Language	English
Publishing date	2024-04-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	434408-x
ISSN	1573-2576 ; 0360-3997
ISSN (online)	1573-2576
ISSN	0360-3997
DOI	10.1007/s10753-024-02013-6
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Article ; Online: Loss-of-function mutation in VCP mimics the characteristic pathology as in FTLD-TARDBP.

Wani, Abubakar / Weihl, Conrad C

Autophagy

2021 Volume 17, Issue 12, Page(s) 4502–4503

Abstract: VCP (valosin containing protein), a member of the AAA+ protein family, is critical for many cellular processes and functions. Dominant VCP mutations cause a rare neurodegenerative disease known as multisystem proteinopathy (MSP). The spectrum of ... ...

Abstract	VCP (valosin containing protein), a member of the AAA+ protein family, is critical for many cellular processes and functions. Dominant VCP mutations cause a rare neurodegenerative disease known as multisystem proteinopathy (MSP). The spectrum of mechanisms causing fronto-temporal dementia with TARDBP/TDP-43 inclusions (FTLD-TARDBP) by VCP disease mutations remains unclear. Our recent work identified VCP activity as a mediator of FTLD-TARDBP. Specifically, brain atrophy, behavioral changes, neuronal loss, gliosis, and TARDBP pathology were observed in
MeSH term(s)	Animals ; Autophagy/genetics ; DNA-Binding Proteins/metabolism ; Frontotemporal Lobar Degeneration/genetics ; Frontotemporal Lobar Degeneration/metabolism ; Humans ; Lysosomes/metabolism ; Mice ; Mutation/genetics ; Neurodegenerative Diseases/genetics ; Neurodegenerative Diseases/metabolism ; Proteomics ; Valosin Containing Protein/genetics ; Valosin Containing Protein/metabolism
Chemical Substances	DNA-Binding Proteins ; VCP protein, human (EC 3.6.4.6) ; Valosin Containing Protein (EC 3.6.4.6) ; Vcp protein, mouse (EC 3.6.4.6)
Language	English
Publishing date	2021-10-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2021.1985880
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Article ; Online: Exploring hand and upper limb function in patients with inclusion body myositis (IBM).

Hunn, Stephanie / Alfano, Lindsay / Seiffert, Michelle / Weihl, Conrad C

Neuromuscular disorders : NMD

2023 Volume 33, Issue 8, Page(s) 643–650

Abstract: Inclusion body myositis (IBM) is an inflammatory myopathy characterized by progressive weakness of knee extensors and finger flexors. Many patients lose independence with fine motor tasks; however, a gap remains as to how these deficits correlate with ... ...

Abstract	Inclusion body myositis (IBM) is an inflammatory myopathy characterized by progressive weakness of knee extensors and finger flexors. Many patients lose independence with fine motor tasks; however, a gap remains as to how these deficits correlate with performance on functional outcome measures. We describe functional hand impairments as measured by performance-based outcome measures in a cross-sectional sample of 74 patients with IBM. Subjects completed a series of outcome measures (Functional Dexterity Test (FDT), Performance of the Upper Limb (PUL), and Sollerman Hand Function Test (SHFT)) alongside a collection of patient reported outcomes (PROs). Assessments were compared to standard IBM measurements, including grip strength and IBM Functional Rating Scale (IBMFRS). FDT and SHFT demonstrated significant correlations to grip (p<0.001; Spearman correlations r=0.48-0.70). Significant correlation was found between all functional outcome measures and IBMFRS (p<0.001; Spearman correlations r=0.51-0.77), as well as PRO Upper Extremity Scale for IBM (IBM-PRO) (p<0.05; Spearman correlations r=0.55-0.73). Non-ambulatory patients demonstrated significantly weaker grip (p<0.001), resulting in lower PUL scores and increased FDT completion times (p<0.001). Collectively, these assessments may provide insight to understanding functional limitations of the hands and potentially allow for more inclusive clinical trials with future validation of hand assessments in IBM.
MeSH term(s)	Humans ; Myositis, Inclusion Body/diagnosis ; Cross-Sectional Studies ; Upper Extremity ; Hand ; Hand Strength ; Myositis
Language	English
Publishing date	2023-06-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1077681-3
ISSN	1873-2364 ; 0960-8966
ISSN (online)	1873-2364
ISSN	0960-8966
DOI	10.1016/j.nmd.2023.06.009
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Article ; Online: Current and Future Approaches to Classify VUSs in LGMD-Related Genes.

Li, Chengcheng / Haller, Gabe / Weihl, Conrad C

Genes

2022 Volume 13, Issue 2

Abstract: Next-generation sequencing (NGS) has revealed large numbers of genetic variants in LGMD-related genes, with most of them classified as variants of uncertain significance (VUSs). VUSs are genetic changes with unknown pathological impact and present a ... ...

Abstract	Next-generation sequencing (NGS) has revealed large numbers of genetic variants in LGMD-related genes, with most of them classified as variants of uncertain significance (VUSs). VUSs are genetic changes with unknown pathological impact and present a major challenge in genetic test interpretation and disease diagnosis. Understanding the phenotypic consequences of VUSs can provide clinical guidance regarding LGMD risk and therapy. In this review, we provide a brief overview of the subtypes of LGMD, disease diagnosis, current classification systems for investigating VUSs, and a potential deep mutational scanning approach to classify VUSs in LGMD-related genes.
MeSH term(s)	Genetic Testing ; High-Throughput Nucleotide Sequencing ; Mutation
Language	English
Publishing date	2022-02-19
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13020382
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Article: Current and Future Approaches to Classify VUSs in LGMD-Related Genes

Li, Chengcheng / Haller, Gabe / Weihl, Conrad C.

Genes. 2022 Feb. 19, v. 13, no. 2

2022

Abstract	Next-generation sequencing (NGS) has revealed large numbers of genetic variants in LGMD-related genes, with most of them classified as variants of uncertain significance (VUSs). VUSs are genetic changes with unknown pathological impact and present a major challenge in genetic test interpretation and disease diagnosis. Understanding the phenotypic consequences of VUSs can provide clinical guidance regarding LGMD risk and therapy. In this review, we provide a brief overview of the subtypes of LGMD, disease diagnosis, current classification systems for investigating VUSs, and a potential deep mutational scanning approach to classify VUSs in LGMD-related genes.
Keywords	disease diagnosis ; phenotype ; risk ; therapeutics
Language	English
Dates of publication	2022-0219
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13020382
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Patterns of Clinical Progression Among Patients With Autosomal Recessive Limb-Girdle Muscular Dystrophy: A Systematic Review.

Cheung, Antoinette / Audhya, Ivana F / Szabo, Shelagh M / Friesen, Michael / Weihl, Conrad C / Gooch, Katherine L

Journal of clinical neuromuscular disease

2023 Volume 25, Issue 2, Page(s) 65–80

Abstract: Objectives: As the clinical course of autosomal recessive limb-girdle muscular dystrophy (LGMDR) is highly variable, this study characterized the frequency of loss of ambulation (LOA) among patients by subtype (LGMDR1, LGMDR2, LGMDR3-6, LGMDR9, LGMDR12) ...

Abstract	Objectives: As the clinical course of autosomal recessive limb-girdle muscular dystrophy (LGMDR) is highly variable, this study characterized the frequency of loss of ambulation (LOA) among patients by subtype (LGMDR1, LGMDR2, LGMDR3-6, LGMDR9, LGMDR12) and progression to cardiac and respiratory involvement among those with and without LOA. Methods: Systematic literature review. Results: From 2929 abstracts screened, 418 patients were identified with ambulatory status data (LOA: 265 [63.4%]). Cardiac and/or respiratory function was reported for 142 patients (34.0%; all with LOA). Among these, respiratory involvement was most frequent in LGMDR3-6 (74.1%; mean [SD] age 23.9 [11.0] years) and cardiac in LGMDR9 (73.3%; mean [SD] age 23.7 [17.7] years). Involvement was less common in patients without LOA except in LGMDR9 (71.4% respiratory and 52.4% cardiac). Conclusions: This study described the co-occurrence of LOA, cardiac, and respiratory involvement in LGMDR and provides greater understanding of the clinical progression of LGMDR.
MeSH term(s)	Humans ; Young Adult ; Adult ; Muscle, Skeletal ; Muscular Dystrophies, Limb-Girdle/genetics ; Disease Progression
Language	English
Publishing date	2023-11-15
Publishing country	United States
Document type	Systematic Review ; Journal Article
ZDB-ID	1454947-5
ISSN	1537-1611 ; 1522-0443
ISSN (online)	1537-1611
ISSN	1522-0443
DOI	10.1097/CND.0000000000000461
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Article ; Online: 272nd ENMC international workshop: 10 Years of progress - revision of the ENMC 2013 diagnostic criteria for inclusion body myositis and clinical trial readiness. 16-18 June 2023, Hoofddorp, The Netherlands.

Lilleker, James B / Naddaf, Elie / Saris, Christiaan G J / Schmidt, Jens / de Visser, Marianne / Weihl, Conrad C

Neuromuscular disorders : NMD

2024 Volume 37, Page(s) 36–51

Abstract: Since the publication of the 2013 European Neuromuscular Center (ENMC) diagnostic criteria for Inclusion Body Myositis (IBM), several advances have been made regarding IBM epidemiology, pathogenesis, diagnostic tools, and clinical trial readiness. Novel ... ...

Abstract	Since the publication of the 2013 European Neuromuscular Center (ENMC) diagnostic criteria for Inclusion Body Myositis (IBM), several advances have been made regarding IBM epidemiology, pathogenesis, diagnostic tools, and clinical trial readiness. Novel diagnostic tools include muscle imaging techniques such as MRI and ultrasound, and serological testing for cytosolic 5'-nucleotidase-1A antibodies. The 272nd ENMC workshop aimed to develop new diagnostic criteria, discuss clinical outcome measures and clinical trial readiness. The workshop started with patient representatives highlighting several understudied symptoms and the urge for a timely diagnosis. This was followed by presentations from IBM experts highlighting the new developments in the field. This report is composed of two parts, the first part providing new diagnostic criteria on which consensus was achieved. The second part focuses on the use of outcome measures in clinical practice and clinical trials, highlighting current limitations and outlining the goals for future studies.
MeSH term(s)	Humans ; Myositis, Inclusion Body/therapy ; Myositis, Inclusion Body/drug therapy ; Netherlands ; Outcome Assessment, Health Care ; Magnetic Resonance Imaging ; Consensus ; Myositis/diagnosis
Language	English
Publishing date	2024-03-07
Publishing country	England
Document type	Clinical Conference
ZDB-ID	1077681-3
ISSN	1873-2364 ; 0960-8966
ISSN (online)	1873-2364
ISSN	0960-8966
DOI	10.1016/j.nmd.2024.03.001
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Article ; Online: Molecular and cellular basis of genetically inherited skeletal muscle disorders.

Dowling, James J / Weihl, Conrad C / Spencer, Melissa J

Nature reviews. Molecular cell biology

2021 Volume 22, Issue 11, Page(s) 713–732

Abstract: Neuromuscular disorders comprise a diverse group of human inborn diseases that arise from defects in the structure and/or function of the muscle tissue - encompassing the muscle cells (myofibres) themselves and their extracellular matrix - or muscle ... ...

Abstract	Neuromuscular disorders comprise a diverse group of human inborn diseases that arise from defects in the structure and/or function of the muscle tissue - encompassing the muscle cells (myofibres) themselves and their extracellular matrix - or muscle fibre innervation. Since the identification in 1987 of the first genetic lesion associated with a neuromuscular disorder - mutations in dystrophin as an underlying cause of Duchenne muscular dystrophy - the field has made tremendous progress in understanding the genetic basis of these diseases, with pathogenic variants in more than 500 genes now identified as underlying causes of neuromuscular disorders. The subset of neuromuscular disorders that affect skeletal muscle are referred to as myopathies or muscular dystrophies, and are due to variants in genes encoding muscle proteins. Many of these proteins provide structural stability to the myofibres or function in regulating sarcolemmal integrity, whereas others are involved in protein turnover, intracellular trafficking, calcium handling and electrical excitability - processes that ensure myofibre resistance to stress and their primary activity in muscle contraction. In this Review, we discuss how defects in muscle proteins give rise to muscle dysfunction, and ultimately to disease, with a focus on pathologies that are most common, best understood and that provide the most insight into muscle biology.
MeSH term(s)	Dystrophin/genetics ; Humans ; Muscle Fibers, Skeletal/metabolism ; Muscle Fibers, Skeletal/pathology ; Muscle Proteins/genetics ; Muscle, Skeletal/metabolism ; Muscle, Skeletal/pathology ; Muscular Dystrophy, Duchenne/genetics ; Muscular Dystrophy, Duchenne/pathology ; Mutation/genetics ; Neuromuscular Diseases/genetics ; Neuromuscular Diseases/pathology
Chemical Substances	Dystrophin ; Muscle Proteins
Language	English
Publishing date	2021-07-13
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2031313-5
ISSN	1471-0080 ; 1471-0072
ISSN (online)	1471-0080
ISSN	1471-0072
DOI	10.1038/s41580-021-00389-z
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