Agrin and low-density lipoprotein-related receptor protein 4 antibodies in amyotrophic lateral sclerosis patients

Rivner, Michael H.; Liu, Siyang; Quarles, Brandy; Fleenor, Brandi; Shen, Chengyong; Pan, Jin-Xiu; Mei, Lin

doi:10.1002/mus.25438

Cited by 41 publications

(47 citation statements)

References 17 publications

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“…Previous studies using electromyographic recordings did not identify sex-specific differences in the global time course and pattern of motor axon loss in SOD1 G93A mice (Hegedus et al, 2009) or in ALS patients (McComas et al, 1971;Dengler et al, 1990;Dantes and McComas, 1991;Schmied et al, 1999). Interestingly though, a recent study identified that women with ALS were twice as likely of having antibodies against two NMJ components, agrin and LRP4 (Rivner et al, 2017). Furthermore, Moloney et al (2017) identified sex-specific differences in botulinum toxin-induced axonal sprouting in mice, with female mice notably exhibiting more sprouting from ALS-vulnerable fast-fatigable MUs.…”

Section: Introductionmentioning

confidence: 95%

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Martineau

Polo

Velde

et al. 2020

eNeuro

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Progressive loss of neuromuscular junctions (NMJs) is an early event in amyotrophic lateral sclerosis (ALS), preceding the global degeneration of motor axons and being accompanied by new axonal sprouting within the same axonal arbor. Some aspects of ALS onset and progression seem to be affected by sex in animal models of the disease. However, whether there are sex-specific differences in the pattern or time course of NMJ loss and repair within single motor axons remains unknown. We performed further analysis of a previously published in vivo dataset, obtained from male and female SOD1 G37R mice. We found that NMJ losses are as frequent in male and female motor axons but, intriguingly, axonal sprouting is more frequent in female than male mice, resulting in a net increase of axonal arborization. Interestingly, these numerous new axonal branches in female mice are associated with a slightly faster decline in grip strength, increased NMJ denervation, and reduced a-motor neuron survival. Collectively, these results suggest that excessive axonal sprouting and motorunit (MU) expansion in female SOD1 G37R mice are maladaptive during ALS progression.Sex-specific differences in amyotrophic lateral sclerosis (ALS) progression have been identified in patients and in some animal models of the disease. However, the physio-pathologic changes underlying these disparities remain poorly defined. In this study, we identified that the pattern of motor axon retraction and regrowth in skeletal muscles is a novel factor to consider in our understanding of sex-linked differences in ALS. Analysis of single motor axons in a model of ALS identified that female motor axons were more likely to form compensatory branches, which was associated with a worse phenotype. These surprising findings highlight the necessity to more systematically evaluate the prevalence of sex-specific differences across animal models of ALS and in patients.

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Section: Introductionmentioning

confidence: 95%

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Martineau

Polo

Velde

et al. 2020

eNeuro

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“…6 The possible links between MG and ALS may be represented by immunological dysfunction and shared autoantibodies against neuromuscular junction proteins including low-density lipoprotein receptor-related protein 4. 10 In a previous review of 12 patients with ALS after MG, males were affected twice as often as females, which might reflect a higher incidence of ALS in the male population. 4 Myasthenic symptoms, AChR-ab positivity, and RNST results are not different from those usually found in MG. 4 In addition, clinical features that are specific to ALS after MG might not exist, and the region of ALS onset seems to vary, independently of previous myasthenia symptoms.…”

Section: Discussionmentioning

confidence: 97%

Uncommon coexistence of myasthenia gravis and amyotrophic lateral sclerosis

Cho

Yang

Jeong

et al. 2019

Ann Clin Neurophysiol

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Myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) are distinct disorders. ALS affects motor neurons that control muscle movement, while MG controls communication between neurons and muscles, which occurs at neuromuscular junctions. However, on rare occasions, ALS develops after MG and vice versa. The coexistence of the two diseases represents a diagnostic challenge and requires thoughtful interpretation of clinical features. We present the case of a 53-year-old Korean male who developed ALS after MG, confirmed by clinical and electrophysiological follow-up.Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction characterized by fluctuating muscle weakness and fatigability. By contrast, amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons in the brain and the spinal cord. MG and ALS are rare diseases, with incidence rates of 2.40/100,000 and 1.20/100,000, respectively, in South Korea. 1,2 However, the co-occurrence of MG and ALS has been described in a few reports, suggesting a possible association of the two conditions. 3-5 There is also evidence that several autoimmune disorders, including MG, are associated with a small but increased risk for ALS. 6 A recent study reported that 0.75% of patients with ALS were also affected by MG, a number that is higher than expected. 5 Here, we report the case of a patient with seropositive ocular MG who later developed ALS. CASEA 53-year-old male presented with ptosis and intermittent diplopia in May 2016. According to his medical history, he underwent thymectomy and postoperative radiotherapy ORCID Eun Bin Cho

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“…LRP4 antibodies were detected in 23.1% of an Italian and Greek population of ALS patients and 14.9% of an Israeli population . In an American population, 9.8% had LRP4 antibodies and 13.8% had agrin antibodies . Interestingly, the incident rate of these antibodies in ALS patients appeared to be higher than that in MG patients.…”

Section: Agrin and Lrp4 Antibodies In Alsmentioning

confidence: 88%

“…67 In an American population, 9.8% had LRP4 antibodies and 13.8% had agrin antibodies. 68 Interestingly, the incident rate of these antibodies in ALS patients appeared to be higher than that in MG patients. However, whether the antibodies are related to ALS development course or clinical symptoms and whether they could serve as a biomarker warrant further studies of larger cohorts with more disease controls.…”

Section: Agrin and Lrp4 Antibodies In Alsmentioning

confidence: 95%

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Agrin and LRP4 antibodies as new biomarkers of myasthenia gravis

Yan

Xing

Xiong

et al. 2018

Annals of the New York Academy of Sciences

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Myasthenia gravis (MG) is a common disorder that affects the neuromuscular junction. It is caused by antibodies against acetylcholine receptor and muscle-specific tyrosine kinase; however, some MG patients do not have antibodies against either of the proteins. Recent studies have revealed antibodies against agrin and its receptor LRP4-both critical for neuromuscular junction formation and maintenance-in MG patients from various populations. Results from experimental autoimmune MG animal models indicate that anti-LRP4 antibodies are causal to MG. Clinical studies have begun to reveal the significance of the new biomarkers. With their identification, MG appears to be a complex disease entity that can be classified into different subtypes with different etiology, each with unique symptoms. Future systematic studies of large cohorts of well-diagnosed MG patients are needed to determine whether each subtype of patients would respond to different therapeutic strategies. Results should contribute to the goal of precision medicine for MG patients. Anti-agrin and anti-LRP4 antibodies are also detectable in some patients with amyotrophic lateral sclerosis or Lou Gehrig's disease; however, whether they are a cause or response to the disorder remains unclear.

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Agrin and low-density lipoprotein-related receptor protein 4 antibodies in amyotrophic lateral sclerosis patients

Cited by 41 publications

References 17 publications

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Sex-Specific Differences in Motor-Unit Remodeling in a Mouse Model of ALS

Uncommon coexistence of myasthenia gravis and amyotrophic lateral sclerosis

Agrin and LRP4 antibodies as new biomarkers of myasthenia gravis

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