Knockout of PA200 improves proteasomal degradation and myelination in a proteotoxic neuropathy.

The cellular response to a decrease in protein degradation by 26S proteasomes in chronic diseases is poorly understood. Pharmacological inhibition of proteasomes increases the expression of proteasome subunits and Proteasome Activator 200 (PA200), an alternative proteasome activator. In the S63del mouse model of the peripheral neuropathy Charcot Marie Tooth 1B (CMT1B), proteasomal protein degradation is decreased and proteasome gene expression is increased. Here, we show an increase in PA200 and PA200-bound proteasomes in the peripheral nerves of S63del mice. To test genetically whether the upregulation of PA200 was compensatory, we generated S63del//PA200-/- mice. Unexpectedly, in the sciatic nerves of these mice, there was greater proteasomal protein degradation than in S63del, less polyubiquitinated proteins and markers of the unfolded protein response, and a greater amount of assembled, active 26S proteasomes. These changes were not seen in PA200-/- controls and were therefore specific to the neuropathy. Furthermore, in S63del//PA200-/- mice, myelin thickness and nerve conduction were restored to WT levels. Thus, the upregulation of PA200 is maladaptive in S63del mice and its genetic ablation prevented neuropathy.

How should newer therapeutic agents be incorporated into the treatment of patients with myasthenia gravis?

Generalized myasthenia gravis (gMG) is a postsynaptic neuromuscular junction disorder that results in fatigable muscle weakness. The traditional treatment approach includes the use of acetylcholinesterase inhibitors, corticosteroids, and steroid-sparing immunosuppressant therapies (ISTs) for chronic management, whereas exacerbations and crises are managed with intravenous immunoglobulin (IVIg) and plasma exchange (PLEX). Over the past 6 years, four new therapeutic agents with novel immunological mechanisms of action-complement and neonatal Fc receptor (FcRn) inhibition-were approved as a result of clinically significant improvement in gMG symptoms of those treated with these newer agents in Phase 3 clinical trials. At present, it is unclear when and in whom to initiate these therapeutic agents and how to integrate them into the current treatment paradigm. When selecting a newer therapeutic agent, we use a simple equation: Value = Clinical Improvement/(Cost + Side Effects + Treatment Burden), which guides our decision-making. We consider using these novel therapeutic agents in two specific clinical situations. Firstly, the newer agents are fast-acting, suggesting they can be used in clinically unstable patients as "bridge therapy," and secondly, they provide additional options for those patients considered treatment-refractory. There are downsides, however, including treatment cost, unique side effect profiles, and intravenous and subcutaneous drug administration (though for some, this may be an advantage). As additional drugs enter the marketplace with unique mechanisms of action, routes of administration, and dosing schedules, the placement of the novel therapeutic agents in the gMG treatment algorithm will likely evolve.

The economic burden of individuals living with generalized myasthenia gravis and facing social determinants of health challenges.

Objective: Better understanding the impact of social determinants of health (SDOH) barriers from the patient perspective is crucial to improve holistic patient support in generalized myasthenia gravis (gMG), a rare autoimmune disorder with high disease and treatment burden. The objective of this study was to identify economic challenges experienced by individuals living with gMG and SDOH barriers to better address current unmet needs. Methods: Adults (18-75 years) living with gMG and experiencing SDOH barriers in the United States were recruited to a mixed-methods study including qualitative interviews and a web-based quantitative survey. Quotas were implemented to include a balanced spread of baseline demographic categories including insurance type, living environment, and employment status among the study sample. Direct and indirect economic challenges were identified by degree of concern. Results: The survey was completed by 38 individuals living with gMG, the majority of whom were enrolled in public insurance and not employed. The most commonly reported major economic concerns were managing funds for emergency care (66%), loss of income (61%), and non-medical expenses (58%), highlighting the diversity of economic challenges. Individuals who were using public insurance plans, living in non-urban environments, and unemployed experienced pronounced challenges around managing non-medical costs and accessing government assistance. Conclusion: Both direct and indirect costs were emphasized as major concerns among individuals living with gMG and SDOH barriers. Increasing access to relevant, personalized, and holistic resources, including care management, should be prioritized to improve disease management and outcomes for individuals living with gMG.

Phase 2 trial in acetylcholine receptor antibody-positive myasthenia gravis of transition from intravenous to subcutaneous immunoglobulin: The MGSCIg study.

BACKGROUND AND PURPOSE: Data on maintenance therapy with subcutaneous immunoglobulin (SCIg) in myasthenia gravis (MG) are limited. We report on transitioning acetylcholine receptor (AChR) antibody-positive (Ab+) MG patients on stable intravenous immunoglobulin (IVIg) regimens as part of routine clinical care to SCIg 1:1.2. METHODS: This multicenter North American open-label prospective investigator-initiated study had two components: the IVIg Stabilization Period (ISP) enrolling patients already on IVIg as part of routine clinical care (Weeks -10 to -1), followed by transition of stable MG subjects to SCIg in the Experimental Treatment Period (ETP; Weeks 0 to 12). We hypothesized that >65% of patients entering the ETP would have a stable Quantitative Myasthenia Gravis (QMG) score from Week 0 to Week 12. Secondary outcome measures included other efficacy measures, safety, tolerability, IgG levels, and treatment satisfaction. RESULTS: We recruited 23 patients in the ISP, and 22 entered the ETP. A total of 12 subjects (54.5%) were female, and 18 (81.8%) were White, with mean age 51.4 ± 17 years. We obtained Week 12 ETP QMG data on 19 of 22; one subject withdrew from ETP owing to clinical deterioration, and two subjects withdrew due to dislike of needles. On primary analysis, 19 of 22 participants (86.4%, 95% confidence interval = 0.72-1.00) were treatment successes using last observation carried forward (p = 0.018). Secondary efficacy measures supported MG stability. SCIg was safe and well tolerated, and IgG levels were stable. Treatment satisfaction was comparable between ISP and ETP. CONCLUSIONS: MG patients on IVIg as part of their routine clinical care remained stable on monthly IVIg dosage, and most maintained similar disease stability on SCIg.

A Symptoms and Signs Approach to the Patient With Neuromuscular Weakness.

PURPOSE OF REVIEW: Muscle weakness is a common feature of many neuromuscular disorders. This article outlines a symptoms and signs approach to the patient presenting with neuromuscular weakness, highlighting key aspects of the clinical history and examination. RECENT FINDINGS: The past several years have seen a dramatic increase in the ability to test for many inherited and autoimmune neuromuscular disorders more reliably and accurately. Similarly, numerous targeted therapies have been recently approved to treat previously untreatable disorders. Therefore, timely and accurate diagnosis is essential so that patients can receive appropriate therapy, ultimately leading to better clinical outcomes. SUMMARY: Muscle weakness is a common symptom resulting from dysfunction that can occur at any level of the neuraxis and is a cardinal feature of many neuromuscular disorders. An accurate and meticulous history and a thorough neurologic examination are paramount in localizing the lesion in order to generate a differential diagnosis and guide appropriate ancillary testing. The patient's age at symptom onset, any identified inciting factors, tempo of symptom progression, pattern of weakness, and associated symptoms and signs are all important diagnostic clues in the evaluation of a patient presenting with muscle weakness.

A new mouse model of Charcot-Marie-Tooth 2J neuropathy replicates human axonopathy and suggest alteration in axo-glia communication.

Myelin is essential for rapid nerve impulse propagation and axon protection. Accordingly, defects in myelination or myelin maintenance lead to secondary axonal damage and subsequent degeneration. Studies utilizing genetic (CNPase-, MAG-, and PLP-null mice) and naturally occurring neuropathy models suggest that myelinating glia also support axons independently from myelin. Myelin protein zero (MPZ or P0), which is expressed only by Schwann cells, is critical for myelin formation and maintenance in the peripheral nervous system. Many mutations in MPZ are associated with demyelinating neuropathies (Charcot-Marie-Tooth disease type 1B [CMT1B]). Surprisingly, the substitution of threonine by methionine at position 124 of P0 (P0T124M) causes axonal neuropathy (CMT2J) with little to no myelin damage. This disease provides an excellent paradigm to understand how myelinating glia support axons independently from myelin. To study this, we generated targeted knock-in MpzT124M mutant mice, a genetically authentic model of T124M-CMT2J neuropathy. Similar to patients, these mice develop axonopathy between 2 and 12 months of age, characterized by impaired motor performance, normal nerve conduction velocities but reduced compound motor action potential amplitudes, and axonal damage with only minor compact myelin modifications. Mechanistically, we detected metabolic changes that could lead to axonal degeneration, and prominent alterations in non-compact myelin domains such as paranodes, Schmidt-Lanterman incisures, and gap junctions, implicated in Schwann cell-axon communication and axonal metabolic support. Finally, we document perturbed mitochondrial size and distribution along MpzT124M axons suggesting altered axonal transport. Our data suggest that Schwann cells in P0T124M mutant mice cannot provide axons with sufficient trophic support, leading to reduced ATP biosynthesis and axonopathy. In conclusion, the MpzT124M mouse model faithfully reproduces the human neuropathy and represents a unique tool for identifying the molecular basis for glial support of axons.

Testosterone Therapy for Dropped Head Syndrome: A Case Report.

ABSTRACT: Dropped head syndrome (DHS) is an impairment of neck extension resulting in a chin-on-chest deformity. DHS is rarely seen but a major hindrance to daily function in affected patients. DHS has been associated with movement disorders, neuromuscular disorders, and electrolyte and endocrine abnormalities. DHS has also been seen in survivors of Hodgkin lymphoma (HL) years after irradiation. HL survivors are also at risk for endocrine hypogonadism after chemotherapy. We present the case of a 58-year-old male HL survivor with dropped head and limited strength in his atrophic neck extensor muscles. Laboratory testing and imaging, nerve conduction studies, electromyography, and muscle biopsy of the neck extensors revealed myopathic and neurogenic changes. Conservative management was unsuccessful. With a desire to avoid surgical fixation, he asked his primary care physician to check his testosterone levels, which returned as low normal. Within 4 months of starting testosterone therapy, he no longer experienced dropped head.

Like a Game of Chess, Every Move Matters: The Role of Antibodies in the Myasthenia Gravis Treatment Landscape.

Symptoms and disease pathophysiology of myasthenia gravis (MG) vary considerably with each patient, and their individual preferences and priorities add to the need for individualized treatment of this autoimmune disease. Research in MG has grown substantially in recent years. New treatments have the potential of being both effective and well tolerated, addressing the trade-off of choosing either efficacy or tolerability when selecting treatments. Promising investigational treatments that may become available in the future may allow more patients than ever before to achieve an asymptomatic state, with the ultimate goal being to turn off abnormal antibody production.

Clinical Significance of Serum Albumin and Implications of FcRn Inhibitor Treatment in IgG-Mediated Autoimmune Disorders.

Serum albumin (SA), the most abundant soluble protein in the body, maintains plasma oncotic pressure and regulates the distribution of vascular fluid and has a range of other important functions. The goals of this review are to expand clinical knowledge regarding the functions of SA, elucidate effects of dysregulated SA concentration, and discuss the clinical relevance of hypoalbuminemia resulting from various diseases. We discuss potential repercussions of SA dysregulation on cholesterol levels, liver function, and other processes that rely on its homeostasis, as decreased SA concentration has been shown to be associated with increased risk for cardiovascular disease, hyperlipidemia, and mortality. We describe the anti-inflammatory and antioxidant properties of SA, as well as its ability to bind and transport a plethora of endogenous and exogenous molecules. SA is the primary serum protein involved in binding and transport of drugs and as such has the potential to affect, or be affected by, certain medications. Of current relevance are antibody-based inhibitors of the neonatal Fc receptor (FcRn), several of which are under clinical development to treat immunoglobulin G (IgG)-mediated autoimmune disorders; some have been shown to decrease SA concentration. FcRn acts as a homeostatic regulator of SA by rescuing it, as well as IgG, from intracellular degradation via a common cellular recycling mechanism. Greater clinical understanding of the multifunctional nature of SA and the potential clinical impact of decreased SA are needed; in particular, the potential for certain treatments to reduce SA concentration, which may affect efficacy and toxicity of medications and disease progression.

A Review of Disease Mechanisms and Current and Emerging Treatment Options for Generalized Myasthenia Gravis.

Generalized myasthenia gravis (gMG) is a disease resulting from impaired neuromuscular transmission due to presence of antibodies that block acetylcholine receptors. Autoantibodies to acetylcholine receptors directly impair the activity of ion channels that conduct nerve impulses, and cross-link acetylcholine receptors resulting in complement-mediated destruction, further worsening functional impairment and patient quality of life. Although current treatments for gMG include thymectomy, immunosuppressive therapies, intravenous immunoglobulins, and plasmapheresis, among other strategies, none of these treatments reduces all immunoglobulin G subfractions. However, with the novel neonatal Fc receptor antagonist efgartigimod, levels of all immunoglobulin G subfractions are reduced, addressing an important aspect of the underlying pathophysiology of gMG. Through this program, clinicians will consider novel mechanisms in gMG therapy, learn to counsel patients on the changing landscape of gMG therapies, and find ways to incorporate the latest efficacy and safety data into practice.

The humanistic burden of myasthenia gravis: A systematic literature review.

BACKGROUND/OBJECTIVES: While the clinical manifestations of myasthenia gravis (MG) are well understood, its humanistic impact is not. The objective of this systematic literature review (SLR) was to provide a comprehensive understanding of the humanistic burden of MG with regards to psychological symptoms and health-related quality of life (HRQoL) according to patients and caregivers. METHODS: A systematic search was conducted on December 27, 2019, in MEDLINE and Embase to identify English-language studies that were published from January 1, 2009-December 27, 2019 and presented relevant information on the humanistic burden among adults with MG and their caregivers. Title/abstract and full-text screening was performed by two investigators, with any discrepancies resolved by a third investigator. RESULTS: Sixty-seven publications were included in the SLR. Compared with the general population, patients with MG experienced worse HRQoL. Studies reporting on psychological symptoms of MG, including depression, anxiety, fatigue, and sleep, were heterogeneous in terms of the scales and instruments used to assess patients, as well as the patient populations themselves. However, in general those with more severe symptoms and hospitalization days had worse depression and anxiety, and fatigue and sleep improved with disease remission and/or improvement. Scores were worse for females compared with males and where evaluated, HRQoL scores generally improved following treatment. CONCLUSION: While the literature demonstrates that symptoms associated with MG get better with disease improvement and remission, additional options in efficacious therapy that adequately address the disease-related symptoms and also improve HRQoL may contribute to beneficial outcomes in a greater number of patients with MG.

Validation of myasthenia gravis diagnosis in the older Medicare population.

INTRODUCTION/AIMS: Administrative health data has been increasingly used to study the epidemiology of myasthenia gravis (MG) but a case ascertainment algorithm is lacking. We aimed to develop a valid algorithm for identifying MG patients in the older population with Medicare coverage. METHODS: Local older patients (age ≥65) who received healthcare at the Cleveland Clinic and possessed Medicare coverage in 2014 and 2015 were selected. Potential MG patients were identified by using a combination of ICD9 or ICD10 codes for MG and MG-related text-word search. Diagnosis was categorized as "definite MG", "possible MG" or "non-MG" after review of clinical summaries by 5 neuromuscular specialists. Performances of various algorithms were tested by use of the definite MG cohort as a reference standard, and calculation of sensitivity, specificity, and predictive values. RESULTS: A total of 118 988 local older patients with Medicare coverage were identified. Usage of MG ICD codes and text-word search resulted in 125 patients with definite and 67 with possible MG. A total of 45 algorithms involving ICD usage, medication prescription, and specialty visit were tested. The best performing algorithm was identified as 2 office visits using MG ICD codes separated by at least 4 weeks or 1 hospital discharge and 1 office visit each using MG ICD codes separated by at least 4 weeks within the two-year period, resulting in a sensitivity and positive predictive value of 80% for identifying definite MG patients. DISCUSSION: Algorithms using ICD codes can reliably identify patients with MG with a high degree of accuracy.

Utilization of MG-ADL in myasthenia gravis clinical research and care.

The Myasthenia Gravis Activities of Living (MG-ADL) scale is an 8-item patient-reported scale that measures myasthenia gravis (MG) symptoms and functional status. The objective of the current review is to summarize the psychometric properties of the MG-ADL and published evidence of MG-ADL use. A targeted literature review for published studies of the MG-ADL was conducted using a database and gray literature search. A total of 48 publications and 35 clinical trials were included. Studies indicated that the MG-ADL is a reliable and valid measure that has been used as an outcome in clinical trials and observational studies to measure MG symptoms and response to treatment. While most often used as a secondary endpoint in clinical trials, its use as a primary endpoint has increased in recent years. The most common MG-ADL endpoint is change in MG-ADL score from baseline, although there has been an increase in the analysis of a responder threshold using the MG-ADL. A new concept of minimal symptom expression (MSE) has emerged more recently. Duration of treatment effect is another important construct that is being increasingly evaluated using the MG-ADL. The use of the MG-ADL as a primary endpoint in clinical trials and in responder threshold analyses to indicate treatment improvement has increased in recent years. MSE using the MG-ADL shows promise in helping to determine success of treatment and may be the aspirational goal of MG treatment for the future once validated, particularly given the evolving treatment landscape in MG.

Raising cGMP restores proteasome function and myelination in mice with a proteotoxic neuropathy.

Agents that raise cyclic guanosine monophosphate (cGMP) by activating protein kinase G increase 26S proteasome activities, protein ubiquitination and degradation of misfolded proteins. Therefore, they may be useful in treating neurodegenerative and other diseases caused by an accumulation of misfolded proteins. Mutations in myelin protein zero (MPZ) cause the peripheral neuropathy Charcot-Marie-Tooth type 1B (CMT1B). In peripheral nerves of a mouse model of CMT1B, where the mutant MPZS63del is expressed, proteasome activities are reduced, mutant MPZS63del and polyubiquitinated proteins accumulate and the unfolded protein response (p-eif2α) is induced. In HEK293 cells, raising cGMP stimulated ubiquitination and degradation of MPZS63del, but not of wild-type MPZ. Treating S63del mice with the phosphodiesterase 5 inhibitor, sildenafil-to raise cGMP-increased proteasome activity in sciatic nerves and reduced the levels of polyubiquitinated proteins, the proteasome reporter ubG76V-GFP and p-elF2α. Furthermore, sildenafil treatment reduced the number of amyelinated axons, and increased myelin thickness and nerve conduction velocity in sciatic nerves. Thus, agents that raise cGMP, including those widely used in medicine, may be useful therapies for CMT1B and other proteotoxic diseases.

Prohibitin 1 is essential to preserve mitochondria and myelin integrity in Schwann cells.

In peripheral nerves, Schwann cells form myelin and provide trophic support to axons. We previously showed that the mitochondrial protein prohibitin 2 can localize to the axon-Schwann-cell interface and is required for developmental myelination. Whether the homologous protein prohibitin 1 has a similar role, and whether prohibitins also play important roles in Schwann cell mitochondria is unknown. Here, we show that deletion of prohibitin 1 in Schwann cells minimally perturbs development, but later triggers a severe demyelinating peripheral neuropathy. Moreover, mitochondria are heavily affected by ablation of prohibitin 1 and demyelination occurs preferentially in cells with apparent mitochondrial loss. Furthermore, in response to mitochondrial damage, Schwann cells trigger the integrated stress response, but, contrary to what was previously suggested, this response is not detrimental in this context. These results identify a role for prohibitin 1 in myelin integrity and advance our understanding about the Schwann cell response to mitochondrial damage.

Macrophages Expressing GALC Improve Peripheral Krabbe Disease by a Mechanism Independent of Cross-Correction.

Many therapies for lysosomal storage disorders rely on cross-correction of lysosomal enzymes. In globoid cell leukodystrophy (GLD), mutations in GALC cause psychosine accumulation, inducing demyelination, a neuroinflammatory "globoid" reaction and neurodegeneration. The efficiency of GALC cross-correction in vivo, the role of the GALC substrate galactosylceramide, and the origin of psychosine are poorly understood. Using a novel GLD model, we show that cross-correction does not occur efficiently in vivo and that Galc-deficient Schwann cells autonomously produce psychosine. Furthermore, macrophages require GALC to degrade myelin, as Galc-deficient macrophages are transformed into globoid cells by exposure to galactosylceramide and produce a more severe GLD phenotype. Finally, hematopoietic stem cell transplantation in patients reduces globoid cells in nerves, suggesting that the phagocytic response of healthy macrophages, rather than cross-correction, contributes to the therapeutic effect. Thus, GLD may be caused by at least two mechanisms: psychosine-induced demyelination and secondary neuroinflammation from galactosylceramide storage in macrophages.