Inflammatory Demyelination In Central Nervous System Research Articles

Obesity, gut microbiota, and multiple sclerosis: Unraveling the connection.

Obesity is associated with chronic mild-grade systemic inflammation and neuroinflammation. Obesity in early childhood and adolescence is also a significant risk factor for multiple sclerosis (MS) development. However, the underlying mechanisms that explain the link between obesity and MS development are not fully explored. An increasing number of studies call attention to the importance of gut microbiota as a leading environmental risk factor mediating inflammatory central nervous system demyelination, particularly in MS. Obesity and high-calorie diet are also associated with disturbances in gut microbiota. Therefore, gut microbiota alteration is a plausible connection between obesity and the increased risk of MS development. A greater understanding of this connection could provide additional therapeutic opportunities, like dietary interventions, microbiota-derived products, and exogenous antibiotics and probiotics. This review summarizes the current evidence regarding the relationships between MS, obesity, and gut microbiota. We discuss gut microbiota as a potential link between obesity and increased risk for MS. Additional experimental studies and controlled clinical trials targeting gut microbiota are warranted to unravel the possible causal relationship between obesity and increased risk of MS.

Seeing Double: a Case of a Massive Type B2 Thymoma Presenting with Pseudo-Internuclear Ophthalmoplegia (P9-13.004)

<h3>Objective:</h3> NA <h3>Background:</h3> Thymomas are rare, malignant epithelial cell tumors usually diagnosed in the 5th decade. Median tumor size is approximately 5 cm. An estimated 20 – 25% present as paraneoplastic myasthenia gravis (MG) with positive acetylcholine receptor antibodies (AChR Ab). A rarely described presentation of MG is pseudo-internuclear ophthalmoplegia (p-INO). This presents a diagnostic conundrum as INO is discretely localizable to the brainstem and more commonly associated with cerebrovascular disease or demyelination. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 27-year-old man presented with a three-month history of binocular horizontal diplopia, night sweats, weight loss and generalized weakness. The rapid progression of weakness occurred almost immediately following the COVID-19 vaccine. Examination demonstrated bilateral INO, worrisome for central nervous system inflammatory demyelination. An MRI of brain and cervical spine showed no evidence of demyelination, but the thoracic MRI showed a large soft tissue mass in the right hemithorax. A chest CT demonstrated a massive multilobulated mass encompassing almost the entirety of the right thoracic cavity. Given the mass in conjunction with the neurological symptoms, AchR Ab was obtained demonstrating positivity (51.2 nmol/L) for MG. Biopsy revealed thymoma type B2 and positron emission tomography showed metastatic disease, stage IVa. The patient was treated with four cycles of cisplatin, cyclophosphamide, and doxorubicin with prednisone, as well as a thymus gland resection. He was additionally started on pyridostigmine 60mg every 4 hours which improved his p-INO and generalized weakness. <h3>Conclusions:</h3> This case represents a rare presentation of myasthenia gravis in a young patient with p-INO. The incidental finding of a large thymoma (measuring ~30cm) discovered on thoracic spine imaging for work-up of demyelinating disease prompts alternative diagnostic consideration when presented with MRI-negative INO. It also evokes the question, should there be more emphasis on expediting CT chest imaging to evaluate for thymoma in patients with antibody positive MG. <b>Disclosure:</b> Dr. Hart has nothing to disclose. Maja Ostojic has nothing to disclose. Dr. Farrell has nothing to disclose. Dr. Esch has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen.

A GABA-producing probiotic for the protection of CNS demyelinating inflammation

Abstract The gut-microbiota-brain axis has emerged as a critical pathway in the regulation of neuroinflammation. The gut microbiome regulates the severity of many experimental models of autoimmune central nervous system (CNS) demyelinating inflammatory diseases. Our most recent findings demonstrate that the microbiota of mice from different sources affects the severity of CNS inflammatory demyelination. Neuroinflammation triggered in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, modified the gut microbiota composition. The disease progression resulted in a significant reduction in the relative abundances of members of lactic acid bacteria when compared to healthy control mice. Among the altered taxa, bacteria producing gamma-aminobutyric acid (GABA) were significantly reduced. We hypothesized that modifying the microbiota with a probiotic while increasing intestinal GABA levels would reduce EAE’s severity. We genetically engineered a Lactococcus lactis probiotic that produces excessed levels of GABA. Real-time quantitative PCR analysis demonstrated an elevated expression of glutamic acid decarboxylase (GAD). GABA-specific ELISA showed a significant increase in neurotransmitter production when exposed to increasing concentrations of glutamic acid and time. In vivo, five times/week oral gavages with 5 × 108 CFU/mouse of GAD L. lactis but not with empty-plasmid carrier L. lactis protects against EAE in mice compared with sham-treated mice and prevents weight loss of animals while modulating the microbiome’s composition. Our results show that the increase of GABA at the intestinal level with the oral treatment with a probiotic strain protects against neuroinflammation in the CNS. Supported by grant from NIH (R15 NS107743)

Novel contributors to B cell activation during inflammatory CNS demyelination; An oNGOing process

Over the past two decades, the development of targeted immunotherapeutics for relapsing-remitting multiple sclerosis has been successfully orchestrated through the efficacious modulation of neuroinflammatory outcomes demonstrated in the experimental autoimmune encephalomyelitis (EAE) model. In this model, the focus of developing immunomodulatory therapeutics has been demonstrated through their effectiveness in modifying the pro-inflammatory Th1 and Th17-dependent neuropathological outcomes of demyelination, oligodendrocytopathy and axonal dystrophy. However, recent successful preclinical and clinical trials have advocated for the significance of B cell-dependent immunopathogenic responses and has led to the development of novel biologicals that target specific B cell phenotypes. In this context, a new molecule, B-cell activating factor (BAFF), has emerged as a positive regulator of B cell survival and differentiation functioning through various signaling pathways and potentiating the activity of various receptor complexes through pleiotropic means. One possible cognate receptor for BAFF includes the Nogo receptor (NgR) and its homologs, previously established as potent inhibitors of axonal regeneration during central nervous system (CNS) injury and disease. In this review we provide current evidence for BAFF-dependent signaling through the NgR multimeric complex, elucidating their association within the CNS compartment and underlying the importance of these potential pathogenic molecular regulators as possible therapeutic targets to limit relapse rates and potentially MS progression.

Exploring the Gut-Brain Axis for the Control of CNS Inflammatory Demyelination: Immunomodulation by Bacteroides fragilis' Polysaccharide A.

The symbiotic relationship between animals and their resident microorganisms has profound effects on host immunity. The human microbiota comprises bacteria that reside in the gastrointestinal tract and are involved in a range of inflammatory and autoimmune diseases. The gut microbiota’s immunomodulatory effects extend to extraintestinal tissues, including the central nervous system (CNS). Specific symbiotic antigens responsible for inducing immunoregulation have been isolated from different bacterial species. Polysaccharide A (PSA) of Bacteroides fragilis is an archetypical molecule for host-microbiota interactions. Studies have shown that PSA has beneficial effects in experimental disease models, including experimental autoimmune encephalomyelitis (EAE), the most widely used animal model for multiple sclerosis (MS). Furthermore, in vitro stimulation with PSA promotes an immunomodulatory phenotype in human T cells isolated from healthy and MS donors. In this review, we discuss the current understanding of the interactions between gut microbiota and the host in the context of CNS inflammatory demyelination, the immunomodulatory roles of gut symbionts. More specifically, we also discuss the immunomodulatory effects of B. fragilis PSA in the gut-brain axis and its therapeutic potential in MS. Elucidation of the molecular mechanisms responsible for the microbiota’s impact on host physiology offers tremendous promise for discovering new therapies.

X linked Charcot-Marie-Tooth disease and multiple sclerosis: emerging evidence for an association

ObjectiveX linked Charcot-Marie-Tooth disease (CMTX) is a hereditary neuropathy caused by mutations in GJB1 coding for connexin-32, a gap junction protein expressed in Schwann cells, but also found in oligodendrocytes....

Defining distinct features of anti-MOG antibody associated central nervous system demyelination

Extensive research over the last decades basically failed to identify a common cause of noninfectious inflammatory central nervous system (CNS) demyelinating disease. To a great extent, this may reflect that the group of inflammatory CNS demyelinating disorders likely contains multiple pathogenetically distinct disease entities. Indeed, the greatest success so far in deciphering the pathogenesis of a CNS demyelinating disorder resulted from the discovery of anti-aquaporin (AQP)-4 antibodies (ab), which allowed progressive delineation of neuromyelitis optica (NMO), formerly considered a variant of the most common CNS demyelinating disorder, multiple sclerosis (MS), as a distinct disease. Nowadays, AQP-4+ NMO is considered an autoimmune astrocytopathy, in which CNS demyelination occurs only as a consequence of a primary destruction of astrocytes. Delineating these patients concomitantly revealed that not all patients presenting with clinically NMO-suggestive disease phenotype express AQP-4 ab, which created the pathogenetically undefined category of NMO spectrum disorders (NMOSD). Recent investigations discovered that a subgroup of these AQP-4– NMOSD patients produce an ab response against myelin oligodendrocyte glycoprotein (MOG), a molecule expressed on the outer lamella of the myelin sheath. Using pathophysiologically meaningful cell-based assays, this humoral response is extremely rare in adult MS and absent in classical AQP-4+ NMO, sharply differentiating the evolving group from both established disorders. In this review, we summarize available clinical, immunological and histopathological data on patients with MOG+ CNS demyelinating disease. By comparing this clearly distinct cohort to AQP-4+ NMO as well as MS, we propose that MOG+ CNS demyelinating disease represents a distinct novel disease entity. In addition to its diagnostic value, we furthermore provide mechanistic insight on how this peripheral anti-MOG ab response may be of pathogenetic relevance in triggering acute flares of inflammatory CNS demyelination.

A bidirectional association between the gut microbiota and CNS disease in a biphasic murine model of multiple sclerosis

ABSTRACTThe gut microbiome plays an important role in the development of inflammatory disease as shown using experimental models of central nervous system (CNS) demyelination. Gut microbes influence the response of regulatory immune cell populations in the gut-associated lymphoid tissue (GALT), which drive protection in acute and chronic experimental autoimmune encephalomyelitis (EAE). Recent observations suggest that communication between the host and the gut microbiome is bidirectional. We hypothesized that the gut microbiota differs between the acute inflammatory and chronic progressive stages of a murine model of secondary-progressive multiple sclerosis (SP-MS). This non-obese diabetic (NOD) model of EAE develops a biphasic pattern of disease that more closely resembles the human condition when transitioning from relapsing-remitting (RR)-MS to SP-MS. We compared the gut microbiome of NOD mice with either mild or severe disease to that of non-immunized control mice. We found that the mice which developed a severe secondary form of EAE harbored a dysbiotic gut microbiome when compared with the healthy control mice. Furthermore, we evaluated whether treatment with a cocktail of broad-spectrum antibiotics would modify the outcome of the progressive stage of EAE in the NOD model. Our results indicated reduced mortality and clinical disease severity in mice treated with antibiotics compared with untreated mice. Our findings support the hypothesis that there are reciprocal effects between experimental CNS inflammatory demyelination and modification of the microbiome providing a foundation for the establishment of early therapeutic interventions targeting the gut microbiome that could potentially limit disease progression.

The Role of Peripheral CNS-Directed Antibodies in Promoting Inflammatory CNS Demyelination.

In central nervous system (CNS) demyelinating disorders, such as multiple sclerosis (MS), neuromyelitis optica (NMO) and related NMO-spectrum disorders (NMO-SD), a pathogenic role for antibodies is primarily projected into enhancing ongoing CNS inflammation by directly binding to target antigens within the CNS. This scenario is supported at least in part, by antibodies in conjunction with complement activation in the majority of MS lesions and by deposition of anti-aquaporin-4 (AQP-4) antibodies in areas of astrocyte loss in patients with classical NMO. A currently emerging subgroup of AQP-4 negative NMO-SD patients expresses antibodies against myelin oligodendrocyte glycoprotein (MOG), again suggestive of their direct binding to CNS myelin. However, both known entities of anti-CNS antibodies, anti-AQP-4- as well as anti-MOG antibodies, are predominantly found in the serum, which raises the questions why and how a humoral response against CNS antigens is raised in the periphery, and in a related manner, what pathogenic role these antibodies may exert outside the CNS. In this regard, recent experimental and clinical evidence suggests that peripheral CNS-specific antibodies may indirectly activate peripheral CNS-autoreactive T cells by opsonization of otherwise unrecognized traces of CNS antigen in peripheral compartments, presumably drained from the CNS by its newly recognized lymphatic system. In this review, we will summarize all currently available data on both possible roles of antibodies in CNS demyelinating disorders, first, directly enhancing damage within the CNS, and second, promoting a peripheral immune response against the CNS. By elaborating on the latter scenario, we will develop the hypothesis that peripheral CNS-recognizing antibodies may have a powerful role in initiating acute flares of CNS demyelinating disease and that these humoral responses may represent a therapeutic target in its own right.

Higher latitude is significantly associated with an earlier age of disease onset in multiple sclerosis

BackgroundAge at onset (AAO) in multiple sclerosis (MS) is an important marker of disease severity and may have prognostic significance. Understanding what factors can influence AAO may shed light on...

Rituximab induces clonal expansion of IgG memory B-cells in patients with inflammatory central nervous system demyelination

Rituximab, a monoclonal B-cell cytolytic antibody, has beneficial effects in patients with inflammatory demyelinating diseases. So far, little data exists on B-cell subset recovery after rituximab treatment in inflammatory demyelinating diseases of the central nervous system (CNS). To elucidate whether rituximab promotes qualitative changes in the IgG memory B-cell repertoire we performed a single cell analysis in three patients with CNS demyelination. We did not observe any qualitative changes but detected an increased clonal expansion in the IgG memory B-cell compartment after treatment, indicating that a single course of rituximab does not eliminate specific IgG memory B-cells.

Mechanisms of immunological tolerance in central nervous system inflammatory demyelination.

Multiple sclerosis is a complex autoimmune disease of the central nervous system that results in a disruption of the balance between pro-inflammatory and anti-inflammatory signals in the immune system. Given that central nervous system inflammation can be suppressed by various immunological tolerance mechanisms, immune tolerance has become a focus of research in the attempt to induce long-lasting immune suppression of pathogenic T cells. Mechanisms underlying this tolerance induction include induction of regulatory T cell populations, anergy and the induction of tolerogenic antigen-presenting cells. The intravenous administration of encephalitogenic peptides has been shown to suppress experimental autoimmune encephalomyelitis and induce tolerance by promoting the generation of regulatory T cells and inducing apoptosis of pathogenic T cells. Safe and effective methods of inducing long-lasting immune tolerance are essential for the treatment of multiple sclerosis. By exploring tolerogenic mechanisms, new strategies can be devised to strengthen the regulatory, anti-inflammatory cell populations thereby weakening the pathogenic, pro-inflammatory cell populations.

Matrine protects neuro-axon from CNS inflammation-induced injury

Neuro-axonal injury in the central nervous system (CNS) is one of the major pathological hallmarks of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has recently been shown to effectively suppress EAE through an anti-inflammatory mechanism. However, whether MAT can also protect myelin/axons from damage is not known. In the present study we show that, while untreated rats developed severe clinical disease, CNS inflammatory demyelination, and axonal damage, these clinical and pathological signs were significantly reduced by MAT treatment. Consistently, MAT treatment reduced the concentration of myelin basic protein in serum and downregulated expression of β-amyloid (Aβ) and B-site APP cleaving enzyme 1 (BACE-1) in the CNS. Further, the CNS of MAT-treated rats exhibited increased expression of brain-derived neurotrophic factor (BDNF), an important factor for neuronal survival and axonal growth. Together, these results demonstrate that MAT effectively prevented neuro-axonal injury, which can likely be attributed to inhibiting risk factors such as BACE-1 and upregulating neuroprotective factors such as BDNF. We conclude that this novel natural reagent, MAT, which effectively protects neuro-axons from CNS inflammation-induced damage, could be a potential candidate for the treatment of neurodegenerative diseases such as MS.

Outcomes after early administration of plasma exchange in pediatric central nervous system inflammatory demyelination.

The use of plasma exchange has been described in steroid-refractory central nervous system inflammatory demyelination in adults, but less has been published regarding its use in children and adolescents. We describe 12 children treated with plasma exchange for acute severe central nervous system inflammatory demyelination. The clinical attack leading to plasma exchange included symptomatic spinal cord lesions in 10 and symptomatic brainstem lesions in 2 children. Diagnosis was acute transverse myelitis in 6, relapsing-remitting multiple sclerosis in 5, and acute disseminated encephalomyelitis in 1 child. Adverse events related to plasma exchange necessitating intervention were observed in 3 children. Median Expanded Disability Status Scale score at plasma exchange start was 7.5 (range 4-9.5). At 3 months, 7 children were ambulatory without aid (Expanded Disability Status Scale score of ≤4). This retrospective study suggests that plasma exchange can be effective in ameliorating symptoms in severe pediatric central nervous system inflammatory demyelination, although lack of randomization or control group limits the ability to attribute this outcome entirely to plasma exchange.

Systemic Injection of Neural Stem/Progenitor Cells in Mice with Chronic EAE

Neural stem/precursor cells (NPCs) are a promising stem cell source for transplantation approaches aiming at brain repair or restoration in regenerative neurology. This directive has arisen from the extensive evidence that brain repair is achieved after focal or systemic NPC transplantation in several preclinical models of neurological diseases. These experimental data have identified the cell delivery route as one of the main hurdles of restorative stem cell therapies for brain diseases that requires urgent assessment. Intraparenchymal stem cell grafting represents a logical approach to those pathologies characterized by isolated and accessible brain lesions such as spinal cord injuries and Parkinson's disease. Unfortunately, this principle is poorly applicable to conditions characterized by a multifocal, inflammatory and disseminated (both in time and space) nature, including multiple sclerosis (MS). As such, brain targeting by systemic NPC delivery has become a low invasive and therapeutically efficacious protocol to deliver cells to the brain and spinal cord of rodents and nonhuman primates affected by experimental chronic inflammatory damage of the central nervous system (CNS). This alternative method of cell delivery relies on the NPC pathotropism, specifically their innate capacity to (i) sense the environment via functional cell adhesion molecules and inflammatory cytokine and chemokine receptors; (ii) cross the leaking anatomical barriers after intravenous (i.v.) or intracerebroventricular (i.c.v.) injection; (iii) accumulate at the level of multiple perivascular site(s) of inflammatory brain and spinal cord damage; and (i.v.) exert remarkable tissue trophic and immune regulatory effects onto different host target cells in vivo. Here we describe the methods that we have developed for the i.v. and i.c.v. delivery of syngeneic NPCs in mice with experimental autoimmune encephalomyelitis (EAE), as model of chronic CNS inflammatory demyelination, and envisage the systemic stem cell delivery as a valuable technique for the selective targeting of the inflamed brain in regenerative neurology.

Systemic injection of neural stem/progenitor cells in mice with chronic EAE.

Neural stem/precursor cells (NPCs) are a promising stem cell source for transplantation approaches aiming at brain repair or restoration in regenerative neurology. This directive has arisen from the extensive evidence that brain repair is achieved after focal or systemic NPC transplantation in several preclinical models of neurological diseases. These experimental data have identified the cell delivery route as one of the main hurdles of restorative stem cell therapies for brain diseases that requires urgent assessment. Intraparenchymal stem cell grafting represents a logical approach to those pathologies characterized by isolated and accessible brain lesions such as spinal cord injuries and Parkinson's disease. Unfortunately, this principle is poorly applicable to conditions characterized by a multifocal, inflammatory and disseminated (both in time and space) nature, including multiple sclerosis (MS). As such, brain targeting by systemic NPC delivery has become a low invasive and therapeutically efficacious protocol to deliver cells to the brain and spinal cord of rodents and nonhuman primates affected by experimental chronic inflammatory damage of the central nervous system (CNS). This alternative method of cell delivery relies on the NPC pathotropism, specifically their innate capacity to (i) sense the environment via functional cell adhesion molecules and inflammatory cytokine and chemokine receptors; (ii) cross the leaking anatomical barriers after intravenous (i.v.) or intracerebroventricular (i.c.v.) injection; (iii) accumulate at the level of multiple perivascular site(s) of inflammatory brain and spinal cord damage; and (i.v.) exert remarkable tissue trophic and immune regulatory effects onto different host target cells in vivo. Here we describe the methods that we have developed for the i.v. and i.c.v. delivery of syngeneic NPCs in mice with experimental autoimmune encephalomyelitis (EAE), as model of chronic CNS inflammatory demyelination, and envisage the systemic stem cell delivery as a valuable technique for the selective targeting of the inflamed brain in regenerative neurology.

RETRACTED: Neurotrophin 3 Transduction Augments Remyelinating and Immunomodulatory Capacity of Neural Stem Cells

Neural stem cells (NSCs) have therapeutic potential in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS); however, to date, their use has resulted in only limited clinical and pathological improvement. To enhance their therapeutic capacity, in the present study, we transduced bone marrow-derived NSCs (BM-NSCs) with neurotrophin 3 (NT-3), a potent neurotrophic factor that is both neuroprotective and immunomodulatory. We found that BM-NSCs transduced with NT-3 reduced central nervous system (CNS) inflammation and neurological deficits in ongoing EAE significantly more than conventional NSC therapy, and, in addition, had the following advantages: (i) enhanced BM-NSC proliferation and differentiation into oligodendrocytes and neurons, as well as inhibited differentiation into astrocytes, thus promoting remyelination and neuronal repopulation, and reducing astrogliosis; (ii) enhanced anti-inflammatory capacity of BM-NSCs, thus more effectively suppressing CNS inflammation and accelerating remyelination; (iii) the easy accessibility of BM-NSCs provides another advantage over brain-derived NSCs for MS therapy; and (iv) a novel Tet-on system we used enables efficient control of NT-3 expression. Thus, our study provides a novel approach to break the vicious inflammation-demyelination cycle, and could pave the way to an easily accessible and highly effective therapy for CNS inflammatory demyelination.

Role of Th17 cells in the pathogenesis of CNS inflammatory demyelination

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). The etiology of MS is not well understood, but it is believed that myelin-specific CD4+ T cells play a central role in initiating and orchestrating CNS inflammation. In this scenario, CD4+ T cells, activated in the periphery, infiltrate the CNS, where, by secreting cytokines and chemokines, they start an inflammatory cascade. Given the central role of CD4+ T cells in CNS autoimmunity, they have been studied extensively, principally by using experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the late 1980s, CD4+ T cells, based on their cytokine production, were divided into two helper lineages, Th1 and Th2 cells. It was postulated that Th1 cells, which produce IFN-γ, mediate inflammation of the CNS in MS/EAE, while Th2 cells, which produce IL-4, have a beneficial effect in disease, because of their antagonistic effect on Th1 cells. The Th1/Th2 paradigm remained the prevailing view of MS/EAE pathogenesis until 2005, when a new lineage, Th17, was discovered. In a relatively short period of time it became apparent that Th17 cells, named after their hallmark cytokine, IL-17A, play a crucial role in many inflammatory diseases, including EAE, and likely in MS as well. The Th17 paradigm developed rapidly, initiating the debate of whether Th1 cells contribute to EAE/MS pathogenesis at all, or if they might even have a protective role due to their antagonistic effects on Th17 cells. Numerous findings support the view that Th17 cells play an essential role in autoimmune CNS inflammation, perhaps mainly in the initial phases of disease. Th1 cells likely contribute to pathogenesis, with their role possibly more pronounced later in disease. Hence, the current view on the role of Th cells in MS/EAE pathogenesis can be called the Th17/Th1 paradigm. It is certain that Th17 cells will continue to be the focus of intense investigation aimed at elucidating the pathogenesis of CNS autoimmunity.

Plasma exchange in pediatric central nervous system inflammatory demyelination

Aims: Evaluation of the clinical features and treatment response to plasma exchange (PLEX) in children with severe inflammatory central nervous system (CNS) demyelination.

A novel mitochondrial DNA deletion producing progressive external ophthalmoplegia associated with multiple sclerosis

We report a previously undescribed 7676 base pair mitochondrial (mt)DNA deletion involving genes of complex I, complex IV subunits 2 and 3 (cytochrome oxidase [Cox] II, III), adenosine triphosphatase 8 and 6, cytochrome b and 8 transfer (t)RNA genes producing myopathy and progressive external ophthalmoplegia (PEO) in a 44-year-old right-handed Caucasian man with features of multiple sclerosis (MS). We performed complete mtDNA sequencing and deletion analysis, spectrophotometric analysis of muscle and platelet respiratory chain activity, measurement of platelet mitochondrial membrane potential with the potentiometric dye JC-1 and magnetic resonance spectroscopy (MRS) and MRI studies of normal-appearing and lesional cerebral tissue. The deletion resulted in significant respiratory chain deficiency in muscle and blood and abnormalities of the platelet mitochondrial membrane potential. However, cerebrospinal fluid analysis, magnetic resonance spectroscopy and MRI features suggested inflammatory central nervous system demyelination rather than a primary respiratory chain disorder. We conclude that this novel mtDNA deletion causing myopathy and PEO is associated with severe muscle and platelet cellular energetic abnormalities. Furthermore, clinical and paraclinical features of multiple sclerosis were found. The potential pathomechanistic interaction between mtDNA variation and multiple sclerosis is reviewed.