HLA-DRB1 differences in allelic distribution between familial and sporadic multiple sclerosis in a Hellenic cohort.

Objective: Familial Multiple Sclerosis (fMS) is reported to have distinct clinical and imaging characteristics in comparison to the sporadic disease (sMS). Nevertheless, the genetic/immunogenetic profile of fMS has never been investigated in depth, so far. In this study, we examined differences of HLA-DRB1 allelic frequencies between 57 fMS and 141 sMS Hellenic patients, with reference to 246 previously genotyped healthy controls (HCs). Patients and Methods: All patients underwent medical interview and DRB1 genotyping, using a low-resolution SSOP technique. Statistical analyses were performed using SPSS v.21.0 software, with significance set at 0.05, and p value corrected according to the Benjamini-Yekutieli method. Results: 29 fMS cases had at least one 1st degree relative affected (fMS 1st), while the rest had at least one 2nd or 3rd degree relative affected (fMS 2nd/3rd). Parent-of-origin effects were observed, with the prevalence of maternal inheritance. Frequency of DRB1*15 was significantly increased in fMS and sMS, in comparison to HCs (p = 0.002 and <0.001, respectively). After fMS stratification, this result was mainly attributed to the fMS 2nd/3rd subgroup. DRB1*11 frequency was significantly decreased only in sMS (p < 0.001) with fMS approximating HCs' frequency, especially for the fMS 1st subgroup. Heterozygosity was favored over homozygosity in all groups. Conclusion: We propose possible HLA-DRB1 allelic distribution differences between fMS and sMS, which become more apparent as proximity of affected relative/-es in fMS increases, supporting a rather degraded role of DRB1 alleles in fMS HLA/immunogenetics and indicating the concomitant implication of other HLA and non-HLA polymorphisms.

Familial multiple sclerosis in Greece: Distinct clinical and imaging characteristics in comparison with the sporadic disease.

OBJECTIVE: Few studies are available worldwide concerning clinical, imaging and genetic/immunogenetic profile of familial multiple sclerosis (fMS). Recent but not systematic data concerning fMS, without direct comparison to sporadic MS (sMS) drove our aim towards further research in the field, given the total lack of information for the Greek population as well. Thus, in this case-control study we examined the clinical and imaging characteristics of 102 fMS-patients, compared to 282 patients suffering sMS. PATIENTS AND METHODS: Patients recruited underwent medical interview (demographic, clinical and family history data collected). They were also assessed for disability and their MRI-scans were analyzed for lesion distribution. Statistical analyses were performed using SPSS v.21.0 software. RESULTS: 49% of unrelated fMS cases had at least one 1st degree relative affected, while the rest had also at least one relative with MS, 3rd degree or closer. Only the former subgroup (1st degree relative) and not the entire fMS sample, had significantly younger age at onset (AAO) compared to sMS cases (mean AAO 28.08 vs 31.33 years, p = 0.036). AAO anticipation was noted in younger generation fMS patients (mean AAO 24.67 years in younger generation vs 37 years in older generation, p = 0.001). With regard to our MRI findings, subcortical lesions were less frequent in fMS (71% in fMS vs 81.9% in sMS patients, p = 0.028), whereas cervical cord lesions more frequent (93% in fMS vs 79.9% in sMS patients, p = 0.033, only in the 1st degree relative subgroup). Double vision was a less common first symptom in fMS (4.1% in fMS vs 14.8% in sMS patients, p = 0.005). 1st degree relatives of fMS patients were more often diagnosed with Hashimoto's (8.9% in fMS relatives vs 3.3% in sMS relatives, p = 0.033). CONCLUSION: Younger AAO and different lesion distribution in brain and possibly spinal cord was observed in fMS in comparison to sMS patients. The hypothesis of increased genetic burden in fMS could offer some explanation for these differences, which needs though further validation as a next step, through genetic/immunogenetic testing in larger cohorts, of different ethnic groups.

HLA-DRB1 15:01 and Epstein-Barr virus in a multiple sclerosis patient with psoriasis, nasopharyngeal and breast cancers. Lessons for possible hidden links for autoimmunity and cancer.

BACKGROUND: Multiple sclerosis (MS) patients have a low general cancer risk and cases of neoplastic comorbidity are attributed by many researchers in chance, or therapeutical side-effects. Human leucocyte antigen (HLA) class II allele DRB1 15:01 is considered the main genetic factor independently associated with increased susceptibility for MS in Caucasians. Epstein-Barr virus (EBV) has also been proven to be a core triggering factor in MS initiation and progress, mainly in HLA-DRB1 15:01 positive MS patients. CASE REPORT: We present an exceptional case of a Greek-origin woman, carrying a distinct immunogenetic profile (HLA-A 26:01-Cw 06:02-DRB1 15:01), which gradually developed psoriasis, nasopharyngeal carcinoma (NPC), MS, breast cancer, uterine leiomyoma and other neoplasms. DISCUSSION: EBV plays a fundamental role in the pathogenesis of both autoimmunity (i.e. MS) and cancer (i.e. NPC). Our patient's immunogenetic profile included HLA alleles which are associated with psoriasis (Cw 06:02), NPC (A 26:01), MS (DRB1 15:01) and increased risk of MS, in patients carrying EBV (DRB1 15:01). We made a targeted review of the literature finding data supporting an EBV-HLA interaction mechanism behind our patient's unique combination of disorders, suggesting that beyond the standard role of each factor, their combination could act as the hidden link, in initiation or/and comorbidity of autoimmunity and cancer.

Body Mass Index in Multiple Sclerosis: Associations with CSF Neurotransmitter Metabolite Levels.

Body weight and height of patients with relapsing-remitting multiple sclerosis (RRMS) or clinically isolated syndrome suggesting MS (CIS) in the age range 18 to 60 years (154 males and 315 females) were compared with those of subjects (146 males and 212 females) free of any major neurological disease. In drug-free patients, CSF levels of the metabolites of noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA), neurotransmitters involved in eating behavior, were estimated in searching for associations with body mass index (BMI). Statistical evaluations were done separately for males and females. Lower BMI was found in female MS patients compared to female controls, more pronounced in RRMS. BMI was not associated with duration of illness, smoking, present or previous drug treatment, or disability score. Body height showed a shift towards greater values in MS patients compared to controls. Patients in the lower BMI quartile (limits defined from control subjects) had lower 5-HIAA and HVA compared to patients in the upper quartile. The results provide evidence for weight reduction during disease process in MS, possibly related to deficits in serotoninergic and dopaminergic activities that develop during disease course, resulting in impairments in food reward capacity and in motivation to eat.

Monosymptomatic clinically isolated syndrome with sudden sensorineural hearing loss: case report and critical review of the literature.

INTRODUCTION: Isolated cranial nerve involvement is rare in patients with multiple sclerosis (10.4%) and extremely rare is an eighth nerve palsy, especially in the context of a clinically isolated syndrome (<1%). CASE REPORT: A 34-year-old male presented with a history of left-sided tinnitus and sudden sensorineural hearing loss (SSNHL). Magnetic resonance imaging of the brain revealed >9, nonenhancing periventricular and corpus callosum lesions. Brainstem auditory evoked potentials were abnormal, ipsilateral to the affected ear, consistent with the presumed underlying demyelinating pathology. Visual evoked potentials showed bilateral prolonged P100 latencies. Oligoclonal bands were not detected in the cerebrospinal fluid, but IgG index was marginally elevated. After administration of corticosteroids, the patient recovered auditory function over a several month period. CONCLUSIONS: This report describes a case of SSNHL in the context of magnetic resonance imaging of the brain and electrophysiological findings consistent with a demyelinating etiology. SSNHL is a rare and possibly underrecognized manifestation of clinically isolated syndrome.

Rare association of polyneuropathy and Crohn's disease: a clinicopathological study of 4 cases.

The purpose of this study is to investigate the clinical, electrophysiological and pathological features of neuropathy in patients with Crohn's disease. Biopsies were selected from over 700 sural nerve biopsies. The diagnosis of Crohn's disease was based on established clinicopathological criteria. Complete laboratory, clinical, electrophysiological and pathological studies were performed in all cases. Nerve biopsies of 4 patients were diagnosed as neuropathy and Crohn's disease. Distal symmetrical sensorimotor polyneuropathy was the pattern of neuropathy. The pathological features were mixed, demyelination with predominant axonal degeneration and a varying pattern of myelinated fiber loss. There were no vasculitic changes found. We conclude that patients with Crohn's disease are complicated frequently with polyneuropathy, and as remission depends on immunosuppressive therapy, it is important to recognise it in the early stage. The diagnosis of polyneuropathy is based on clinical and electrophysiological studies, but precise histology, immunohistochemistry and morphometric studies of the peripheral nerve biopsy may be decisive in establishing the diagnosis.

Aberrant modulation of a delayed rectifier potassium channel by glutamate in Alzheimer's disease.

In Alzheimer's disease (AD), potassium channel abnormalities have been reported in both neural and peripheral tissues. Herein, using whole-cell patch-clamp, we demonstrate an aberrant glutamate-dependent modulation of K(V)1.3 channels in T lymphocytes of AD patients. Although intrinsic K(V)1.3 properties in patients were similar to healthy individuals, glutamate (1-1000 microM) failed to yield the hyperpolarizing shift normally observed in K(V)1.3 steady-state inactivation (-4.4+/-2.7 mV in AD vs. -14.3+/-2.5 mV in controls, 10 microM glutamate), resulting in a 4-fold increase of resting channel activity. Specific agonist and antagonist data indicate that this abnormality is due to dysfunction of cognate group II mGluRs. Given that glutamate is present in plasma and that both mGluRs and K(V)1.3 channels regulate T-lymphocyte responsiveness, our finding may account for the presence of immune-associated alterations in AD. Furthermore, if this aberration reflects a corresponding one in neural tissue, it could provide a potential target in AD pathogenesis.

Reduced expression of metabotropic glutamate receptor 2mRNA in T cells of ALS patients.

Metabotropic glutamate receptors alter the vulnerability of neurons to excitotoxic damage and are reported to display abnormal expression in the central nervous system of ALS patients. Using reverse transcriptase polymerase chain reaction, we investigated the mRNA expression of specific metabotropic glutamate receptor subtypes in T lymphocytes of 20 patients with sporadic ALS, compared with healthy age-matched control subjects and patients with other neurological disorders. The levels of metabotropic glutamate receptor 2 mRNA were markedly reduced, whereas the expression of other subtypes (1b, 3, 8) was similar to control levels. Our findings may provide a reliable peripheral marker of the glutamatergic dysfunction that characterizes ALS.

Nonsystemic vasculitic neuropathy: a clinicopathological study of 22 cases.

OBJECTIVE: The involvement of the peripheral nervous system in patients with systemic vasculitis has been reported, but nonsystemic peripheral nervous system vasculitis is not so well known. We investigated the clinical, electrophysiological, and pathological features of nonsystemic vasculitic neuropathy (NSVN) in order to establish the clinical and histological manifestations and to promote the earlier diagnosis of the syndrome. METHODS: Biopsies were selected from over 700 sural nerve biopsies performed at the Section of Neuropathology, Neurological Clinic of Athens University Hospital. The diagnosis of vasculitis was based on established clinicopathological criteria. Other causes of peripheral neuropathy were excluded. Complete laboratory, clinical, electrophysiological, and pathological studies were performed in all cases. RESULTS: Nerve biopsies of 22 patients were diagnosed as NSVN. The pathological features were vasculitis and predominant axonal degeneration with a varying pattern of myelinated fiber loss. The vasculitic changes were found mainly in small epineural blood vessels. Mononeuritis multiplex and distal symmetrical sensorimotor neuropathy were equally frequent. CONCLUSION: NSVN should be suspected in a case of unexplained polyneuropathy without evidence of systemic involvement. Clinical and neurophysiological studies are essential for the detection of nerve involvement, but the specific diagnosis of NSVN may be missed unless a biopsy is performed.

Novel mutations and repeated findings of mutations in familial Alzheimer disease.

Twenty-one unrelated patients with a history of suspected familial Alzheimer disease (FAD) were screened for mutations in PSEN1, PSEN2, and APP, the known FAD genes encoding the presenilins (PS1 and PS2) and the amyloid precursor protein (APP). The mutation detection rate was 57%. Of the nine pathogenic mutations found in 12 cases, three were in APP, one in PSEN2, and five in PSEN1, including two novel Greek mutations (L113Q and N135S). Whereas our findings suggest the possibility of single founders for the majority of mutations, we found evidence of recurrence of the APP mutations V717L and V717I.

Modulation of voltage-gated potassium channels in human T lymphocytes by extracellular glutamate.

Glutamate is present in the plasma under tightly regulated concentrations. However, under conditions of immune deficiency, such as AIDS and malignancy, its plasma levels are highly elevated. In vitro, glutamate interacts with T lymphocytes, affecting mitogen-induced calcium responses, whereas at high doses, it impairs T lymphocyte proliferation, a process strongly dependent on the activity of voltage-gated potassium channels. In this study, we demonstrate novel dose-related effects of the endogenous ligand glutamate and its metabotropic and non-N-methyl-D-aspartic acid receptor agonists on the electrophysiological properties of native Kv1.3 channels of human T lymphocytes. Glutamate, at concentrations within normal plasma levels, positively modulates Kv1.3 channel gating, causing currents to activate faster and at significantly more hyperpolarized potentials, hence rendering the T lymphocyte readily responsive to immune stimuli. This effect is maximal at 1 microM Glu and is fully mimicked by a 100 microM concentration of the metabotropic receptor agonist trans-(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid. Most importantly, Glu, at concentrations > or =100 microM, which in vitro produce suppression of mitogen-induced proliferation, significantly decreases whole-cell potassium currents by increasing current and steady-state inactivation. This effect saturates at 1000 microM and seems to result from the subsequent activation of low-affinity metabotropic Glu receptors, as suggested by specific agonist data. Therefore, the antiproliferative effects of high glutamate may, at least in part, result from its inhibitory effect on the potassium current, suggesting an in vivo immunosuppressive role of elevated plasma glutamate.

Friedreich's ataxia mimicking hereditary motor and sensory neuropathy.

Four patients from three unrelated families, with clinical and electrophysiological findings compatible with the diagnosis of hereditary motor and sensory neuropathy, are presented. The molecular analysis showed that the affected individuals were homozygous for the mutation in the X25 gene, characteristic of Friedreich's ataxia. These patients seem to represent a form of Friedreich's ataxia mimicking Charcot-Marie-Tooth disease.