Panagiota Davaki

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.

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. Ann Neurol 2006

Friedreich's ataxia mimicking hereditary motor and sensory neuropathy

Abstract. 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 Friedreichs ataxia. These patients seem to represent a form of Friedreichs ataxia mimicking Charcot-Marie-Tooth disease.

Neuropathy following acute intoxication with Mecarbam (OP ester)

Only a small number of organophosphorous compounds, of the many thousands circulating on the market, has been reported as causing neuropathy with delayed onset. A case is presented of a young male who in an attempt to commit suicide by taking a massive dose of Mecarbam, developed polyneuropathy accompanied by a mild involvement of the CNS. Mecarbam is herewith reported for the first time as an agent which can affect the peripheral nervous system.

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 patients 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 patients 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.

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

In Alzheimers 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.

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.

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 Hashimotos (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* alleles genotyping in chronic inflammatory demyelinating polyneuropathy in Greek patients.

Dear Editor, Chronic inflammatory demyelinating polyneuropathy (CIDP) or polyradiculoneuropathy is an acquired non-length-dependent peripheral neuropathy characterized by multifocal demyelination of spinal roots, plexuses, or proximal nerve trunks. The estimated prevalence of the disorder among different populations ranges from 1.9 to 7.7 per 100,000 (Laughlin et al., 2009). Several associated risk factors have been identified, such as history of vaccination, previous infections, and pregnancy (Said, 2006). Concerning genetic factors, there are only two genes which have been implicated in CIDP pathogenesis: SH2D2A (a gene encoding for SH2 domain protein which is a T-cell-specific adapter protein implicated in the negative control of early T-cell activation) and the M3 allele of alpha-1 antitrypsin (McCombe et al., 1985; Notturno et al., 2008; Uncini et al., 2011). Both celland humoral-mediated autoimmune mechanisms have been incriminated in CIDP pathogenesis, presumably as a result of a decreased number of circulating CD4+ CD25+ T-regulatory cells which has been found in CIDP patients (van Schaik, 2008). In CIDP, antigen-presentation is sub-served mainly by macrophages, although, surprisingly, Schwann cells have also the capacity to present antigens to T-cells by expressing major histocompatibility complex (MHC) proteins in their cell membranes (Murata and Dalakas, 2000; Hughes et al., 2006). As such, human leukocyte antigen (HLA) on chromosome 6p21.3 HLA could be a candidate genetic risk factor for CIDP. So far, few international studies have examined the role of HLA in CIDP and none in the Greek population. In two oldest studies HLA-AW30, AW31, HLA-A1, -B8, -DRw3, and -Dw3 were found to be associated with CIDP (Stewart et al., 1978; Adams et al., 1979). In a study by Feeney et al., a non-significant increase of HLA-A3, -B7, and -DR2 frequencies along