Antonella La Russa

ApoE Epsilon4 allele and disease duration affect verbal learning in mild temporal lobe epilepsy

Summary:  Purpose: To clarify the possible role of other factors including the ApoE ɛ4 allele for memory decline in temporal lobe epilepsy (TLE).

Prodynorphin Gene Promoter Polymorphism and Temporal Lobe Epilepsy

∗†Antonio Gambardella, †Ida Manna, ∗†Angelo Labate, ‡Rosanna Chifari, †Paolo Serra, †Antonella La Russa, §Emilio LePiane, †Rita Cittadella, †Virginia Andreoli, §Francesco Sasanelli, ∗†Mario Zappia, §Umberto Aguglia, and ∗†Aldo Quattrone ∗Institute of Neurology, School of Medicine, Catanzaro; †Institute of Neurological Sciences, National Research Council, Cosenza; ‡Clinic of Neurology, Hospital of Melegnano, Milan; and §Regional Epilepsy Centre, Hospital of Reggio Calabria, Italy

A phenotypic variation of dominant optic atrophy and deafness (ADOAD) due to a novel OPA1 mutation.

Sirs: Autosomal Dominant Optic Atrophy (ADOA or Kier’s disease, OMIM #165500) is one of the most frequent forms of inherited optic atrophy [1], often presenting in the first decade of life with progressive impairment of visual acuity, variably combined with dyschromatopsia and optic nerve pallor [2]. More than 90 mutations spanning throughout the Optic Atrophy 1 (OPA1) gene were disease-associated with most cases of ADOA (http://lbbma.univ-angers.fr/ eOPA1/) [3]; the gene encodes a dynamin-related GTPase involved in mitochondrial biogenesis [4]. Genotype-phenotype comparisons have been inconclusive except for ADOA complicated with a rare sensorineural deafness (ADOAD); some authors reported that only the R445H mutation could be linked to ADOAD, as hearing loss has never been associated to other OPA1 mutations [5, 6]. Here we present a family with an unusual phenotype of ADOAD and peripheral polineuropathy associated with a novel OPA1 mutation. The proband (IV.13) (pedigree reported in Fig. 1) was a 38-year-old man from Southern Italy, who complained of bilateral and progressive reduction of visual acuity since the age of 7 years. In the second decade of his life, he experienced progressive deafness followed by development of an ataxic gait. At the time of the evaluation, he was legally blind (bilateral visual acuity less than 0.3) and almost deaf (loss of hearing more than 90 dB); on neurological examination he presented bilateral ophthalmoplegia, mild ataxia, distal weakness and severe reduction of proprioception. The auditory brainstem responses (ABRs) were suggestive of bilateral neurosensorial deafness; the electrodiagnostic study of his legs showed decreased amplitude of sensory potentials and motor responses which were consistent with a peripheral axonal neuropathy. Brain and spinal cord MRI were normal. Complete clinical, ophthalmological and audiological examinations were performed on the living family members (Fig. 1a). They were negative except for the proband’s daughter (V.14), a 6year-old child who was showing modest but progressive difficulties in visual acuity and hearing abilities during the last year. The ophthalmologic examination revealed mild bilateral optic pallor and the ABRs were bilaterally impaired (hearing loss < 40 dB); brain MRI and peripheral nerves electrophysiology were normal. After informed consent, genomic DNA was obtained from the proband and his relatives (the proband’s father, his daughter and wife, the 7 siblings and their spouses). The entire coding region and the intron-exon junctions of OPA1 were sequenced by ABIPRISM 3130xl Genetic Analyzer (Applied Biosystems – Foster City, CA), as described elsewhere [7]. A novel missense 1316 G > T mutation was found in exon 14 of the proband and his daughter (Fig. 1b–c). This base change causes the amino acid substitution of a highly conserved Glycine to Valine at codon 439 (G439V) in the GTPase domain of OPA1 gene. No other family members harbored the same DNA mutation. For confirmation, 100 gender, age and ethnicity matched chromosomes controls were analyzed with the same procedure; no one carried the novel OPA1 mutation. OPA1 is believed to play a key role in mitochondrial morphology and function, by promoting its fusion (with the interaction of Mitofusin-1,2) and regulating mitochondrial apoptosis. Frezza et al. [8] demonstrated that oligomerization of OPA1 regulates mitochondrial apoptosis by maintaining the tightness of cristae junctions. Experimental data suggested that the pathogenesis of ADOA may result from haploinsufficiency, with most of the OPA1 mutations causing loss of function of the mutant allele [7, 9]. Recently, the authors reported that OPA1 mutations spanning the GTP-binding pocket disorganize the mitochondrial pathway by abolishing GTPase activity or affecting the self-assembly of OPA1 proteins. These mechanisms could impair the energy supply in the highly energy-demanding compartments, LETTER TO THE EDITORS

Lack of association between estrogen receptor 1 gene polymorphisms and multiple sclerosis in southern Italy in humans.

Estrogen receptor 1 gene polymorphisms (ESR1) have been found to be associated with multiple sclerosis (MS) in both Japanese and Finnish populations. We investigated the association between ESR1 polymorphisms (PvuII and XbaI) and MS in a study of 132 MS patients and 129 controls from the same geographic background (southern Italy). Allelic and genotypic frequencies were not different between MS patients and population controls for either the PvuII or XbaI polymorphism. This result suggests that the association between a given disease and a genomic characteristic must be confirmed by separate investigations in different populations.

Single nucleotide polymorphism in the MMP-9 gene is associated with susceptibility to develop multiple sclerosis in an Italian case-control study.

To investigate the role of the matrix metalloproteinase-9 gene (MMP-9) in multiple sclerosis (MS), we analyzed the functional -1562C/T and -90 (CA)(n) repeat polymorphisms in 243 Italian patients with MS and 173 healthy controls. A significant increase of the -1562T allele carriers was found in patients with MS compared to controls. Moreover, haplotype analysis showed that the haplotype formed by the -1562T allele and the L allele ((CA)(<or=20)) was over-represented in patients with MS versus controls. These results suggest that a genetic polymorphism of the MMP-9 promoter region may influence the susceptibility to MS.

Association between Synapsin III gene promoter polymorphisms and multiple sclerosis.

Abstract.Although multiple sclerosis (MS) is considered to be an inflammatory demyelinating disease, increasing evidence indicates that it is also an axonal pathology; indeed, studies of experimental allergic encephalitis showed that several neuronal proteins such as synapsins take part in the pathogenesis of the axonal dysfunction.Synapsins are a family of abundant neuron-specific phosphoproteins with crucial roles in synaptogenesis and neuronal plasticity. Distinct genes encode the three different isolated proteins (I, II and III); of interest, the gene of synapsin III (SYN3) is located in the chromosome 22q12-q13, a locus close to one of the candidate susceptibility regions (22q13.1) for MS.In the present study we selected two polymorphisms (g.–631C > G and g.–196A > G) within the SYN3 5’-promoter region because of the protein’s role and genetic location; we analysed the allele and genotype distributions of these polymorphisms in a selected MS population of southern Italy.An inverse association between MS and the g-631C > G polymorphism was found; indeed, the two polymorphisms were in almost complete linkage disequilibrium and the haplotype analysis showed that the C631/A196 haplotype seemed to confer a significant protection against MS.

Association between the M129V variant allele of PRNP gene and mild temporal lobe epilepsy in women.

Specific variations in the prion protein gene (PRNP) are associated with, and prevalent in patients with intractable temporal lobe epilepsy (TLE) and influence the surgical outcome. We investigated whether or not the PRNP gene is a susceptibility gene in temporal lobe epileptic patients with mild epilepsy. We systematically screened the entire open reading frame of the PRNP gene and evaluated the genetic contribution of the functional PRNP M129V polymorphism in 289 patients with mild TLE compared with a neurologically unaffected age and sex matched control group (n=272). Statistical analysis revealed a moderate difference in the distribution at codon 129 of the PRNP gene between sporadic mild TLE patients and healthy controls (p=0.036; OR=1.30; 95% CI=1.01-1.68). Although, there was no statistically significant difference in the genotype distribution within the study groups (p=0.101), a further analysis showed that the 129V allele was highly represented only in women with TLE compared with control group (p=0.006, OR=1.632; 95%CI=1.15-2.31). This is the first publication of data that support the hypothesis that the common methionine/valine polymorphism at codon 129 of the PRNP gene may modify the susceptibility of women to mild TLE.

Leber’s hereditary optic neuropathy associated with a multiple-sclerosis-like picture in a man

A 35-year-old young man displayed Leber’s optic neuropathy (LHON) due to T14484C and multiple sclerosis (MS) phenotype that was dominated by symptoms and signs of spinal cord impairment. Magnetic resonance imaging (MRI) revealed demyelinating lesions extending from D6 to D11 in the spinal cord with gadolinium enhancement, while only three linear demyelinating lesions were seen on brain MRI. In the literature, a major involvement of the spinal cord was already reported in three of four male patients with the 14484 LHON mutation who developed MS, but the reasons of this peculiar association remain unknown, and further research in this area is needed.

Preliminary evidences of a NOS2A protective effect from Relapsing–Remitting Multiple Sclerosis

The gene encoding the inducible form of Nitric Oxide Synthase (NOS2A) has been considered with interest in the evaluation of the genetic predisposition to Multiple Sclerosis (MS). The aim of the present study was to address the possible contribution of two microsatellites repeats of the NOS2A promoter region - (CCTTT)(n) and (AAAT)(n) - to MS susceptibility. One hundred and thirteen Italian patients with clinically definite RRMS and 237 age and sex matched healthy controls from Calabria (South Italy) were studied. The distribution analysis of the markers frequencies showed that the (CCTTT)(14) allele was found in 11.5% of the RRMS patients and in 25.3% of the healthy subjects, with a statistically significant difference (chi(2)=8.843, p=0.003). This data seems to confer a significant protection against MS (OR=0.348; 95% CI=0.174-0.693, corrected for age and gender). No association with MS susceptibility was observed for the bi-allelic (AAAT)(n) microsatellite. In conclusion, we found that the NOS2A (CCTTT)(14) allele was detected more frequently in the control group than in the RRMS patients, thus confirming the scientific interest on this marker.

Presenilin enhancer-2 gene: Identification of a novel promoter mutation in a patient with early-onset familial Alzheimer’s disease

γ‐Secretase proteins complex cleaves the amyloid precursor protein (APP) to generate amyloid‐β (Aβ) peptides. Considerable evidence suggests that alterations in genes encoding these proteins exert their influence on the pathogenesis of familial Alzheimers disease (FAD). Presenilin enhancer‐2 gene (PEN‐2) is a necessary component of the γ‐Secretase complex. Recently, it has been shown that PEN‐2 mutations could be involved in Alzheimers disease (AD). We performed a mutational screening of all PEN‐2 coding and promoter regions in a FAD cohort derived from Southern Italy. Four hundred and fifty‐two subjects (FAD: 97; Controls: 355) were recruited for this study. We identified for the first time in a key region necessary for the promoter activity a novel 3 bp deletion in a subject with early‐FAD. Our genetic data demonstrate that the mutant allele may influence the transcriptional activity of the PEN‐2 gene. Although the effective role of the PEN‐2 promoter deletion in AD is not entirely clear, these findings might lead to more studies on its functional and genetic role.