A novel c.5308_5311delGAGA mutation in Senataxin in a Cypriot family with an autosomal recessive cerebellar ataxia

<p>Abstract</p> <p>Background</p> <p>Senataxin (chromosome 9q34) was recently identified as the causative gene for an autosomal recessive form of Ataxia (ARCA), termed as Ataxia with Oculomotor Apraxia, type 2 (AOA2) and characterized by generalized incoordination, cerebellar atrophy, peripheral neuropathy, "oculomotor apraxia" and increased alpha-fetoprotein (AFP). Here, we report a novel Senataxin mutation in a Cypriot ARCA family.</p> <p>Methods</p> <p>We studied several Cypriot autosomal recessive cerebellar ataxia (ARCA) families for linkage to known ARCA gene loci. We linked one family (909) to the SETX locus on chromosome 9q34 and screened the proband for mutations by direct sequencing.</p> <p>Results</p> <p>Sequence analysis revealed a novel c.5308_5311delGAGA mutation in exon 11 of the SETX gene. The mutation has not been detected in 204 control chromosomes from the Cypriot population, the remaining Cypriot ARCA families and 37 Cypriot sporadic cerebellar ataxia patients.</p> <p>Conclusion</p> <p>We identified a novel SETX homozygous c.5308_5311delGAGA mutation that co-segregates with ARCA with cerebellar atrophy and raised AFP.</p

The influence of environmental risk factors in the development of ALS in the Mediterranean Island of Cyprus

IntroductionAmyotrophic lateral sclerosis (ALS) is a devastating, uniformly lethal degenerative disease of motor neurons, presenting with relentlessly progressive muscle atrophy and weakness. The etiology of ALS remains unexplained for over 85% of all cases, suggesting that besides the genetic basis of the disease, various environmental factors are implicated in the pathogenesis of ALS. This study aimed to investigate the contribution of known environmental risk factors of ALS in the Cypriot population.MethodsWe conducted a case–control study with a total of 56 ALS cases and 56 healthy gender/age-matched controls of Cypriot nationality. Demographic, lifestyle characteristics, medical conditions, and environmental exposures were collected through the use of a detailed questionnaire. Statistical analyses using the R programming language examined the association between the above environmental factors and ALS.ResultsA chi-square test analysis revealed a statistically significant (p = 0.000461) difference in smoking status between the two groups. In addition, univariate logistic regression analysis showed a statistically significant association between ALS cases for head trauma/injury (p = 0.0398) and exposure to chemicals (p = 0.00128), compared to controls.ConclusionThis case–control investigation has shed some light on the epidemiological data of ALS in Cyprus, by identifying environmental determinants of ALS, such as smoking, head trauma, and chemical exposure, in the Cypriot population

Mitochondrial superclusters influence age of onset of Parkinson’s disease in a gender specific manner in the Cypriot population: A case-control study

Despite evidence supporting an involvement of mitochondrial dysfunction in the pathogenesis of some neurodegenerative disorders, there are inconsistent findings concerning mitochondrial haplogroups and their association to neurodegenerative disorders, including idiopathic Parkinson's disease (PD).To test this hypothesis for the Greek-Cypriot population, a cohort of 230 PD patients and 457 healthy matched controls were recruited. Mitochondrial haplogroup distributions for cases and controls were determined. Association tests were carried out between mitochondrial haplogroups and PD.Mitochondrial haplogroup U was associated with a reduced PD risk in the Cypriot population. After pooling mitochondrial haplogroups together into haplogroup clusters and superclusters, association tests demonstrated a significantly protective effect of mitochondrial haplogroup cluster N (xR) and supercluster LMN for PD risk only in females. In addition, for female PD cases belonging to UKJT and R (xH, xUKJT) haplogroup, the odds of having a later age of onset of PD were 13 and 15 times respectively higher than the odds for female cases with an H haplogroup.Statistically significant associations regarding PD risk and PD age of onset were mostly detected for females thus suggesting that gender is a risk modifier between mitochondrial haplogroups and PD status / PD age of onset. The biological mechanisms behind this gender specificity remain to be determined

Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome

Background: Pathogenic variants of GNB5 encoding the β5 subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia. Methods: We used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5 loss in mouse. Results: We delineated a key role of Gnb5 in heart sinus conduction and showed that Gnb5-inhibitory signalling is essential for parasympathetic control of heart rate (HR) and maintenance of the sympathovagal balance. Gnb5-/- mice were smaller and had a smaller heart than Gnb5+/+ and Gnb5+/-, but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation resulted in a higher baseline HR in Gnb5-/- mice. In contrast, Gnb5-/- mice exhibited profound bradycardia on treatment with carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous Gnb5 loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described 13 affected individuals, increasing the IDDCA cohort to 44 patients. Conclusions: Our data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in Gnb5-/- mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unravelling the mechanism of Gnb5 signalling in the autonomic control of the heart will pave the way for future drug screening

Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants.

Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1-/- mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy

Dietary Intake, Mediterranean Diet Adherence and Caloric Intake in Huntington’s Disease: A Review

Decades of research and experimental studies have investigated Huntington&rsquo;s disease (HD), a rare neurodegenerative disease. Similarly, several studies have investigated whether high/moderate adherence to the Mediterranean Diet and specific macro and micronutrients can decrease cognitive loss and provide a neuroprotective function to neurons. This review systematically identifies and examines studies that have investigated Mediterranean Diet adherence, micro- and macronutrients, supplementation and caloric intake in people with HD, in order to identify if dietary exposures resulted in improvement of disease symptoms, a delay in age of onset or if they contributed to an earlier age of onset in people with HD. A systematic search of PubMed, Directory of open access journal and HubMed was performed independently by two reviewers using specific search terms criteria for studies. The identified abstracts were screened and the studies were included in the review if they satisfied predetermined inclusion criteria. Reference screening of included studies was also performed. A total of 18 studies were included in the review. A few studies found that patients who had high/moderate adherence to Mediterranean Diet showed a slight improvement in their Unified Huntington&rsquo;s Disease Rating Scale and Total Functional Capacity. In addition, people with HD who had high Mediterranean Diet adherence showed an improvement in both cognitive and motor scores and had a better quality of life compared to patients who had low Mediterranean Diet adherence. Furthermore, a few studies showed that supplementation with specific nutrients, such as triheaptanoin, L-acetyl-carnitine and creatine, had no beneficial effect on the patients&rsquo; Unified Huntington&rsquo;s Disease Rating Scale score. A few studies suggest that the Mediterranean Diet may confer a motor and cognitive benefit to people with HD. Unfortunately, there was little consistency among study findings. It is important for more research to be conducted to have a better understanding of which dietary exposures are beneficial and may result delaying age of onset or disease progression in people with HD

Investigation of in-phase bilateral exercise effects on corticospinal plasticity in relapsing remitting multiple sclerosis: A registered report single-case concurrent multiple baseline design across five subjects

Relapsing-remitting Multiple Sclerosis is the most common demyelinating neurodegenerative disease and is characterized by periods of relapses and generation of various motor symptoms. These symptoms are associated with the corticospinal tract integrity, which is quantified by means of corticospinal plasticity which can be probed via transcranial magnetic stimulation and assessed with corticospinal excitability measures. Several factors, such as exercise and interlimb coordination, can influence corticospinal plasticity. Previous work in healthy and in chronic stroke survivors showed that the greatest improvement in corticospinal plasticity occurred during in-phase bilateral exercises of the upper limbs. During in-phase bilateral movement, both upper limbs are moving simultaneously, activating the same muscle groups and triggering the same brain region respectively. Altered corticospinal plasticity due to bilateral cortical lesions is common in MS, yet, the impact of these type of exercises in this cohort is unclear. The aim of this concurrent multiple baseline design study is to investigate the effects of in-phase bilateral exercises on corticospinal plasticity and on clinical measures using transcranial magnetic stimulation and standardized clinical assessment in five people with relapsing-remitting MS. The intervention protocol will last for 12 consecutive weeks (30-60 minutes /session x 3 sessions/week) and include in-phase bilateral movements of the upper limbs, adapted to different sports activities and to functional training. To define functional relation between the intervention and the results on corticospinal plasticity (central motor conduction time, resting motor threshold, motor evoked potential amplitude and latency) and on clinical measures (balance, gait, bilateral hand dexterity and strength, cognitive function), we will perform a visual analysis and if there is a potential sizeable effect, we will perform statistical analysis. A possible effect from our study, will introduce a proof-of-concept for this type of exercise that will be effective during disease progression. Trial registration: ClinicalTrials.gov NCT05367947

Investigation of in-phase bilateral exercise effects on corticospinal plasticity in relapsing remitting multiple sclerosis: A registered report single-case concurrent multiple baseline design across five subjects.

Relapsing-remitting Multiple Sclerosis is the most common demyelinating neurodegenerative disease and is characterized by periods of relapses and generation of various motor symptoms. These symptoms are associated with the corticospinal tract integrity, which is quantified by means of corticospinal plasticity which can be probed via transcranial magnetic stimulation and assessed with corticospinal excitability measures. Several factors, such as exercise and interlimb coordination, can influence corticospinal plasticity. Previous work in healthy and in chronic stroke survivors showed that the greatest improvement in corticospinal plasticity occurred during in-phase bilateral exercises of the upper limbs. During in-phase bilateral movement, both upper limbs are moving simultaneously, activating the same muscle groups and triggering the same brain region respectively. Altered corticospinal plasticity due to bilateral cortical lesions is common in MS, yet, the impact of these type of exercises in this cohort is unclear. The aim of this concurrent multiple baseline design study is to investigate the effects of in-phase bilateral exercises on corticospinal plasticity and on clinical measures using transcranial magnetic stimulation and standardized clinical assessment in five people with relapsing-remitting MS. The intervention protocol will last for 12 consecutive weeks (30-60 minutes /session x 3 sessions/week) and include in-phase bilateral movements of the upper limbs, adapted to different sports activities and to functional training. To define functional relation between the intervention and the results on corticospinal plasticity (central motor conduction time, resting motor threshold, motor evoked potential amplitude and latency) and on clinical measures (balance, gait, bilateral hand dexterity and strength, cognitive function), we will perform a visual analysis and if there is a potential sizeable effect, we will perform statistical analysis. A possible effect from our study, will introduce a proof-of-concept for this type of exercise that will be effective during disease progression. Trial registration: ClinicalTrials.gov NCT05367947

Retrospective longitudinal study of ALS in Cyprus: Clinical characteristics, management and survival.

INTRODUCTION:Amyotrophic lateral sclerosis (ALS) is a rare, progressive neurodegenerative disease. There is heterogeneity of clinical phenotypes while a clinical characterization of ALS in Cyprus is still lacking. The aim of this 30-year retrospective study of ALS in Cyprus is to determine the demographic characteristics of patients, the clinical features of the disease, the uptake of supportive therapies and factors influencing survival. METHODS:All ALS patients seen at the Cyprus Institute of Neurology and Genetics from January 1985 until July 2015 were included. Medical records of eligible patients were used for data extraction and compilation of an ALS database. Clinical features were compared between gender categories using univariate tests, while survival was assessed using Kaplan-Meier curves. Cox proportional hazards models were used to identify prognostic factors for survival. RESULTS:One hundred and seventy-nine ALS patients were included in the study, of whom 7 had a positive family history. Most clinical characteristics of ALS did not differ from what is observed in other European countries. However, some clinical characteristics were unique to our population, such as an increased acceptability and utilisation of supportive treatments such as gastrostomy. CONCLUSIONS:Overall, clinical characteristics of patients with ALS in the Republic of Cyprus do not differ from other European counties. Our study demonstrates a high acceptance and utilisation of supportive interventions enhancing survival, in the context of a multidisciplinary approach offered in the single tertiary centre that services the whole Cypriot ALS population. The findings of this paper are of value to the health professionals treating ALS in Cyprus