Executive Dysfunction, Social Cognition Impairment, and Gray Matter Pathology in Myotonic Dystrophy Type 2: A Pilot Study.

BACKGROUND: In contrast to myotonic dystrophy type 1, the cognitive and radiologic profile of myotonic dystrophy type 2 (DM2) is relatively poorly characterized. OBJECTIVE: To conduct a pilot study to systematically evaluate cognitive and radiologic features in a cohort of Greek individuals with DM2. METHOD: Eleven genetically confirmed individuals with DM2 and 26 age- and education-matched healthy controls were administered the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS) to screen for impairment in multiple cognitive domains. MRI data were evaluated by morphometric analyses to identify disease-specific gray and white matter alterations. The following statistical thresholds were used for cognitive comparisons: PFDR < 0.05 and Bayes factor (BF 10 ) >10. RESULTS: The DM2 group exhibited cognitive impairment (ECAS Total score; PFDR = 0.001; BF 10 = 108.887), which was dominated by executive impairment ( PFDR = 0.003; BF 10 = 25.330). A trend toward verbal fluency impairment was also identified. No significant impairments in memory, language, or visuospatial function were captured. The analysis of subscores revealed severe impairments in social cognition and alternation. Voxel-based morphometry identified widespread frontal, occipital, and subcortical gray matter atrophy, including the left superior medial frontal gyrus, right medial orbitofrontal gyrus, right operculum, right precuneus, bilateral fusiform gyri, and bilateral thalami. CONCLUSION: DM2 may be associated with multifocal cortical and thalamic atrophy, which is likely to underpin the range of cognitive manifestations mostly characterized by executive impairment and specifically by impaired social cognition.

Serum miRNAs as biomarkers for the rare types of muscular dystrophy.

Muscular dystrophies are a group of disorders that cause progressive muscle weakness. There is an increasing interest for the development of biomarkers for these disorders and specifically for Duchene Muscular Dystrophy. Limited research however, has been performed on the biomarkers' development for the most rare muscular dystrophies, like the Facioscapulohumeral Muscular Dystrophy, Limb-Girdle Muscular Dystrophy and Myotonic Dystrophy type 2. Here, we aimed to identify novel serum-based miRNA biomarkers for these rare muscular dystrophies, through high-throughput next-generation RNA sequencing. We identified many miRNAs that associate with muscular dystrophy patients compared to controls. Based on a series of selection criteria, the two best candidate miRNAs for each of these disorders were chosen and validated in a larger number of patients. Our results showed that miR-223-3p and miR-206 are promising serum-based biomarkers for Facioscapulohumeral Muscular Dystrophy type 1, miR-143-3p and miR-486-3p for Limb-Girdle Muscular Dystrophy type 2A whereas miR-363-3p and miR-25-3p associate with Myotonic Dystrophy type 2. Some of the identified miRNAs were significantly elevated in the serum of the patients compared to controls, whereas some others were lower. In conclusion, we provide new evidence that certain circulating miRNAs may be used as biomarkers for three types of rare muscular dystrophies.

Circulating small RNA signatures differentiate accurately the subtypes of muscular dystrophies: small-RNA next-generation sequencing analytics and functional insights.

Muscular dystrophies are a group of rare and severe inherited disorders mainly affecting the muscle tissue. Duchene Muscular Dystrophy, Myotonic Dystrophy types 1 and 2, Limb Girdle Muscular Dystrophy and Facioscapulohumeral Muscular Dystrophy are some of the members of this family of disorders. In addition to the current diagnostic tools, there is an increasing interest for the development of novel non-invasive biomarkers for the diagnosis and monitoring of these diseases. miRNAs are small RNA molecules characterized by high stability in blood thus making them ideal biomarker candidates for various diseases. In this study, we present the first genome-wide next-generation small RNA sequencing in serum samples of five different types of muscular dystrophy patients and healthy individuals. We identified many small RNAs including miRNAs, lncRNAs, tRNAs, snoRNAs and snRNAs, that differentially discriminate the muscular dystrophy patients from the healthy individuals. Further analysis of the identified miRNAs showed that some miRNAs can distinguish the muscular dystrophy patients from controls and other miRNAs are specific to the type of muscular dystrophy. Bioinformatics analysis of the target genes for the most significant miRNAs and the biological role of these genes revealed different pathways that the dysregulated miRNAs are involved in each type of muscular dystrophy investigated. In conclusion, this study shows unique signatures of small RNAs circulating in five types of muscular dystrophy patients and provides a useful resource for future studies for the development of miRNA biomarkers in muscular dystrophies and for their involvement in the pathogenesis of the disorders.

CADASIL in Greece: Mutational spectrum and clinical characteristics based on a systematic review and pooled analysis of published cases.

BACKGROUND: Differences have been noted in the clinical presentation and mutational spectrum of CADASIL among various geographical areas. The aim of the present study was to investigate the mode of clinical presentation and genetic mutations reported in Greece. METHODS: After a systematic literature search, we performed a pooled analysis of all published CADASIL cases from Greece. RESULTS: We identified 14 studies that reported data from 14 families comprising 54 patients. Migraine with aura was reported in 39%, ischemic cerebrovascular diseases in 68%, behavioral-psychiatric symptoms in 47% and cognitive decline in 60% of the patients. The mean (±SD) age of onset for migraine with aura, ischemic cerebrovascular diseases, behavioral-psychiatric symptoms and cognitive decline was 26.2 ± 8.7, 49.3 ± 14.6, 47.9 ± 9.4 and 42.9 ± 10.3, respectively; the mean age at disease onset and death was 34.6 ± 12.1 and 60.2 ± 11.2 years. With respect to reported mutations, mutations in exon 4 were the most frequently reported (61.5% of all families), with the R169C mutation being the most common (30.8% of all families and 50% of exon 4 mutations), followed by R182C mutation (15.4% of all families and 25% of exon 4 mutations). CONCLUSIONS: The clinical presentation of CADASIL in Greece is in accordance with the phenotype encountered in Caucasian populations, but differs from the Asian phenotype, which is characterized by a lower prevalence of migraine and psychiatric symptoms. The genotype of Greek CADASIL pedigrees is similar to that of British pedigrees, exhibiting a high prevalence of exon 4 mutations, but differs from Italian and Asian populations, where mutations in exon 11 are frequently encountered.

HSV-Encephalitis Resembling Acute Cerebral Infarction in a Patient With Atrial Fibrillation: Beware of Stroke Mimics.

INTRODUCTION: Herpes simplex virus-1 (HSV-1) encephalitis, the most common and potentially life-threatening type of encephalitis, may rarely present as a stroke mimic. Prompt diagnosis is of paramount importance for the timely initiation of antiviral treatment and to avert intravenous thrombolysis. CASE REPORT: A 60-year-old man with a history of lone paroxysmal atrial fibrillation without prior antithrombotic treatment was admitted due to mild gait unsteadiness and intermittent dysarthria of acute onset. On admission, the patient was afebrile, whereas neurological examination revealed only a mild pronator drift on the left. Brain magnetic resonance imaging (MRI) showed an extensive right temporo-occipital and thalamic lesion with restricted diffusion and 3 small-sized hemorrhagic foci. Brain MR-angiography did not show large vessel stenosis or occlusion. On the basis of careful observation and the depiction of several imaging discrepancies, such as early vasogenic edema and hemorrhagic transformation, as well as uncus involvement, but also the lack of significant neurological deficits despite the size of the brain lesion we suspected viral encephalitis which was confirmed by the detection of HSV-1 DNA in the cerebrospinal fluid. CONCLUSION: HSV-encephalitis might occasionally result in the development of unilateral brain MRI lesions with extensive cytotoxic edema, resembling an acute ischemic stroke. Therefore, HSV-encephalitis must be considered in the differential diagnosis of acute ischemic stroke with atypical presentation. The presence of a significant dissociation between the brain MRI lesion volume and the neurological deficits, as well as certain brain MRI imaging discrepancies might serve as "red flags" to extend the diagnostic workup.

miR-223-3p and miR-24-3p as novel serum-based biomarkers for myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy, primarily characterized by muscle wasting and weakness. Many biomarkers already exist in the rapidly developing biomarker research field that aim to improve patients' care. Limited work, however, has been performed on rare diseases, including DM1. We have previously shown that specific microRNAs (miRNAs) can be used as potential biomarkers for DM1 progression. In this report, we aimed to identify novel serum-based biomarkers for DM1 through high-throughput next-generation sequencing. A number of miRNAs were identified that are able to distinguish DM1 patients from healthy individuals. Two miRNAs were selected, and their association with the disease was validated in a larger panel of patients. Further investigation of miR-223-3p, miR-24-3p, and the four previously identified miRNAs, miR-1-3p, miR-133a-3p, miR-133b-3p, and miR-206-3p, showed elevated levels in a DM1 mouse model for all six miRNAs circulating in the serum compared to healthy controls. Importantly, the levels of miR-223-3p, but not the other five miRNAs, were found to be significantly downregulated in five skeletal muscles and heart tissues of DM1 mice compared to controls. This result provides significant evidence for its involvement in disease manifestation.

Spectral Composition of Body Sway in Persistent Postural-Perceptual Dizziness.

OBJECTIVE: Previous studies in phobic postural vertigo patients showed characteristic frequency changes in body sway fluctuations, raising the question whether similar spectral changes can be also observed in the recently defined syndrome of persistent postural-perceptual dizziness (PPPD). STUDY DESIGN: Cross-sectional prospective study. SETTING: Tertiary referral center. SUBJECTS: Sixty-one PPPD patients and 41 healthy controls. INTERVENTIONS: Static balance was assessed while standing on firm surface with eyes open or closed (conditions 1 and 2) and while standing on foam with eyes open or closed (conditions 3 and 4). Postural sway was analyzed by means of time (sway area and standard deviation) and frequency domain metrics. The latter was based on comparisons of the percentage of energy in each of three frequency bands: low (0-0.5 Hz), middle (0.05-2 Hz), and high frequency (2-20 Hz). MAIN OUTCOME MEASURE: Stabilometric time and frequency domain parameters. RESULTS: Time domain metrics deteriorated significantly from conditions 1 through condition 4 in patients and controls. Spectral changes, however, were more abundant in PPPD subjects than in controls. Patients showed increased low frequency, but decreased high frequency spectral power in condition 3 as compared to condition 2. Dizziness Handicap Inventory score was positively correlated with middle frequency and negatively correlated with low frequency fluctuations. CONCLUSIONS: We conclude that PPPD patients exhibit a time domain sway pattern in different conditions which is grossly similar to that of controls. However, sensory feedback conditions with equal sway area show unique differences in their spectral content in PPPD patients. Moreover, perceived severity of dizziness is associated with greater body oscillations in the middle frequency band.

Neuropsychological Assessment Should Always be Considered in Myotonic Dystrophy Type 2.

Myotonic dystrophies (DMs) are hereditary, multisystem, slowly progressive myopathies. One of the systems they affect is the CNS. In contrast to the well-established cognitive profile of myotonic dystrophy type 1 (DM1), only a few studies have investigated cognitive dysfunction in individuals with myotonic dystrophy type 2 (DM2), and their findings have been inconsistent. To identify the most commonly affected cognitive domains in individuals with DM2, we performed a formal comprehensive review of published DM2 studies. Using the terms "myotonic dystrophy type 2" AND "cognitive deficits," "cognitive," "cognition," "neuropsychological," "neurocognitive," and "neurobehavioral" in all fields, we conducted an advanced search on PubMed. We read and evaluated all of the available original research articles (13) and one case study, 14 in total, and included them in our review. Most of the research studies of DM2 reported primary cognitive deficits in executive functions (dysexecutive syndrome), memory (short-term nonverbal, verbal episodic memory), visuospatial/constructive-motor functions, and attention and processing speed; language was rarely reported to be affected. Based on the few neuroimaging and/or multimodal DM2 studies we could find, the cognitive profile of DM2 is associated with brain abnormalities in several secondary and high-order cortical and subcortical regions and associative white matter tracts. The limited sample size of individuals with DM2 was the most prominent limitation of these studies. The multifaceted profile of cognitive deficits found in individuals with DM2 highlights the need for routine neuropsychological assessment at both baseline and follow-up, which could unveil these individuals' cognitive strengths and deficits.

Preserved eye movements in adults with spinal muscular atrophy.

INTRODUCTION: Spinal muscular atrophy (SMA) most prominently affects proximal limb and bulbar muscles. Despite older case descriptions, ocular motor neuron palsies or other oculomotor abnormalities are not considered part of the phenotype. METHODS: We investigated oculomotor function by testing saccadic eye movements of 15 patients with SMA. Their performance was compared with that of age-matched healthy controls. Horizontal rightward and leftward saccades were recorded by means of video-oculography, whereas subjects looked at light-emitting diode targets placed at ±5°, ±10°, and ±15° eccentricities. RESULTS: No differences in saccade amplitude gains, peak velocities, peak velocity-to-amplitude ratios, or durations were observed between controls and patients. More specifically, for 5° target eccentricities, patients had a mean saccadic peak velocity of 153°/s, whereas for 10° and 15° these values were 268°/s and 298°/s, respectively. The corresponding mean peak velocities of the control group were 151°/s, 264°/s, and 291°/s. DISCUSSION: Our results indicate that patients with SMA perform fast and accurate horizontal saccades without evidence of extraocular muscle weakness. These quantitative oculomotor data corroborate clinical experience that neuro-ophthalmic symptoms in SMA are not common and, if present, should prompt suspicion for an alternative neuromuscular disorder.

Effect of long term enzyme replacement therapy in late onset Pompe disease: A single-centre experience.

Late onset Pompe disease (LOPD) is a slowly progressive metabolic myopathy with variable clinical severity. The advent of enzyme replacement therapy (ERT) has modified the natural course of the disease, though the treatment effect on adult patients is modest compared to infants with the classic form. This study aims to describe the long-term clinical outcome of the Greek LOPD cohort, as assessed by 6 min walk test, muscle strength using MRC grading scale and spirometry. ERT efficacy was estimated using statistical methodology that is novel in the context of Pompe disease, which at the same time is well-suited to longitudinal studies with small samples and missing data (local non-linear regression analysis). Improvement over baseline was significant at 1 year for motor performance and muscle strength (p < 0.05), and at 2 years for FVC-U and FVC-S (p < 0.05). A subgroup analysis showed that the onset of the disease before adulthood (18 years), a male gender, and a latency of more than 2 years between the onset of symptoms and ERT administration are unfavorable prognostic factors. Conclusively, this study presents longitudinal data from the Greek LOPD cohort supporting previous observations, that therapeutic delay is related to worse prognosis and treatment effects may decline after several years of ERT.

Endovascular treatment for basilar artery occlusion: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Independent randomized controlled clinical trials (RCTs) have provided robust evidence for endovascular treatment (EVT) as the standard of care treatment for acute large vessel occlusions in the anterior circulation. We examined available studies specific to posterior cerebral circulation ischemic strokes to see if any conclusions can be drawn regarding EVT options. METHODS: We performed a systematic literature search to identify studies evaluating the safety and efficacy of EVT versus standard medical treatment for patients with acute basilar artery occlusion (BAO). We extracted data for outcomes of interest and presented associations between the two groups with the use of risk ratios (RRs) or odds ratios (ORs), with corresponding 95% confidence intervals (CIs). We used a random-effects model to pool the effect estimates. RESULTS: We identified five studies (two RCTs, three observational cohorts) including a total of 1098 patients. Patients receiving EVT had a higher risk of symptomatic intracranial hemorrhage (sICH) compared to those receiving non-interventional medical management (RR 5.42, 95% CI 2.74-10.71). Nonsignificant trends towards modified Rankin Scale (mRS) scores 0-2 (RR 1.02, 95% CI 0.74-1.41), mRS scores 0-3 (RR = 0.97, 95% CI 0.64-1.47), overall functional improvement (OR 0.93, 95% CI 0.57-1.51), and all-cause mortality (RR 1.03, 95% CI 0.78-1.35) at 3 months were seen. CONCLUSION: Although EVT increases the probability of sICH, the available data do not exclude the possibility of improved functional outcomes over standard therapy. As larger studies are challenged by the perceived lack of equipoise in this vulnerable patient population, results of ongoing RCTs are expected to provide substantial input for future meta-analyses.

Effect of exercise training on functional capacity and body composition in myotonic dystrophy type 2 patients.

BACKGROUND: Myotonic dystrophy type 2 (DM2) is a neuromuscular disorder characterized by myotonia and muscle weakness, with no medical treatment to prevent a decline in decline. It is unknown whether exercise training is effective in DM2. The aim of this study was to investigate the effect of exercise training on functional capacity and body composition in these patients. METHODS: Body composition and functional capacity were evaluated at the beginning (T1) and end (T2) of a 12 wk control period, and again after 16 wk of exercise training (T3) in 10 patients. RESULTS: No changes were recorded after the control period. Handgrip strength, 5× sit to stand, timed up and go, 6 min walk distance, lean body mass (LBM), and bone mineral density (BMD) increased while arterial pressure decreased after training. CONCLUSIONS: These results suggest that supervised exercise training improves functional capacity, LBM, and BMD in ambulatory DM2 patients.

Open Label Prospective Experience of Supplementation with a Fixed Combination of Magnesium, Vitamin B2, Feverfew, Andrographis Paniculata and Coenzyme Q10 for Episodic Migraine Prophylaxis.

BACKGROUND: To investigate the efficacy and safety of supplementation with a fixed combination of magnesium, vitamin B2, feverfew, andrographis paniculata and coenzyme Q10 in episodic migraine (EM) prevention. METHODS: A pilot, single-arm, open-label study was conducted. After a one-month baseline period, the above-described supplementation was introduced in 113 EM Greek patients, who were prospectively followed-up for three months. The primary endpoint was the change in monthly migraine days between baseline period (BSL) and the third month of supplementation (T3). Secondary endpoints included changes in mean intensity of migraine and in days with use of acute migraine medications. Changes in scores of Migraine Disability Assessment questionnaire (MIDAS), Headache Impact Test-6 (HIT-6), Migraine Therapy Assessment questionnaire (MTAQ), Migraine-Specific Quality-of-life questionnaire (MSQ-QOL), Hospital Anxiety and Depression Scale (HADS) were also evaluated. Those with ≥50% reduction in monthly migraine days at T3, compared to BSL were considered supplementation-responders. RESULTS: The mean number of migraine days was significantly decreased between BSL and T3 (9.4 ± 3.7 vs. 6.1 ± 3.5; p < 0.001). Likewise, days with peak headache intensity of >4/10 (5.7 ± 3.4 vs. 4.9 ± 3.1; p < 0.001) as well as days using acute headache medications per month (8.9 ± 3.6 vs. 5.7 ± 3.4; p < 0.001) were significantly reduced. At T3, 64 patients (56.6%) were classified as responders. The beneficial effect of supplementation was also associated with significant changes in HIT-6, MIDAS, MTAQ and MSQ-QOL scores. There were no safety concerns. CONCLUSIONS: The supplementation we have tested appears to be an effective and well-tolerated preventive approach against EM. A randomized, placebo-controlled study is needed to confirm our results.

Primary headache subtypes and thyroid dysfunction: Is there any association?

BACKGROUND: Primary headaches, and particularly migraine and tension-type headache (TTH) as well as hypothyroidism are common medical conditions. To date, numerous studies have suggested a possible bidirectional relationship between migraine and hypothyroidism, although certain studies had contradictory results. OBJECTIVE: To investigate whether there is any association between primary headache subtypes and thyroid disorders. METHODS: A retrospective study of consecutive patients aged ≥18 years referred to the Headache Outpatient Clinic of Aeginition Hospital and diagnosed with primary headache and any thyroid disorder. RESULTS: Out of 427 patients (males/females=76/351), 253 (59.3%) were diagnosed with migraine without aura, 53 (12.4%) with TTH, 49 (11.5%) with migraine with aura, 29 (6.8%) with medication-overuse headache, 23 (5.4%) with mixed-type headache (migraine with/without aura and TTH), nine (2.1%) with cluster headache, and 11 (2.6%) with other types of primary headaches. The prevalence of any type of thyroid disorder was 20.8% (89/427 patients). In the total sample, 27 patients (6.3%) reported hypothyroidism, 18 (4.2%) unspecified thyroidopathy, 14 (3.3%) thyroid nodules, 12 (2.8%) Hashimoto thyroiditis, 12 (2.8%) thyroidectomy, three (0.7%) thyroid goiter, and three (0.7%) hyperthyroidism. Further statistical analysis between categorical variables did not reveal any significant association between headache subtypes and thyroid dysfunction. CONCLUSIONS: No specific association was found between primary headache subtypes and specific thyroid disorder. However, a high prevalence of thyroid dysfunction in general and specifically hypothyroidism was demonstrated among patients with primary headaches, which lays the foundation for further clarification in prospective longitudinal studies.

Primary headache subtypes and thyroid dysfunction: Is there any association? / Subtipos de cefaleia primária e disfunção tireoidiana: existe alguma associação?

ABSTRACT Background: Primary headaches, and particularly migraine and tension-type headache (TTH) as well as hypothyroidism are common medical conditions. To date, numerous studies have suggested a possible bidirectional relationship between migraine and hypothyroidism, although certain studies had contradictory results. Objective: To investigate whether there is any association between primary headache subtypes and thyroid disorders. Methods: A retrospective study of consecutive patients aged ≥18 years referred to the Headache Outpatient Clinic of Aeginition Hospital and diagnosed with primary headache and any thyroid disorder. Results: Out of 427 patients (males/females=76/351), 253 (59.3%) were diagnosed with migraine without aura, 53 (12.4%) with TTH, 49 (11.5%) with migraine with aura, 29 (6.8%) with medication-overuse headache, 23 (5.4%) with mixed-type headache (migraine with/without aura and TTH), nine (2.1%) with cluster headache, and 11 (2.6%) with other types of primary headaches. The prevalence of any type of thyroid disorder was 20.8% (89/427 patients). In the total sample, 27 patients (6.3%) reported hypothyroidism, 18 (4.2%) unspecified thyroidopathy, 14 (3.3%) thyroid nodules, 12 (2.8%) Hashimoto thyroiditis, 12 (2.8%) thyroidectomy, three (0.7%) thyroid goiter, and three (0.7%) hyperthyroidism. Further statistical analysis between categorical variables did not reveal any significant association between headache subtypes and thyroid dysfunction. Conclusions: No specific association was found between primary headache subtypes and specific thyroid disorder. However, a high prevalence of thyroid dysfunction in general and specifically hypothyroidism was demonstrated among patients with primary headaches, which lays the foundation for further clarification in prospective longitudinal studies.

RESUMO Introdução: Cefaleias primárias e, particularmente, enxaqueca e cefaleia do tipo tensional (CTT), bem como hipotiroidismo, constituem condições médicas comuns. Até o momento, vários estudos sugeriram uma possível relação bidirecional entre enxaqueca e hipotireoidismo, embora alguns estudos tenham resultados contraditórios. Objetivo: Investigar se existe associação entre subtipos de cefaleia primária e distúrbios da tireoide. Métodos: Estudo retrospectivo de pacientes consecutivos com idade ≥18 anos encaminhados ao Ambulatório de Cefaleia do Hospital Aeginition, com diagnóstico de cefaleia primária e qualquer distúrbio da tireoide. Resultados: De 427 pacientes (homens/mulheres=76/351), 253 pacientes (59,3%) foram diagnosticados com enxaqueca sem aura, 53 (12,4%) com CTT, 49 (11,5%) com enxaqueca com aura, 29 (6,8 %) com cefaleia por uso excessivo de medicamentos, 23 (5,4%) com cefaleia mista (enxaqueca com/sem aura e CTT), nove (2,1%) com cefaleia em salvas e 11 (2,6%) com outros tipos de cefaleias primárias. A prevalência de qualquer tipo de distúrbio tireoidiano foi de 20,8% (89/427 pacientes). Na amostra total, 27 pacientes (6,3%) relataram hipotireoidismo, 18 (4,2%) tireoidopatia não especificada, 14 (3,3%) nódulos de tireoide, 12 (2,8%) tireoidite de Hashimoto, 12 (2,8%) tireoidectomia, três (0,7%) bócio da tireoide e três (0,7%) hipertireoidismo. Uma análise estatística posterior entre as variáveis categóricas não revelou qualquer associação significativa entre os subtipos de cefaleia e disfunção tireoidiana. Conclusões: Não encontramos associação entre subtipos de cefaleia primária e distúrbio específico da tireoide. No entanto, foi observada prevalência elevada de disfunção tireoidiana em geral e especificamente hipotireoidismo entre pacientes com cefaleia primária, o que estabelece base para maiores esclarecimentos em estudos longitudinais prospectivos.

Mild myopathic phenotype in a patient with homozygous c.416C > T mutation in TK2 gene.

The mitochondrial DNA depletion syndrome (MDDS) is characterized by extensive phenotypic variability and is due to nuclear gene mutations resulting in reduced mtDNA copy number. Thymidine kinase 2 (TK2) mutations are well known to be associated with MDDS. Few severely affected cases carrying the c.416C > T mutation in TK2 gene have been described so far. We describe the case of a 14months boy with the aforementioned TK2 gene pathogenic mutation at a homozygous state, presenting with a mild clinical phenotype. In addition to severe mitochondrial pathology on muscle biopsy, there was also histochemical evidence of adenylate deaminase deficiency. Overall, this report serves to further expand the clinical spectrum of TK2 mutations associated with MDDS.

Update on Congenital Myopathies in Adulthood.

Congenital myopathies (CMs) constitute a group of heterogenous rare inherited muscle diseases with different incidences. They are traditionally grouped based on characteristic histopathological findings revealed on muscle biopsy. In recent decades, the ever-increasing application of modern genetic technologies has not just improved our understanding of their pathophysiology, but also expanded their phenotypic spectrum and contributed to a more genetically based approach for their classification. Later onset forms of CMs are increasingly recognised. They are often considered milder with slower progression, variable clinical presentations and different modes of inheritance. We reviewed the key features and genetic basis of late onset CMs with a special emphasis on those forms that may first manifest in adulthood.

Dimensions of pain catastrophising and specific structural and functional alterations in patients with chronic pain: Evidence in medication-overuse headache.

OBJECTIVES: We examined the neuroanatomical substrate of different pain catastrophising (PC) dimensions (i.e. rumination; magnification; helplessness) in patients with medication-overuse headache (MOH). METHODS: We included 18 MOH patients who were administered the Pain Catastrophizing Scale (PCS) and scanned in a 3T-MRI. We conducted whole-brain volumetric and resting-state functional connectivity (FC) analysis to examine the association between grey matter (GM) density and FC strength and PCS dimensions controlling for depression and anxiety. RESULTS: Higher total PCS score was associated with decreased GM density in precentral and inferior temporal gyrus, increased FC between middle temporal gyrus and cerebellum and reduced FC between precuneus and inferior temporal gyrus, as well as between frontal pole and temporal fusiform cortex. Regarding PCS dimensions, we mainly observed the involvement of (1) somatosensory cortex, supramarginal gyrus, basal ganglia, core default-mode network (DMN) in rumination; (2) somatosensory cortex, core DMN, dorsal medial prefrontal cortex (DMPFC)-DMN subsystem and cerebellum in magnification; and (3) temporal regions, DMN and basal ganglia in helplessness. CONCLUSIONS: PC dimensions are associated with a specific structural and functional neuroanatomical pattern, which is different from the pattern observed when PC is considered as a single score. The involvement of basal ganglia and cerebellum needs further investigation.