Nuove metodiche riabilitative nelle malattie neuromuscolari e neurodegenerative

Introduction Myotonic Dystrophy type I (DM1) and Hereditary Spastic Paraparesis (HSP) are inherited rare disorders characterized by severe muscular impairment. At present, no effective pharmacological treatment is available. To date, only a limited number of clinical studies on rehabilitation in DM1 and HSP patients have been conducted. Moreover there is an increasing need to identify innovative rehabilitation approaches, especially for those patients who are more severely compromised and therefore at a greater risk of adverse events. Functional Electrical Stimulation (FES) is a rehabilitative approach that combines electrical stimulation with a functional task. Several studies performed on patients with cerebrovascular disease or spinal cord lesions evidenced the positive effects of this approach in improving muscle mass, and cardiovascular performances. So far, no studies have been conducted on FES in rare diseases. Objective The main objective of the study is to evaluate the safety and efficacy of FES-cycling in DM1 and HSP. Design We conducted two controlled pilot studies. In the first we assessed patients with DM1 while in the second subjects with HSP. In each study, participants were divided in two groups matched for clinical variables, who performed two types of treatment: FES cycling training and conventional stretching, resistance and aerobic training. The modified MRC scale, Ashworth scale and functional assessments were performed before and after treatment. Cohen d effect size was used for statistical analysis. Results FES induced lower extremity training was well tolerated and resulted in a greater improvement of tibialis anterior muscle strength (d= 1,583 DM1; d= 0.840 HSP), overall muscle strength (d=1,723 DM1; d= 0.582 HSP), spasticity (d= 1.334 HSP), walking speed (d= 0.820 HSP) and endurance (d=0,626 DM1) than conventional training Conclusions FES might be considered a safe and valid tool to improve muscle function, also in muscles severely compromised in which no other restorative options are available. Confirmation of FES efficacy through further clinical trials is strongly advised

Nuove metodiche riabilitative nelle malattie neuromuscolari e neurodegenerative

Introduction Myotonic Dystrophy type I (DM1) and Hereditary Spastic Paraparesis (HSP) are inherited rare disorders characterized by severe muscular impairment. At present, no effective pharmacological treatment is available. To date, only a limited number of clinical studies on rehabilitation in DM1 and HSP patients have been conducted. Moreover there is an increasing need to identify innovative rehabilitation approaches, especially for those patients who are more severely compromised and therefore at a greater risk of adverse events. Functional Electrical Stimulation (FES) is a rehabilitative approach that combines electrical stimulation with a functional task. Several studies performed on patients with cerebrovascular disease or spinal cord lesions evidenced the positive effects of this approach in improving muscle mass, and cardiovascular performances. So far, no studies have been conducted on FES in rare diseases. Objective The main objective of the study is to evaluate the safety and efficacy of FES-cycling in DM1 and HSP. Design We conducted two controlled pilot studies. In the first we assessed patients with DM1 while in the second subjects with HSP. In each study, participants were divided in two groups matched for clinical variables, who performed two types of treatment: FES cycling training and conventional stretching, resistance and aerobic training. The modified MRC scale, Ashworth scale and functional assessments were performed before and after treatment. Cohen d effect size was used for statistical analysis. Results FES induced lower extremity training was well tolerated and resulted in a greater improvement of tibialis anterior muscle strength (d= 1,583 DM1; d= 0.840 HSP), overall muscle strength (d=1,723 DM1; d= 0.582 HSP), spasticity (d= 1.334 HSP), walking speed (d= 0.820 HSP) and endurance (d=0,626 DM1) than conventional training Conclusions FES might be considered a safe and valid tool to improve muscle function, also in muscles severely compromised in which no other restorative options are available. Confirmation of FES efficacy through further clinical trials is strongly advised.Introduzione La Distrofia Miotonica di tipo 1 (DM1) e le Paraparesi Spastiche Ereditarie (HSP) sono malattie rare geneticamente determinate, caratterizzate da severo impairment motorio, per le quali non sono ancora disponibili trattamenti farmacologici risolutivi. Le opportunità riabilitative attualmente presenti in ambito neuromotorio, non sono ancora sufficientemente studiate. E’ crescente inoltre l’esigenza di individuare e ricorrere a metodiche riabilitative innovative, soprattutto per i pazienti con deficit neurologico più severo per i quali non è possibile attualmente alcun recupero motorio. L’Elettrostimolazione Funzionale (FES) è una metodica riabilitativa caratterizzata dalla somministrazione di correnti eccitatorie a livello neuromuscolare in associazione ad un task funzionale (es. cammino, pedalata). Gli studi finora condotti sulle malattie cerebrovascolari e sulle lesioni midollari, hanno dimostrato il ruolo di tale metodica nel contrastare l’atrofia ed aumentare la massa muscolare migliorando nel contempo le prestazioni cardiovascolari. Il suo impiego nelle malattie rare è innovativo e non è mai stata studiato. Obiettivi L’obiettivo generale dello studio è quello di valutare la sicurezza e l’efficacia della FES-cycling nei pazienti affetti da DM1 e da HSP. Disegno Sono stati condotti due studi pilota controllati. Nel primo sono stati considerati pazienti con diagnosi di DM1, nel secondo soggetti con diagnosi di HSP. In ciascuno studio i partecipanti sono stati suddivisi in due gruppi, omogenei per variabili cliniche, che hanno eseguito due tipi di trattamento : FES-cycling e training convenzionale comprendente esercizi di rinforzo, attività aerobica e stretching. La scala MRC modificata, la scala di Ashworth e le valutazioni funzionali sono state effettuate all’inizio ed al termine del trattamento riabilitativo. L’analisi statistica è stata condotta mediante l’indice d di Cohen. Risultati Il trattamento con FES è stato ben tollerato ed è risultato più efficace del trattamento convenzionale nel migliorare la forza del muscolo tibiale anteriore (d= 1,583 DM1; d= 0.840 HSP), la forza muscolare globale (d= 1,723 DM1; d= 0.582 HSP), la spasticità, (d= 1.334 HSP), la velocità del cammino (d= 0.820 HSP), e la resistenza alla fatica (d= 0,626 DM1). Conclusioni La FES può essere considerata una metodica sicura ed efficace nel migliorare le performances motorie, anche in muscoli severamente compromessi nei quali non sono possibili altri interventi terapeutici. La conferma dell’efficacia delle FES attraverso ulteriori trials clinici su vasta scala è auspicabile

Contribution of Large Genomic Rearrangements in Italian Lynch Syndrome Patients: Characterization of a Novel Alu-Mediated Deletion

Lynch syndrome is associated with germ-line mutations in the DNA mismatch repair (MMR) genes, mainly MLH1 and MSH2. Most of the mutations reported in these genes to date are point mutations, small deletions, and insertions. Large genomic rearrangements in the MMR genes predisposing to Lynch syndrome also occur, but the frequency varies depending on the population studied on average from 5 to 20%. The aim of this study was to examine the contribution of large rearrangements in the MLH1 and MSH2 genes in a well-characterised series of 63 unrelated Southern Italian Lynch syndrome patients who were negative for pathogenic point mutations in the MLH1, MSH2, and MSH6 genes. We identified a large novel deletion in the MSH2 gene, including exon 6 in one of the patients analysed (1.6% frequency). This deletion was confirmed and localised by long-range PCR. The breakpoints of this rearrangement were characterised by sequencing. Further analysis of the breakpoints revealed that this rearrangement was a product of Alu-mediated recombination. Our findings identified a novel Alu-mediated rearrangement within MSH2 gene and showed that large deletions or duplications in MLH1 and MSH2 genes are low-frequency mutational events in Southern Italian patients with an inherited predisposition to colon cancer

Clinical and anamnestic evaluation rôle for the diagnosis and treatment of families affected by Lynch syndrome. Case report and review of the literature

The Lynch syndrome increases the chances of developing cancer in individuals at risk, so prevention by instrumental screening of the more frequent cancers becomes very important. Genetic testing allows us to diagnose the disease with certainty and to identify individuals at risk. However, there are also reliable clinical and anamnestic criteria by which to diagnose the syndrome. The clinical case reported in our study shows that, in the absence of genetic characterization, clinical criteria alone rapidly suggested the correct approach leading to early treatment of relatives in the case in point

Neurophysiological Evidence of Motor Network Reorganization in Myotonic Dystrophy Type 1: A Pilot Magnetoencephalographic Study

PURPOSE: Myotonic dystrophy type 1 is the most common muscular dystrophy in adults. Although brain involvement is well recognized, the relationship between cortical motor control and voluntary movement has not been sufficiently explored. This study aims at assessing magnetoencephalographic (MEG) rhythms at oscillatory and connectivity levels to map central motor control. METHODS: Magnetoencephalographic data were acquired from healthy subjects and five myotonic dystrophy type 1 subjects during resting state and foot movement. Resting state EEG band power, event-related desynchronization/synchronization, functional connectivity, and network features (node strength and betweenness centrality) were estimated. A statistical comparison of these indexes between the two groups was run; a linear correlation between event-related desynchronization and motor performance was obtained. RESULTS: Myotonic dystrophy type 1 subjects showed higher theta power over central motor regions and lower beta power over frontal areas, with a decrease of beta node strength over the dominant hemisphere and an increase of betweenness centrality over the vertex. Foot movement in the most impaired myotonic dystrophy type 1 subjects was inefficient in evoking event-related desynchronization. In less severely impaired participants, dominant foot movement was related to a bilateral sensorimotor event-related desynchronization. CONCLUSIONS: Results provide proof of a central dysfunction of movement. Identification of neurophysiological motor patterns in myotonic dystrophy type 1 could provide a guide for tailored therapy

A Novel KCNA1 Mutation Identified in an Italian Family Affected by Episodic Ataxia Type 1.

Episodic ataxia type 1 (EA1) is a rare human neurological syndrome characterized by continuous myokymia and attacks of generalized ataxia that can be triggered by abrupt movements, emotional stress and fatigue. An Italian family has been identified where related members displayed continuous myokymia, episodes of ataxia, attacks characterized by myokymia only, and neuromyotonia. A novel missense mutation (F414C), in the C-terminal region of the K+ channel Kv1.1, was identified in the affected individuals. The mutant homotetrameric channels were non-functional in Xenopus laevis oocytes. In addition, heteromeric channels resulting from the co-expression of wild-type Kv1.1 and Kv1.1(F414C), or wild-type Kv1.2 and Kv1.1(F414C) subunits displayed reduced current amplitudes and altered gating properties. This indicates that the pathogenic effect of this KCNA1 mutation is likely to be related to the defective functional properties we have identified. © 2008 IBRO

A large cohort of myotonia congenita probands: novel mutations and a high-frequency mutation region in exons 4 and 5 of the CLCN1 gene.

Myotonia congenita is a genetic disease characterized by impaired muscle relaxation after forceful contraction (myotonia) and caused by mutations in the chloride channel voltage-sensitive 1 (CLCN1) gene, encoding the voltage-gated chloride channel of skeletal muscle (ClC-1). In a large cohort of clinically diagnosed unrelated probands, we identified 75 different CLCN1 mutations in 106 individuals, among which 29 were novel mutations and 46 had already been reported. Despite the newly described mutations being scattered throughout the gene, in our patients, mutations were mostly found in exons 4 and 5. Most of the novel mutations located in the region comprising the intramembrane helices are involved in the ion-conducting pathway and predicted to affect channel function. We report for the first time that two mutations, inherited on the same allele as a heterozygous trait, abrogate disease expression, although when inherited singularly they were pathogenic. Such a mode of inheritance might explain the incomplete penetrance reported for autosomal dominant mutations in particular families