Atassie eredodegenerative ad esordio precoce: descrizione del pattern di alterazione patologica mediante neuroimaging avanzato e studio neuropsicologico per la definizione di indicatori paraclinici utili al monitoraggio dell'evoluzione o alla verifica di efficacia del trattamento.

Background/aims Friedreich's ataxia (FRDA) is an autosomal-recessive neurodegenrative conditions caused by a GAA repeat triplet. There are no quantitative objective biomarkers to show reliable correlations with progression rate and disease severity. Methods or Materials or Case Report Twenty-one early-onset molecularly-defined FRDA patients underwent clinical-neuropsychological assessment. A subgroup of patients (n=17) and age-matched healthy controls (HC) underwent a neuroimaging study protocol on a 3T-MRI (DTI, fMRI). Non-parametric voxel-based permutations were performed on the WM-maps regions-of-interest (ROI), via a general linear model (GLM) (p<0.05). An fMRI sequence was acquired during a simple block-design finger-tapping task. Results All patients were homozygous for GAA expansion (mean GAA1 653.7±221), but one with a point-mutaion/170GAA. Age-at-onset: 10.6±4.6yrs, age-at-assessment 26.9±10.3yrs, disease-duration 16.3±8.8yrs. Deficit on executive and attentive functions were ob-served. We found altered FA and MD parameters, through voxel- and ROI-based analysis, in the cerebellar peduncles; corticospinal, lemnisceal systems, major commissural fibres, thalamic and optic radiations. A finger-tapping task demonstrated significantly higher cerebellar-cortex activation (lobule V, IV) in HC compared to FRDA. Conclusion We report our clinical and neuroimaging experience of a FRDA cohort in order to explore WM con-nectivity and motor dysfunction. DTI changes in selected areas and BOLD-signal in the cerebellar, ipsilateral cerebellar-cortex in response to a simple motor task show strong intergroup-discriminating power and may prove to be useful paraclinical disease markers. A longitudinal study is needed to investigate and validate the sensitivity of these indicators

Trends observed in bilateral cerebral palsy during a thirty-year period: A cohort study with an ICF-based overview.

Background To describe trends observed across thirty years in demographic and clinical characteristics and rehabilitation of patients with bilateral cerebral palsy. Methods This retrospective study includes 464 (261 M and 203 F) inpatients with bilateral cerebral palsy, born from 1967 to 1997 and discharged from an outpatient rehabilitative facility from 1985 to 2015. Data concerning the health profile were collected from medical reports and organized in the domains of Body Functions and Structure; Activity and participation and Personal and Environmental factors as proposed in the International Classification of Functioning Disability and Health (ICF). The trend observed over the three birth decades was discussed. Results The duration of the rehabilitative treatment decreased across decades approximately by two years per decade (from an initial 16.2 yrs to 12.3 yrs). Across the decades the rate of quadriplegia decreased, whereas rates of diplegia increased; spasticity was the prevalent observed motor type for all decades. The most frequent musculoskeletal disorder involved the middle inferior part of the body; among comorbidities a steady decrease in psychiatric disorders was found. With respect to the first decade a slight improvement was observed in the gross motor functioning and in the hand dexterity. No particular trend was observed concerning communication abilities. An increase in the use of pharmacological and surgical treatments for motor symptoms was observed. Conclusion This study presents and describes the functioning of a large sample of Italian patients with bilateral CP on the basis of the ICF framework and it discussed the trend observed across decades

Effectiveness of rehabilitation intervention in persons with Friedreich ataxia

IntroductionThe relevance of rehabilitation in progressive neurological disorders, such as Friedreich’s Ataxia (FRDA), has yet to be convincingly proven. FRDA is characterized by ataxia, loss of gait, scoliosis, cardiomyopathy, dysarthria and dysphagia, with reduced life expectancy. The disease onset is usually in adolescence, leading to progressive disability. Omaveloxolone has been recently approved as the first pharmacological treatment for FRDA in adults and adolescents aged 16 years and older. Regarding non-pharmacological therapies, neurorehabilitation is a valuable aid in addressing the symptoms and in maintaining the residual functioning. We performed a prospective observational cohort study to evaluate the efficacy of inpatient rehabilitation (IR) for people with FRDA.MethodsA total of 42 individuals (29 adults and 13 children) with FRDA were recruited. There were 27 ambulant and 15 non-ambulant participants. The patients underwent IR of 3 and 4 weeks in children and adults, respectively. The IR treatment was designed to be applied within a multidisciplinary setting, so FRDA patients underwent, in addition to physiotherapy, also occupational therapy, practical manual activities and psychological support aiming to enhance transferable skills useful in the activities of daily living. The primary outcome was the Scale for the Assessment and Rating of Ataxia (SARA). Other measures were: Friedreich Ataxia Rating Scale (FARS) and Nine Hole Peg Test (NHPT). Furthermore, we used the 6 Minute Walk Test (6MWT), the Timed Up and Go (TUG) and the Berg Balance Scale (BBS) only on ambulant subjects. Outcomes were evaluated at baseline and at the end of the treatment.ResultsWe report that the IR significantly improves motor performance and ataxia symptoms in patients with FRDA. Our study shows significant functional improvement in all the outcome measures used, except for NHPT bilaterally. FARS and SARA scores post-IR are significatively reduced when compared (p &lt; 0.001).DiscussionWe demonstrate that IR programs in FRDA can provide a meaningful clinical improvement in terms of outcome measures. These findings could be useful when approaching progressive neurological disorders

Functional MRI Studies in Friedreich's Ataxia: A Systematic Review

Friedreich's ataxia (FRDA) is an inherited neurodegenerative movement disorder with early onset, widespread cerebral and cerebellar pathology, and no cure still available. Functional MRI (fMRI) studies, although currently limited in number, have provided a better understanding of brain changes in people with FRDA. This systematic review aimed to provide a critical overview of the findings and methodologies of all fMRI studies conducted in genetically confirmed FRDA so far, and to offer recommendations for future study designs. About 12 cross-sectional and longitudinal fMRI studies, included 198 FRDA children and young adult patients and, 205 healthy controls (HCs), according to the inclusion criteria. Details regarding GAA triplet expansion and demographic and clinical severity measures were widely reported. fMRI designs included motor and cognitive task paradigms, and resting-state studies, with widespread changes in functionally activated areas and extensive variability in study methodologies. These studies highlight a mixed picture of both hypoactivation and hyperactivation in different cerebral and cerebellar brain regions depending on fMRI design and cohort characteristics. Functional changes often correlate with clinical variables. In aggregate, the findings provide support for cerebro-cerebellar loop damage and the compensatory mechanism hypothesis. Current literature indicates that fMRI is a valuable tool for gaining in vivo insights into FRDA pathology, but addressing that its limitations would be a key to improving the design, interpretation, and generalizability of studies in the future

Functional and Structural Brain Damage in Friedreich's Ataxia

Friedreich's ataxia (FRDA) is a rare hereditary neurodegenerative disorder caused by a GAA repeat expansion in the FXN gene. There is still no cure or quantitative biomarkers reliaby correlating with the progression rate and disease severity. Investigation of functional and structural alterations characterizing white (WM) and gray matter (GM) in FRDA are needed prerequisite to monitor progression and response to treatment. Here we report the results of a multimodal cross-sectional MRI study of FRDA including Voxel-Based Morphometry (VBM), diffusion-tensor imaging (DTI), functional MRI (fMRI), and a correlation analysis with clinical severity scores. Twenty-one early-onset FRDA patients and 18 age-matched healthy controls (HCs) were imaged at 3T. All patients underwent a complete cognitive and clinical assessment with ataxia scales. VBM analysis showed GM volume reduction in FRDA compared to HCs bilaterally in lobules V, VI, VIII (L&gt;R), as well as in the crus of cerebellum, posterior lobe of the vermis, in the flocculi and in the left tonsil. Voxel-wise DTI analysis showed a diffuse fractional anisotropy reduction and mean, radial, axial (AD) diffusivity increase in both infratentorial and supratentorial WM. ROI-based analysis confirmed the results showing differences of the same DTI metrics in cortico-spinal-tracts, forceps major, corpus callosum, posterior thalamic radiations, cerebellar penduncles. Additionally, we observed increased AD in superior (SCP) and middle cerebellar peduncles. The WM findings correlated with age at onset (AAO), short-allelle GAA, and disease severity. The intragroup analysis of fMRI data from right-handed 14 FRDA and 15 HCs showed similar findings in both groups, including activation in M1, insula and superior cerebellar hemisphere (lobules V–VIII). Significant differences emerged only during the non-dominant hand movement, with HCs showing a stronger activation in the left superior cerebellar hemisphere compared to FRDA. Significant correlations were found between AAO and the fMRI activation in cerebellar anterior and posterior lobes, insula and temporal lobe. Our multimodal neuroimaging protocol suggests that MRI is a useful tool to document the extension of the neurological impairment in FRDA

Atassie eredodegenerative ad esordio precoce: descrizione del pattern di alterazione patologica mediante neuroimaging avanzato e studio neuropsicologico per la definizione di indicatori paraclinici utili al monitoraggio dell'evoluzione o alla verifica di efficacia del trattamento.

Background/aims Friedreich's ataxia (FRDA) is an autosomal-recessive neurodegenrative conditions caused by a GAA repeat triplet. There are no quantitative objective biomarkers to show reliable correlations with progression rate and disease severity. Methods or Materials or Case Report Twenty-one early-onset molecularly-defined FRDA patients underwent clinical-neuropsychological assessment. A subgroup of patients (n=17) and age-matched healthy controls (HC) underwent a neuroimaging study protocol on a 3T-MRI (DTI, fMRI). Non-parametric voxel-based permutations were performed on the WM-maps regions-of-interest (ROI), via a general linear model (GLM) (p<0.05). An fMRI sequence was acquired during a simple block-design finger-tapping task. Results All patients were homozygous for GAA expansion (mean GAA1 653.7±221), but one with a point-mutaion/170GAA. Age-at-onset: 10.6±4.6yrs, age-at-assessment 26.9±10.3yrs, disease-duration 16.3±8.8yrs. Deficit on executive and attentive functions were ob-served. We found altered FA and MD parameters, through voxel- and ROI-based analysis, in the cerebellar peduncles; corticospinal, lemnisceal systems, major commissural fibres, thalamic and optic radiations. A finger-tapping task demonstrated significantly higher cerebellar-cortex activation (lobule V, IV) in HC compared to FRDA. Conclusion We report our clinical and neuroimaging experience of a FRDA cohort in order to explore WM con-nectivity and motor dysfunction. DTI changes in selected areas and BOLD-signal in the cerebellar, ipsilateral cerebellar-cortex in response to a simple motor task show strong intergroup-discriminating power and may prove to be useful paraclinical disease markers. A longitudinal study is needed to investigate and validate the sensitivity of these indicators.Atassia di Friedreich (FRDA) e' una malattia neurodegenrativa a decorso progressivo. E' causata dall'espansione della tripletta GAA. Non esistono biomarkatori soggettivi per dimostrare efficacemente correlazioni valide con la progressione e la gravita' di malattia. Metodi: Abbiamo valutato 21 pazienti tramite un protocollo clinico/neuropsicologico. Un sottogruppo di 17 pazienti ed un gruppo di 13 soggetti sani sono stati sottoposti ad uno studio con protocollo di neuroimaging DTI e fMRI su uno scanner di 3Tesla. Sono state eseguite delle valutazioni non parametriche tipo permutazioni voxel-based sulle regioni di interesse (ROI) della sostanza bianca dell'encefalo tramite l'utilizzo di una modello lineare generale (GLM) (p < 0.05). Una sequenza di fMRI e' stata acquisita come semplice disegno a blocco di un compito motorio tipo finger tapping. Risultati: Tutti i pazienti erano omozigoti per l'espansione GAA (media GAA1 653.7±221), uno di loro era eterozigote con 170 GAA ed una mutazione puntiforme. Eta' all'esordio 10.6, eta' alla visita 26.9±10.3aa, durata di malattia 16.3±8.8aa. Sono stati rilevati deficit delle funzioni attentive ed esecutive. Sono stati evidenziati alterazioni a carico dei parametri FA e MD, tramite un analisi voxel-based e ROI based localizzate come segue: peduncoli cerebellari, sistemi di fibre corticospinali, lemniscali, le grandi fibre commissurali, radiazioni ottiche e talamiche. Dall'analisi della fMRI con il compito motorie, e' risultato una maggiore attivazione della corteccia cerebellare (lobuli V e VI) nei controlli rispetto ai pazienti. Conclusioni Riportiamo uno studio clinico e di neuroimaging dalla nostra esperienza con un campione di pazienti con FRDA con l'obiettivo di esplorare la connettivita' e la funzionalita' motoria. Le variazioni DTI ed il segnale BOLD nella corteccia cerebellar in risposta ad uno stimolo motorio dimostrano una capacit' discriminativa intergruppo e potrebbero risultare marcatori paraclinici utili. Futuri studi longitudinali sono necessari per stdudiare e validare la sensitivita' di questi indicatori

Data from the European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC)

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Data from the European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC)

Background: The European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) was launched to register rare muscle glycogenoses in Europe, to facilitate recruitment for research trials and to learn about the phenotypes and disseminate knowledge about the diseases through workshops and websites. A network of twenty full and collaborating partners from eight European countries and the US contributed data on rare muscle glycogenosis in the EUROMAC registry. After approximately 3 years of data collection, the data in the registry was analysed. Results: Of 282 patients with confirmed diagnoses of muscle glycogenosis, 269 had McArdle disease. New phenotypic features of McArdle disease were suggested, including a higher frequency (51.4%) of fixed weakness than reported before, normal CK values in a minority of patients (6.8%), ptosis in 8 patients, body mass index above background population and number of comorbidities with a higher frequency than in the background population (hypothyroidism, coronary heart disease). Conclusions: The EUROMAC project and registry have provided insight into new phenotypic features of McArdle disease and the variety of co-comorbidities affecting people with McArdle disease. This should lead to better management of these disorders in the future, including controlling weight, and preventive screening for thyroid and coronary artery diseases, as well as physical examination with attention on occurrence of ptosis and fixed muscle weakness. Normal serum creatine kinase in a minority of patients stresses the need to not discard a diagnosis of McArdle disease even though creatine kinase is normal and episodes of myoglobinuria are absent.Sin financiación4.123 JCR (2020) Q2, 64/175 Genetics & Heredity1.274 SJR (2020) Q1, 365/2448 Medicine (miscellaneous)No data IDR 2019UE

Data from the European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC)

The European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) was launched to register rare muscle glycogenoses in Europe, to facilitate recruitment for research trials and to learn about the phenotypes and disseminate knowledge about the diseases through workshops and websites. A network of twenty full and collaborating partners from eight European countries and the US contributed data on rare muscle glycogenosis in the EUROMAC registry. After approximately 3 years of data collection, the data in the registry was analysed. Of 282 patients with confirmed diagnoses of muscle glycogenosis, 269 had McArdle disease. New phenotypic features of McArdle disease were suggested, including a higher frequency (51.4%) of fixed weakness than reported before, normal CK values in a minority of patients (6.8%), ptosis in 8 patients, body mass index above background population and number of comorbidities with a higher frequency than in the background population (hypothyroidism, coronary heart disease). The EUROMAC project and registry have provided insight into new phenotypic features of McArdle disease and the variety of co-comorbidities affecting people with McArdle disease. This should lead to better management of these disorders in the future, including controlling weight, and preventive screening for thyroid and coronary artery diseases, as well as physical examination with attention on occurrence of ptosis and fixed muscle weakness. Normal serum creatine kinase in a minority of patients stresses the need to not discard a diagnosis of McArdle disease even though creatine kinase is normal and episodes of myoglobinuria are absen

Clinical and Paraclinical Indicators of Motor System Impairment in Hereditary Spastic Paraplegia: A Pilot Study

<div><p>Background</p><p>Hereditary spastic paraplegias (HSP) are a composite and genetically heterogeneous group of conditions mainly expressed by the impairment of the central motor system (“pure” forms). The involvement of other components of the central nervous system or of other systems is described in the “complicate” forms. The definition of an investigation protocol capable, by assembling clinical and paraclinical indicators to fully represent the extent of the motor system impairment, would help both the clinical handling of these conditions and contribute to our understanding of their pathogenesis.</p><p>Methods</p><p>We applied a clinical and paraclinical protocol which included tools exploring motor and non motor functioning, neurophysiology and MRI to a composite cohort of 70 molecularly defined HSP patients aged 3 to 65, to define for each indicator its significance in detailing the presence and the severity of the pathology.</p><p>Results</p><p>Clinically increased deep tendon reflexes and lower limb (LL) weakness are constant findings in all patients. The “complicated” forms are characterized by peripheral motor impairment, cognitive and cerebellar involvement. The Spastic Paraplegia Rating Scale efficiently reflects the severity of functional problems and correlates with disease duration. Neurophysiology consistently documents the impairment of the central motor pathway to the LLs. Nevertheless, the upper extremities and sensory system involvement is a frequent finding. MRI diffusion tensor imaging (DTI) highlighted a significant alteration of FA and MD. Combining the sampling of the various portion of the cortico-spinal tract (CST) DTI consistently discriminated patients from controls.</p><p>Conclusion</p><p>We propose a graded clinical and paraclinical protocol for HSP phenotype definition, indicating for each tool the discriminative and descriptive capacity. Our protocol applied to 9 different forms of HSP showed that the functional impairment often extends beyond the CST. The novel DTI approach may add significant elements in disease recognition, staging and mapping.</p></div