Publications by authors named "Olimpia Musumeci"

88 Publications

Movement Disorders in Children with a Mitochondrial Disease: A Cross-Sectional Survey from the Nationwide Italian Collaborative Network of Mitochondrial Diseases.

J Clin Med 2021 May 12;10(10). Epub 2021 May 12.

IRCCS Fondazione Stella Maris, 56018 Pisa, Italy.

Movement disorders are increasingly being recognized as a manifestation of childhood-onset mitochondrial diseases (MDs). However, the spectrum and characteristics of these conditions have not been studied in detail in the context of a well-defined cohort of patients. We retrospectively explored a cohort of individuals with childhood-onset MDs querying the Nationwide Italian Collaborative Network of Mitochondrial Diseases database. Using a customized online questionnaire, we attempted to collect data from the subgroup of patients with movement disorders. Complete information was available for 102 patients. Movement disorder was the presenting feature of MD in 45 individuals, with a mean age at onset of 11 years. Ataxia was the most common movement disorder at onset, followed by dystonia, tremor, hypokinetic disorders, chorea, and myoclonus. During the disease course, most patients (67.7%) encountered a worsening of their movement disorder. Basal ganglia involvement, cerebral white matter changes, and cerebellar atrophy were the most commonly associated neuroradiological patterns. Forty-one patients harbored point mutations in the mitochondrial DNA, 10 carried mitochondrial DNA rearrangements, and 41 cases presented mutations in nuclear-DNA-encoded genes, the latter being associated with an earlier onset and a higher impairment in activities of daily living. Among our patients, 32 individuals received pharmacological treatment; clonazepam and oral baclofen were the most commonly used drugs, whereas levodopa and intrathecal baclofen administration were the most effective. A better delineation of the movement disorders phenotypes starting in childhood may improve our diagnostic workup in MDs, fine tuning management, and treatment of affected patients.
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http://dx.doi.org/10.3390/jcm10102063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151313PMC
May 2021

SARS-CoV-2 infection in patients with primary mitochondrial diseases: Features and outcomes in Italy.

Mitochondrion 2021 05 30;58:243-245. Epub 2021 Mar 30.

IRCCS Istituto Delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Italy.

Patients with mitochondrial diseases, who usually manifest a multisystem disease, are considered potentially at-risk for a severe coronavirus disease 2019 (COVID-19). The objective of this study is to analyze the clinical features, prognosis and outcomes of COVID-19 in patients with primary mitochondrial diseases in a cohort of patients followed in Italy. We searched for patients with primary mitochondrial diseases and COVID-19 followed by the Italian Collaborative Network of Mitochondrial Diseases. In a total of 1843 patients followed by the National Network, we have identified from March 1st to January 30th, 2021, 27 SARS-CoV-2 infection. Most of the patients were pauci or asymptomatic (85%) and treated at home. The most common signs of COVID-19 were fever (78,9%), fatigue (47,4%), myalgia (42,1%), cough and headache (36,8%), and dyspnea (31,6%). Those who required COVID-19 therapy were treated with low-molecular-weight heparin, glucocorticoids, and antibiotics (mainly azithromycin) without serious side effects related to the therapy. Five patients (18,5%) clinically deteriorated during the infection, and one of them died for pneumonia. Primary mitochondrial diseases infected individuals seemed to be similarly affected by SARS-CoV-2 compared with the general Italian population in terms of clinical presentation and outcome.
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http://dx.doi.org/10.1016/j.mito.2021.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007531PMC
May 2021

Statin-Induced Myopathy: Translational Studies from Preclinical to Clinical Evidence.

Int J Mol Sci 2021 Feb 19;22(4). Epub 2021 Feb 19.

Section of Pharmacology, Department of Pharmacy and Drug Sciences, University of Bari "Aldo Moro", 70125 Bari, Italy.

Statins are the most prescribed and effective drugs to treat cardiovascular diseases (CVD). Nevertheless, these drugs can be responsible for skeletal muscle toxicity which leads to reduced compliance. The discontinuation of therapy increases the incidence of CVD. Thus, it is essential to assess the risk. In fact, many studies have been performed at preclinical and clinical level to investigate pathophysiological mechanisms and clinical implications of statin myotoxicity. Consequently, new toxicological aspects and new biomarkers have arisen. Indeed, these drugs may affect gene transcription and ion transport and contribute to muscle function impairment. Identifying a marker of toxicity is important to prevent or to cure statin induced myopathy while assuring the right therapy for hypercholesterolemia and counteracting CVD. In this review we focused on the mechanisms of muscle damage discovered in preclinical and clinical studies and highlighted the pathological situations in which statin therapy should be avoided. In this context, preventive or substitutive therapies should also be evaluated.
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http://dx.doi.org/10.3390/ijms22042070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921957PMC
February 2021

Polarized mitochondria as guardians of NK cell fitness.

Blood Adv 2021 01;5(1):26-38

INSERM U1223, Paris, France.

Distinct metabolic demands accompany lymphocyte differentiation into short-lived effector and long-lived memory cells. How bioenergetics processes are structured in innate natural killer (NK) cells remains unclear. We demonstrate that circulating human CD56Dim (NKDim) cells have fused mitochondria and enhanced metabolism compared with CD56Br (NKBr) cells. Upon activation, these 2 subsets showed a dichotomous response, with further mitochondrial potentiation in NKBr cells vs paradoxical mitochondrial fission and depolarization in NKDim cells. The latter effect impaired interferon-γ production, but rescue was possible by inhibiting mitochondrial fragmentation, implicating mitochondrial polarization as a central regulator of NK cell function. NKDim cells are heterogeneous, and mitochondrial polarization was associated with enhanced survival and function in mature NKDim cells, including memory-like human cytomegalovirus-dependent CD57+NKG2C+ subsets. In contrast, patients with genetic defects in mitochondrial fusion had a deficiency in adaptive NK cells, which had poor survival in culture. These results support mitochondrial polarization as a central regulator of mature NK cell fitness.
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http://dx.doi.org/10.1182/bloodadvances.2020003458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805327PMC
January 2021

STIG study: real-world data of long-term outcomes of adults with Pompe disease under enzyme replacement therapy with alglucosidase alfa.

J Neurol 2021 Jul 5;268(7):2482-2492. Epub 2021 Feb 5.

Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians University Munich, Ziemssenstr. 1, 80336, Munich, Germany.

Background: Pompe disease is one of the few neuromuscular diseases with an approved drug therapy, which has been available since 2006. Our study aimed to determine the real-world long-term efficacy and safety of alglucosidase alfa.

Methods: This multicenter retrospective study (NCT02824068) collected data from adult Pompe disease patients receiving ERT for at least 3 years. Demographics and baseline characteristics, muscle strength, lung function (FVC), walking capability (6MWT), and safety were assessed once a year. Evaluation was done on the group and individual levels, using quantitative linear models (t test) and general univariate linear models (ANOVA).

Findings: Sixty-eight adult Pompe disease patients from four countries (Spain, Taiwan, Italy, Germany (STIG)) participated. The mean follow-up was 7.03 years ± 2.98. At group level in all outcome measures, an initial improvement followed by a secondary decline was observed. After 10 years, the 6MWT showed the most sustained positive effect (p = 0.304). The MRC remained stable with a mild decline (p = 0.131), however, FVC deteriorated significantly (p < 0.001) by 14.93% over 10 years of ERT. The progression rate of FVC under ERT could be explained in most of the patients (83.5%) by the disease severity at baseline. Furthermore, our study shows a decline in the FVC combined with an increase in non-invasive and invasive ventilation requirements in adult Pompe disease patients over time.

Conclusions: The STIG real-world study confirms an initial efficacy of ERT in the first years with a secondary sustained decline in multiple outcome measures. Further efforts are required to establish a more valid long-term monitoring and improved therapies.
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http://dx.doi.org/10.1007/s00415-021-10409-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862044PMC
July 2021

Favourable course in a cohort of Parkinson's disease patients infected by SARS-CoV-2: a single-centre experience.

Neurol Sci 2021 Mar 13;42(3):811-816. Epub 2021 Jan 13.

Covid Hospital AOU Policlinico G. Martino, Messina, Italy.

The COVID-19 outbreak has had a dramatic impact on the healthcare system due to the rapid, worldwide spread of the virus, highlighting several considerations on the best management of infected patients and also potential risks and prognostic factors in patients with pre-existing chronic diseases exposed to the virus. Neurodegenerative disorders are known to be chronic, disabling diseases that imply a higher vulnerability to infections, and for this reason, it has been suggested that SARS-CoV-2 infection may have a worse course in these patients. In the present study, we report our experience with 12 patients affected by Parkinson's disease (PD) who became infected with SARS-Cov-2 due to a COVID-19 outbreak in a care residency, and thus hospitalised in our COVID hospital. Most of the PD patients had a long disease duration and multiple comorbidities even though SARS-CoV-2 manifestations were mild, and none required intensive care. Despite lung conditions, most of our PD patients had mild symptoms: 7 patients were clinically asymptomatic (58.3%); 3 patients had fever, cough, and myalgia (25%) and 2 patients had dyspnoea (16%) that needed high-flow oxygen therapy. Few complications related to PD were seen. All patients were discharged after a mean hospitalisation period of 30 days. Mortality rate during hospitalisation was zero. Our findings suggest that SARS-CoV-2 infection does not have a poor prognosis in patients with PD. More extensive data and evaluations, however, are needed to confirm our data, and caution is warranted.
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http://dx.doi.org/10.1007/s10072-020-05001-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803661PMC
March 2021

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

Orphanet J Rare Dis 2020 11 24;15(1):330. Epub 2020 Nov 24.

Copenhagen Neuromuscular Center, Section 6921, Rigshospitalet, University of Copenhagen, 2100, Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1186/s13023-020-01562-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687836PMC
November 2020

Primary mitochondrial myopathy: Clinical features and outcome measures in 118 cases from Italy.

Neurol Genet 2020 Dec 20;6(6):e519. Epub 2020 Oct 20.

Department of Clinical and Experimental Medicine (V.M., F.G., G.S., M.M.), Neurological Clinic, University of Pisa, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna (V.C., M.L.V.), UOC Clinica Neurologica, Bologna, Italy; Department of Biomedical and Neuromotor Sciences (DIBINEM) (V.C., M.L.V.), University of Bologna, Italy; Dino Ferrari Centre (G.P.C.), Department of Pathophysiology and Transplantation (DEPT), University of Milan, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (G.P.C., M.M.), Neuromuscular and Rare Disease Unit; Unit of Neurology (M.F.), ASST "Spedali Civili" and University of Brescia, Italy; UO Medical Genetics and Neurogenetics (C.L., S.M.), Fondazione IRCCS Istituto Neurologico C.Besta, Milan, Italy; Neuromuscular Unit (M.T., S.B.), Department of Neurosciences, University of Torino, Italy; Department of Clinical and Experimental Medicine (O.M., A.T., G.T.), UOC Neurologia e Malattie Neuromuscolari, University of Messina, Italy; UOC Neurofisiopatologia Fondazione Policlinico Universitario A. Gemelli IRCCS (S.S., G.P.), Roma, Italy; Dipartimento Universitario di Neuroscienze, Università Cattolica del Sacro Cuore (S.S., G.P.), Roma, Italy; Department of Neurosciences (P.T.), Biomedicine and Movement Sciences, Section of Clinical Neurology, University of Verona, Italy; Neurorehabilitation Unit (A.M.), Department of Neurosciences, University Hospital of Verona, Italy; Neuromuscular Unit (S.B.), Department of Neurosciences, University of Torino, Italy.

Objective: To determine whether a set of functional tests, clinical scales, patient-reported questionnaires, and specific biomarkers can be considered reliable outcome measures in patients with primary mitochondrial myopathy (PMM), we analyzed a cohort of Italian patients.

Methods: Baseline data were collected from 118 patients with PMM, followed by centers of the Italian network for mitochondrial diseases. We used the 6-Minute Walk Test (6MWT), Timed Up-and-Go Test (x3) (3TUG), Five-Times Sit-To-Stand Test (5XSST), Timed Water Swallow Test (TWST), and Test of Masticating and Swallowing Solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional Pain Inventory as patient-reported outcome measures; and FGF21, GDF15, lactate, and creatine kinase (CK) as biomarkers.

Results: A total of 118 PMM cases were included. Functional outcome measures (6MWT, 3TUG, 5XSST, TWST, and TOMASS) and biomarkers significantly differed from healthy reference values and controls. Moreover, functional measures correlated with patients' perceived fatigue and pain severity. Patients with either mitochondrial or nuclear DNA point mutations performed worse in functional measures than patients harboring single deletion, even if the latter had an earlier age at onset but similar disease duration. Both the biomarkers FGF21 and GDF15 were significantly higher in the patients compared with a matched control population; however, there was no relation with severity of disease.

Conclusions: We characterized a large cohort of PMM by evaluating baseline mitochondrial biomarkers and functional scales that represent potential outcome measures to monitor the efficacy of treatment in clinical trials; these outcome measures will be further reinvestigated longitudinally to define the natural history of PMM.
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http://dx.doi.org/10.1212/NXG.0000000000000519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670572PMC
December 2020

Intracranial aneurysm management in patients with late-onset Pompe disease (LOPD).

Neurol Sci 2021 Jun 17;42(6):2411-2419. Epub 2020 Oct 17.

Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

Pompe disease is a rare hereditary metabolic disorder caused by α-glucosidase (GAA) deficiency. The late-onset form of the disease (LOPD) is considered a multisystemic disorder which could involve vascular system with cerebrovascular abnormalities such as intracranial aneurysms or dolichoectasia. Intracranial aneurysm rupture may represent a life-threatening emergency. A possible treatment of unruptured intracranial aneurysms (UIAs) should consider both aneurysm-related (aneurysmal size, shape, localization, numbers and hemodynamic factors) and patient-related risk factors (patient's age and sex, hypertension, smoke exposure). Moreover, UIAs management of LOPD patients needs also to take into account the altered blood vessels integrity and elasticity, whose consistency is likely weakened by the deficient GAA activity as a further potential risk factor. We herein present our approach for of UIAs management in three patients with LOPD. Among them, only one patient with a left saccular UIA of the anterior communicating artery, after careful consideration of risk factors, underwent the endovascular treatment. The other two patients were scheduled for a 1-year follow-up, according to radiological, clinical, and risk evaluation features. Finally, we would like to suggest some general recommendations for UIAs management. In particular, if no risk factors are identified, a cautious yearly follow-up is suggested; otherwise, if risk factors are present, endovascular treatment should be considered.
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http://dx.doi.org/10.1007/s10072-020-04819-2DOI Listing
June 2021

Estimating the impact of COVID-19 pandemic on services provided by Italian Neuromuscular Centers: an Italian Association of Myology survey of the acute phase.

Acta Myol 2020 Jun 1;39(2):57-66. Epub 2020 Jun 1.

Child and Adolescent Unit, IRCCS Mondino Foundation, Pavia, Italy.

Introduction: Since February 2020, the outbreak of COVID-19 in Italy has forced the health care system to undergo profound rearrangements in its services and facilities, especially in the worst-hit areas in Northern Italy. In this setting, inpatient and outpatient services had to rethink and reorganize their activities to meet the needs of patients during the "lockdown". The Italian Association of Myology developed a survey to estimate the impact of these changes on patients affected by neuromuscular disorders and on specialized neuromuscular centers during the acute phase of COVID-19 pandemic.

Methods: We developed an electronic survey that was sent to neuromuscular centers affiliated with the Italian Association of Myology, assessing changes in pharmacological therapies provision, outpatient clinical and instrumental services, support services (physiotherapy, nursing care, psychological support) and clinical trials.

Results: 40% of surveyed neuromuscular centers reported a reduction in outpatient visit and examinations (44.5% of centers in Northern regions; 25% of centers in Central regions; 50% of centers in Southern regions). Twenty-two% of centers postponed in-hospital administration of therapies for neuromuscular diseases (23.4% in Northern regions; 13.0% in Central regions; 20% in Southern regions). Diagnostic and support services (physiotherapy, nursing care, psychological support) were suspended in 57% of centers (66/43/44% in Northern, Central and Southern centers respectively) Overall, the most affected services were rehabilitative services and on-site outpatient visits, which were suspended in 93% of centers. Strategies adopted by neuromuscular centers to overcome these changes included maintaining urgent on-site visits, addressing patients to available services and promoting remote contact and telemedicine.

Conclusions: Overall, COVID-19 pandemic resulted in a significant disruption of clinical and support services for patients with neuromuscular diseases. Despite the efforts to provide telemedicine consults to patients, this option could be promoted and improved further. A close collaboration between the different neuromuscular centers and service providers as well as further implementation of telehealth platforms are necessary to ensure quality care to NMD patients in the near future and in case of recurrent pandemic waves.
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http://dx.doi.org/10.36185/2532-1900-008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460733PMC
June 2020

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network.

J Inherit Metab Dis 2021 Mar 8;44(2):376-387. Epub 2020 Sep 8.

Department of Clinical Movement Neurosciences, Royal Free Campus, University College of London, Queen Square Institute of Neurology, London, UK.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations. The onset typically occurs in the second decade of life and mean age at death is 37 years. Signs and symptoms of MNGIE are heterogeneous and confirmatory diagnostic tests are not routinely performed by most laboratories, accounting for common misdiagnosis. Factors predictive of progression and appropriate tests for monitoring are still undefined. Several treatment options showed promising results in restoring the biochemical imbalance of MNGIE. The lack of controlled studies with appropriate follow-up accounts for the limited evidence informing diagnostic and therapeutic choices. The International Consensus Conference (ICC) on MNGIE, held in Bologna, Italy, on 30 March to 31 March 2019, aimed at an evidence-based consensus on diagnosis, prognosis, and treatment of MNGIE among experts, patients, caregivers and other stakeholders involved in caring the condition. The conference was conducted according to the National Institute of Health Consensus Conference methodology. A consensus development panel formulated a set of statements and proposed a research agenda. Specifically, the ICC produced recommendations on: (a) diagnostic pathway; (b) prognosis and the main predictors of disease progression; (c) efficacy and safety of treatments; and (f) research priorities on diagnosis, prognosis, and treatment. The Bologna ICC on diagnosis, management and treatment of MNGIE provided evidence-based guidance for clinicians incorporating patients' values and preferences.
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http://dx.doi.org/10.1002/jimd.12300DOI Listing
March 2021

A Family With a Complex Phenotype Caused by Two Different Rare Metabolic Disorders: GLUT1 and Very-Long-Chain Fatty Acid Dehydrogenase (VLCAD) Deficiencies.

Front Neurol 2020 23;11:514. Epub 2020 Jun 23.

Unit of Neurology and Neuromuscular Disorders, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

GLUT1 Deficiency Syndrome (GLUT1-DS) is a rare and potentially treatable neurometabolic condition, caused by a reduced glucose transport into the brain and clinically characterized by an epileptic encephalopathy with movement disorders. A wide inter-intrafamilial phenotypic variability has been reported. Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inherited metabolic disorder of mitochondrial long-chain fatty acid oxidation (FAO) with also a variable age of onset and clinical presentation including cardiomyopathy, hypoketotic hypoglycemia, and liver disease. Sometimes, VLCAD manifests later with a prevalent muscle involvement characterized by exercise intolerance and recurrent rhabdomyolysis. We report a 40-year-old man with mild mental retardation and sporadic choreo-athetoid movements, who complained of recurrent episodes of rhabdomyolysis triggered by exercise or fasting since his twenties. His 15-year-old son had a psychomotor developmental delay with episodes of drowsiness mainly at fasting and exercise-induced choreo-athetoid movements but no history of pigmenturia. Clinical and laboratory findings in the son suggested a diagnosis of GLUT1-DS confirmed by genetic analysis that revealed a heterozygous mutation c.997C>T (p.R333W) that was also found in the proband. However, the presence in the latter of recurrent exercise-induced rhabdomyolysis, never reported in GLUT1-DS, implied a second metabolic disorder. Increased plasma C14:1-carnitine levels and the identification of two known heterozygous mutations c. 553G>A (p.G185S) and c.1153C>T (p.R385W) in confirmed the additional diagnosis of VLCAD deficiency in the proband. Nowadays, there is an increasing evidence of "double trouble" cases of genetic origin. Consequently, when atypical features accompany a known phenotype, associated comorbidities should be considered.
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http://dx.doi.org/10.3389/fneur.2020.00514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324651PMC
June 2020

Ultrasound assessment of diaphragm function in patients with late-onset Pompe disease.

Neurol Sci 2020 Aug 11;41(8):2175-2184. Epub 2020 Mar 11.

Unità Operativa Complessa di Neurologia e Malattie Neuromuscolari, Dipartimento di Medicina Clinica e Sperimentale, Università di Messina, Messina, Italy.

Introduction: Late-Onset Pompe Disease (LOPD) is characterized by progressive limb-girdle muscle weakness and respiratory dysfunction. Diaphragm is the most impaired muscle in LOPD and its dysfunction cause major respiratory symptoms. The aim of this study was to evaluate the correlation between diaphragm thickness and mobility assessed by ultrasonography and respiratory function and muscle strength tests in patients with LOPD.

Methods: 17 patients with LOPD (9 female, 47 ± 15 years) and 17 age and gender-matched healthy controls underwent spirometry, muscle strength testing, and ultrasound evaluation of diaphragm excursion and thickness.

Results: The following parameters were significantly reduced in LOPD patients versus controls (all p < 0.001): forced vital capacity (FVC) in seated and supine position, maximum inspiratory and expiratory pressure (MIP and MEP), diaphragm excursion, thickness at functional residual capacity (FRC) and total lung capacity (TLC), and thickness fraction (TF). Ultrasound studies of diaphragm thickness at FRC correlated with MIP (r = 0.74; p < 0.0001) and seated FVC(r = 0.73; p < 0.05). Diaphragm thickness at TLC correlated with MIP (r = 0.85; p < 0.0001) and FVC in both seated (r = 0.77; p < 0.0001) and supine position (r = 0.68; p < 0.05). TF correlated significantly with MIP (r = 0.80; p < 0.001), FVC in both seated (r = 0.66; p < 0,005) and supine position (r = 0.61; p < 0.05). Interestingly diaphragm thickness at FRC correlated with disease duration (years) in LOPD patients (r = -0.53; p < 0,05). Ultrasound diaphragm mobility correlated with diaphragm thickness at TLC(r = 0.87; p < 0.0001), FRC (r = 0.84; p < 0.005) and TF (r = 0.73; p < 0.05). Moreover diaphragm mobility correlated with FVC in seated(r = 0.79; p < 0.005) and supine position(r = 0.74; p < 0.05) and MIP (r = 0.81; p < 0.005).

Conclusion: Diaphragm ultrasonography is a simple and reproducible technique for manage respiratory dysfunction in LOPD patients.
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http://dx.doi.org/10.1007/s10072-020-04316-6DOI Listing
August 2020

Awareness of rare and genetic neurological diseases among italian neurologist. A national survey.

Neurol Sci 2020 Jun 27;41(6):1567-1570. Epub 2020 Jan 27.

Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.

Rare neurological diseases (RNDs) are a heterogeneous group of disorders mainly affecting the central and peripheral nervous systems, representing almost 50% of all rare diseases; this explains why neurologists are very often involved in their diagnosis, treatment and research. The purpose of this study was to quantitatively describe the awareness of RNDs among the neurological community of the Italian Society of Neurology (SIN). A survey of the Italian Neurogenetics and Rare diseases group of the SIN, similar to what was submitted to the members of the EAN Task Force on Rare Neurologic Diseases and to EAN Panels Scientific Committee Management Groups, was launched in January 2019 in order to verify the specific Italian situations and possibly the regional differences. Answers were collected online. We observed that Italian Members of the SIN Neurogenetics and Rare Neurologic Diseases Scientific Group are well aware of the burden posed by RNDs but at the national and regional level, the relative awareness is sketchy and disparate. Although many national initiatives have been undertaken to facilitate the diagnosis and management in Italy, our survey reveals that much works has to be done in supporting RNDs patients, including a deeper collaboration between politics, universities and all stakeholders in the field.
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http://dx.doi.org/10.1007/s10072-020-04271-2DOI Listing
June 2020

Mitochondrial epilepsy: a cross-sectional nationwide Italian survey.

Neurogenetics 2020 04 3;21(2):87-96. Epub 2020 Jan 3.

IRCCS Fondazione Stella Maris, Pisa, Italy.

Many aspects of epilepsy in mitochondrial disorders (MDs) need to be further clarified. To this aim, we explored retrospectively a cohort of individuals with MDs querying the "Nationwide Italian Collaborative Network of Mitochondrial Diseases" (NICNMD) database (1467 patients included since 2010 to December 2016). We collected information on age at epilepsy onset, seizure type and frequency, genetic findings, and antiepileptic drugs (AEDs). At the time of our survey, 147/1467 (10%) patients in the NICNMD database had epilepsy. Complete information was available only for 98 patients, 52 males and 46 females, aged 5-92 years (mean age 40.4 ± 18.4; 14/98 children/teenagers and 84 adults). Epilepsy was the presenting feature of MD in 46/98 (47%) individuals, with onset at a median age of 19 years (range, 0.2-68; < 3 years in 14/97 (14%), 3-19 years in 36/97 (37%), > 19 years in 47/97 (49%)). Moreover, 91/98 patients (93%) displayed multiple seizures, with daily or weekly frequency in 25/91 (28%). Interictal EEG was abnormal in 70/78 (90%) patients, displaying abnormal background (47/70; 67%) and/or interictal paroxysms (53/70; 76%). Eighty of 90 patients (89%) displayed a 50-100% reduction of seizures on AEDs; levetiracetam was the most commonly used. Forty-one patients (42%) carried the m.3243A>G mutation, 16 (16%) the m.8344A>G, and 9 (9%) nuclear DNA (nDNA) mutations. Individuals with early-onset seizures mainly carried nDNA mutations and had a more severe epilepsy phenotype, higher seizure frequency, and disorganized background EEG activity. A better definition of epilepsy in MDs may foster the diagnostic workup, management, and treatment of affected patients, and allow more homogeneous patient stratification.
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http://dx.doi.org/10.1007/s10048-019-00601-5DOI Listing
April 2020

Diagnostic tools in late onset Pompe disease (LOPD).

Ann Transl Med 2019 Jul;7(13):286

Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

Pompe disease is a rare metabolic disorder due to deficiency of the lysosomal acid alpha-glucosidase (GAA) that causes glycogen accumulation in all tissues with a predominant involvement of skeletal muscle. The late onset form of Pompe disease (LOPD) is characterized by a progressive weakness of proximal and axial muscles, often mimicking limb-girdle muscular dystrophies or inflammatory myopathies, with respiratory distress mainly due to a diaphragmatic weakness. Diagnostic delay is still common, and clinicians need a high index of suspicion to recognize this condition because the disorder is quite rare, the clinical spectrum is wide, and signs and symptoms are not distinguishable from those in other neuromuscular disorders that present in a similar fashion. Diagnostic laboratory tests are quite fast and reliable to detect the enzymatic deficiency. Enzyme replacement therapy has been available for several years, and other new therapeutic strategies such as gene therapy are underway. Here, we discuss the main diagnostic tools currently used for the evaluation of patients with suspected LOPD.
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http://dx.doi.org/10.21037/atm.2019.06.60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642940PMC
July 2019

Multisystem late onset Pompe disease (LOPD): an update on clinical aspects.

Ann Transl Med 2019 Jul;7(13):284

Neurology and Neuromuscular Disorders Unit, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

Pompe disease is classified by age of onset, organ involvement, severity, and rate of progression in two main forms: the first one, infantile onset Pompe disease (IOPD), presents before the age of 12 months with generalized muscle weakness, hypotonia, respiratory distress, and hypertrophic cardiomyopathy as main clinical features. The second form, late onset Pompe disease (LOPD), is characterized by an onset at the age of 12 months to adulthood, hyperCKemia, and limb-girdle and axial muscle weakness, often complicated by respiratory muscles degeneration. In the last 10-15 years, an increasing interest in Pompe disease has led to multiple studies in an effort to clarify the emerging clinical aspects, to find out the best diagnostic tools to identify the disease as early as possible, and to offer new therapeutic options apart from enzyme replacement therapy (ERT). Since 2006, ERT-the first treatment for Pompe disease-has been universally accepted in the majority of countries all over the world. Although for years Pompe disease has been primarily considered a muscle disorder, nowadays it is clear that the involvement of several other organs has changed the cultural approach to this entity which is now viewed as a multisystem disorder. The emerging clinical aspects have greatly expanded the spectrum of the disease manifestations. In fact, central, peripheral, and autonomous nervous systems are often involved; vascular malformations and heart involvement are frequently observed; musculoskeletal and bone changes as well as oro-gastrointestinal and urinary tract alterations have been better defined. A great deal of effort has been made to clarify the clinical aspects of Pompe disease, to raise awareness of the LOPD patients' problems and to improve their quality of life.
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http://dx.doi.org/10.21037/atm.2019.07.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642938PMC
July 2019

A genetic modifier of symptom onset in Pompe disease.

EBioMedicine 2019 May 25;43:553-561. Epub 2019 Mar 25.

Department of Pediatrics, Erasmus University Medical Center, Rotterdam, Netherlands; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands; Center for Lysosomal and Metabolic Diseases, Erasmus University Medical Center, 3015 GE Rotterdam, Netherlands. Electronic address:

Background: Neonatal screening for Pompe disease is complicated by difficulties in predicting symptom onset in patients with the common c.-32-13T>G (IVS1) variant/null (i.e. fully deleterious) acid α-glucosidase (GAA) genotype. This splicing variant occurs in 90% of Caucasian late onset patients, and is associated with a broad range of symptom onset.

Methods: We analyzed a cohort of 143 compound heterozygous and 10 homozygous IVS1 patients, and we assessed ages at symptom onset, the presence of cis-acting single nucleotide variants (SNVs), and performed splicing analysis and enzyme activity assays.

Findings: In compound heterozygous IVS1 patients, the synonymous variant c.510C>T was uniquely present on the IVS1 allele in 9/33 (27%) patients with childhood onset, but was absent from 110 patients with onset in adulthood. GAA enzyme activity was lower in fibroblasts from patients who contained c.510C>T than it was in patients without c.510C>T. By reducing the extent of leaky wild-type splicing, c.510C>T modulated aberrant splicing caused by the IVS1 variant. The deleterious effect of c.510C>T was also found in muscle cells, the main target cells in Pompe disease. In homozygous IVS1 patients, the c.510C>T variant was absent in 4/4 (100%) asymptomatic individuals and present in 3/6 (50%) symptomatic patients. In cells from homozygous IVS1 patients, c.510C>T caused reduced leaky wild-type splicing.

Interpretation: c.510C>T is a genetic modifier in compound heterozygous and homozygous IVS1 patients. This finding is important for neonatal screening programs for Pompe disease. FUND: This work was funded by grants from Sophia Children's Hospital Foundation (SSWO, grant S17-32) and Metakids (2016-063).
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http://dx.doi.org/10.1016/j.ebiom.2019.03.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562017PMC
May 2019

Assessing the Role of Anti rh-GAA in Modulating Response to ERT in a Late-Onset Pompe Disease Cohort from the Italian GSDII Study Group.

Adv Ther 2019 05 16;36(5):1177-1189. Epub 2019 Mar 16.

Department of Clinical and Experimental Medicine, UOC di Neurologia e Malattie Neuromuscolari, University of Messina, Messina, Italy.

Introduction: Patients with late-onset Pompe disease (LOPD) receiving enzyme replacement therapy (ERT) may develop IgG antibodies against alglucosidase alpha (anti-rhGAA) in the first 3 months of treatment. The exact role of these antibodies in modulating efficacy of ERT in this group of patients is still not fully understood. To assess whether anti rh-GAA antibodies interfere with ERT efficacy, we studied a large Italian cohort of LOPD patients.

Methods: We analyzed clinical findings and performed serial measurements of IgG anti rh-GAA antibody titers from 64 LOPD patients treated with ERT. The first examination (T0) was completed on average at 17.56 months after starting ERT, while the follow-up (T1) was collected on average at 38.5 months. Differences in T0-T1 delta of the six-minute walking test (6MWT), MRC sum score (MRC), gait, stairs and chair performance (GSGC) and forced vital capacity (FVC) were considered and then related to the antibody titers.

Results: Almost 22% of the patients never developed antibodies against GAA, while 78.1% had a positive titer (31.2% patients developed a low titer, 43.8% a medium titer and 3.1% a high titer). No statistical significance was found in relating the T0-T1 delta differences and antibody titers, except for MRC sum score values in a subgroup of patients treated < 36 months, in which those with a null antibody titer showed a greater clinical improvement than patients with a positive titer.

Conclusion: Our results confirm that in a large cohort of LOPD patients, anti rh-GAA antibody generation did not significantly affect either clinical outcome or ERT efficacy. However, in the first 36 months of treatment, a possible interference of low-medium antibody titers with the clinical status could be present. Therefore, a careful and regular evaluation of antibody titers, especially in cases with evidence of clinical decline despite ERT, should be performed.
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http://dx.doi.org/10.1007/s12325-019-00926-5DOI Listing
May 2019

Lipomatosis Incidence and Characteristics in an Italian Cohort of Mitochondrial Patients.

Front Neurol 2019 27;10:160. Epub 2019 Feb 27.

Department of Clinical and Experimental Medicine, UOC Neurologia e Malattie Neuromuscolari, University of Messina, Messina, Italy.

Lipomas have often been associated with mtDNA mutations and were mainly observed in patients with mutation in mitochondrial tRNAlysine which is also the most frequent mutation associated with MERRF. Up to date, no systematic studies have been developed in order to assess the incidence of lipomas in large cohorts of mitochondrial patients.The aim of this study is to analyze the incidence and characteristics of lipomas among an Italian cohort of patients with mitochondrial diseases. A retrospective, database-based study (Nation-wide Italian Collaborative Network of Mitochondrial Diseases) of patients with lipomas was performed. A total of 22 (1.7%) patients with lipomas have been identified among the 1,300 mitochondrial patients, enrolled in the Italian database. In about 18% multiple systemic lipomatosis (MSL) was the only clinical manifestation; 54% of patients showed a classical MERRF syndrome. Myopathy, alone or in association with other symptoms, was found in 27% of patients. Lactate was elevated in all the 12 patients in which was measured. Muscle biopsy was available in 18/22 patients: in all of them mitochondrial abnormalities were present. Eighty six percent had mutations in mtDNA coding for tRNA lysine. In most of patients, lipomas were localized along the cervical-cranial-thoracic region. In 68% of the patients were distributed symmetrically. Only two patients had lipomas in a single anatomical site (1 in right arm and 1 in gluteus maximum). MSL is often overlooked by clinicians in patients with mitochondrial diseases where the clinical picture could be dominated by a severe multi-systemic involvement. Our data confirmed that MSL is a rare sign of mitochondrial disease with a strong association between multiple lipomas and lysine tRNA mutations. MSL could be considered, even if rare, a red flag for mitochondrial disorders, even in patients with an apparently isolated MSL.
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http://dx.doi.org/10.3389/fneur.2019.00160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402385PMC
February 2019

Mitochondrial Disease (MELAS Syndrome) Discovered at the Start of Pregnancy in a Patient with Advanced CKD: A Clinical and Ethical Challenge.

J Clin Med 2019 Mar 4;8(3). Epub 2019 Mar 4.

Department of Clinical and Biological Sciences, University of Torino, 10100 Torino, Italy.

Pregnancy is a challenge in the life of a woman with chronic kidney disease (CKD), but also represents an occasion for physicians to make or reconsider diagnosis of kidney disease. Counselling is particularly challenging in cases in which a genetic disease with a heterogeneous and unpredictable phenotype is discovered in pregnancy. The case reported regards a young woman with Stage-4 CKD, in which "Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes" (MELAS syndrome), was diagnosed during an unplanned pregnancy. A 31-year-old Caucasian woman, being followed for Stage-4 CKD, sought her nephrologist's advice at the start of an unplanned pregnancy. Her most recent data included serum creatinine 2⁻2.2 mg/dL, Blood urea nitrogen (BUN) 50 mg/dL, creatinine clearance 20⁻25 mL/min, proteinuria at about 2 g/day, and mild hypertension which was well controlled by angiotensin-converting enzyme inhibitors (ACEi); her body mass index (BMI) was 21 kg/m² (height 152 cm, weight 47.5 kg). Her medical history was characterized by non-insulin-dependent diabetes mellitus (at the age of 25), Hashimoto's thyroiditis, and focal segmental glomerulosclerosis. The patient's mother was diabetic and had mild CKD. Mild hearing impairment and cardiac hypertrophy were also detected, thus leading to suspect a mitochondrial disease (i.e., MELAS syndrome), subsequently confirmed by genetic analysis. The presence of advanced CKD, hypertension, and proteinuria is associated with a high, but difficult to quantify, risk of preterm delivery and progression of kidney damage in the mother; MELAS syndrome is per se associated with an increased risk of preeclampsia. Preterm delivery, associated with neurological impairment and low nephron number can worsen the prognosis of MELAS in an unpredictable way. This case underlines the importance of pregnancy as an occasion to detect CKD and reconsider diagnosis. It also suggests that mitochondrial disorders should be considered in the differential diagnosis of kidney impairment in patients who display an array of other signs and symptoms, mainly type-2 diabetes, kidney disease, and vascular problems, and highlights the difficulties encountered in counselling and the need for further studies on CKD in pregnancy.
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http://dx.doi.org/10.3390/jcm8030303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462991PMC
March 2019

Genetic neuromuscular disorders: living the era of a therapeutic revolution. Part 2: diseases of motor neuron and skeletal muscle.

Neurol Sci 2019 Apr 25;40(4):671-681. Epub 2019 Feb 25.

Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

This is the second part of a two-part document intended to discuss recent therapeutic progresses in genetic neuromuscular disorders. The present review is for diseases of motor neuron and skeletal muscle, some of which reached recently the most innovative therapeutic approaches. Nusinersen, an SMN2 mRNA splicing modifier, was approved as first-ever therapy of spinal muscular atrophy (SMA) by FDA in 2016 and by EMA in 2017. The orally administered small-molecule risdiplam, which increases SMN protein levels similarly but also in peripheral organs, is tested in ongoing phase 2 and 3 trials. After positive results with phase 1 treatment with AAV9-SMN, the first gene therapy for SMA, a phase 3 clinical trial is ongoing. Ataluren is the first approved drug for Duchenne muscular dystrophy (DMD) patients with premature stop codon mutations and its indication has been recently extended since the age of 2 years. Exon skipping technology was and is currently tested in many phase 3 trials, and eteplirsen received a conditional approval by FDA for patients amenable to exon 51 skipping, but not by EMA. Many other compounds with different mechanisms of action are now tested in DMD by phase 2 and 3 trials, including phase 1 gene therapy. Other innovative approaches are under investigation, i.e., gene therapy in X-linked myotubular myopathy and Pompe disease, and antisense oligonucleotides in myotonic dystrophy type 1. Positive evidences are discussed about lamotrigine and ranolazine in non-dystrophic myotonias, chaperons in Pompe disease, and nucleosides in mitochondrial DNA depletion induced by thymidine kinase 2 deficiency.
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http://dx.doi.org/10.1007/s10072-019-03764-zDOI Listing
April 2019

Late and Severe Myopathy in a Patient With Glycogenosis VII Worsened by Cyclosporine and Amiodarone.

Front Neurol 2019 7;10:77. Epub 2019 Feb 7.

Department of Clinical and Experimental Medicine, UOC di Neurologia e Malattie Neuromuscolari, University of Messina, Messina, Italy.

Glycogenosis VII (GSD VII) is a rare autosomal recessive glycogen storage disorder caused by mutations in the gene encoding the phosphofructokinase (PFK) enzyme. A classical form with exercise intolerance, contractures, and myoglobinuria, a severe multisystem infantile form, an hemolytic variant and a late-onset form usually presenting with muscle pain and mild fixed proximal weakness have been reported. We describe a 65-year-old man affected by muscle PFK deficiency who, since the age of 33, presented with exercise intolerance and myoglobinuria. Muscle biopsy showed a vacuolar myopathy with glycogen storage. The biochemical assay of PFK-M showed very low residual activity (6%). Genetic analysis of gene evidenced the presence of the heterozygote c.1817A>C (p.Asp543Ala) and c.488 G>A (p.Arg100Gln) pathogenic mutations. In his fifth decade, he started cyclosporine after liver transplantation for hepatocellular carcinoma and, then, amiodarone because of atrial fibrillation. In the following years, he developed a progressive and severe muscle weakness, mainly involving lower limbs, up to a loss of independent walking. Muscle MRI showed adipose substitution of both anterior and posterior thigh muscles with selective sparing of the medial compartment. Marked signs of adipose substitution were also documented in the legs with a selective replacement of gemelli and peroneus muscles. The temporal relationship between the patient's clinical worsening and chronic treatment with cyclosporine and amiodarone suggests an additive toxic damage by these two potentially myotoxic drugs determining such an unusually severe phenotype, also confirmed by muscle MRI findings.
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http://dx.doi.org/10.3389/fneur.2019.00077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374292PMC
February 2019

Muscle pain in mitochondrial diseases: a picture from the Italian network.

J Neurol 2019 Apr 2;266(4):953-959. Epub 2019 Feb 2.

Neurological Clinic, University of Pisa, Pisa, Italy.

Muscle pain may be part of many neuromuscular disorders including myopathies, peripheral neuropathies and lower motor neuron diseases. Although it has been reported also in mitochondrial diseases (MD), no extensive studies in this group of diseases have been performed so far. We reviewed clinical data from 1398 patients affected with mitochondrial diseases listed in the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases", to assess muscle pain and its features. Muscle pain was present in 164 patients (11.7%). It was commonly observed in subjects with chronic progressive external ophthalmoplegia (cPEO) and with primary myopathy without cPEO, but also-although less frequently-in multisystem phenotypes such as MELAS, MERFF, Kearns Sayre syndrome, NARP, MNGIE and Leigh syndrome. Patients mainly complain of diffuse exercise-related muscle pain, but focal/multifocal and at rest myalgia were often also reported. Muscle pain was more commonly detected in patients with mitochondrial DNA mutations (67.8%) than with nuclear DNA changes (32.2%). Only 34% of the patients showed a good response to drug therapy. Interestingly, patients with nuclear DNA mutations tend to have a better therapeutic response than patients with mtDNA mutations. Muscle pain is present in a significant number of patients with MD, being one of the most common symptoms. Although patients with a myopathic phenotype are more prone to develop muscle pain, this is also observed in patients with a multi system involvement, representing an important and disabling symptom having poor response to current therapy.
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http://dx.doi.org/10.1007/s00415-019-09219-xDOI Listing
April 2019

Posterior reversible encephalopathy syndrome (PRES) and infection: a systematic review of the literature.

Neurol Sci 2019 May 2;40(5):915-922. Epub 2019 Jan 2.

Department of Biomedical Sciences and Morphological and Functional Imaging, University of Messina, Policlinico "G. Martino" Via Consolare Valeria 1, 98100, Messina, Italy.

Posterior reversible encephalopathy syndrome (PRES) is an encephalopathy characterized by a rapid onset of symptoms including headache, seizures, confusion, blurred vision, and nausea associated with a typical magnetic resonance imaging appearance of reversible subcortical vasogenic edema prominent and not exclusive of parieto-occipital lobes. Vasogenic edema is caused by a blood-brain barrier leak induced by endothelial damage or a severe arterial hypertension exceeding the limits of cerebral blood flow autoregulation. Although the exact pathophysiological mechanism is still unclear, frequent conditions that may induce PRES include severe hypertension, eclampsia/pre-eclampsia, acute kidney diseases and failure, immunosuppressive therapy, solid organ, or bone marrow transplantation. Conversely to other conditions, which may induce PRES, the link between severe infection or sepsis and PRES, often associated with gram-positive bacteria, is still poorly understood and less well known. Clinicians from multiple disciplines, such as neurologists and internists, may encounter during their profession patients with severe infection or sepsis and should consider the possible association between PRES and these conditions. We systematically reviewed the literature about this association in order to provide a helpful clinical insight of such complex pathophysiological mechanism, highlighting the importance of recognizing PRES in such a complex clinical scenario.
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http://dx.doi.org/10.1007/s10072-018-3651-4DOI Listing
May 2019

Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study.

Front Neurol 2018 4;9:981. Epub 2018 Dec 4.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Medical Genetics, University of Genoa, Genoa, Italy.

Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity-there are over 80 potential disease-associated genes-and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel () comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy.
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http://dx.doi.org/10.3389/fneur.2018.00981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289125PMC
December 2018

Vacuolated PAS-Positive Lymphocytes on Blood Smear: An Easy Screening Tool and a Possible Biomarker for Monitoring Therapeutic Responses in Late Onset Pompe Disease (LOPD).

Front Neurol 2018 22;9:880. Epub 2018 Oct 22.

Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

Primary aim was to investigate the diagnostic value of PAS-positive vacuolated lymphocytes on blood smear in Late Onset Pompe Disease (LOPD) patients and, secondly, to evaluate its potential utility in monitoring treatment effects. We examined blood smear of 26 LOPD patients. We evaluated 10 treated and 16 untreated LOPD patients. Among the latter group, 7 patients later initiated ERT and were tested again 6 months after start. Blood smear was also sampled from 82 controls and 19 patients with other muscle glycogenoses (MGSDs). PAS staining was used to evaluate: (1) presence of lymphocytes with glycogen-filled vacuoles, (2) quantification of vacuolated lymphocytes. We found that PAS-positive lymphocytes were significantly higher in LOPD patients than in controls or other MGSDs ( < 0.05 and < 0.001, respectively). ROC curve for discriminating between untreated LOPD patients and controls yielded an AUC of 1.00 (95%CI 1.00-1.00; < 0.0001). PAS-positive lymphocyte cutoff level of >10 yielded sensitivity of 100% (95%CI 78-100%), specificity of 100% (95%CI 96-100%), and positive predictive value of 100%. Patients studied before and after ERT showed a dramatic decrease of PAS-positive vacuolated lymphocytes number ( = 0.016). In other MGSDs, PAS-positive lymphocytes were significantly lower that untreated LOPD patients but higher than controls. Our data suggest that the Blood Smear Examination (BSE) for PAS-positive lymphocytes quantification could be used as a simple and sensitive test for a quick screening of suspected Pompe disease. The quantification of vacuolated lymphocytes appears to be also a valuable tool for monitoring the efficacy of treatment in LOPD patients.
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http://dx.doi.org/10.3389/fneur.2018.00880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204381PMC
October 2018

Copy Number Variants Account for a Tiny Fraction of Undiagnosed Myopathic Patients.

Genes (Basel) 2018 Oct 26;9(11). Epub 2018 Oct 26.

Fondazione Hospital S.Camillo IRCCS, 30126 Venezia, Italy.

Next-generation sequencing (NGS) technologies have led to an increase in the diagnosis of heterogeneous genetic conditions. However, over 50% of patients with a genetically inherited disease are still without a diagnosis. In these cases, different hypotheses are usually postulated, including variants in novel genes or elusive mutations. Although the impact of copy number variants (CNVs) in neuromuscular disorders has been largely ignored to date, missed CNVs are predicted to have a major role in disease causation as some very large genes, such as the dystrophin gene, have prone-to-deletion regions. Since muscle tissues express several large disease genes, the presence of elusive CNVs needs to be comprehensively assessed following an accurate and systematic approach. In this multicenter cohort study, we analyzed 234 undiagnosed myopathy patients using a custom array comparative genomic hybridization (CGH) that covers all muscle disease genes at high resolution. Twenty-two patients (9.4%) showed non-polymorphic CNVs. In 12 patients (5.1%), the identified CNVs were considered responsible for the observed phenotype. An additional ten patients (4.3%) presented candidate CNVs not yet proven to be causative. Our study indicates that deletions and duplications may account for 5⁻9% of genetically unsolved patients. This strongly suggests that other mechanisms of disease are yet to be discovered.
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http://dx.doi.org/10.3390/genes9110524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267442PMC
October 2018

Hippo signaling pathway is altered in Duchenne muscular dystrophy.

PLoS One 2018 10;13(10):e0205514. Epub 2018 Oct 10.

Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.

Hippo signaling pathway is considered a key regulator of tissue homeostasis, cell proliferation, apoptosis and it is involved in cancer development. In skeletal muscle, YAP, a downstream target of the Hippo pathway, is an important player in myoblast proliferation, atrophy/hypertrophy regulation, and in mechano-trasduction, transferring mechanical signals into transcriptional responses. We studied components of Hippo pathway in muscle specimens from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, limb-girdle muscular dystrophy type 2A and type 2B and healthy subjects. Only DMD muscles had decreased YAP1 protein expression, increased LATS1/2 kinase activity, low Survivin mRNA expression and high miR-21 expression. In light of our novel results, a schematic model is postulated: low levels of YOD1 caused by increased inhibition by miR-21 lead to an increase of LATS1/2 activity which in turn augments phosphorylation of YAP. Reduced amount of active YAP, which is also a target of increased miR-21, causes decreased nuclear expression of YAP-mediated target genes. Since it is known that YAP has beneficial roles in promoting tissue repair and regeneration after injury so that its activation may be therapeutically useful, our results suggest that some components of Hippo pathway could become novel therapeutic targets for DMD treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205514PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179272PMC
March 2019

ZFYVE26/SPASTIZIN and SPG11/SPATACSIN mutations in hereditary spastic paraplegia types AR-SPG15 and AR-SPG11 have different effects on autophagy and endocytosis.

Autophagy 2019 01 13;15(1):34-57. Epub 2018 Sep 13.

a Scientific Institute, IRCCS E. Medea, Laboratory of Molecular Biology , Bosisio Parini , Lecco , Italy.

ZFYVE26/Spastizin and SPG11/Spatacsin encode 2 large proteins that are mutated in hereditary autosomal-recessive spastic paraplegia/paraparesis (HSP) type 15 (AR-SPG15) and type 11 (AR-SPG11), respectively. We previously have reported that AR-SPG15-related ZFYVE26 mutations lead to autophagy defects with accumulation of immature autophagosomes. ZFYVE26 and SPG11 were found to be part of a complex including the AP5 (adaptor related protein complex 5) and to have a critical role in autophagic lysosomal reformation with identification of autophagic and lysosomal defects in cells with both AR-SPG15- and AR-SPG11-related mutations. In spite of these similarities between the 2 proteins, here we report that ZFYVE26 and SPG11 are differently involved in autophagy and endocytosis. We found that both ZFYVE26 and SPG11 interact with RAB5A and RAB11, 2 proteins regulating endosome trafficking and maturation, but only ZFYVE26 mutations affected RAB protein interactions and activation. ZFYVE26 mutations lead to defects in the fusion between autophagosomes and endosomes, while SPG11 mutations do not affect this step and lead to a milder autophagy defect. We thus demonstrate that ZFYVE26 and SPG11 affect the same cellular physiological processes, albeit at different levels: both proteins have a role in autophagic lysosome reformation, but only ZFYVE26 acts at the intersection between endocytosis and autophagy, thus representing a key player in these 2 processes. Indeed expression of the constitutively active form of RAB5A in cells with AR-SPG15-related mutations partially rescues the autophagy defect. Finally the model we propose demonstrates that autophagy and the endolysosomal pathway are central processes in the pathogenesis of these complicated forms of hereditary spastic paraparesis. Abbreviations: ALR, autophagic lysosome reformation; AP5, adaptor related protein complex 5; AR, autosomal-recessive; HSP, hereditary spastic paraplegia/paraparesis; ATG14, autophagy related 14; BafA, bafilomycin A; BECN1, beclin 1; EBSS, Earle balanced salt solution; EEA1, early endosome antigen 1; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; GDP, guanosine diphosphate; GFP, green fluorescent protein; GTP, guanosine triphosphate; HSP, hereditary spastic paraplegias; LBPA, lysobisphosphatidic acid; MAP1LC3B/LC3B, microtubule associated protein 1 light chain 3 beta; MVBs, multivesicular bodies; PIK3C3, phosphatidylinositol 3-kinase, catalytic subunit type 3; PIK3R4, phosphoinositide-3-kinase regulatory subunit 4; PtdIns3P, phosphatidylinositol-3-phosphate; RFP, red fluorescent protein; RUBCN, RUN and cysteine rich domain containing beclin 1 interacting protein; shRNA, short hairpin RNA; SQSTM1/p62, sequestosome 1; TCC: thin corpus callosum; TF, transferrin; UVRAG, UV radiation resistance associated.
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http://dx.doi.org/10.1080/15548627.2018.1507438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287682PMC
January 2019
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