Publications by authors named "Roberto Massa"

59 Publications

Movement disorders in primary central nervous system lymphoma: two unreported cases and a review of literature.

Neurol Sci 2021 Mar 14;42(3):905-910. Epub 2021 Jan 14.

Neurology Unit, Department of Systems Medicine, University of Roma Tor Vergata, via Montpellier 1, 00133, Rome, Italy.

Background: Recognition of secondary movement disorders (SMDs) is fundamental either to alleviate disabling disturbances or to treat potentially life-threatening conditions, such as brain tumors. Primary CNS lymphoma (PCNSL) is a rare form of CNS cancer that is often located in subcortical areas, accounting for both neuropsychiatric and motoric disorders. Nevertheless, an overview on PCNSL-related movement disorders (MDs) phenomenology has not been provided yet.

Objective: To outline the main features of PCNSL-related MDs.

Methods: A retrospective analysis was conducted on a cohort of patients with PCNSL presenting with MDs, including all existing cases identified by a systematic literature review (source: Medline; period: 1946-2020) and two unreported cases. Data on phenomenology, neuroimaging, histology, and clinical course were collected.

Results: A total cohort of fifteen subjects was defined, enrolling thirteen previously described patients extracted from eleven published studies, and our two unreported cases. A parkinsonian syndrome appearing at about 60 years of age, unresponsive to levodopa, associated to other neurological signs, resulted as the most common presentation of PCNSL-related MD. Chorea, dystonia, and dyskinesia occurred less frequently, with some degree of responsiveness to symptomatic treatments. Basal ganglia were involved in most cases and motoric disturbances often ameliorated after tumor mass reduction.

Conclusions: This study identified those features of PCNSL-related MDs that could support an appropriate approach to such a rare condition. In fact, while the outcome remains still poor, the therapeutic scenario of PCNSL is changing; an early diagnosis together with an adequate management will be thus crucial for timely and successful interventions.
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http://dx.doi.org/10.1007/s10072-020-04985-3DOI Listing
March 2021

Cochlear Dysfunction Is a Frequent Feature of Facioscapulohumeral Muscular Dystrophy Type 1 (FSHD1).

Otol Neurotol 2021 Jan;42(1):18-23

Department of Systems Medicine, Neuromuscular Diseases Unit.

Introduction: Facioscapulohumeral muscular dystrophy type 1 (FSHD) represents one of the most common forms of muscular hereditary diseases and it is characterized by a great clinical variability with the typical muscular symptoms and other clinical features, including hearing impairment. However, etiopathogenetic mechanisms of auditory dysfunction are still not completely understood and it has been suggested that it could be assigned to a cochlear alteration that is present even in those subjects with a normal pure tonal audiometry (PTA) examination.

Methods: We found out the cochlear function in 26 patients with molecular diagnosis of FSHD1 and in healthy controls. All patients underwent complete neurological and audiological examinations, including FSHD clinical score, pure-tone audiometry (PTA), and otoacoustic emissions (OAEs), in particular transient evoked otoacoustic emissions (TEOAEs) and distortion product evoked otoacoustic emissions (DPOAEs).

Results: All FSHD1 patients showed significantly reduced DPOAEs and TEOAEs, bilaterally and at all frequencies, even when considering only subjects with a normal PTA or a mild muscular involvement (FSHD score ≤ 2). No correlation between OAEs and FSHD clinical score was found.

Discussion: Cochlear echoes represent a sensitive tool in detecting subclinical cochlear dysfunction in FSHD1 even in subjects with normal hearing and/or subtle muscle involvement. Our study is focused on the importance of evaluating the cochlear alteration through OAEs and, in particular, by performing TEOAEs and DPOAEs sequentially, to evaluate more frequent specificities of cochlear dysfunction with a wider spectrum of analysis.
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http://dx.doi.org/10.1097/MAO.0000000000002877DOI Listing
January 2021

How to capture activities of daily living in myotonic dystrophy type 2?

Neuromuscul Disord 2020 10 1;30(10):796-806. Epub 2020 Aug 1.

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

Myotonic dystrophy type 2 (DM2) lacks validated patients´ reported outcomes (PROs). This represents a limit for monitoring disease progression and perceived efficacy of symptomatic treatments. Our aim was to investigate whether PROs for activities of daily living designed for other neuromuscular diseases could be used in DM2. Sixty-six DM2 patients completed the following PROs: DM1-Activ-c, Rasch-built Pompe-specific activity (R-PAct) scale, McGill-pain questionnaire, fatigue and daytime sleepiness scale and Beck depression inventory (BDI-II). Clinical data and motor outcome measures (6-minutes walking test - 6MWT, manual muscle testing, quick motor function test and myotonia behavior scale) were collected as well. Patients underwent one visit at baseline and one after 10 months. Ceiling/flooring effects, criterion validity and discriminant validity were calculated. DM1-activ-c and R-PAct showed acceptable ceiling effects despite being built for myotonic dystrophy type 1 and Pompe disease, respectively. The difficulty hierarchy of the single items was better preserved in R-PAct than in DM1-Activ-c. Both tests showed excellent criterion validity highly correlating with 6MWT, quick motor function test, myalgia and disease duration. They could partially discriminate patients with different disability grades. These results suggest that DM1-Activ-c, slightly better than R-PAct, might be adopted for monitoring activities of daily living also in DM2, at least until disease-specific PROs will be available.
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http://dx.doi.org/10.1016/j.nmd.2020.07.011DOI Listing
October 2020

Validation of Motor Outcome Measures in Myotonic Dystrophy Type 2.

Front Neurol 2020 21;11:306. Epub 2020 Apr 21.

Department of Neurology, Friedrich-Baur-Institute, Klinikum der Universität, Ludwig-Maximilians-University, Munich, Germany.

Myotonic dystrophy type 2 (DM2) lacks disease-specific, validated, motor outcome measures (OMs), and patients' reported outcomes (PROs). This represents a limit for the monitoring of disease progression and treatment response. Our aim was to identify the most appropriate OMs to be translated in clinical practice and clinical trials on DM2. This study has been registered on clinicaltrials.gov NCT03603171 (https://clinicaltrials.gov/ct2/show/NCT03603171). Sixty-six patients with genetically confirmed DM2 underwent a baseline and a follow-up visit after 1 year. The tested OMs included: hand opening time, pressure pain threshold (PPT), manual muscle testing (MMT), hand held dynamometry (HHD), scale for the assessment and rating of ataxia (SARA), quantitative motor function test (QMFT), gait stairs Gowers chair (GSGC), 30-s sit to stand test, functional index 2 (FI-2) and 6MWT. The PROs included DM1-Active-C, Rasch-built Pompe-specific activity scale (R-Pact), fatigue and daytime sleepiness (FDSS), brief pain inventory short form (BPI-sf), myotonia behavior scale (MBS), and the McGill pain questionnaire. All patients completed the MBS and the results correlated well with the hand-opening time. The PPT showed a low reliability, no correlation with pain questionnaires, and did not differentiate patients with or without myalgia. Both muscle strength assessments, MMT and HHD, showed good construct validity. The QMFT showed an acceptable ceiling effect (14.5%), good convergent and differential validity and performed overall better than GSGC. The SARA score showed high flooring effect and is not useful in DM2. 6MWT proved a valid outcome measure in DM2. The 30-s sit to stand is a feasible test with good convergent validity, showing a flooring effect of 20% as it cannot be used in more severely affected patients. The FI-2 is time-consuming and has a high ceiling effect. At the 1-year visit the only assessments able to detect a worsening of DM2 were HHD, QMFT, and 6MWT, which are the most sensitive to change, and therefore clinically meaningful OMs in DM2. The clinical meaningful motor outcome measures that best depict the multifaceted phenotype of DM2 and its slow progression are MBS, MMT, or HHD (depending on the clinical setting), QMFT, and the 6MWT.
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http://dx.doi.org/10.3389/fneur.2020.00306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186332PMC
April 2020

Design of a multiplex ligation-dependent probe amplification assay for SLC20A2: identification of two novel deletions in primary familial brain calcification.

J Hum Genet 2019 Nov 9;64(11):1083-1090. Epub 2019 Sep 9.

Department of Medical Sciences, University of Torino, Turin, Italy.

Primary familial brain calcification (PFBC) is a rare disease characterized by brain calcifications that mainly affect the basal ganglia, thalamus, and cerebellum. Among the four autosomal-dominant genes known to be associated with the disease, SLC20A2 pathogenic variants are the most common, accounting for up to 40% of PFBC dominant cases; variants include both point mutations, small insertions/deletions and intragenic deletions. Over the last 7 years, we have collected a group of 50 clinically diagnosed PFBC patients, who were screened for single nucleotide changes and small insertions/deletions in SLC20A2 by Sanger sequencing. We found seven pathogenic/likely pathogenic variants: four were previously described by our group, and three are reported here (c.303delG, c.21delG, and c.1795-1G>A). We developed and validated a synthetic Multiplex Ligation-dependent Probe Amplification (MLPA) assay for SLC20A2 deletions, covering all ten coding exons and the 5' UTR (SLC20A2-MLPA). Using this method, we screened a group of 43 PFBC-patients negative for point mutations and small insertions/deletions, and identified two novel intragenic deletions encompassing exon 6 NC_000008.10:g.(42297172_42302163)_(423022281_42317413)del, and exons 7-11 including the 3'UTR NC_000008.10:g.(?_42275320)_(42297172_42302163)del. Overall, SLC20A2 deletions may be highly underestimated PFBC cases, and we suggest MLPA should be included in the routine molecular test for PFBC diagnosis.
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http://dx.doi.org/10.1038/s10038-019-0668-3DOI Listing
November 2019

Reply to the letter entitled "Predictors of respiratory impairment in patients with myotonic dystrophy type 1".

J Neurol Sci 2019 08 24;403:166-167. Epub 2019 May 24.

Department of Neurology, Fondazione Policlinico Universitario A. Gemelli IRCSS, Largo A. Gemelli 8, 00168 Rome, Italy; Institute of Neurology, Catholic University of the Sacred Heart, Largo F. Vito 1, 00168 Rome, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2019.05.025DOI Listing
August 2019

Prevalence and predictor factors of respiratory impairment in a large cohort of patients with Myotonic Dystrophy type 1 (DM1): A retrospective, cross sectional study.

J Neurol Sci 2019 Apr 7;399:118-124. Epub 2019 Feb 7.

Department of Neurology, Fondazione Policlinico Universitario A. Gemelli IRCSS, Largo A. Gemelli 8, 00168 Rome, Italy; Institute of Neurology, Catholic University of the Sacred Heart, Largo F. Vito 1, 00168 Rome, Italy. Electronic address:

Introduction: Respiratory complications are relevant in DM1, leading to a significantly increased morbidity and mortality risk in these patients; however, so far only few studies concerning respiratory function have been conducted in DM1 patients. We report a retrospective, multicenter, cross sectional study on a large cohort of DM1 patients widely characterized in the phenotype, to assess prevalence and identify predictors of restrictive respiratory syndrome.

Methods: 268 DM1 subjects aged >18 years, who had recently performed spirometric tests were included; restrictive syndrome was diagnosed if forced vital capacity (FVC) <80% of predicted. This cut-off was used for statistical univariate and multivariate analysis.

Results: 51.9% patients showed a restrictive syndrome, and half of them had indication to non-invasive ventilation (NIV), yet only 50% resulted compliant to NIV. CTG expansion size in leukocytes, clinical muscle severity, most functional parameters of respiratory muscle involvement, presence of cardiac conduction disturbances, pacemaker (PMK), exertion dyspnea, obstructive sleep apnea, and indication and compliance to NIV were all significantly associated with restrictive syndrome at the univariate analysis; in the multivariate model only the first two factors resulted independent predictors.

Discussion: A high prevalence of restrictive syndrome in our DM1 cohort, mainly due to respiratory muscles weakness, was observed and documented; the severity of muscle impairment and the CTG expansion size confirmed to be independent predictors of respiratory restriction. Our data suggest that optimization of respiratory therapeutic management, particularly regarding launching of NIV, might help to reduce the rate of deaths due to respiratory complications in DM1.
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http://dx.doi.org/10.1016/j.jns.2019.02.012DOI Listing
April 2019

Italian recommendations for the diagnosis and treatment of myasthenia gravis.

Neurol Sci 2019 Jun 18;40(6):1111-1124. Epub 2019 Feb 18.

Unit of Neurology and Neuromuscular Diseases, University of Messina, Messina, Italy.

Myasthenia gravis is a well-treatable disease, in which a prompt diagnosis and an adequate management can achieve satisfactory control of symptoms in the great majority of patients. Improved knowledge of the disease pathogenesis has led to recognition of patient subgroups, according to associated antibodies, age at onset and thymus pathology, and to a more personalized treatment. When myasthenia gravis is suspected on clinical grounds, diagnostic confirmation relies mainly on the detection of specific antibodies. Neurophysiological studies and, to a lesser extent, clinical response to cholinesterase inhibitors support the diagnosis in seronegative patients. In these cases, the differentiation from congenital myasthenia can be challenging. Treatment planning must consider weakness extension and severity, disease subtype, thymus pathology, together with patient characteristics and comorbidities. Since most subjects with myasthenia gravis require long-term immunosuppressive therapy, surveillance of expected and potential adverse events is critical. For patients refractory to conventional immunosuppression, the use of biologic agents is highly promising. These recommendations are addressed to non-experts on neuromuscular transmission disorders. The diagnostic procedures and therapeutic approaches hereafter described are largely accessible in Italy.
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http://dx.doi.org/10.1007/s10072-019-03746-1DOI Listing
June 2019

Thymomatous myasthenia gravis: novel association with HLA DQB1*05:01 and strengthened evidence of high clinical and serological severity.

J Neurol 2019 Apr 11;266(4):982-989. Epub 2019 Feb 11.

Laboratorio d'Immunogenetica dei Trapianti, Dipartimento di Oncoematologia e Terapia Cellulare e Genica, IRCCS OPBG, Rome, Italy.

Background: The relative prevalence of myasthenia gravis (MG) subtypes is changing, and their differential features and association with HLA class II alleles are not completely understood.

Methods: Age at onset, presence/absence of autoantibodies (Ab) and thymoma were retrospectively considered in 230 adult Italian patients. Clinical severity, assessed by MGFA scale, and the highest Ab titer were recorded. Furthermore, we performed low/high resolution typing of HLA-DRB1 and HLA-DQB1 alleles to detect associations of these loci with MG subtypes.

Results: There were two peaks of incidence: under 41 years of age, with female preponderance, and over 60 years, with higher male prevalence. The former group decreased and the latter increased significantly when comparing onset period 2008-2015 to 2000-2007. Thymomatous (TMG) patients showed a higher prevalence of severe phenotype and significantly higher anti-AChR Ab titer than non-thymomatous (NTMG) patients. Among the latter, those with onset after 60 years of age (LO-NTMG) displayed significantly higher Ab titers but lower MGFA grade compared to early-onset patients (< 41 years; EO-NTMG). Significant associations were found between HLA DQB1*05:01 and TMG patients and between DQB1*05:02 and DRB1*16 alleles and LO-NTMG with anti-AChR Ab.

Conclusions: Two distinct cutoffs (< 41 and > 60 years) conveniently define EO-NTMG and LO-NTMG, with different characteristics. LO-NTMG is the most frequent disease subtype, with an increasing incidence. TMG patients reach higher clinical severity and higher antibody titers than NTMG patients. Moreover, TMG and LO-NTMG with anti-AChR Ab differ in their HLA-DQ association, providing further evidence that these two forms may have different etiologic mechanisms.
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http://dx.doi.org/10.1007/s00415-019-09225-zDOI Listing
April 2019

Comparative Sleep Disturbances in Myotonic Dystrophy Types 1 and 2.

Curr Neurol Neurosci Rep 2018 10 31;18(12):102. Epub 2018 Oct 31.

System Medicine Department, University of Rome Tor Vergata, Rome, Italy.

Purpose Of Review: To update current knowledge regarding sleep disturbances and myotonic dystrophies so as to better understand if sleep symptoms may help in the early recognition of the two genetic subtypes: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2).

Recent Findings: Sleep-disordered breathing (SDB), restless legs syndrome, periodic limb movements in sleep, hypersomnia, and REM sleep dysregulation are frequently described in DM1 patients. SDB does not always explain hypersomnia, but a central dysregulation of sleep-wake modulation is reported mainly in DM1. Sleep apnea, restless legs syndrome, and REM sleep without atonia have been reported in single case reports and small case series of DM2. DM2 is less prevalent and more recently described than DM1, with a milder phenotype than DM1. The most frequent sleep disorders in DM1 are hypersomnia, SDB, periodic limb movements, and a narcoleptic-like phenotype, whereas restless legs syndrome, SDB, and REM sleep without atonia seem to be the most frequent sleep disorders in DM2. Comparative sleep studies are strongly required to delineate the sleep phenotype of myotonic dystrophies.
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http://dx.doi.org/10.1007/s11910-018-0903-xDOI Listing
October 2018

Validation of the Nine Hole Peg Test as a measure of dexterity in myotonic dystrophy type 1.

Neuromuscul Disord 2018 11 31;28(11):947-951. Epub 2018 Aug 31.

Neuromuscular Diseases Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. Electronic address:

We aimed to validate the Nine Hole Peg Test as a measure of dexterity in myotonic dystrophy type 1 (DM1). Fifty patients with adult-onset, genetically confirmed DM1 were evaluated by Nine Hole Peg Test and re-evaluated at one week. Myotonia was not a limiting factor. The first test was compared with that performed by normal subjects (n = 28). Contextually, patients underwent handgrip and three-finger pinch assessments by handheld dynamometer. The Nine Hole Peg Test showed high intra-rater and inter-rater reliability in DM1 [ICC 0.86/0.83 for dominant and 0.90/0.88 for non-dominant hand, respectively]. Inverse correlation with handgrip and pinch strength values (r = -0.4; p < 0.01) and direct correlation with Muscular Impairment Rating Scale (r = 0.4; p < 0.01) were found for both DH and NDH. The test was able to differentiate severe DM1 patients, stratified by extent of muscle impairment, from mildly affected and normal controls, with a sensitivity of 97% and 95% for dominant hand and non-dominant hand, respectively (p < 0.0001). In conclusion, we showed that the Nine Hole Peg Test is a reliable, valid and sensitive test of dexterity in DM1, and that it can be considered as a candidate outcome measure to monitor natural history of disease and, possibly, therapeutic response in clinical trials.
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http://dx.doi.org/10.1016/j.nmd.2018.08.011DOI Listing
November 2018

Generation and Neuronal Differentiation of hiPSCs From Patients With Myotonic Dystrophy Type 2.

Front Physiol 2018 27;9:967. Epub 2018 Jul 27.

Medical Genetics Section, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.

Human induced pluripotent stem cells (hiPSCs)-patient specific are an innovative tool to reproduce a model of disease and summarize the pathological phenotype and the disease etiopathology. Myotonic dystrophy type 2 (DM2) is caused by an unstable (CCTG)n expansion in intron 1 of the gene, leading to a progressive multisystemic disease with muscle, heart and central nervous dysfunctions. The pathogenesis of CNS involvement in DM2 is poorly understood since no cellular or animal models fully recapitulate the molecular and clinical neurodegenerative phenotype of patients. In this study, we generated for the first time, two DM2 and two wild type hiPSC lines from dermal fibroblasts by polycistronic lentiviral vector (hSTEMCCA-loxP) expressing , , , and genes and containing loxP-sites, excisable by Cre recombinase. Specific morphological, molecular and immunocytochemical markers have confirmed the stemness of DM2 and wild type-derived hiPSCs. These cells are able to differentiate into neuronal population (NP) expressing tissue specific markers. hiPSCs-derived NP cells maintain (CCTG)n repeat expansion and intranuclear RNA foci exhibiting sequestration of MBNL1 protein, which are pathognomonic of the disease. DM2 hiPSCs represent an important tool for the study of CNS pathogenesis in patients, opening new perspectives for the development of cell-based therapies in the field of personalized medicine and drug screening.
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http://dx.doi.org/10.3389/fphys.2018.00967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6074094PMC
July 2018

Towards clinical outcome measures in myotonic dystrophy type 2: a systematic review.

Curr Opin Neurol 2018 10;31(5):599-609

Friedrich-Baur-Institut, Department of Neurology, Ludwig-Maximilians University, Ziemssenstrasse 1a, Munich, Germany.

Purpose Of Review: Myotonic dystrophies are the most frequent muscular dystrophies in adulthood; however, myotonic dystrophy type 2 (DM2) is by far less prevalent than myotonic dystrophy type 1 (DM1). Consequently, studies on large cohorts are lacking and disease-specific outcome measures have not been developed (see video abstract, Supplemental Digital Content 1, http://links.lww.com/CONR/A44).The aim of this review is to systematically evaluate the outcome measures applied in patients with DM2 and to identify tests adopted from other neuromuscular disorders potentially suitable for DM2.A systematic review of functional tests and patient reported outcomes (PROs) previously used in DM2 has been performed. In addition, we reviewed functional tests and PROs previously used in neuromuscular diseases (NMDs). Based on this approach, we propose a battery of tests to be validated in DM2.

Recent Findings: No outcome measures or PROs have been validated in DM2. The most used PROs in DM2 were INQoL, SF-36, MPQ, and BPI. It is not clear whether it is better to use MMT or QMT to assess muscle strength. The algometer seems to be a useful tool to assess myalgia. No currently adopted tests or PROs seem effective to assess the mild myotonia of DM2. Several outcome measures used in other NMDs (e.g. 6MWT, QMFT, GSGC) might be suitable for DM2; however, their disease-specific validity needs to be explored.

Summary: Although DM2 has a milder and more heterogeneous phenotype than DM1, there is an urgent need to develop validated outcome measures in DM2. The current lack of validated DM2 tests will delay the start of therapeutic trials.
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http://dx.doi.org/10.1097/WCO.0000000000000591DOI Listing
October 2018

Neurofibromatous neuropathy: An ultrastructural study.

Ultrastruct Pathol 2018 May-Jun;42(3):312-316. Epub 2018 Mar 27.

a Neuromuscular Unit, Department of Systems Medicine , University of Rome Tor Vergata , Rome , Italy.

Plexiform neurofibroma is pathognomonic of neurofibromatosis 1 (NF1). An NF1-associated peripheral neuropathy has been described in a small minority of NF1 patients but its histopathological features are poorly characterized. We report the case of a 46-year-old woman presenting with bilateral supraclavicular painful masses without other stigmata of NF1. MRI showed bilateral plexiform lesions extending from cervical roots to the elbows. Nerve conduction studies documented a sensory motor polyneuropathy. Morphometric analysis of sural nerve biopsy showed a preferential loss of large-caliber myelinated fibers with a g ratio of 0.515, and the presence of regeneration clusters. By electron microscopy, marked and diffuse endoneurial fibrosis with an altered relationship between Schwann cells (SC) and collagen fibrils was observed. Moreover both myelinating and non-myelinating SC were characterized by the presence of various cell degradation products. These changes suggest that, in neurofibromatous neuropathy, a widespread axonal atrophy and degeneration take place independently on the presence of tumoral infiltration, possibly due to an impairment in SC-axon cross talk. In this case, the coexistence of plexiform neurofibromas with a peripheral neuropathy strongly suggests a diagnosis of NF1 even without fulfillment of clinical criteria. We propose that in the presence of plexiform neurofibromas, electrophysiological studies should be performed also in asymptomatic patients, in order to detect the existence of a subclinical neuropathy.
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http://dx.doi.org/10.1080/01913123.2018.1454562DOI Listing
October 2018

Expanded [CCTG]n repetitions are not associated with abnormal methylation at the CNBP locus in myotonic dystrophy type 2 (DM2) patients.

Biochim Biophys Acta Mol Basis Dis 2018 Mar 29;1864(3):917-924. Epub 2017 Dec 29.

Dept. of Biomedicine and Prevention, Medical Genetics Section, University of Rome Tor Vergata, Italy. Electronic address:

Myotonic Dystrophy type 2 (DM2) is a multisystemic disorder associated with an expanded [CCTG]n repeat in intron 1 of the CNBP gene. Epigenetic modifications have been reported in many repeat expansion disorders, including myotonic dystrophy type 1 (DM1), either as a mechanism to explain somatic repeat instability or transcriptional alterations in disease genes. The purpose of our work was to determine the effect of DM2 mutation on the methylation status of CpG islands localized in the 5' promoter region and in the 3' end of the [CCTG]n expansion of the CNBP gene. By bisulfite pyrosequencing, we characterized the methylation profile of two different CpG islands within these regions, either in whole blood and skeletal muscle tissues of DM2 patients (n=72 and n=7, respectively) and controls (n=50 and n=7, respectively). Moreover, we compared the relative mRNA transcript levels of CNBP gene in leukocytes and in skeletal muscle tissues from controls and DM2 patients. We found that CpG sites located in the promoter region showed hypomethylation, whereas CpG sites at 3' end of the CCTG array are hypermethylated. Statistical analyses did not demonstrate any significant differences in the methylation profile between DM2 patients and controls in both tissues analyzed. According to the methylation analysis, CNBP gene expression levels are not significantly altered in DM2 patients. These results show that [CCTG]n repeat expansion, differently from the DM1 mutation, does not influence the methylation status of the CNBP gene and suggest that other molecular mechanisms are involved in the pathogenesis of DM2.
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http://dx.doi.org/10.1016/j.bbadis.2017.12.037DOI Listing
March 2018

Aquaporin 4 expression in human skeletal muscle fiber types.

Muscle Nerve 2018 05 20;57(5):856-858. Epub 2017 Dec 20.

Neuromuscular Unit, Department of Systems Medicine, University of Rome Tor Vergata, Roma, Italy.

Introduction: Aquaporins (AQPs) are a family of transmembrane proteins involved in the maintenance of osmotic gradients. AQP4 is abundant in skeletal muscle, where it seems to be associated with glycolytic metabolism. We investigated the pattern of expression of AQP4 in normal human myofibers relative to the main forms of myosin heavy chain (MHC).

Methods: Six normal human muscle biopsies were analyzed by double immunofluorescence for co-expression of AQP4 and slow or fast MHC.

Results: A high percentage (64-99%) of MHC-fast positive fibers showed immunoreaction for AQP4. Immunoreactivity for AQP4 was also present in MHC-slow positive fibers, but with a higher variability (5-72%) among biopsies.

Discussion: The expression pattern of AQP4 in human myofibers is highly variable among different patients and cannot be predicted for single fibers depending on MHC type expression. Other factors, possibly related to muscle activity, may modulate AQP4 expression. Muscle Nerve 57: 856-859, 2018.
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http://dx.doi.org/10.1002/mus.26024DOI Listing
May 2018

Nodular morphea in a patient with Steinert disease.

G Ital Dermatol Venereol 2019 Apr 8;154(2):209-210. Epub 2017 Sep 8.

Department of Dermatology, University of Tor Vergata, Rome, Italy.

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http://dx.doi.org/10.23736/S0392-0488.17.05624-3DOI Listing
April 2019

Minimalist thoracoscopic resection of thymoma associated with myasthenia gravis.

J Thorac Cardiovasc Surg 2017 10 22;154(4):1463-1465. Epub 2017 Jun 22.

Department of Thoracic Surgery, Assaf Harofeh Medical Center, affiliated with the Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel.

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http://dx.doi.org/10.1016/j.jtcvs.2017.05.084DOI Listing
October 2017

A case of fulminant subacute sclerosing panencephalitis presenting with acute myoclonic-astatic epilepsy.

Ann Ist Super Sanita 2017 Apr-Jun;53(2):167-169

Laboratorio Nazionale di Riferimento per il Morbillo e la Rosolia, Dipartimento di Malattie Infettive, Istituto Superiore di Sanità, Rome, Italy.

The neurologic sequelae post-measles are less common than other complications measles-related and can lead to severe disability or death: primary measles encephalitis (PME), acute post-infectious measles encephalomyelitis (APME), measles inclusion body encephalitis (MIBE), and subacute sclerosing panencephalitis (SSPE). SSPE syndrome can affect people years from the acute measles virus infection, as result of the persistence of defective viral particles in brain cells. Clinical onset typically manifests with progressive intellectual deterioration, behavioral changes, and myoclonic jerks. The course of SSPE in the majority of affected children is that of a progressive worsening with fatal outcome within two years. This report described an Italian case of fulminant SSPE syndrome that led to death within few months from the initial onset.
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http://dx.doi.org/10.4415/ANN_17_02_15DOI Listing
April 2018

Muscle MRI in neutral lipid storage disease (NLSD).

J Neurol 2017 Jul 13;264(7):1334-1342. Epub 2017 May 13.

Department of Neurology, San Filippo Neri Hospital, Rome, Italy.

Neutral lipid storage disease (NLSD) is a rare inherited disorder of lipid metabolism resulting in lipid droplets accumulation in different tissues. Skeletal muscle could be affected in both two different form of disease: NLSD with myopathy (NLSD-M) and NLSD with ichthyosis (NLSD-I). We present the muscle imaging data of 12 patients from the Italian Network for NLSD: ten patients presenting NLSD-M and two patients with NLSD-I. In NLSD-M gluteus minimus, semimembranosus, soleus and gastrocnemius medialis in the lower limbs and infraspinatus in the upper limbs were the most affected muscles. Gracilis, sartorius, subscapularis, pectoralis, triceps brachii and sternocleidomastoid were spared. Muscle involvement was not homogenous and characteristic "patchy" replacement was observed in at least one muscle in all the patients. Half of the patients showed one or more STIR positive muscles. In both NLSD-I cases muscle involvement was not observed by T1-TSE sequences, but one of them showed positive STIR images in more than one muscle in the leg. Our data provides evidence that muscle imaging can identify characteristic alterations in NLSD-M, characterized by a specific pattern of muscle involvement with "patchy" areas of fatty replacement. Larger cohorts are needed to assess if a distinct pattern of muscle involvement exists also for NLSD-I.
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http://dx.doi.org/10.1007/s00415-017-8498-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502068PMC
July 2017

Neutral Lipid Storage Diseases: clinical/genetic features and natural history in a large cohort of Italian patients.

Orphanet J Rare Dis 2017 05 12;12(1):90. Epub 2017 May 12.

IRCCS Fondazione Ospedale S. Camillo, Venice, Italy.

Background: A small number of patients affected by Neutral Lipid Storage Diseases (NLSDs: NLSD type M with Myopathy and NLSD type I with Ichthyosis) have been described in various ethnic groups worldwide. However, relatively little is known about the progression and phenotypic variability of the disease in large specific populations. The aim of our study was to assess the natural history, disability and genotype-phenotype correlations in Italian patients with NLSDs. Twenty-one patients who satisfied the criteria for NLSDs were enrolled in a retrospective cross-sectional study to evaluate the genetic aspects, clinical signs at onset, disability progression and comorbidities associated with this group of diseases.

Results: During the clinical follow-up (range: 2-44 years, median: 17.8 years), two patients (9.5%, both with NLSD-I) died of hepatic failure, and a further five (24%) lost their ability to walk or needed help when walking after a mean period of 30.6 years of disease. None of the patients required mechanical ventilation. No patient required a heart transplant, one patient with NLSD-M was implanted with a cardioverter defibrillator for severe arrhythmias.

Conclusion: The genotype/phenotype correlation analysis in our population showed that the same gene mutations were associated with a varying clinical onset and course. This study highlights peculiar aspects of Italian NLSD patients that differ from those observed in Japanese patients, who were found to be affected by a marked hypertrophic cardiopathy. Owing to the varying phenotypic expression of the same mutations, it is conceivable that some additional genetic or epigenetic factors affect the symptoms and progression in this group of diseases.
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http://dx.doi.org/10.1186/s13023-017-0646-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427600PMC
May 2017

Cutaneous features of myotonic dystrophy types 1 and 2: Implication of premature aging and vitamin D homeostasis.

Neuromuscul Disord 2017 Feb 16;27(2):163-169. Epub 2016 Nov 16.

Department of Systems Medicine, Division of Neurology, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy; Department of Experimental Medicine and Surgery, Division of Clinical Biochemistry, University of Rome Tor Vergata, Viale Oxford 81, 00133 Rome, Italy. Electronic address:

Skin changes have been described in myotonic dystrophy type 1 (DM1). However, whether and in which way skin is a target of specific disease alterations in DM1 and DM2 has not been yet clarified. This study aims to explore cutaneous features of DM1 and DM2 patients. Skin examination was performed in 60 DM1, 15 DM2, and 103 control, unselected patients by means of dermoscopy. It revealed quantitative and qualitative abnormalities of nevi and typical signs of premature aging in both DM1 and DM2 patients, with a significantly higher frequency of dysplastic nevi, alopecia, xerosis and seborrheic dermatitis. Twenty-eight nevi were excised in DM patients and none showed histological features of melanoma, although 12 of them were diagnosed as dysplastic and the remaining 16 presented histological irregularity in melanin distribution. In DM1 patients, the number of nevi correlated with CTG expansion size, whereas the presence of dysplastic nevi and xerosis inversely correlated with vitamin D levels. DM1 and DM2 patients display a high frequency of skin abnormalities, the most common of which correlate with genotype severity and serum vitamin D levels. Skin examination is highly informative in these patients and reveals features suggestive of premature aging and impaired vitamin D homeostasis.
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http://dx.doi.org/10.1016/j.nmd.2016.11.004DOI Listing
February 2017

Identification and characterization of 5' CCG interruptions in complex DMPK expanded alleles.

Eur J Hum Genet 2017 02 23;25(2):257-261. Epub 2016 Nov 23.

Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy.

Myotonic dystrophy type 1 is a multisystemic autosomal dominant disorder caused by the expansion of (CTG) triplets in the 3'UTR of the DMPK gene, on chromosome 19q13.3. In the last years, few DM1 patients with different patterns of CCG/CTC interruptions at the 3' end of the DMPK expanded tract have been described. However, the role of these interruptions in DM1 pathogenesis is still unclear. To study the frequency, stability and the structure of DMPK variant expanded alleles in the Italian population, we have re-evaluated 254 Italian DM1 patients using triplet-primed PCR (TP-PCR), at both the 3' and 5' ends of the CTG expansion. In addition, three DM1 families were also investigated in order to analyze the intergenerational stability of the interrupted DMPK alleles. Fourteen DM1 patients showed a TP-PCR electrophoretic profile indicating CCG/CTC interruptions within the CTG expansion. Interestingly, interruptions have been detected and, for the first time, sequenced at the 5' end of the CTG array. Analysis of five intergenerational transmissions revealed a substantial intrafamilial stability of the DM1 mutation among relatives. Our results support the hypothesis that CCG/CTC interruptions within the DMPK expanded alleles have a stabilizing effect on the mutational dynamics and can modulate the severity of symptoms in DM1 patients.
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http://dx.doi.org/10.1038/ejhg.2016.148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5255948PMC
February 2017

Neuromuscular transmission abnormalities in myotonic dystrophy type 1: A neurophysiological study.

Clin Neurol Neurosurg 2016 Nov 29;150:84-88. Epub 2016 Aug 29.

Neuromuscular and Neurological Rare Diseases Centre, Neurology and Neurophysiology Unit, S. Camillo Forlanini Hospital, C. Gianicolense, 87-00152, Rome, Italy. Electronic address:

Objectives: Weakness and fatigue are frequent symptoms in myotonic dystrophy type 1 (DM1), mainly as a result of muscle impairment. However, neuromuscular junction (NMJ) abnormalities could play an additional role in determining these manifestations. We aimed to document the possible NMJ involvement in DM1.

Patients And Methods: In order to substantiate this hypothesis we performed low rate repetitive nerve stimulation (RNS) and single fiber electromyography (SFEMG), in 14 DM1 subjects.

Results: RNS resulted abnormal in four patients while SFEMG revealed a pathological jitter in ten. A significative correlation was found between jitter values and decrementing response (p<0.000311; r=0.822).

Conclusion: These results suggest a possible involvement of NMJ in DM1.
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http://dx.doi.org/10.1016/j.clineuro.2016.08.020DOI Listing
November 2016

Myoimaging in the NGS era: the discovery of a novel mutation in MYH7 in a family with distal myopathy and core-like features--a case report.

BMC Med Genet 2016 Mar 22;17:25. Epub 2016 Mar 22.

Molecular Medicine, IRCCS Stella Maris, via dei Giacinti 2, 56128, Calambrone, Pisa, Italy.

Background: Myosin heavy chain 7 related myopathies are rare disorders characterized by a wide phenotypic spectrum and heterogeneous pathological features. In the present study, we performed clinical, morphological, genetic and imaging investigations in three relatives affected by autosomal dominant distal myopathy. Whilst earlier traditional Sanger investigations had pointed to the wrong gene as disease causative, next-generation sequencing allowed us to obtain the definitive molecular genetic diagnosis in the family.

Case Presentation: The proposita, being found to harbor a novel heterozygous mutation in the RYR1 gene (p.Glu294Lys), was initially diagnosed with core myopathy. Subsequently, consideration of muscle magnetic resonance imaging (MRI) features and extension of family study led this diagnosis to be questioned. Use of next-generation sequencing analysis identified a novel mutation in the MYH7gene (p.Ser1435Pro) that segregated in the affected family members.

Conclusions: This study identified a novel mutation in MYH7 in a family where the conclusive molecular diagnosis was reached through a complicated path. This case report might raise awareness, among clinicians, of the need to interpret NGS data in combination with muscle MRI patterns so as to facilitate the pinpointing of the main molecular etiology in inherited muscle disorders.
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http://dx.doi.org/10.1186/s12881-016-0288-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804697PMC
March 2016

An Age-Standardized Prevalence Estimate and a Sex and Age Distribution of Myotonic Dystrophy Types 1 and 2 in the Rome Province, Italy.

Neuroepidemiology 2016 17;46(3):191-7. Epub 2016 Feb 17.

National Centre for Epidemiology, Surveillance and Health Promotion, National Institute of Health, Rome, Italy.

Background: Prevalence estimates for the 2 forms of myotonic dystrophy types 1 and 2 (DM1 and DM2) are not exhaustive or non-available. Our aim was to estimate the minimum prevalence of DM1 and DM2 in Italy in the Rome province, applying standards of descriptive epidemiology.

Methods: All patients with a molecular diagnosis of DM1/DM2 and residents in the Rome province in 2013 have been enrolled, and the age-standardized prevalence has been calculated, assuming a Poisson distribution and adjusting for age.

Results: We identified 395 DM1 patients: the age-standardized prevalence for total, females and males was 9.65, 8.35 and 11.07/100,000, respectively. The mean age of subjects differed considerably according to CTG repeat length (p = 0.001). Forty DM2 patients were identified. The age-standardized prevalence for total, females and males was 0.99, 1.07 and 0.90/100,000, respectively. The mean age was 57.05.

Conclusions: We estimated for the first time the age-standardized prevalence and the sex and age distribution of DM1 and DM2 in a general population. A higher prevalence of males in DM1 and females in DM2 and a higher mean age of DM2 patients (+8 years) were ascertained. Prevalence of DM2 was 10% that of DM1. These prevalence values are probably lower than mutational rates due to the incomplete penetrance of DM1 mutations and to the clinical elusiveness of DM2. Our findings will be useful in designing cohort studies and for developing a disease registry.
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http://dx.doi.org/10.1159/000444018DOI Listing
December 2016

Increased risk of tumor in DM1 is not related to exposure to common lifestyle risk factors.

J Neurol 2016 Mar 6;263(3):492-8. Epub 2016 Jan 6.

Department of Geriatrics, Neuroscience and Orthopedics, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Rome, Italy.

Recent studies documented an increased risk of neoplasm in patients with myotonic dystrophies (DM). Yet, none of these studies evaluated the contribution of common cancer risk factors in such observation. In this study, we included a cohort of patients (n = 255) with an established molecular diagnosis of DM type 1 (DM1), and who receives their treatment in one of the four centers with recognized expertise in neuromuscular disorders in Rome. We estimated the prevalence of benign and malignant tumors, and assessed if lifestyle factors and/or specific disease features would be associated to their occurrence. Overall, 59 benign tumors in 54 patients and 19 malignant tumors in 17 patients were diagnosed. The most common malignant neoplasms were cancers of the skin (31.6%), thyroid (21.0%), ovary (10.5%), and breast (10.5%). Uterine fibroid was the most common benign tumor (37.6%) in women, while pilomatricoma was the most common in men (28.6%). Age at enrollment (OR = 1.02, 95% CI 1.00-1.05), and female gender (OR = 5.71, 95% CI 2.90-11.22) were associated with tumor development in DM1 patients, while thyroid disorders was associated with malignant tumors only in women (OR = 5.12, 95% CI 1.35-19.37). There was no association between tumor development and evaluated lifestyle factors. In conclusion, the lack of association between common cancer risk factors and tumor development in DM1 support a pathogenic link between tumors and DM1 itself, emphasizing the need for a systematic surveillance. Our observation of an association between thyroid diseases in women and cancer development needs confirmation.
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http://dx.doi.org/10.1007/s00415-015-8006-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814867PMC
March 2016

Neutral lipid-storage disease with myopathy and extended phenotype with novel PNPLA2 mutation.

Muscle Nerve 2016 Apr 22;53(4):644-8. Epub 2016 Feb 22.

Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Rome, Italy.

Introduction: Neutral lipid-storage disease with myopathy is caused by mutations in PNPLA2, which produce skeletal and cardiac myopathy. We report a man with multiorgan neutral lipid storage and unusual multisystem clinical involvement, including cognitive impairment.

Methods: Quantitative brain MRI with voxel-based morphometry and extended neuropsychological assessment were performed. In parallel, the coding sequences and intron/exon boundaries of the PNPLA2 gene were screened by direct sequencing.

Results: Neuropsychological assessment revealed global cognitive impairment, and brain MRI showed reduced gray matter volume in the temporal lobes. Molecular characterization revealed a novel homozygous mutation in exon 5 of PNPLA2 (c.714C>A), resulting in a premature stop codon (p.Cys238*).

Conclusions: Some PNPLA2 mutations, such as the one described here, may present with an extended phenotype, including brain involvement. In these cases, complete neuropsychological testing, combined with quantitative brain MRI, may help to characterize and quantify cognitive impairment.
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http://dx.doi.org/10.1002/mus.24983DOI Listing
April 2016