Publications by authors named "Luigia Passamano"

16 Publications

  • Page 1 of 1

Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.

J Neurol Neurosurg Psychiatry 2020 Nov 11;91(11):1166-1174. Epub 2020 Sep 11.

Department of Neurosciences, University of Padua, Padova, Veneto, Italy.

Objective: To retrospectively investigate safety and efficacy of nusinersen in a large cohort of adult Italian patients with spinal muscular atrophy (SMA).

Methods: Inclusion criteria were: (1) clinical and molecular diagnosis of SMA2 or SMA3; (2) nusinersen treatment started in adult age (>18 years); (3) clinical data available at least at baseline (T0-beginning of treatment) and 6 months (T6).

Results: We included 116 patients (13 SMA2 and 103 SMA3) with median age at first administration of 34 years (range 18-72). The Hammersmith Functional Rating Scale Expanded (HFMSE) in patients with SMA3 increased significantly from baseline to T6 (median change +1 point, p<0.0001), T10 (+2, p<0.0001) and T14 (+3, p<0.0001). HFMSE changes were independently significant in SMA3 sitter and walker subgroups. The Revised Upper Limb Module (RULM) in SMA3 significantly improved between T0 and T14 (median +0.5, p=0.012), with most of the benefit observed in sitters (+2, p=0.018). Conversely, patients with SMA2 had no significant changes of median HFMSE and RULM between T0 and the following time points, although a trend for improvement of RULM was observed in those with some residual baseline function. The rate of patients showing clinically meaningful improvements (as defined during clinical trials) increased from 53% to 69% from T6 to T14.

Conclusions: Our data provide further evidence of nusinersen safety and efficacy in adult SMA2 and SMA3, with the latter appearing to be cumulative over time. In patients with extremely advanced disease, effects on residual motor function are less clear.
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http://dx.doi.org/10.1136/jnnp-2020-323822DOI Listing
November 2020

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.

Dino Ferrari Centre, Department of Pathophysiology and Transplantation (DEPT), Neuroscience Section, University of Milan, 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

Deletion of the Williams Beuren syndrome critical region unmasks facioscapulohumeral muscular dystrophy.

Eur J Paediatr Neurol 2020 Jul 22;27:25-29. Epub 2020 May 22.

Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; Department of of Molecular, Cell and Cancer Biology, University of Massachsetts Medical School, Worcester, USA. Electronic address:

Among 1339 unrelated cases accrued by the Italian National Registry for facioscapulohumeral muscular dystrophy (FSHD), we found three unrelated cases who presented signs of Williams-Beuren Syndrome (WBS) in early childhood and later developed FSHD. All three cases carry the molecular defects associated with the two disorders. The rarity of WBS and FSHD, 1 in 7500 and 1 in 20,000 respectively, makes a random association of the two diseases unlikely. These cases open novel and unexpected interpretation of genetic findings. The nonrandom association of both FSHD and WBS points at a gene co-expression network providing hints for the identification of modules and functionally enriched pathways in the two conditions.
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http://dx.doi.org/10.1016/j.ejpn.2020.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427329PMC
July 2020

Molecular Characterization in 19 South-Italian Patients With Dominant and Recessive Type of Myotonia Congenita.

Front Neurol 2020 6;11:63. Epub 2020 Feb 6.

Cardiomiology and Medical Genetics, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Myotonia congenita is a genetic disease characterized by impaired muscle relaxation after forceful contraction (myotonia). It is caused by mutations in the gene, encoding the voltage-gated chloride channel of skeletal muscle, ClC-1. According to the pattern of inheritance, two distinct clinical forms have been described, Thomsen disease, inherited as an autosomal dominant trait and Becker disease inherited as an autosomal recessive trait. We report genetic and clinical data concerning 19 patients-13 familial and six isolated cases-all but one originating from the Campania Region, in southern Italy. Twelve patients (63.2%) present Becker type myotonia and 7 (36.8%) Thomsen type. Sex ratio M:F in Becker type is 6:6, while in Thomsen myotonia 4:3. The age of onset of the disease ranged from 2 to 15 years in Becker patients, and from 4 to 20 years in Thomsen. Overall 18 mutations were identified, 10 located in the coding part of the gene (exons 1, 3, 4, 5, 7, 8, 13, 15, 21, 22), and four in the intron part (introns 1, 2, 10, 18). All the exon mutations but two were missense mutations. Some of them, such as > > and > recurred more frequently. About 70% of mutations was inherited with an autosomal recessive pattern, two (c.86A and >) with both mechanisms. Three novel mutations were identified, never described in the literature: p.Gly276Ser, p.Phe486Ser, and p.Gln812, associated with Becker phenotype. Furthermore, we identified three mutations-c.86A>C + c.2551G > A, c.313C > T + c.501C > G and 899G > A + c.2284+5C > T, two of them inherited on the same allele, in three unrelated families. The concomitant occurrence of both clinical pictures-Thomsen and Becker-was observed in one family. Intra-familial phenotypic variability was observed in two families, one with Becker phenotype, and one with Thomsen disease. In the latter an incomplete penetrance was hypothesized.
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http://dx.doi.org/10.3389/fneur.2020.00063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016095PMC
February 2020

Cardiac diseases as a predictor warning of hereditary muscle diseases. The case of laminopathies.

Acta Myol 2019 Jun 1;38(2):33-36. Epub 2019 Jun 1.

Cardiomiology and Medical Genetics, Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Mutations in the gene are associated with a wide spectrum of disease phenotypes, ranging from neuromuscular, cardiac and metabolic disorders to premature aging syndromes. Skeletal muscle involvement may present with different phenotypes: limb-girdle muscular dystrophy type 1B or -related dystrophy; autosomal dominant Emery-Dreifuss muscular dystrophy; and a congenital form of muscular dystrophy, frequently associated with early onset of arrhythmias. Heart involvement may occur as part of the muscle involvement or independently, regardless of the presence of the myopathy. Notably conduction defects and dilated cardiomyopathy may exist without a muscle disease. This paper will focus on cardiac diseases presenting as the first manifestation of skeletal muscle hereditary disorders such as laminopathies, inspired by two large families with cardiovascular problems long followed by conventional cardiologists who did not suspect a genetic muscle disorder underlying these events. Furthermore it underlines the need for a multidisciplinary approach in these disorders and how the figure of the may play a key role in facilitating the diagnostic process, and addressing the adoption of appropriate prevention measures.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598412PMC
June 2019

Longitudinal evaluation of SMN levels as biomarker for spinal muscular atrophy: results of a phase IIb double-blind study of salbutamol.

J Med Genet 2019 05 28;56(5):293-300. Epub 2018 Dec 28.

Muscle Pathology and Neuroimmunology Unit, Neurological Institute Carlo Besta, Milano, Italy.

Background: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, due to the loss of function of the survival motor neuron () gene. The first treatment for the condition, recently approved, is based on the reduction of exon 7 skipping in mRNAs produced by a highly homologous gene (). The primary objective of the present study was to evaluate the applicability of the dosage of SMN gene produts in blood, as biomarker for SMA, and the safety of oral salbutamol, a beta2-adrenergic agonist modulating levels.

Methods: We have performed a 1-year multicentre, double-blind, placebo-controlled study with salbutamol in 45 adult patients with SMA. Patients assumed 4 mg of salbutamol or placebo/three times a day. Molecular tests were copy number, SMN transcript and protein levels. We have also explored the clinical effect, by the outcome measures available at the time of study design.

Results: Thirty-six patients completed the study. Salbutamol was safe and well tolerated. We observed a significant and progressive increase in full-length levels in peripheral blood of the salbutamol-treated patients (p<0.00001). The exploratory analysis of motor function showed an improvement in most patients.

Conclusions: Our data demonstrate safety and molecular efficacy of salbutamol. We provide the first longitudinal evaluation of SMN levels (both transcripts and protein) in placebo and in response to a compound modulating the gene expression: transcript dosage in peripheral blood is reliable and may be used as pharmacodynamic marker in clinical trials with systemic compounds modifying levels.

Trial Registration Number: EudraCT no. 2007-001088-32.
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http://dx.doi.org/10.1136/jmedgenet-2018-105482DOI Listing
May 2019

Targeted gene panel screening is an effective tool to identify undiagnosed late onset Pompe disease.

Neuromuscul Disord 2018 07 9;28(7):586-591. Epub 2018 Apr 9.

Dipartimento di Medicina di Precisione, Università degli Studi della Campania "Luigi Vanvitelli", Napoli, Italy; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.

Mutations in the GAA gene may cause a late onset Pompe disease presenting with proximal weakness without the characteristic muscle pathology, and therefore a test for GAA activity is the first tier analysis in all undiagnosed patients with hyperCKemia and/or limb-girdle muscular weakness. By using MotorPlex, a targeted gene panel for next generation sequencing, we analyzed GAA and other muscle disease-genes in a large cohort of undiagnosed patients with suspected inherited skeletal muscle disorders (n = 504). In this cohort, 275 patients presented with limb-girdle phenotype and/or an isolated hyperCKemia. Mutational analysis identified GAA mutations in ten patients. Further seven affected relatives were identified by segregation studies. All the patients carried the common GAA mutation c.-32-13T >G and a second, previously reported mutation. In the subcohort of 275 patients with proximal muscle weakness and/or hyperCKemia, we identified late-onset Pompe disease in 10 patients. The clinical overlap between Pompe disease and LGMDs or other skeletal muscle disorders suggests that GAA and the genes causing a metabolic myopathy should be analyzed in all the gene panels used for testing neuromuscular patients. However, enzymatic tests are essential for the interpretation and validation of genetic results.
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http://dx.doi.org/10.1016/j.nmd.2018.03.011DOI Listing
July 2018

The genetic basis of undiagnosed muscular dystrophies and myopathies: Results from 504 patients.

Neurology 2016 07 8;87(1):71-6. Epub 2016 Jun 8.

From the Dipartimento di Biochimica Biofisica e Patologia Generale (M.S., G.D.F., A. Torella, A.G., T.G., F.D.V.B., G.E., G.P., V.N.), Seconda Università di Napoli; Telethon Institute of Genetics and Medicine (M.S., G.D.F., A. Torella, M. Mutarelli, V.S.M., A.G., T.G., G.E., V.N.), Pozzuoli; U.O.C. Neurologia Pediatrica e Malattie Muscolari (C.F., C.M., C.B.), IRCCS Istituto Giannina Gaslini, Genova; Centro Dino Ferrari, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti (F.M., D.R., G.P.C.), and Neuromuscular and Rare Disease Unit, Dipartimento di Neuroscienze (M. Moggio), Università degli Studi di Milano, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan; Dipartimento di Neuroscienze (M. Fanin, E.P.), Università di Padova; Dipartimento di Neuroscienze e Scienze Riproduttive ed Odontostomatologiche (L.R., L.S.), Università degli Studi di Napoli "Federico II," Napoli; Dipartimento di Medicina Clinica e Sperimentale (G.R., G.S.), Università degli Studi di Pisa; Medicina Molecolare (G.A., F.M.S.), IRCCS Fondazione Stella Maris, Pisa; Dipartimento di Medicina Sperimentale (L. Passamano, P.D., R.P., L. Politano) and Dipartimento di Scienze Mediche, Chirurgiche, Neurologiche, Metaboliche, e dell'Invecchiamento (O.F., S.S., G.D.I.), Seconda Università di Napoli; Dipartimento di Neuroscienze (A.R., M. Mora, L.M.), Istituto Besta, Milano; Don Carlo Gnocchi ONLUS Foundation (G.T.), Milano; Dipartimento di Neuroscienze (A.D., E.B.), IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy; Center for Medical Genetics (S.J., K.C.) and Department of Neurology (J.D.B.), Ghent University Hospital, Belgium; Dipartimento di Neuroscienze (O.M., C.R., S.M., A. Toscano), Università degli Studi di Messina, Italy; Folkhälsan Institute of Genetics (A.E., P.H., B.U.), University of Helsinki, Finland; Section for Neuromuscular Diseases and Neuropathies (M. Filosto), Unit of Clinical Neurology, University Hospital 'Spedali Civili,' Brescia, Italy; Neuromusc

Objective: To apply next-generation sequencing (NGS) for the investigation of the genetic basis of undiagnosed muscular dystrophies and myopathies in a very large cohort of patients.

Methods: We applied an NGS-based platform named MotorPlex to our diagnostic workflow to test muscle disease genes with a high sensitivity and specificity for small DNA variants. We analyzed 504 undiagnosed patients mostly referred as being affected by limb-girdle muscular dystrophy or congenital myopathy.

Results: MotorPlex provided a complete molecular diagnosis in 218 cases (43.3%). A further 160 patients (31.7%) showed as yet unproven candidate variants. Pathogenic variants were found in 47 of 93 genes, and in more than 30% of cases, the phenotype was nonconventional, broadening the spectrum of disease presentation in at least 10 genes.

Conclusions: Our large DNA study of patients with undiagnosed myopathy is an example of the ongoing revolution in molecular diagnostics, highlighting the advantages in using NGS as a first-tier approach for heterogeneous genetic conditions.
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http://dx.doi.org/10.1212/WNL.0000000000002800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932234PMC
July 2016

Clinical features of patients with dystrophinopathy sharing the 45-55 exon deletion of DMD gene.

Acta Myol 2015 May;34(1):9-13

Cardiomiology and Medical Genetics, Department of Experimental Medicine;

Becker muscular dystrophy (BMD) was first described in 1953 by Emile Becker as a benign variant of Duchenne muscular Dystrophy (DMD). Compared with DMD, BMD is clinically more heterogeneous, with initial presentation in the teenage years and loss of ambulation beyond the age of 16 and a wide spectrum of clinical presentations, ranging from only myalgias and muscle cramps to exercise intolerance and myoglobinuria, asymptomatic elevation of serum creatin-kinase, or mild limb-girdle weakness and quadriceps myopathy. About 50% of patients become symptomatic by the age of 10 and the most part by the age of 20 years. However few patients can be free of symptoms till their fifties and cases of late-onset Becker Muscular Dystrophy have also been described. In this report we describe the clinical features of patients with dystrophinopathy sharing a deletion of exons 45-55, occasionally or retrospectively diagnosed. These data are important for both the prognostic aspects of children presenting this dystrophin gene mutation, and for the genetic counseling in these families (reassuring them on the benign course of the disease), and last but not least to keep in mind a diagnosis of BMD in asymptomatic adults with mild hyperckemia.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478772PMC
May 2015

Intraocular pressure in patients with muscular dystrophies.

Ophthalmology 2013 Jun;120(6):1306-7.e1

Department of Medicine and Surgery, University of Salerno, Salerno, Italy.

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http://dx.doi.org/10.1016/j.ophtha.2012.12.046DOI Listing
June 2013

Improvement of survival in Duchenne Muscular Dystrophy: retrospective analysis of 835 patients.

Acta Myol 2012 Oct;31(2):121-5

Cardiomyology and Medical Genetics, Department of Experimental Medicine, Second University of Naples, Italy.

Duchenne Muscular Dystrophy (DMD) is the most common muscle disease in children. Historically, DMD results in loss of ambulation between ages 7 and 13 years and death in the teens or 20s. In order to determine whether survival has improved over the decades and whether the impact of nocturnal ventilation combined with a better management of cardiac involvement has been able to modify the pattern of survival, we reviewed the notes of 835 DMD patients followed at the Naples Centre of Cardiomyology and Medical Genetics from 1961 to 2006. Patients were divided, by decade of birth, into 3 groups: 1) DMD born between 1961 and 1970; 2) DMD born between 1971 and 1980; 3) DMD born between 1981 and 1990; each group was in turn subdivided into 15 two-year classes, from 14 to 40 years of age. Age and causes of death, type of cardiac treatment and use of a mechanical ventilator were carefully analyzed.The percentage of survivors in the different decades was statistically compared by chi-square test and Kaplan-Meier survival curves analyses. A significant decade on decade improvement in survival rate was observed at both the age of 20, where it passed from 23.3% of patients in group 1 to 54% of patients in group 2 and to 59,8% in patients in group 3 (p < 0.001) and at the age of 25 where the survival rate passed from 13.5% of patients in group 1 to 31.6% of patients in group 2 and to 49.2% in patients in group 3 (p < 0.001).The causes of death were both cardiac and respiratory, with a prevalence of the respiratory ones till 1980s. The overall mean age for cardiac deaths was 19.6 years (range 13.4-27.5), with an increasing age in the last 15 years. The overall mean age for respiratory deaths was 17.7 years (range 11.6-27.5) in patients without a ventilator support while increased to 27.9 years (range 23-38.6) in patients who could benefit of mechanical ventilation.This report documents that DMD should be now considered an adulthood disease as well, and as a consequence more public health interventions are needed to support these patients and their families as they pass from childhood into adult age.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3476854PMC
October 2012

Clinical and molecular cross-sectional study of a cohort of adult type III spinal muscular atrophy patients: clues from a biomarker study.

Eur J Hum Genet 2013 Jun 17;21(6):630-6. Epub 2012 Oct 17.

Medical Genetics Institute, Catholic University, Rome, Italy.

Proximal spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations of the SMN1 gene. Based on severity, three forms of SMA are recognized (types I-III). All patients usually have 2-4 copies of a highly homologous gene (SMN2), which produces insufficient levels of functional survival motor neuron (SMN) protein due to the alternative splicing of exon 7. The availability of potential candidates to the treatment of SMA has raised a number of issues, including the availability of biomarkers. This study was aimed at evaluating whether the quantification of SMN2 products in peripheral blood is a suitable biomarker for SMA. Forty-five adult type III patients were evaluated by Manual Muscle Testing, North Star Ambulatory Assessment scale, 6-min walk test, myometry, forced vital capacity, and dual X-ray absorptiometry. Molecular assessments included SMN2 copy number, levels of full-length SMN2 (SMN2-fl) transcripts and those lacking exon 7 and SMN protein. Clinical outcome measures strongly correlated to each other. Lean body mass correlated inversely with years from diagnosis and with several aspects of motor performance. SMN2 copy number and SMN protein levels were not associated with motor performance or transcript levels. SMN2-fl levels correlated with motor performance in ambulant patients. Our results indicate that SMN2-fl levels correlate with motor performance only in patients preserving higher levels of motor function, whereas motor performance was strongly influenced by disease duration and lean body mass. If not taken into account, the confounding effect of disease duration may impair the identification of potential SMA biomarkers.
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http://dx.doi.org/10.1038/ejhg.2012.233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658179PMC
June 2013

Cardiac involvement in patients with spinal muscular atrophies.

Acta Myol 2011 Dec;30(3):175-8

Cardiomyology and Medical Genetics, Department of Experimental Medicine, Second University of Naples, Italy.

The spinal muscular atrophies (SMAs) include a group of disorders characterized by progressive weakness of the lower motor neurons. Several types of SMAs have been described based on age onset of clinical features: Acute infantile (SMA type I), chronic infantile (SMA type II), chronic juvenile (SMA type III), and adult onset (SMA type IV) forms. The incidence is about 1:6,000 live births with a carrier frequency of 1:40 for the severe form and 1:80 for the juvenile form. The mortality and/or morbidity rates of SMAs are inversely correlated with the age at onset. SMAs are believed to only affect skeletal muscles; however, new data on SMA mice models suggest they may also impact the heart. Aim of the study was to retrospectively examine the cardiological records of 37 type molecularly confirmed II/III SMA patients, aged 6 to 65 years, in order to evaluate the onset and evolution of the cardiac involvement in these disorders. All patients had a standard ECG and a routine echocardiography. The parameters analysed were the following: Heart rate (HR), PQ interval, PQ segment, Cardiomyopathic Index (ratio QT/PQs), ventricular and supraventricular ectopic beats, pauses > or = 2,5 msec, ventricle diameters, wall and septum thickness, ejection fraction, fiber shortening. The results showed that HR and the other ECG parameters were within the normal limits except for the Cardiomyopathic Index that was higher than the normal values (2,6-4,2) in 2 patients. Left ventricular systolic function was within the normal limits in all patients. A dilation of the left ventricle without systolic dysfunction was observed in only 2 patients, aged respectively 65 and 63 years; however they were hypertensive and/or affected by coronary artery disease. Data here reported contribute to reassure patients and their clinicians that type II/III SMAs do not present heart dysfunction.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3298107PMC
December 2011

Mutations that impair interaction properties of TRIM32 associated with limb-girdle muscular dystrophy 2H.

Hum Mutat 2008 Feb;29(2):240-7

Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.

TRIM32 belongs to a large family of proteins characterized by a tripartite motif, possibly involved in the ubiquitination process, acting as an E3 ligase. In addition, TRIM32 has six NHL repeats with putative interaction properties. A homozygous mutation at the third NHL repeat (D487N) has been found in patients with limb girdle muscular dystrophy 2H (LGMD2H). This mutation was only identified in the inbred Manitoba Hutterite or their descendants. Interestingly, a mutation in the B-box domain of TRIM32 cosegregates with Bardet-Biedl syndrome type 11 (BBS11). The signs of BBS11 include obesity, pigmentary and retinal malformations, diabetes, polydactyly, and no muscular dystrophy, suggesting an alternative disease mechanism. We aim to ascertain whether D487N is the only pathological LGMD2H allele, limited to Hutterites. We studied the TRIM32 gene in 310 LGMD patients with no mutations at the other known loci. We identified four patients with novel mutated alleles. Two mutations were homozygous and missing in controls. These mutations also clustered at the NHL domain, suggesting that a specific (interaction) property might be abolished in LGMD2H patients. No mutations were found at the B-box region where the BBS11 mutation is found. We tested TRIM32 and its mutants by yeast-two-hybrid assay, developing an interaction test to validate mutations. All LGMD2H mutants, but not the BBS11, lost their ability to self-interact. The interaction of TRIM32 mutants with E2N, a protein involved in the ubiquitination process, was similarly impaired. In conclusion, the mutations here reported may cause muscular dystrophy by affecting the interaction properties of TRIM32.
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http://dx.doi.org/10.1002/humu.20633DOI Listing
February 2008

A preliminary randomized study of growth hormone administration in Becker and Duchenne muscular dystrophies.

Eur Heart J 2003 Apr;24(7):664-72

Department of Internal Medicine and Cardiovascular Sciences, University Federico II, Naples, Italy.

Aim: Since growth hormone (GH) has proven beneficial in experimental heart failure, and the natural history of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) is frequently complicated by the development of dilated cardiomyopathy, we administered GH to six patients with DMD and 10 with BMD, with the evidence of cardiac involvement.

Methods And Results: Patients were randomized to receive for 3 months either placebo or recombinant human GH, in a double-blind fashion. In GH-treated patients, left ventricular (LV) mass increased by 16% in BMD and by 29% in DMD (both p<0.01), with a significant increase of relative wall thickness (+19%). Systemic blood pressure remained unchanged, while LV end-systolic stress fell significantly by 13% in BMD and by 33% in DMD, with a slight increase of systolic function indexes. No changes were observed related to cardiac arrhythmias and skeletal muscle function in the patient groups during the treatment period, nor any side effects were observed. Brain natriuretic peptide, interleukin-6, and tumor necrosis factor-alpha circulating levels were elevated at baseline. While brain natriuretic peptide decreased by 40%, cytokine levels did not exhibit significant variations during the treatment period.

Conclusions: The 3-month GH therapy in patients with DMD and BMD induces a hypertrophic response associated with a significant reduction of brain natriuretic peptide plasma levels and a slight improvement of systolic function, no changes in skeletal muscle function, and no side effects.
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http://dx.doi.org/10.1016/s0195-668x(02)00740-6DOI Listing
April 2003

Pulsed Doppler tissue imaging in dystrophinopathic cardiomyopathy.

J Am Soc Echocardiogr 2002 Sep;15(9):891-9

Medical Surgical Institute of Cardiology, II University of Naples, Parco Grifeo 28, 80121 Naples, Italy.

Cardiac dysfunction is a primary feature in patients and female carriers of Becker muscular dystrophy (BMD). Conventional echocardiography and pulsed Doppler tissue imaging (DTI) were performed in 28 patients with BMD, in 20 female carriers, and in 38 control participants (20 men and 18 women). Left ventricular ejection fraction (LVEF) was lower in BMD patients (P <.02) and carriers (P <.02) than in normal participants. Two subgroups of BMD patients were identified: A1 = LVEF > or = 55% (n = 20) and A2 = LVEF < 55% (n = 8). The carriers displayed LVEF > or = 55%. Compared with control participants the diastolic alterations by conventional echocardiography were lower early filling peak in the subgroup A1 (P <.05) and prolonged isovolumic relaxation time in A1, A2, and in carriers (at least P <.02). Furthermore, pulsed DTI showed lower early diastolic wave peak at basal septum in A2 (P <.05) and in carriers (P <.0001); at lateral mitral annulus and at basal inferior wall in A1, A2, and in carriers (at least P <.05); lower early/late diastolic wave ratio at basal septum and lateral mitral annulus (P <.05) in carriers; and prolonged isovolumic relaxation time in A1, A2, and in carriers (at least P <.02), except at lateral mitral annulus of carriers. Systolic parameters investigated by pulsed DTI detected lower peak systolic wave at basal septum in A1, A2, and carriers (P <.02); at lateral mitral annulus in carriers (P <.02); at basal inferior wall in A1, A2 (P <.02), and in carriers (P <.0001); and lower time-velocity integral of S wave at each segment in A1, A2, and in carriers. In dystrophinopathic cardiomyopathy, pulsed DTI may be a useful technique to assess diastolic dysfunction and appears to be a promising tool in identifying early regional systolic alterations in patients and carriers with normal LVEF.
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http://dx.doi.org/10.1067/mje.2002.121197DOI Listing
September 2002