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BACKGROUND: Duchenne muscular dystrophy (DMD) is characterized by progressive weakness and wasting of skeletal, cardiac, and respiratory muscles, with consequent cardiopulmonary failure as the main cause of death. Reliable outcome measures able to demonstrate specific trends over disease progression are essential. PURPOSE: To investigate MRI as a noninvasive imaging modality to assess diaphragm impairment in DMD. In particular, we sought to correlate MRI measurement of diaphragm structure and function with pulmonary function tests and with the abdominal volumes (VAB ) measured by optoelectronic plethysmography, being an index of the action of the diaphragm. STUDY TYPE: Cross-sectional study. POPULATION: Twenty-six DMD patients (17.9 ± 6.2 years) and 12 age-matched controls (17.8 ± 5.9 years). FIELD STRENGTH/SEQUENCE: 3-Point gradient echo Dixon sequence at 3T. ASSESSMENT: Images were acquired in breath-hold at full-expiration (EXP) and full-inspiration (INSP). INSP and EXP lung volumes were segmented and the diaphragm surface was reconstructed as the bottom surface of the left and the right lung. The inspiratory and the expiratory diaphragm surfaces were aligned by a nonrigid iterative closest point algorithm. On MRI we measured: 1) craniocaudal diaphragmatic excursion; 2) diaphragm fatty infiltration. STATISTICAL TESTS: Three-parameter sigmoid regression, one-way analysis of variance (ANOVA), Spearman's correlation. RESULTS: In patients, diaphragm excursion decreased with age (r2 = 0.68, P < 0.0001) and fat fraction increased (r2 = 0.51, P = 0.0002). In healthy subjects, diaphragm excursion and fat fraction had no relationship with age. Diaphragm excursion decreased with decreasing FEV1 %pred (r = 0.78, P < 0.0001) and FVC %pred (r = 0.76, P < 0.0001) and correlated with VAB (r = 0.60, P = 0.0002). Fatty infiltration increased with decreasing FEV1 %pred (r = -0.88, P < 0.0001) and FVC %pred (r = -0.88, P < 0.0001). DATA CONCLUSION: The progressive structural and functional diaphragm impairment is highly related to pulmonary function tests and to VAB . The results suggest that MRI might represent a new and noninvasive tool for the functional and structural assessment of the diaphragm. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2020;51:461-471.
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Distrofia Muscular de Duchenne , Adolescente , Adulto , Niño , Estudios Transversales , Diafragma/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Distrofia Muscular de Duchenne/diagnóstico por imagen , Pruebas de Función Respiratoria , Adulto JovenRESUMEN
Patients at risk of developing respiratory dysfunctions, such as patients with severe forms of muscular dystrophy, need a careful respiratory assessment, and periodic follow-up visits to monitor the progression of the disease. In these patients, at-home continuous monitoring of respiratory activity patterns could provide additional understanding about disease progression, allowing prompt clinical intervention. The core aim of the present study is thus to investigate the feasibility of using an innovative wearable device for respiratory monitoring, particularly breathing frequency variation assessment, in patients with muscular dystrophy. A comparison of measurements of breathing frequency with gold standard methods showed that the device based on the inertial measurement units (IMU-based device) provided optimal results in terms of accuracy errors, correlation, and agreement. Participants positively evaluated the device for ease of use, comfort, usability, and wearability. Moreover, preliminary results confirmed that breathing frequency is a valuable breathing parameter to monitor, at the clinic and at home, because it strongly correlates with the main indexes of respiratory function.
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Distrofias Musculares , Dispositivos Electrónicos Vestibles , Humanos , Monitoreo Fisiológico , Distrofias Musculares/diagnóstico , Distrofias Musculares/fisiopatología , Proyectos Piloto , RespiraciónRESUMEN
In Duchenne muscular dystrophy (DMD), it is still to be determined if specific timepoints can be identified during the natural evolution of respiratory dysfunction from childhood to adulthood and if scoliosis, steroid therapy and nocturnal noninvasive mechanical ventilation (NIMV) have any effect on it.In a 7-year retrospective study performed on 115 DMD patients (6-24â years), evaluated once or twice per year, with 574 visits in total, evolution mean curves of spirometry, lung volumes, spontaneous breathing and thoraco-abdominal pattern (measured by optoelectronic plethysmography) parameters were obtained by nonlinear regression model analysis.While predicted values of forced vital capacity, forced expiratory volume in 1â s, and peak expiratory flow decline continuously since childhood, during spontaneous breathing the following parameters become significantly different than normal in sequence: abdominal contribution to tidal volume (lower after 14.8â years), tidal volume (lower after 17.2â years), minute ventilation (lower after 18.1â years) and respiratory rate (higher after 22.1â years). Restrictive lung pattern and diaphragmatic impairment are exacerbated by scoliosis severity, slowed by steroids treatment and significantly affected by NIMV.Spirometry, lung volumes, breathing pattern and thoraco-abdominal contributions show different evolution curves over time. Specific timepoints of respiratory impairment are identified during disease progression. These should be considered when defining outcome measures in clinical trials and treatment strategies in DMD.
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Pulmón/fisiopatología , Distrofia Muscular de Duchenne/fisiopatología , Distrofia Muscular de Duchenne/terapia , Escoliosis/complicaciones , Adolescente , Niño , Femenino , Volumen Espiratorio Forzado , Humanos , Italia , Masculino , Ventilación no Invasiva/efectos adversos , Ápice del Flujo Espiratorio , Pletismografía , Análisis de Regresión , Frecuencia Respiratoria , Estudios Retrospectivos , Escoliosis/fisiopatología , Espirometría , Esteroides/uso terapéutico , Volumen de Ventilación Pulmonar , Capacidad Vital , Adulto JovenRESUMEN
INTRODUCTION: The aim of this study was to apply quantitative MRI (qMRI) to assess structural modifications in thigh muscles of subjects with limb girdle muscular dystrophy (LGMD) 2A and 2B with long disease duration. METHODS: Eleven LGMD2A, 9 LGMD2B patients and 11 healthy controls underwent a multi-parametric 3T MRI examination of the thigh. The protocol included structural T1-weighted images, DIXON sequences for fat fraction calculation, T2 values quantification and diffusion MRI. Region of interest analysis was performed on 4 different compartments (anterior compartment, posterior compartment, gracilis, sartorius). RESULTS: Patients showed high levels of fat infiltration as measured by DIXON sequences. Sartorius and anterior compartment were more infiltrated in LGMD2B than LGMD2A patients. T2 values were mildly reduced in both disorders. Correlations between clinical scores and qMRI were found. CONCLUSIONS: qMRI measures may help to quantify muscular degeneration, but careful interpretation is needed when fat infiltration is massive. Muscle Nerve 58: 550-558, 2018.
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Tejido Adiposo/diagnóstico por imagen , Músculos Isquiosurales/diagnóstico por imagen , Distrofia Muscular de Cinturas/diagnóstico por imagen , Músculo Cuádriceps/diagnóstico por imagen , Adulto , Estudios de Casos y Controles , Femenino , Músculos Isquiosurales/fisiopatología , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Limitación de la Movilidad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/fisiopatología , Distrofia Muscular de Cinturas/fisiopatología , Músculo Cuádriceps/fisiopatología , Muslo , Adulto JovenRESUMEN
INTRODUCTION: Limb girdle muscular dystrophies (LGMDs) are characterized by high molecular heterogeneity, clinical overlap, and a paucity of specific biomarkers. Their molecular definition is fundamental for prognostic and therapeutic purposes. METHODS: We created an Italian LGMD registry that included 370 molecularly defined patients. We reviewed detailed retrospective and prospective data and compared each LGMD subtype for differential diagnosis purposes. RESULTS: LGMD types 2A and 2B are the most frequent forms in Italy. The ages at disease onset, clinical progression, and cardiac and respiratory involvement can vary greatly between each LGMD subtype. In a set of extensively studied patients, targeted next-generation sequencing (NGS) identified mutations in 36.5% of cases. CONCLUSION: Detailed clinical characterization combined with muscle tissue analysis is fundamental to guide differential diagnosis and to address molecular tests. NGS is useful for diagnosing forms without specific biomarkers, although, at least in our study cohort, several LGMD disease mechanisms remain to be identified. Muscle Nerve 55: 55-68, 2017.
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Diagnóstico Diferencial , Distrofia Muscular de Cinturas/diagnóstico , Distrofia Muscular de Cinturas/epidemiología , Adolescente , Adulto , Edad de Inicio , Anciano , Creatina Quinasa/sangre , Femenino , Estudios de Asociación Genética , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Distrofia Muscular de Cinturas/complicaciones , Distrofia Muscular de Cinturas/genética , Sistema de Registros , Trastornos Respiratorios/etiología , Estadísticas no Paramétricas , Adulto JovenRESUMEN
Background: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes. Methods and Results: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (-0.80%) and SF (-0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (-11.01âmL/m2, pâ=â0.03) while for dp116 were correlated with decreased EF (-4.14%, pâ=â<0.001). The rs10880 genotype in the LTBP4 gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, pâ=â0.002, and -10.62âmL/m2, pâ=â0.008) with a recessive model. Conclusions: We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD.
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Cardiomiopatías , Distrofia Muscular de Duchenne , Humanos , Distrofina/genética , Distrofina/metabolismo , Haplotipos , Estudios Retrospectivos , Volumen Sistólico , Función Ventricular Izquierda , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/complicaciones , Cardiomiopatías/etiología , Cardiomiopatías/genética , Isoformas de Proteínas/genética , Proteínas de Unión a TGF-beta Latente/genéticaRESUMEN
This open-label, single centre pilot study was designed to evaluate safety and tolerability of the combination of the drugs isosorbide dinitrate, a nitric oxide donor, and ibuprofen, a non steroid anti-inflammatory drug, in a cohort of adult dystrophic patients (Duchenne, Becker and Limb-Girdle Muscular Dystrophy). Seventy-one patients were recruited: 35, treated with the drug combination for 12 months, and 36 untreated. Safety and adverse events were assessed by reported signs and symptoms, physical examinations, blood tests, cardiac and respiratory function tests. Exploratory outcomes measure, such as the motor function measure scale, were also applied. Good safety and tolerability profiles of the long-term co-administration of the drugs were demonstrated. Few and transient side effects (i.e. headache and low blood pressure) were reported. Additionally, exploratory outcomes measures were feasible in all the disease population studied and evidenced a trend towards amelioration that reached statistical significance in one dimension of the MFM scale. Systemic administration of ibuprofen and isosorbide dinitrate provides an adequate safety margin for clinical studies aimed at assessing efficacy.
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Antiinflamatorios no Esteroideos/uso terapéutico , Ibuprofeno/uso terapéutico , Dinitrato de Isosorbide/uso terapéutico , Distrofias Musculares/tratamiento farmacológico , Donantes de Óxido Nítrico/uso terapéutico , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Duchenne and Becker Muscular dystrophies (DMD/BMD) are allelic disorders caused by mutations in the dystrophin gene, which encodes a sarcolemmal protein responsible for muscle integrity. Deletions and duplications account for approximately 75% of mutations in DMD and 85% in BMD. The implementation of techniques allowing complete gene sequencing has focused attention on small point mutations and other mechanisms underlying complex rearrangements. METHODS: We selected 47 patients (41 families; 35 DMD, 6 BMD) without deletions and duplications in DMD gene (excluded by multiplex ligation-dependent probe amplification and multiplex polymerase chain reaction analysis). This cohort was investigated by systematic direct sequence analysis to study sequence variation. We focused our attention on rare mutational events which were further studied through transcript analysis. RESULTS: We identified 40 different nucleotide alterations in DMD gene and their clinical correlates; altogether, 16 mutations were novel. DMD probands carried 9 microinsertions/microdeletions, 19 nonsense mutations, and 7 splice-site mutations. BMD patients carried 2 nonsense mutations, 2 splice-site mutations, 1 missense substitution, and 1 single base insertion. The most frequent stop codon was TGA (n=10 patients), followed by TAG (n=7) and TAA (n=4). We also analyzed the molecular mechanisms of five rare mutational events. They are two frame-shifting mutations in the DMD gene 3'end in BMD and three novel splicing defects: IVS42: c.6118-3C>A, which causes a leaky splice-site; c.9560A>G, which determines a cryptic splice-site activation and c.9564-426 T>G, which creates pseudoexon retention within IVS65. CONCLUSION: The analysis of our patients' sample, carrying point mutations or complex rearrangements in DMD gene, contributes to the knowledge on phenotypic correlations in dystrophinopatic patients and can provide a better understanding of pre-mRNA maturation defects and dystrophin functional domains. These data can have a prognostic relevance and can be useful in directing new therapeutic approaches, which rely on a precise definition of the genetic defects as well as their molecular consequences.
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Distrofina/genética , Distrofia Muscular de Duchenne/genética , Adolescente , Adulto , Alelos , Empalme Alternativo , Niño , Preescolar , Codón sin Sentido , Codón de Terminación , Estudios de Cohortes , Mutación del Sistema de Lectura , Humanos , Persona de Mediana Edad , Distrofia Muscular de Duchenne/diagnóstico , Mutagénesis Insercional , Mutación Missense , Fenotipo , Análisis de Secuencia de ADNRESUMEN
We aimed to describe the natural history of Limb Girdle Muscular Dystrophy type 2A and 2B over more than three decades by considering muscular strength, motor, cardiac and respiratory function. 428 visits of nineteen 2A and twenty 2B patients were retrospectively analysed through a regression model to create the curves of evolution with disease duration of muscle strength (through Medical Research Council grading), motor function measure scale (D1, D2 and D3 domains) and cardio-pulmonary function tests. Clinically relevant muscular and motor function alterations occurred after the first decade of disease, while mild respiratory function alterations started after the second, with preserved cardiac function. Although type 2A showed relatively stronger distal lower limb muscles, while type 2B started with relatively stronger upper limb muscles, the corresponding motor functions were similar, becoming severely compromised after 25 years of disease. This was the longest retrospective study in types 2A and 2B. It defined curves of disease evolution not only from a neuromuscular, but also from functional, cardiac, and respiratory points of view, to be used to evaluate how the natural progression is changed by therapies. Due to slow disease progression, it was not possible to identify time sensitive endpoints.
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Modelos Teóricos , Distrofia Muscular de Cinturas/fisiopatología , Adulto , Progresión de la Enfermedad , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Actividad Motora , Fuerza Muscular , Músculo Esquelético/fisiopatología , Fenotipo , Estudios Retrospectivos , Capacidad VitalRESUMEN
BACKGROUND: Living with a progressive disease as muscular dystrophy (MD) can be challenging for the patient and the entire family from both emotional and practical point of view. We aimed to extend our previously published data about mental health in patients with MDs, also investigating coping profiles of both themselves and their parents. Furthermore, we wanted to verify whether psychological adaptation of patients can be predicted by coping strategies, taking also into account physical impairment, cognitive level and socioeconomic status. METHODS: 112 patients with MDs, aged 2-32 were included. Their emotional and behavioural features were assessed through parent- and self-report Achenbach System for Empirically Based Assessment questionnaires and Strength and Difficulties Questionnaires. Development and Well-Being Assessment or Autism Diagnostic Observation Schedule were administered to confirm suspected diagnoses. Coping profile of both parents and patients was assessed through the self-administered New Italian Version of the Coping Orientation to the Problems Experienced questionnaire and its relationship with emotional/behavioural outcome was examined in linear regression analyses. RESULTS: High prevalence of intellectual disability and autism spectrum disorders was confirmed in Duchenne MD. Despite the high rate of internalizing symptomatology, we did not report higher rate of psychopathological disorders compared to general population. Parents tend to rely more on positive reinterpretation and less on disengagement coping. Avoidance coping, whether used by parents or patients, and ID, predicted increased emotional/behavioural problems. CONCLUSIONS: Psychosocial interventions should address problems of anxiety and depression that people with MDs frequently experience, even through fostering parents' and childrens' engagement coping over disengagement coping.
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Adaptación Psicológica , Trastorno del Espectro Autista , Síntomas Conductuales , Familia , Discapacidad Intelectual , Distrofias Musculares , Adaptación Psicológica/fisiología , Adolescente , Adulto , Síntomas Afectivos/epidemiología , Síntomas Afectivos/fisiopatología , Síntomas Afectivos/psicología , Ansiedad/epidemiología , Ansiedad/fisiopatología , Ansiedad/psicología , Trastorno del Espectro Autista/epidemiología , Síntomas Conductuales/epidemiología , Síntomas Conductuales/fisiopatología , Síntomas Conductuales/psicología , Niño , Preescolar , Depresión/epidemiología , Depresión/fisiopatología , Depresión/psicología , Familia/psicología , Femenino , Humanos , Discapacidad Intelectual/epidemiología , Masculino , Distrofias Musculares/epidemiología , Distrofias Musculares/fisiopatología , Distrofias Musculares/psicología , Distrofia Muscular de Duchenne/epidemiología , Distrofia Muscular de Duchenne/fisiopatología , Distrofia Muscular de Duchenne/psicología , Adulto JovenRESUMEN
The identification of efficient markers of disease progression and response to possibly effective treatments is a key priority for slowly progressive, rare and neurodegenerative diseases, such as Friedreich's ataxia. Various imaging modalities have documented specific abnormalities in Friedreich's ataxia that could be tracked to provide useful indicators of efficacy in clinical trials. Advanced MRI imaging (diffusion tensor imaging, DTI; functional MRI, fMRI; and resting-state fMRI, rs-fMRI) and retinal imaging (optical coherence tomography, OCT) were tested longitudinally in a small group of Friedreich's ataxia patients participating in an open-label clinical trial testing the safety and the efficacy of 6-month treatment with interferon gamma. While the DTI indices documented the slow progression of fractional anisotropy loss, fMRI and rs-fMRI were significantly modified during and after treatment. The fMRI changes significantly correlated with the Scale for the Assessment and Rating of Ataxia, which is used to monitor clinical response. OCT documented the known thickness reduction of the retinal nerve fiber layer thickness, but there was no change over time. This pilot study provides indications for the potential utility of fMRI and rs-fMRI as ancillary measures in clinical trials for Friedreich's ataxia.
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OBJECTIVE: Respiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). METHODS AND RESULTS: Generalized estimating equation analysis of 1852 PFTs from 327 Italian DMD patients, over an average follow-up time of 4.5 years, estimated that forced vital capacity (FVC) declined yearly by -4.2%, forced expiratory volume in 1 sec by -5.0%, and peak expiratory flow (PEF) by -2.9%. Glucocorticoid (GC) treatment was associated with higher values of all PFT measures (approximately + 15% across disease stages). Mutations situated 3' of DMD intron 44, thus predicted to alter the expression of short dystrophin isoforms, were associated with lower (approximately -6%) PFT values, a finding independently validated in the CINRG-DNHS. Deletions amenable to skipping of exon 51 and 53 were independently associated with worse PFT outcomes. A meta-analysis of the two cohorts identified detrimental effects of SPP1 rs28357094 and CD40 rs1883832 minor alleles on both FVC and PEF. INTERPRETATION: These findings support GC efficacy in delaying respiratory insufficiency, and will be useful for the design and interpretation of clinical trials focused on respiratory endpoints in DMD.
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Glucocorticoides/farmacología , Distrofia Muscular de Duchenne/genética , Pruebas de Función Respiratoria , Insuficiencia Respiratoria/genética , Adolescente , Adulto , Antígenos CD40/genética , Niño , Preescolar , Distrofina/genética , Estudios de Seguimiento , Humanos , Masculino , Distrofia Muscular de Duchenne/complicaciones , Distrofia Muscular de Duchenne/tratamiento farmacológico , Osteopontina/genética , Insuficiencia Respiratoria/tratamiento farmacológico , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/fisiopatología , Estudios Retrospectivos , Capacidad Vital , Adulto JovenRESUMEN
OBJECTIVE: To evaluate through a comprehensive protocol, the psychopathological profile of DMD boys. The primary aim of this observational study was to describe the emotional and behavioural profile and the neurodevelopmental problems of Italian boys with Duchenne Muscular Dystrophy (DMD); the secondary aim was to explore the relation between psychopathological profile and DMD genotype. METHOD: 47 DMD boys, aged 2-18, were included in the study and assessed through structured and validated tools including Wechsler scales or Griffiths for cognitive ability, Child Behavior Check List (CBCL), Youth Self Report (YSR) and Strengths and Difficulties Questionnaire (SDQ) for emotional and behavioural features. Patients "at risk" based on questionnaires scores were evaluated by a clinical structured interview using Development and Well Being Assessment (DAWBA) or Autism Diagnostic Observation Schedule (ADOS), as required. RESULTS: The 47 enrolled patients, defined with a Full Scale Intelligence Quotient (FSIQ) of 80.38 (one SD below average), and presenting a large and significant difference in FSIQ in relation to the site of mutation along the dystrophin gene (distal mutations associated with a more severe cognitive deficit), were showing Internalizing Problems (23.4%) and Autism Spectrum Disorders (14.8%). Interestingly, an association of internalizing problems with distal deletion of the DMD gene is documented. CONCLUSION: Even though preliminary, these data show that the use of validated clinical instruments, that focus on the impact of emotional/behaviour problems on everyday life, allows to carefully identify clinically significant psychopathology.
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Distrofia Muscular de Duchenne/psicología , Trastornos del Neurodesarrollo/epidemiología , Trastornos del Neurodesarrollo/etiología , Adolescente , Niño , Preescolar , Femenino , Genotipo , Humanos , Pruebas de Inteligencia , Masculino , Salud Mental , Distrofia Muscular de Duchenne/complicaciones , Distrofia Muscular de Duchenne/genética , Mutación , Escalas de WechslerRESUMEN
Limb-girdle muscular dystrophy (LGMD) 2L, caused by mutations in the anoctamin 5 (ANO5) gene, is the third most common LGMD in Northern and Central Europe, where the c.191dupA mutation causes the majority of cases. We evaluated data from 228 Italian LGMD patients to determine the prevalence of LGMD2L and the c.191dupA mutation, and to describe the clinical, muscle biopsy, and magnetic resonance imaging findings in these patients. Forty-three patients who lacked molecular diagnosis were studied for ANO5 mutations, and four novel mutations were found in three probands. Only one proband carried the c.191dupA mutation, which was compound heterozygous with c.2516T>G. Two probands were homozygous for the c.1627dupA and c.397A>T mutations, respectively, while a fourth proband had a compound heterozygous status (c.220C>T and c.1609T>C). Therefore occurrence and molecular epidemiology of LGMD2L in this Italian cohort differed from those observed in other European countries. ANO5 mutations accounted for â¼2% of our sample. Affected patients exhibited benign progression with variable onset and an absence of cardiac and respiratory impairment; muscle biopsy generally showed mild signs, except when performed on the quadriceps muscles; MRI showed predominant involvement of the posterior thigh. Overall these common clinical, morphological and imaging findings could be useful in differential diagnosis.