Al-Haggar M.,Mansoura University |
Madej-Pilarczyk A.,Neuromuscular Unit |
Kozlowski L.,International Institute of Molecular and Cell Biology |
Bujnicki J.M.,International Institute of Molecular and Cell Biology |
And 7 more authors.
European Journal of Human Genetics | Year: 2012
Mandibuloacral dysplasia (MAD) is a rare disease resulting from a mutation of LMNA gene encoding lamins A and C. The most common mutation associated with this disease is a homozygous arginine 527 replacement by histidine. Three female patients originating from two unrelated families from Northeast Egypt were examined. Their growth was retarded; they had microcephaly, widened cranial sutures, prominent eyes and cheeks, micrognathia, dental crowding, hypoplastic mandible, acro-osteolysis of distal phalanges, and joint contractures. In addition, they presented some progeroid features, such as pinched nose, premature loss of teeth, loss of hair, scleroderma-like skin atrophy, spine rigidity, and waddling gait. The clinical presentation of the disease varied between the patient originating from Family 1 and patients from Family 2, suggesting that unknown, possibly epigenetic factors, modify the course of the disease. The first symptoms of the disease appeared at the age of 2.5 (a girl from Family 1), 5, and 3 years (girls from Family 2). All patients had the same, novel homozygous c.1580G>T LMNA mutation, resulting in the replacement of arginine 527 by leucine. Computational predictions of such substitution effects suggested that it might alter protein stability and increase the tendency for protein aggregation, and as a result, might influence its interaction with other proteins. In addition, restriction fragment-length polymorphism analysis performed in 178 unrelated individuals showed that up to 1.12% of inhabitants of Northeast Egypt might be heterozygous carriers of this mutation, suggesting the presence of a founder effect in this area. © 2012 Macmillan Publishers Limited. All rights reserved.
Fernandez-Torron R.,Neuromuscular Unit |
Garcia-Puga M.,Donostia Universitary Hospital |
Emparanza J.-I.,Neuromuscular Unit |
Maneiro M.,Neurosciences Area |
And 12 more authors.
Neurology | Year: 2016
Objective: Describe the incidence of cancer in a large cohort of patients with myotonic dystrophy type 1 (DM1) and to unravel the underlying molecular mechanisms. Methods: Standardized incidence ratios (SIRs) were calculated in the Gipuzkoa DM1 cohort (1985-2013), dividing observed numbers by expected numbers for all cancers combined and stratified by sex. An estimation of the expected incidence was achieved by multiplying the age- and sex-specific incidence rates from the Basque population cancer registry by the person-years observed in the study cohort. Large-scale gene expression of peripheral blood mononuclear cell samples derived from 10 individuals with DM1 (5 men, 5 women) and 10 healthy matched controls was analyzed by the Human Gene 1.0 ST Affymetrix microarray. Results: During 18,796 person-years of follow-up, corresponding to 424 patients with DM1, we observed 70 cancers in 62 patients giving a 1.81-fold risk (95% confidence interval [CI] 1.37-2.36), which was stronger in women than in men. Ovary (SIR 8.33, 95% CI 1.72-24.31) and endometrium (SIR 6.86, 95% CI 2.23-16.02) in women and thyroid (SIR 23.33, 95% CI 9.38-48.08) and brain (SIR 9.80, 95% CI 3.18-22.88) in both sexes were tumor sites with significantly higher risks in DM1. There were differences in gene expression between healthy controls and patients with DM1 and between men and women with DM1; all patients with DM1 combined and female patients with DM1 displayed significant downregulation of the microRNA (miRNA)-200c/141 tumor suppressor family. Conclusions: Oncologic risk is increased in DM1, especially in women and for gynecologic, brain, and thyroid cancer. Expression of the miRNA-200/miRNA-141 tumor suppressor family is decreased in women with DM1. © 2016 American Academy of Neurology.
Cassandrini D.,IRCCS Fondazione Stella Maris |
Cilio M.R.,Bambino Gesu Childrens Research Hospital |
Cilio M.R.,University of California at San Francisco |
Bianchi M.,Bambino Gesu Childrens Research Hospital |
And 19 more authors.
Journal of Inherited Metabolic Disease | Year: 2013
Recessive mutations in the mitochondrial arginyl-transfer RNA synthetase (RARS2) gene have been associated with early onset encephalopathy with signs of oxidative phosphorylation defects classified as pontocerebellar hypoplasia 6. We describe clinical, neuroimaging and molecular features on five patients from three unrelated families who displayed mutations in RARS2. All patients rapidly developed a neonatal or early-infantile epileptic encephalopathy with intractable seizures. The long-term follow-up revealed a virtual absence of psychomotor development, progressive microcephaly, and feeding difficulties. Mitochondrial respiratory chain enzymes in muscle and fibroblasts were normal in two. Blood and CSF lactate was abnormally elevated in all five patients at early stages while appearing only occasionally abnormal with the progression of the disease. Cerebellar vermis hypoplasia with normal aspect of the cerebral and cerebellar hemispheres appeared within the first months of life at brain MRI. In three patients follow-up neuroimaging revealed a progressive pontocerebellar and cerebral cortical atrophy. Molecular investigations of RARS2 disclosed the c.25A>G/p.I9V and the c.1586+3A>T in family A, the c.734G>A/p.R245Q and the c.1406G>A/p.R469H in family B, and the c.721T>A/p.W241R and c.35A>G/p.Q12R in family C. Functional complementation studies in Saccharomyces cerevisiae showed that mutation MSR1-R531H (equivalent to human p.R469H) abolished respiration whereas the MSR1-R306Q strain (corresponding to p.R245Q) displayed a reduced growth on non-fermentable YPG medium. Although mutations functionally disrupted yeast we found a relatively well preserved arginine aminoacylation of mitochondrial tRNA. Clinical and neuroimaging findings are important clues to raise suspicion and to reach diagnostic accuracy for RARS2 mutations considering that biochemical abnormalities may be absent in muscle biopsy. © 2012 SSIEM and Springer.
Fiorillo C.,Neuromuscular Unit |
Moro F.,Molecular Medicine |
Brisca G.,IRCCS G. Gaslini |
Astrea G.,Neuromuscular Unit |
And 15 more authors.
Neurogenetics | Year: 2012
Inherited disorders characterized by motor neuron loss and muscle weakness are genetically heterogeneous. The recent identification of mutations in the gene encoding transient receptor potential vanilloid 4 (TRPV4) in distal spinal muscular atrophy (dSMA) prompted us to screen for TRPV4 mutations in a small group of children with compatible phenotype. In a girl with dSMA and vocal cord paralysis, we detected a new variant (p.P97R) localized in the cytosolic N-terminus of the TRPV4 protein, upstream of the ankyrin-repeat domain, where the great majority of disease-associated mutations reside. In another child with congenital dSMA, in this case associated with bone abnormalities, we detected a previously reported mutation (p.R232C). Functional analysis of the novel p.P97R mutation in a heterologous system demonstrated a loss-of-function mechanism. Protein localization studies in muscle, skin, and cultured skin fibroblasts from both patients showed normal protein expression. No TRPV4 mutations were detected in four children with dSMA without bone or vocal cord involvement. Adding to the clinical and molecular heterogeneity of TRPV4-associated diseases, our results suggest that molecular testing of the TRPV4 gene is warranted in cases of congenital dSMA with bone abnormalities and vocal cord paralysis. © 2012 Springer-Verlag.
PubMed | NeuroMuscular Unit, Bambin Gesu Childrens Hospital, University of Padua, University of Pavia and 4 more.
Type: Comparative Study | Journal: Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology | Year: 2015
This study explored the burden in parents and healthy siblings of 4-17 year-old patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies, and whether the burden varied according to clinical aspects and social resources. Data on socio-demographic characteristics, patients clinical history, parent and healthy children burden, and on parents social resources were collected using self-reported questionnaires administered to 336 parents of patients with DMD (246) and BMD (90). Parents of patients with DMD reported higher burden than those of patients with BMD, especially concerning feeling of loss (84.3% DMD vs. 57.4% BMD), stigma (44.2% DMD vs. 5.5% BMD) and neglect of hobbies (69.0% DMD vs. 32.5% BMD). Despite the burden, 66% DMD and 62.4% BMD parents stated the caregiving experience had a positive impact on their lives. A minority of parents believed MD has a negative influence on the psychological well-being (31.0% DMD vs. 12.8% BMD), and social life of unaffected children (25.7% vs. 18.4%). In the DMD group, burden correlated with duration of illness and parent age, and burden was higher among parents with lower social contacts and support in emergencies. In DMD, difficulties among healthy children were reported as higher by parents who were older, had higher burden and lower social contacts. In both groups, burden increased in relation to patient disability. These findings underline that the psychological support to be provided to parents of patients with MD, should take into account clinical features of the disease.
Magliano L.,The Second University of Naples |
Patalano M.,The Second University of Naples |
Sagliocchi A.,The Second University of Naples |
Scutifero M.,The Second University of Naples |
And 26 more authors.
Journal of Neurology | Year: 2014
This paper focuses on the psychological benefits of caregiving in key relatives of patients with muscular dystrophies (MD), a group of rare diseases characterized by progressive weakness and restriction of the patient's functional abilities. We describe whether relatives perceived caregiving to be a positive experience and test whether relatives' perceptions vary in relation to their view of the patient as a valued person, the degree of involvement in care, and the level of support provided by social network and professionals. The study sample included 502 key relatives of patients aged 4-25 years, suffering from Duchenne, Becker, or limb-girdle MD, in treatment for at least 6 months to one of the eight participating centers, living with at least one relative aged 18-80 years. Of key relatives, 88 % stated that they had gotten something positive out of the situation, 96 % considered their patients to be sensitive, and 94 % viewed their patients as talented. Positive aspects of caregiving were more recognized by key relatives who were more convinced that the patient was sensitive and who perceived that they received higher level of professional help and psychological social support. These results suggest that most key relatives consider that their caregiving experience has had a positive impact on their lives, despite the practical difficulties of caring for patients with MD. Professionals should help relatives to identify the benefits of caregiving without denying its difficulties. Clinicians themselves should develop positive attitudes towards family involvement in the care of patients with long-term diseases. © 2013 The Author(s).
Magliano L.,The Second University of Naples |
D'Angelo M.G.,NeuroMuscular Unit |
Vita G.,Messina University |
Pane M.,Catholic University |
And 5 more authors.
Acta Myologica | Year: 2015
This study explored the burden in parents and healthy siblings of 4-17 year-old patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies, and whether the burden varied according to clinical aspects and social resources. Data on socio-demographic characteristics, patient's clinical history, parent and healthy children burden, and on parent's social resources were collected using self-reported questionnaires administered to 336 parents of patients with DMD (246) and BMD (90). Parents of patients with DMD reported higher burden than those of patients with BMD, especially concerning feeling of loss (84.3% DMD vs. 57.4% BMD), stigma (44.2% DMD vs. 5.5% BMD) and neglect of hobbies (69.0% DMD vs. 32.5% BMD). Despite the burden, 66% DMD and 62.4% BMD parents stated the caregiving experience had a positive impact on their lives. A minority of parents believed MD has a negative influence on the psychological well-being (31.0% DMD vs. 12.8% BMD), and social life of unaffected children (25.7% vs. 18.4%). In the DMD group, burden correlated with duration of illness and parent age, and burden was higher among parents with lower social contacts and support in emergencies. In DMD, difficulties among healthy children were reported as higher by parents who were older, had higher burden and lower social contacts. In both groups, burden increased in relation to patient disability. These findings underline that the psychological support to be provided to parents of patients with MD, should take into account clinical features of the disease.
Anichini A.,University of Padua |
Anichini A.,Venetian Institute of Molecular Medicine |
Fanin M.,University of Padua |
Fanin M.,Venetian Institute of Molecular Medicine |
And 6 more authors.
Neurological Research | Year: 2011
Objectives: The adult or 'muscular' form of carnitine-palmitoyl-transferase II (CPT II) deficiency presents with recurrent rhabdomyolytic episodes and myoglobinuria, usually triggered by prolonged exercise. The aim of this study was to investigate a large series of patients in order to provide genotype-phenotype correlations. Methods: Our muscle tissue bank was surveyed for patients showing attacks of rhabdomyolysis with myoglobinuria. After exclusion of cases affected with toxic myoglobinuria, McArdle's disease and Becker muscular dystrophy, over 100 patients were selected for isotope-exchange radioenzymatic assay of CPT enzyme activity in muscle, and 25 cases resulted to be defective. Acylcarnitine profile was performed in five patients using tandem mass spectrometry. Mutations in the CPT2 gene were identified using DNA sequencing. Results: Although the clinical features were rather homogeneous, some patients presented life-threatening events (acute renal failure) and muscle weakness, and low levels of residual CPT activity. The typical acylcarnitine profile found in mutant patients confirmed its value as a screening method for further diagnostic investigations. We found a high frequency of the common p.Ser113Leu mutation, the recurrence of the rare p.Arg631Cys mutation in a genetic isolate in Southern Italy, and identified four novel mutations. In some affected patients only one mutant allele was found, suggesting either incomplete mutation detection or the possibility they are symptomatic carriers. Discussion: Null mutations and homozygous mutations were frequently associated with a more severe phenotype and biochemical defect. The identification of symptomatic obligate heterozygous carriers might suggest that additional epigenetic or environmental factors may contribute to determine the phenotype. © 2011 W. S. Maney & Son Ltd.
PubMed | NeuroMuscular Unit, Bambin Gesu Childrens Hospital, IRCSS San Camillo, University of Padua and 6 more.
Type: Journal Article | Journal: Muscle & nerve | Year: 2015
This study explores burden and social and professional support in families of young patients with muscular dystrophies (MDs) in Italy.The study was carried out on 502 key relatives of 4- to 25-year-old patients suffering from Duchenne, Becker, or Limb-Girdle MD who were living with at least 1 adult relative.A total of 77.1% of relatives reported feelings of loss, 74.0% had feelings of sadness, and 59.1% had constraints in leisure activities. Burden was higher among relatives of patients with higher disability and who spent more daily hours in caregiving. Practical difficulties were higher among relatives who perceived lower help in patient emergencies and less practical support by their social network. Psychological burden was higher in those relatives who were unemployed, those with poorer support in emergencies, and those with lower social contacts.Caring for patients with MDs may be demanding for relatives even in the early stages of these disorders, especially when social support is poor and the patients disability increases.