Publications (47)177.77 Total impact
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Article: Characterization of a rare case of Ullrich congenital muscular dystrophy due to truncating mutations within the COL6A1 gene C-Terminal domain: a case report.
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ABSTRACT: BACKGROUND: Mutations within the C-terminal region of the COL6A1 gene are only detected in Ullrich/Bethlem patients on extremely rare occasions. CASE PRESENTATION: Herein we report two Brazilian brothers with a classic Ullrich phenotype and compound heterozygous for two truncating mutations in COL6A1 gene, expected to result in the loss of the alpha1(VI) chain C2 subdomain. Despite the reduction in COL6A1 RNA level due to nonsense RNA decay, three truncated alpha1 (VI) chains were produced as protein variants encoded by different out-of-frame transcripts. Collagen VI matrix was severely decreased and intracellular protein retention evident. CONCLUSION: The altered deposition of the fibronectin network highlighted abnormal interactions of the mutated collagen VI, lacking the alpha1(VI) C2 domain, within the extracellular matrix, focusing further studies on the possible role played by collagen VI in fibronectin deposition and organization.BMC Medical Genetics 06/2013; 14(1):59. · 2.33 Impact Factor -
Article: Centronuclear myopathy related to dynamin 2 mutations: Clinical, morphological, muscle imaging and genetic features of an Italian cohort.
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ABSTRACT: Mutations in dynamin 2 (DNM2) gene cause autosomal dominant centronuclear myopathy and occur in around 50% of patients with centronuclear myopathy. We report clinical, morphological, muscle imaging and genetic data of 10 unrelated Italian patients with centronuclear myopathy related to DNM2 mutations. Our results confirm the clinical heterogeneity of this disease, underlining some peculiar clinical features, such as severe pulmonary impairment and jaw contracture that should be considered in the clinical follow-up of these patients. Muscle MRI showed a distinct pattern of involvement, with predominant involvement of soleus and tibialis anterior in the lower leg muscles, followed by hamstring muscles and adductor magnus at thigh level and gluteus maximus. The detection of three novel DNM2 mutations and the first case of somatic mosaicism further expand the genetic spectrum of the disease.Neuromuscular Disorders 02/2013; · 2.80 Impact Factor -
Article: 24 month longitudinal data in ambulant boys with duchenne muscular dystrophy.
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ABSTRACT: The aim of the study was i) to assess the spectrum of changes over 24 months in ambulant boys affected by Duchenne muscular dystrophy, ii) to establish the difference between the first and the second year results and iii) to identify possible early markers of loss of ambulation. One hundred and thirteen patients (age range 4.1-17, mean 8.2) fulfilled the inclusion criteria, 67 of the 113 were on daily and 40 on intermittent steroids, while 6 were not on steroids. All were assessed using the 6 Minute Walk Test (6MWT), the North Star Ambulatory Assessment (NSAA) and timed test. On the 6MWT there was an average overall decline of -22.7 (SD 81.0) in the first year and of -64.7 (SD 123.1) in the second year. On the NSAA the average overall decline was of -1.86 (SD 4.21) in the first year and of -2.98 (SD 5.19) in the second year. Fourteen children lost ambulation, one in the first year and the other 13 in the second year of the study. A distance of at least 330 meters on the 6MWT, or a NSAA score of 18 at baseline reduced significantly the risk of losing ambulation within 2 years. These results can be of help at the time of using inclusion criteria for a study in ambulant patients in order to minimize the risk of patients who may lose ambulation within the time of the trial.PLoS ONE 01/2013; 8(1):e52512. · 4.09 Impact Factor -
Article: Metabolic neuropathies and myopathies.
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ABSTRACT: Inborn errors of metabolism may impact on muscle and peripheral nerve. Abnormalities involve mitochondria and other subcellular organelles such as peroxisomes and lysosomes related to the turnover and recycling of cellular compartments. Treatable causes are β-oxidation defects producing progressive neuropathy; pyruvate dehydrogenase deficiency, porphyria, or vitamin B12 deficiency causing recurrent episodes of neuropathy or acute motor deficit mimicking Guillain-Barré syndrome. On the other hand, lysosomal (mucopolysaccharidosis, Gaucher and Fabry diseases), mitochondriopathic (mitochondrial or nuclear mutations or mDNA depletion), peroxisomal (adrenomyeloneuropathy, Refsum disease, sterol carrier protein-2 deficiency, cerebrotendinous xanthomatosis, α-methylacyl racemase deficiency) diseases are multisystemic disorders involving also the heart, liver, brain, retina, and kidney. Pathophysiology of most metabolic myopathies is related to the impairment of energy production or to abnormal production of reactive oxygen species (ROS). Main symptoms are excercise intolerance with myalgias, cramps and recurrent myoglobinuria or limb weakness associated with elevation of serum creatine kinase. Carnitine palmitoyl transferase deficiency, followed by acid maltase deficiency, and lipin deficiency, are the most common cause of isolated rhabdomyolysis. Metabolic myopathies are frequently associated to extra-neuromuscular disorders particularly involving the heart, liver, brain, retina, skin, and kidney.Handbook of Clinical Neurology 01/2013; 113:1437-55. -
Article: Riboflavin transporter 3 involvement in infantile Brown-Vialetto-Van Laere disease: two novel mutations.
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ABSTRACT: BACKGROUND: Brown-Vialetto-Van Laere (BVVL) syndrome is a rare disorder characterised by progressive pontobulbar palsy and sensorineural deafness. Causative mutations in genes encoding human riboflavin transporter 2 (hRFT2) and 3 (hRFT3) have been identified in BVVL patients. METHODS AND RESULTS: We report the clinical and molecular features of a severe BVVL patient in whom screening of SLC52A3/hRFT2 was negative. Sequence analysis identified two novel compound heterozygous mutations in SLC52A2/hRFT3, namely c.155C>T and c.1255G>A, leading to the amino acid changes p.S52F and p.G419S, respectively. Functional studies show that these defects impair the gene expression of the corresponding transporter, resulting in a significant reduction of riboflavin transport. CONCLUSIONS: These findings support the pathogenetic role of SLC52A2/hRFT3 in BVVL with important clinical and therapeutic implications.Journal of Medical Genetics 12/2012; · 6.36 Impact Factor -
Article: Exon 45 Skipping Through U1-snRNA Antisense Molecules Recovers the Dys-nNOS Pathway and Muscle Differentiation in Human DMD Myoblasts.
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ABSTRACT: Exon skipping has been demonstrated to be a successful strategy for the gene therapy of Duchenne muscular dystrophy (DMD): the rational being to convert severe Duchenne forms into milder Becker ones. Here, we show the selection of U1 snRNA-antisense constructs able to confer effective rescue of dystrophin synthesis in a Δ44 Duchenne genetic background, through skipping of exon 45; moreover, we demonstrate that the resulting dystrophin is able to recover timing of myogenic marker expression, to relocalize neuronal nitric oxide synthase (nNOS) and to rescue expression of miRNAs previously shown to be sensitive to the Dystrophin-nNOS-HDAC2 pathway. Becker mutations display different phenotypes, likely depending on whether the shorter protein is able to reconstitute the wide range of wild-type functions. Among them, efficient assembly of the dystrophin-associated protein complex (DAPC) and nNOS localization are important. Comparing different Becker deletions we demonstrate the correlation between the ability of the mutant dystrophin to relocalize nNOS and the expression levels of two miRNAs, miR-1 and miR29c, known to be involved in muscle homeostasis and to be controlled by the Dys-nNOS-HDAC2 pathway.Molecular Therapy (2012); doi:10.1038/mt.2012.178.Molecular Therapy 09/2012; · 6.87 Impact Factor -
Article: Genetic characterization in symptomatic female DMD carriers: lack of relationship between X-inactivation, transcriptional DMD allele balancing and phenotype.
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ABSTRACT: Although Duchenne and Becker muscular dystrophies, X-linked recessive myopathies, predominantly affect males, a clinically significant proportion of females manifesting symptoms have also been reported. They represent an heterogeneous group characterized by variable degrees of muscle weakness and/or cardiac involvement. Though preferential inactivation of the normal X chromosome has long been considered the principal mechanism behind disease manifestation in these females, supporting evidence is controversial. Eighteen females showing a mosaic pattern of dystrophin expression on muscle biopsy were recruited and classified as symptomatic (7) or asymptomatic (11), based on the presence or absence of muscle weakness. The causative DMD gene mutations were identified in all cases, and the X-inactivation pattern was assessed in muscle DNA. Transcriptional analysis in muscles was performed in all females, and relative quantification of wild-type and mutated transcripts was also performed in 9 carriers. Dystrophin protein was quantified by immunoblotting in 2 females. The study highlighted a lack of relationship between dystrophic phenotype and X-inactivation pattern in females; skewed X-inactivation was found in 2 out of 6 symptomatic carriers and in 5 out of 11 asymptomatic carriers. All females were characterized by biallelic transcription, but no association was found between X-inactivation pattern and allele transcriptional balancing. Either a prevalence of wild-type transcript or equal proportions of wild-type and mutated RNAs was observed in both symptomatic and asymptomatic females. Moreover, very similar levels of total and wild-type transcripts were identified in the two groups of carriers. This is the first study deeply exploring the DMD transcriptional behaviour in a cohort of female carriers. Notably, no relationship between X-inactivation pattern and transcriptional behaviour of DMD gene was observed, suggesting that the two mechanisms are regulated independently. Moreover, neither the total DMD transcript level, nor the relative proportion of the wild-type transcript do correlate with the symptomatic phenotype.BMC Medical Genetics 08/2012; 13:73. · 2.33 Impact Factor -
Article: Brown-Vialetto-van Laere and Fazio-Londe overlap syndromes: A clinical, biochemical and genetic study.
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ABSTRACT: Brown-Vialetto-van Laere (BVVL) and Fazio-Londe (FL) are rare and clinically overlapping motor neurons syndromes. Recently BVVL has been associated with mutations in C20orf54/hRFT2 and defective riboflavin transport. We compared clinical and laboratory features of 6 patients (age range 11-17years), with features of BVVL and FL overlap syndromes. Patients were assessed as following: blood levels of riboflavin and redox status, electrophysiological, neuroradiological and pulmonary studies, ALS functional rating scale and molecular genetic analysis. Two patients manifested deafness at ages of 3 and 10years, and developed later subacute progressive ponto-bulbar palsy. A third patient markedly improved after intravenous immunoglobulins (IVIG), but then relapsed remaining unresponsive to treatment; he was not deaf although had abnormal auditory evoked responses (BAERs). The remaining 3 patients had no deafness, although likewise manifested subacute progressive ponto-bulbar palsy. We found hRFT2 mutations in 3/6 patients manifesting deafness or abnormal BAERs. No patient had reduced riboflavin blood levels. However, on riboflavin supplementation (10mg/kg/day) the most severely affected BVVL patient stopped progression of symptoms following 8months of treatment. BVVL and FL are severe progressive diseases with overlapping symptoms although only hRFT2 mutated patients manifest deafness. Riboflavin supplementation seems to stabilize and improve progression of the disease.Neuromuscular Disorders 07/2012; · 2.80 Impact Factor -
Article: Importance of SPP1 genotype as a covariate in clinical trials in Duchenne muscular dystrophy.
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ABSTRACT: To test the effect of the single nucleotide polymorphism -66 T>G (rs28357094) in the osteopontin gene (SPP1) on functional measures over 12 months in Duchenne muscular dystrophy (DMD). This study was conducted on a cohort of ambulatory patients with DMD from a network of Italian neuromuscular centers, evaluated longitudinally with the north star ambulatory assessment (NSAA) and the 6-minute walk test (6MWT) at study entry and after 12 months. Genotype at rs28357094 was determined after completion of the clinical evaluations. Patients were stratified in 2 groups according to a dominant model (TT homozygotes vs TG heterozygotes and GG homozygotes) and clinical data were retrospectively compared between groups. Eighty patients were selected (age 4.1-19.3 years; mean 8.3 ± 2.7 SD). There were no differences in age or steroid treatment between the 2 subgroups. Paired t test showed a significant difference in both NSAA (p = 0.013) and 6MWT (p = 0.03) between baseline and follow-up after 12 months in patients with DMD carrying the G allele. The difference was not significant in the T subgroup. The analysis of covariance using age and baseline values as covariate and SPP1 genotype as fixed effect showed that these parameters are significantly correlated with the 12-month values. These data provide evidence of the role of SPP1 genotype as a disease modifier in DMD and support its relevance in the selection of homogeneous groups of patients for future clinical trials.Neurology 06/2012; 79(2):159-62. · 8.31 Impact Factor -
Article: Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: definition of the clinical spectrum and molecular findings in five patients.
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ABSTRACT: 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.Journal of Inherited Metabolic Disease 05/2012; · 3.58 Impact Factor -
Article: Attention deficit hyperactivity disorder and cognitive function in duchenne muscular dystrophy: phenotype-genotype correlation.
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ABSTRACT: To assess attention deficit hyperactivity disorder (ADHD) in boys affected by Duchenne muscular dystrophy (DMD) and to explore the relationship with cognitive abilities and genetic findings. Boys with DMD (n = 103; 4-17 years of age, mean: 12.6) were assessed using a cognitive test (Wechsler scales). Assessment of ADHD was based on the Diagnostic Statistical Manual, Fourth Edition, Text Revision criteria and on the long version of the Conners Parents and Teachers Rating Scales. ADHD was found in 33 of the 103 boys with DMD. Attention problems together with hyperactivity (17/33) or in isolation (15/33) were more frequent than hyperactivity alone, which was found in 1 patient. Intellectual disability (ID) was found in 27/103 (24.6%). Sixty-two of the 103 boys had no ID and no ADHD, 9 had ID but no ADHD, 14 had ADHD but no ID, and 18 had both. ADHD occurred more frequently in association with mutations predicted to affect Dp140 expression (exon 45-55) and in those with mutations predicted to affect all dystrophin product, including Dp71 (ie, those that have promoter region and specific first exon between exons 62 and 63 but were also relatively frequent). Our results suggest that ADHD is a frequent feature in DMD. The risk of ADHD appears to be higher in patients carrying mutations predicted to affect dystrophin isoforms expressed in the brain and are known to be associated with higher risk of cognitive impairment.The Journal of pediatrics 05/2012; 161(4):705-709.e1. · 4.02 Impact Factor -
Article: Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy.
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ABSTRACT: Protein-o-mannosyl transferase 1 (POMT1) is a glycosyltransferase involved in α-dystroglycan (α-DG) glycosylation. Clinical phenotype in POMT1-mutated patients ranges from congenital muscular dystrophy (CMD) with structural brain abnormalities, to limb-girdle muscular dystrophy (LGMD) with microcephaly and mental retardation, to mild LGMD. No cardiac involvement has until now been reported in POMT1-mutated patients. We report three patients who harbored compound heterozygous POMT1 mutations and showed left ventricular (LV) dilation and/or decrease in myocardial contractile force: two had a LGMD phenotype with a normal or close-to-normal cognitive profile and one had CMD with mental retardation and normal brain MRI. Reduced or absent α-DG immunolabeling in muscle biopsies were identified in all three patients. Bioinformatic tools were used to study the potential effect of POMT1-detected mutations. All the detected POMT1 mutations were predicted in silico to interfere with protein folding and/or glycosyltransferase function. The report on the patients described here has widened the clinical spectrum associated with POMT1 mutations to include cardiomyopathy. The functional impact of known and novel POMT1 mutations was predicted with a bioinformatics approach, and results were compared with previous in vitro studies of protein-o-mannosylase function.European Journal of Human Genetics advance online publication, 2 May 2012; doi:10.1038/ejhg.2012.71.European journal of human genetics: EJHG 05/2012; · 3.56 Impact Factor -
Article: Fetal acetylcholine receptor inactivation syndrome and maternal myasthenia gravis: a case report.
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ABSTRACT: Fetal acetylcholine receptor inactivation syndrome is a rare condition occurring in newborns of myasthenic mothers, characterized by bulbar and facial weakness after recovery from the generalized muscle weakness. Antibodies against fetal subunit of acetylcholine receptor seem to have a pathogenetic role leading to long-lasting injury in vulnerable muscle groups. We report a girl, born to a myasthenic mother, who presented with this peculiar phenotype associated with high titers of antibodies specific to the fetal acetylcholine receptor. Although the infant had partial clinical improvement she died prematurely of aspiration pneumonia. We believe that this is a rare but possibly unrecognized condition that should be considered in newborns with persistent myasthenic features even in asymptomatic mothers, and clinicians should consider supportive intervention to avoid fatal complications.Neuromuscular Disorders 02/2012; 22(6):546-8. · 2.80 Impact Factor -
Article: Congenital muscular dystrophies: a brief review.
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ABSTRACT: Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous neuromuscular disorders with onset at birth or in infancy in which the muscle biopsy is compatible with a dystrophic myopathy. In the past 10 years, knowledge of neuromuscular disorders has dramatically increased, particularly with the exponential boost of disclosing the genetic background of CMDs. This review will highlight the clinical description of the most important forms of CMD, paying particular attention to the main keys for diagnostic approach. The diagnosis of CMDs requires the concurrence of expertise in multiple specialties (neurology, morphology, genetics, neuroradiology) available in a few centers worldwide that have achieved sufficient experience with the different CMD subtypes. Currently, molecular diagnosis is of paramount importance not only for phenotype-genotype correlations, genetic and prenatal counseling, and prognosis and aspects of management, but also concerning the imminent availability of clinical trials and treatments.Seminars in pediatric neurology 12/2011; 18(4):277-88. -
Article: Spinal muscular atrophy.
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ABSTRACT: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. Estimated incidence is 1 in 6,000 to 1 in 10,000 live births and carrier frequency of 1/40-1/60. This disease is characterized by generalized muscle weakness and atrophy predominating in proximal limb muscles, and phenotype is classified into four grades of severity (SMA I, SMAII, SMAIII, SMA IV) based on age of onset and motor function achieved. This disease is caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene, and the diagnostic test demonstrates in most patients the homozygous deletion of the SMN1 gene, generally showing the absence of SMN1 exon 7. The test achieves up to 95% sensitivity and nearly 100% specificity. Differential diagnosis should be considered with other neuromuscular disorders which are not associated with increased CK manifesting as infantile hypotonia or as limb girdle weakness starting later in life. Considering the high carrier frequency, carrier testing is requested by siblings of patients or of parents of SMA children and are aimed at gaining information that may help with reproductive planning. Individuals at risk should be tested first and, in case of testing positive, the partner should be then analyzed. It is recommended that in case of a request on carrier testing on siblings of an affected SMA infant, a detailed neurological examination should be done and consideration given doing the direct test to exclude SMA. Prenatal diagnosis should be offered to couples who have previously had a child affected with SMA (recurrence risk 25%). The role of follow-up coordination has to be managed by an expert in neuromuscular disorders and in SMA who is able to plan a multidisciplinary intervention that includes pulmonary, gastroenterology/nutrition, and orthopedic care. Prognosis depends on the phenotypic severity going from high mortality within the first year for SMA type 1 to no mortality for the chronic and later onset forms.Orphanet Journal of Rare Diseases 11/2011; 6:71. · 5.83 Impact Factor -
Article: Allelic and phenotypic heterogeneity in 49 Italian patients with the muscle form of CPT-II deficiency.
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ABSTRACT: As genotype-phenotype correlations require the study of large patient populations, we investigated 49 Italian patients (33 unreported) with the muscle form of carnitine-palmitoyl-transferase-II (CPT-II) deficiency and CPT2 gene mutations. CPT enzyme activity below 25% of controls would lead to the development of muscle symptoms, and CPT activity below 15% would cause a relatively severe phenotype of the muscle form. Of the 15 different mutations found, 6 are novel (40%). A functional significance of mutations could be derived only for the two homozygous missense mutations found: both the p.S113L and the p.R631C (recurring in four unrelated patients from a genetic isolate) alleles caused a severe CPT enzyme defect (15% and 7%, respectively) and a relatively severe clinical phenotype of the muscle form. We identified three genotypes (homozygous p.R631C, homozygous p.S113L, and heterozygous null mutations) usually associated with a relatively severe and often life-threatening condition, which should be considered both in the clinical management of newly diagnosed patients (to prevent symptoms) and in their possible inclusion in therapeutic trials. We confirmed the existence of symptomatic heterozygous patient(s), through a family study, providing an important issue when offering genetic counseling and suggesting the crucial role of polymorphisms or environmental factors in determining the phenotype.Clinical Genetics 09/2011; 82(3):232-9. · 3.13 Impact Factor -
Article: A new form of alpha-dystroglycanopathy associated with severe drug-resistant epilepsy and unusual EEG features.
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ABSTRACT: We describe two unrelated girls with congenital muscular dystrophy associated with alpha-dystroglycan deficit with no identified genetic defect, both presenting severe drug-resistant epilepsy with predominant myoclonic seizures and an unusual similar EEG pattern. Severe epilepsy has been unusually described in patients with congenital muscular dystrophies, mainly associated with Walker-Warburg, Fukuyama and muscle-eye-brain diseases. [Published with video sequences].Epileptic disorders: international epilepsy journal with videotape 09/2011; 13(3):259-62. · 1.50 Impact Factor -
Article: Rituximab in a childhood-onset idiopathic refractory chronic inflammatory demyelinating polyneuropathy.
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ABSTRACT: Childhood-onset chronic inflammatory demyelinating polyneuropathy (CIDP) are generally responsive to conventional immunosuppressant treatments. However about 20% of patients may be refractory to several treatments and the disease has poor outcome. Rituximab is becoming a promising treatment in selected adult cases of severe CIDPs. We report the effectiveness of Rituximab in a refractory childhood-onset CIDP and we suggest this treatment as an effective choice in unresponsive childhood CIDP.European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society 09/2011; 16(3):301-3. · 2.01 Impact Factor -
Article: The use of muscle biopsy in the diagnosis of undefined ataxia with cerebellar atrophy in children.
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ABSTRACT: Childhood cerebellar ataxias, and particularly congenital ataxias, are heterogeneous disorders and several remain undefined. We performed a muscle biopsy in patients with congenital ataxia and children with later onset undefined ataxia having neuroimaging evidence of cerebellar atrophy. Significant reduced levels of Coenzyme Q10 (COQ10) were found in the skeletal muscle of 9 out of 34 patients that were consecutively screened. A mutation in the ADCK3/Coq8 gene (R347X) was identified in a female patient with ataxia, seizures and markedly reduced COQ10 levels. In a 2.5-years-old male patient with non syndromic congenital ataxia and autophagic vacuoles in the muscle biopsy we identified a homozygous nonsense mutation R111X mutation in SIL1 gene, leading to early diagnosis of Marinesco-Sjogren syndrome. We think that muscle biopsy is a valuable procedure to improve diagnostic assesement in children with congenital ataxia or other undefined forms of later onset childhood ataxia associated to cerebellar atrophy at MRI.European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society 08/2011; 16(3):248-56. · 2.01 Impact Factor -
Article: GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings.
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ABSTRACT: GM1 gangliosidosis and Morquio B syndrome, both arising from beta-galactosidase (GLB1) deficiency, are very rare lysosomal storage diseases with an incidence of about 1:100,000-1:200,000 live births worldwide. Here we report the beta-galactosidase gene (GLB1) mutation analysis of 21 unrelated GM1 gangliosidosis patients, and of 4 Morquio B patients, of whom two are brothers. Clinical features of the patients were collected and compared with those in literature. In silico analyses were performed by standard alignments tools and by an improved version of GLB1 three-dimensional models. The analysed cohort includes remarkable cases. One patient with GM1 gangliosidosis had a triple X syndrome. One patient with juvenile GM1 gangliosidosis was homozygous for a mutation previously identified in Morquio type B. A patient with infantile GM1 gangliosidosis carried a complex GLB1 allele harbouring two genetic variants leading to p.R68W and p.R109W amino acid changes, in trans with the known p.R148C mutation. Molecular analysis showed 27 mutations, 9 of which are new: 5 missense, 3 microdeletions and a nonsense mutation. We also identified four new genetic variants with a predicted polymorphic nature that was further investigated by in silico analyses. Three-dimensional structural analysis of GLB1 homology models including the new missense mutations and the p.R68W and p.R109W amino acid changes showed that all the amino acid replacements affected the resulting protein structures in different ways, from changes in polarity to folding alterations. Genetic and clinical associations led us to undertake a critical review of the classifications of late-onset GM1 gangliosidosis and Morquio B disease.Biochimica et Biophysica Acta 07/2011; 1812(7):782-90. · 4.66 Impact Factor
Top Journals
Institutions
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2006–2013
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Ospedale Pediatrico Bambino Gesù
- Unit of Muscular and Neurodegenerative Diseases
Roma, Latium, Italy
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2010
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Università Cattolica del Sacro Cuore
Roma, Latium, Italy
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