Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous neuromuscular... more 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.
Genome-wide gene expression profiling of skeletal muscle from Duchenne muscular dystrophy (DMD) p... more Genome-wide gene expression profiling of skeletal muscle from Duchenne muscular dystrophy (DMD) patients has been used to describe muscle tissue alterations in DMD children older than 5 years. By studying the expression profile of 19 patients younger than 2 years, we describe with high resolution the gene expression signature that characterizes DMD muscle during the initial or "presymptomatic" phase of the disease. We show that in the first 2 years of the disease, DMD muscle is already set to express a distinctive gene expression pattern considerably different from the one expressed by normal, age-matched muscle. This "dystrophic" molecular signature is characterized by a coordinate induction of genes involved in the inflammatory response, extracellular matrix (ECM) remodeling and muscle regeneration, and the reduced transcription of those involved in energy metabolism. Despite the lower degree of muscle dysfunction experienced, our younger patients showed abnormal expression of most of the genes reported as differentially expressed in more advanced stages of the disease. By analyzing our patients as a time series, we provide evidence that some genes, including members of three pathways involved in morphogenetic signaling-Wnt, Notch, and BMPare progressively induced or repressed in the natural history of DMDexpression profiling in the early phases of DMD: a constant molecular signature characterizes DMD muscle from early postnatal life throughout disease progression. FASEB J. 21, 1210 -1226
Limb-girdle muscle dystrophy type 2I is associated with mutations in the gene encoding Fukutin-re... more Limb-girdle muscle dystrophy type 2I is associated with mutations in the gene encoding Fukutin-related protein. Clinical phenotypes are heterogeneous, ranging from isolated hyperCkemia to severe congenital muscular dystrophy. Affected patients frequently develop dilated cardiomyopathy, depending on evolution of their skeletal myopathy. We report on an 8 years-old boy presenting a severe dilated cardiomyopathy requiring heart transplantation. The child harbored a homozygous p.Leu276Ile mutation in Fukutin-related protein gene (FKRP). At the current age of 20 years, the patient shows persistent hyperCKemia but no clinical muscle weakness, CT scan showing very mild features of muscle involvement. Our findings add to the array of clinical presentations of FKRP mutations.
The aim of this study was to validate the Hammersmith functional motor scale for children with sp... more The aim of this study was to validate the Hammersmith functional motor scale for children with spinal muscular atrophy in a large cohort of 90 non-ambulant children with spinal muscular atrophy type 2 or 3. All had a baseline assessment (T0) and were reassessed either at 3 months (T1) (n = 66) or at 6 months (T2) (n = 24). Inter-observer reliability, tested on 13 children among 3 examiners, was > 95%. Of the 66 children examined after 3 months 4 had adverse effects in between assessments and were excluded from the analysis. Forty-two (68%) of the remaining 62 reassessed had no variation in scores between T0 and T1 and 13 (21%) were within +/- 1 point. 9 (37.5%) of the 24 children reassessed after 6 months had no variation in scores between T0 and T2 and another 9 (37.5%) had variations within +/- 1 point. Our study confirms previous observations of the reliability of the scale and helps to establish a baseline for assessing changes of functional ability over 3 and 6 month intervals. This information can be valuable in view of therapeutic trials.
The aim of this study was to evaluate tolerability and efficacy of phenylbutyrate (PB) in patient... more The aim of this study was to evaluate tolerability and efficacy of phenylbutyrate (PB) in patients with spinal muscular atrophy (SMA). Ten patients with SMA type II confirmed by DNA studies (age range 2.6 -12.7 years, mean age 6.01) were started on oral PB (tri Butyrate w ) in powder or tablets. The dosage was 500 mg/kg per day (maximum dose 19 g/d), divided in five doses (every 4 h, skipping one night-dose) using an intermittent schedule (7 days on and 7 days off). Measures of efficacy were the change in motor function from baseline to 3 and 9 weeks, by means of the Hammersmith functional motor scale. In children older than 5 years, muscle strength, assessed by myometry, and forced vital capacity were also measured.
Mutations in POMT1 have been identified in Walker-Warburg syndrome and in patients with limb-gird... more Mutations in POMT1 have been identified in Walker-Warburg syndrome and in patients with limb-girdle muscular dystrophy and mental retardation (LGMD2K). The authors report new POMT1 mutations in three unrelated children with severe motor impairment, leg hypertrophy, and mental retardation but without brain and ocular malformations. These patients are similar to LGMD2K but have earlier onset and more severe motor disability. The current findings expand the spectrum of POMT1-associated phenotypes.
Journal of Molecular and Cellular Cardiology, 2007
We report on a 2-year-old male child with both nemaline myopathy and hypertrophic cardiomyopathy ... more We report on a 2-year-old male child with both nemaline myopathy and hypertrophic cardiomyopathy (HCM). Sequencing of the ACTA1 gene showed a ''de novo'' missense heterozygous mutation a > g in exon 7 (Lys336Glu). Two-dimensional electrophoresis showed 28% mutant actin present in his muscle biopsy. Actin was isolated from the muscle biopsy and examined by in vitro motility assay. The sliding speed was 13 ± 3% less than normal and the affinity of actin for the Z-line protein a-actinin was reduced 10 fold. This is the first report on a hypertrophic cardiomyopathy associated with nemaline myopathy and an ACTA1 mutation.
Abnormal low-frequency entrainment in sensorimotor cortical areas of Parkinson's disease (PD) pat... more Abnormal low-frequency entrainment in sensorimotor cortical areas of Parkinson's disease (PD) patients has been observed in MEG recordings. Efficacy of high-frequency stimulation of subthalamic nucleus (STN) in treating PD may result from blocking such abnormal oscillations. Artifacts elicited by stimulation have precluded MEG study of such patients. We recorded spontaneous MEG activity with a 306-channel Elekta Neuromag® instrument from a Parkinsonian patient with an implanted neurostimulator, with electrodes in both subthalamic nuclei when 130-Hz STN stimulation was on and off. Auditory evoked fields (AEFs) were recorded as well. Brain activity was revealed by applying temporally extended signal space separation on the signals strongly contaminated by stimulation-related artifacts. Bipolar STN stimulation decreased spontaneous activity in the 3-20 Hz range over the right sensorimotor cortex both when eyes were open and closed. Less systematic changes were observed over the left hemisphere where monopolar stimulation was associated with an increase of the low-frequency activity. Suppression of occipital alpha activity in eyes open condition as well as AEF source locations corresponded with those in normal subjects. The results suggest that STN stimulation modifies spontaneous activity over the sensorimotor cortices.
Background and purpose: Chronic inflammatory conditions, such as granulomas, are associated with ... more Background and purpose: Chronic inflammatory conditions, such as granulomas, are associated with angiogenesis. Mast cells represent the main cell type orchestrating angiogenesis, through the release of their granule content. Therefore, compounds able to modulate mast cell behaviour may be considered as a new pharmacological approach to treat angiogenesis-dependent events. Here, we tested the effect of selective cannabinoid (CB) receptor agonists in a model of angiogenesis-dependent granuloma formation induced by l-carrageenin in rats. Experimental approach: Granulomas were induced by l-carrageenin-soaked sponges implanted subcutaneously on the back of male Wistar rats. After 96 h, implants were removed and granuloma formation was measured (wet weight); angiogenesis was evaluated by histological analysis and by the measurement of haemoglobin content. Mast cells in the granulomas were evaluated histologically and by RT-PCR and immunoblotting analysis for mast cell-derived proteins (rat mast cell protease-5 (rMCP-5) and nerve growth factor). Selective CB 1 and CB 2 receptor agonists , ACEA and JWH-015 (0.001-0.1 mg mL À1 ), were given locally only once, at the time of implantation. Key results: The CB 1 and CB 2 receptor agonists decreased the weight and vascularization of granulomas after 96 h. This treatment also reduced mast cell number and activation in granulomatous tissue. Specifically, these compounds prevented the transcription and expression of rMCP-5, a protein involved in sprouting and advance of new blood vessels. Conclusion and implications: Modulation of mast cell function by cannabinoids reduced granuloma formation and associated angiogenesis. Therefore cannabinoid-related drugs may be useful in the management of granulomatous diseases accompanied by angiogenesis.
A series of pyrrole-substituted porphyrin monomers have been rationally prepared to tune the prop... more A series of pyrrole-substituted porphyrin monomers have been rationally prepared to tune the properties of the resulting polymeric film. Free-base porphyrins and their metallic complexes have been deposited onto Indium-Tin-Oxide (ITO) glass electrodes by electropolymerization technique. Electropolymers were characterized by UV-visible spectroscopy and Atomic Force Microscopy (AFM). Cyclic voltammetry has been utilised to study the electropolymerisation mechanism and to evaluate the polymer surface coverge parameters. The obtained porphyrin electropolymers have been exploited as sensing materials for hyphenated potentiometric and optical measurements with CSPT-potentiometric analytical system. Different food matrices, such as mineral waters, wines and vegetable oils, have been analysed by means of the resulting porphyrin based CSPT-potentiometric system.
Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous neuromuscular... more 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.
Genome-wide gene expression profiling of skeletal muscle from Duchenne muscular dystrophy (DMD) p... more Genome-wide gene expression profiling of skeletal muscle from Duchenne muscular dystrophy (DMD) patients has been used to describe muscle tissue alterations in DMD children older than 5 years. By studying the expression profile of 19 patients younger than 2 years, we describe with high resolution the gene expression signature that characterizes DMD muscle during the initial or "presymptomatic" phase of the disease. We show that in the first 2 years of the disease, DMD muscle is already set to express a distinctive gene expression pattern considerably different from the one expressed by normal, age-matched muscle. This "dystrophic" molecular signature is characterized by a coordinate induction of genes involved in the inflammatory response, extracellular matrix (ECM) remodeling and muscle regeneration, and the reduced transcription of those involved in energy metabolism. Despite the lower degree of muscle dysfunction experienced, our younger patients showed abnormal expression of most of the genes reported as differentially expressed in more advanced stages of the disease. By analyzing our patients as a time series, we provide evidence that some genes, including members of three pathways involved in morphogenetic signaling-Wnt, Notch, and BMPare progressively induced or repressed in the natural history of DMDexpression profiling in the early phases of DMD: a constant molecular signature characterizes DMD muscle from early postnatal life throughout disease progression. FASEB J. 21, 1210 -1226
Limb-girdle muscle dystrophy type 2I is associated with mutations in the gene encoding Fukutin-re... more Limb-girdle muscle dystrophy type 2I is associated with mutations in the gene encoding Fukutin-related protein. Clinical phenotypes are heterogeneous, ranging from isolated hyperCkemia to severe congenital muscular dystrophy. Affected patients frequently develop dilated cardiomyopathy, depending on evolution of their skeletal myopathy. We report on an 8 years-old boy presenting a severe dilated cardiomyopathy requiring heart transplantation. The child harbored a homozygous p.Leu276Ile mutation in Fukutin-related protein gene (FKRP). At the current age of 20 years, the patient shows persistent hyperCKemia but no clinical muscle weakness, CT scan showing very mild features of muscle involvement. Our findings add to the array of clinical presentations of FKRP mutations.
The aim of this study was to validate the Hammersmith functional motor scale for children with sp... more The aim of this study was to validate the Hammersmith functional motor scale for children with spinal muscular atrophy in a large cohort of 90 non-ambulant children with spinal muscular atrophy type 2 or 3. All had a baseline assessment (T0) and were reassessed either at 3 months (T1) (n = 66) or at 6 months (T2) (n = 24). Inter-observer reliability, tested on 13 children among 3 examiners, was > 95%. Of the 66 children examined after 3 months 4 had adverse effects in between assessments and were excluded from the analysis. Forty-two (68%) of the remaining 62 reassessed had no variation in scores between T0 and T1 and 13 (21%) were within +/- 1 point. 9 (37.5%) of the 24 children reassessed after 6 months had no variation in scores between T0 and T2 and another 9 (37.5%) had variations within +/- 1 point. Our study confirms previous observations of the reliability of the scale and helps to establish a baseline for assessing changes of functional ability over 3 and 6 month intervals. This information can be valuable in view of therapeutic trials.
The aim of this study was to evaluate tolerability and efficacy of phenylbutyrate (PB) in patient... more The aim of this study was to evaluate tolerability and efficacy of phenylbutyrate (PB) in patients with spinal muscular atrophy (SMA). Ten patients with SMA type II confirmed by DNA studies (age range 2.6 -12.7 years, mean age 6.01) were started on oral PB (tri Butyrate w ) in powder or tablets. The dosage was 500 mg/kg per day (maximum dose 19 g/d), divided in five doses (every 4 h, skipping one night-dose) using an intermittent schedule (7 days on and 7 days off). Measures of efficacy were the change in motor function from baseline to 3 and 9 weeks, by means of the Hammersmith functional motor scale. In children older than 5 years, muscle strength, assessed by myometry, and forced vital capacity were also measured.
Mutations in POMT1 have been identified in Walker-Warburg syndrome and in patients with limb-gird... more Mutations in POMT1 have been identified in Walker-Warburg syndrome and in patients with limb-girdle muscular dystrophy and mental retardation (LGMD2K). The authors report new POMT1 mutations in three unrelated children with severe motor impairment, leg hypertrophy, and mental retardation but without brain and ocular malformations. These patients are similar to LGMD2K but have earlier onset and more severe motor disability. The current findings expand the spectrum of POMT1-associated phenotypes.
Journal of Molecular and Cellular Cardiology, 2007
We report on a 2-year-old male child with both nemaline myopathy and hypertrophic cardiomyopathy ... more We report on a 2-year-old male child with both nemaline myopathy and hypertrophic cardiomyopathy (HCM). Sequencing of the ACTA1 gene showed a ''de novo'' missense heterozygous mutation a > g in exon 7 (Lys336Glu). Two-dimensional electrophoresis showed 28% mutant actin present in his muscle biopsy. Actin was isolated from the muscle biopsy and examined by in vitro motility assay. The sliding speed was 13 ± 3% less than normal and the affinity of actin for the Z-line protein a-actinin was reduced 10 fold. This is the first report on a hypertrophic cardiomyopathy associated with nemaline myopathy and an ACTA1 mutation.
Abnormal low-frequency entrainment in sensorimotor cortical areas of Parkinson's disease (PD) pat... more Abnormal low-frequency entrainment in sensorimotor cortical areas of Parkinson's disease (PD) patients has been observed in MEG recordings. Efficacy of high-frequency stimulation of subthalamic nucleus (STN) in treating PD may result from blocking such abnormal oscillations. Artifacts elicited by stimulation have precluded MEG study of such patients. We recorded spontaneous MEG activity with a 306-channel Elekta Neuromag® instrument from a Parkinsonian patient with an implanted neurostimulator, with electrodes in both subthalamic nuclei when 130-Hz STN stimulation was on and off. Auditory evoked fields (AEFs) were recorded as well. Brain activity was revealed by applying temporally extended signal space separation on the signals strongly contaminated by stimulation-related artifacts. Bipolar STN stimulation decreased spontaneous activity in the 3-20 Hz range over the right sensorimotor cortex both when eyes were open and closed. Less systematic changes were observed over the left hemisphere where monopolar stimulation was associated with an increase of the low-frequency activity. Suppression of occipital alpha activity in eyes open condition as well as AEF source locations corresponded with those in normal subjects. The results suggest that STN stimulation modifies spontaneous activity over the sensorimotor cortices.
Background and purpose: Chronic inflammatory conditions, such as granulomas, are associated with ... more Background and purpose: Chronic inflammatory conditions, such as granulomas, are associated with angiogenesis. Mast cells represent the main cell type orchestrating angiogenesis, through the release of their granule content. Therefore, compounds able to modulate mast cell behaviour may be considered as a new pharmacological approach to treat angiogenesis-dependent events. Here, we tested the effect of selective cannabinoid (CB) receptor agonists in a model of angiogenesis-dependent granuloma formation induced by l-carrageenin in rats. Experimental approach: Granulomas were induced by l-carrageenin-soaked sponges implanted subcutaneously on the back of male Wistar rats. After 96 h, implants were removed and granuloma formation was measured (wet weight); angiogenesis was evaluated by histological analysis and by the measurement of haemoglobin content. Mast cells in the granulomas were evaluated histologically and by RT-PCR and immunoblotting analysis for mast cell-derived proteins (rat mast cell protease-5 (rMCP-5) and nerve growth factor). Selective CB 1 and CB 2 receptor agonists , ACEA and JWH-015 (0.001-0.1 mg mL À1 ), were given locally only once, at the time of implantation. Key results: The CB 1 and CB 2 receptor agonists decreased the weight and vascularization of granulomas after 96 h. This treatment also reduced mast cell number and activation in granulomatous tissue. Specifically, these compounds prevented the transcription and expression of rMCP-5, a protein involved in sprouting and advance of new blood vessels. Conclusion and implications: Modulation of mast cell function by cannabinoids reduced granuloma formation and associated angiogenesis. Therefore cannabinoid-related drugs may be useful in the management of granulomatous diseases accompanied by angiogenesis.
A series of pyrrole-substituted porphyrin monomers have been rationally prepared to tune the prop... more A series of pyrrole-substituted porphyrin monomers have been rationally prepared to tune the properties of the resulting polymeric film. Free-base porphyrins and their metallic complexes have been deposited onto Indium-Tin-Oxide (ITO) glass electrodes by electropolymerization technique. Electropolymers were characterized by UV-visible spectroscopy and Atomic Force Microscopy (AFM). Cyclic voltammetry has been utilised to study the electropolymerisation mechanism and to evaluate the polymer surface coverge parameters. The obtained porphyrin electropolymers have been exploited as sensing materials for hyphenated potentiometric and optical measurements with CSPT-potentiometric analytical system. Different food matrices, such as mineral waters, wines and vegetable oils, have been analysed by means of the resulting porphyrin based CSPT-potentiometric system.
Uploads
Papers by A. D'Amico