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Francesco Muntoni

Publications and source records attributed to Francesco Muntoni.

90 records · Page 5Linked to original sources
PubMed2002

A novel muscle-specific enhancer identified within the deletion overlap region of two XLDC patients lacking muscle exon 1 of the human dystrophin gene.

Previous studies point to the involvement of several discrete transcriptional enhancers in the modulation of dystrophin gene expression in skeletal and cardiac muscle. Analysis of deletion breakpoints in two X-linked dilated cardiomyopathy patients with mutations that remove muscle exon 1 identified a 3.2-kb deletion overlap region (XLDC3.2) between -1199 and +2057 bp predicted to contain regulatory elements essential for dystrophin gene expression in cardiac muscle. A novel-sequence-based search strategy was used to identify a 543-bp region downstream of muscle exon 1 rich in cardiac-specific transcriptional elements. Designated dystrophin muscle enhancer 2 (DME2), this candidate enhancer was seen to function in a position- and orientation-independent manner in muscle cell lines but not in fibroblasts. As only modest activity was observed in primary neonatal rat cardiomyocytes, DME2 is thought to play a role in dystrophin gene regulation at later stages of cardiac muscle development.

3T3 Cells↗
PubMed2002

Muscle development genes: their relevance in neuromuscular disorders.

Myogenesis is a complex cascade of events that involves the specification and differentiation of muscle precursor cells or myoblasts, their fusion to form primary and secondary myotubes and subsequent maturation into muscle fibres. In addition, the development of axial muscle requires the migration of muscle precursor cells. These events are under strict genetic control. The contribution of individual genes to this process has been highlighted both by the phenotype of mice with targeted inactivation of individual myogenic regulatory factors and by rare human disorders in which the involvement of these genes has been demonstrated. The inactivation of known myogenic regulatory genes is associated with abnormal regulation of skeletal muscle differentiation and has an effect on regeneration but does not cause progressive muscle weakness or wasting. This review summarises recent developments in this field and will be of particular relevance to those interested in neuromuscular disorders. We also examine the possibility that some rare human conditions associated with abnormal muscle formation may be due to genetic defects in one of the myogenic regulatory genes.

Animals↗
PubMed2002

Clinical and imaging findings in six cases of congenital muscular dystrophy with rigid spine syndrome linked to chromosome 1p (RSMD1).

We report clinical and imaging findings in six cases from five families affected by the form of congenital muscular dystrophy with rigid spine linked to the locus rigid spine muscular dystrophy 1 on chromosome 1p35-36. All cases showed rigidity of the spine, predominant neck and trunk weakness and frequent and severe thoracic scoliosis. Respiratory impairment was always observed in the first decade. Muscle imaging showed a marked involvement of adductors, sartorius and biceps femoris while rectus femoris and gracilis were relatively spared. This pattern of selective muscle involvement was consistent in all six cases and could be easily observed on either computerised tomography or magnetic resonance imaging. The results of this study suggest that muscle imaging, in combination with clinical assessment can help to identify the rigid spine muscular dystrophy 1 form of congenital muscular dystrophy and can help to target the appropriate genetic investigations.

Adolescent↗
PubMed2002

Nebulin mutations in autosomal recessive nemaline myopathy: an update.

We report mutational analysis of the last 42 exons of the nebulin gene (NEB) in 77 patients with various forms of nemaline myopathy. In addition to the previously described six mutations in five families, we identified 12 novel recessive mutations in 13 families. Affected individuals were homozygous for the mutations in five families and compound heterozygous in two, while in the remaining cases only one heterozygous mutation was identified. The majority of the mutations were frameshifts due to small deletions or insertions; also common were point mutations causing premature stop codons or abnormal splicing, while missense mutations appeared rare. There were no obvious mutational hotspots, although four unrelated patients showed mutations in the differentially expressed exon 177d, and another three showed mutations in exon 184. Most of the mutations are predicted to result in truncated or internally deleted proteins. Mutations in the differentially expressed exons are expected to reduce the nebulin isoform diversity necessary for normal muscle development.

Biopsy↗
PubMed2002

An effective, low-dosage, intermittent schedule of prednisolone in the long-term treatment of early cases of Duchenne dystrophy.

The aim of this study was to evaluate the long-term effects in young children with Duchenne dystrophy of an intermittent low dosage regime of prednisolone (0.75 mg/kg per day for 10 days per month, or 10 days on and 10 days off). Six children under 5 years with Duchenne dystrophy have been commenced on this schedule, four of whom have been followed for at least 30 months and are reported here. All four presented with classical Duchenne dystrophy, and had an out-of-frame deletion in the Duchenne gene and absence of dystrophin in their muscle. All four showed a rapid and dramatic response in muscle function and strength. In three of the four there was an almost complete remission of all clinical signs of dystrophy. Their functional scores remained well above the average scores recorded in untreated Duchenne boys at the same age. There was no increase in weight, stunting of growth, decreased bone density or any other significant side effects related to the prednisolone. Our current experience suggests that this intermittent, low-dosage prednisolone regime is well tolerated and can be safely given long-term in young children with Duchenne dystrophy. The striking response also suggests that there may be an optimal window for treatment of Duchenne dystrophy in the early stages of the disease.

Body Weight↗
PubMed2002

Steroids in Duchenne muscular dystrophy: from clinical trials to genomic research.

Steroids represent the only pharmacological palliative treatment for Duchenne muscular dystrophy. However, they do have side effects and despite a large number of published studies showing their efficacy, they are still not universally used. This is largely due to the lack of functional outcome and quality of life measures in most of the published studies and suggests that further trials might be required to answer some of the still unclear aspects of their role. Another important aspect of steroid therapy in Duchenne dystrophy is that we do not know how they work in dystrophic muscle. We have initiated a collaborative study on gene profiling using microarray in steroid-treated mdx mice. cDNA microarray studies were performed to examine the levels of skeletal muscle gene expression in a pool of mdx mice treated with prednisolone for 1 and 6 weeks. Interesting preliminary data on untreated mdx mice suggest that the gene profiling of young (7 weeks) versus older (12 weeks) mice is very significantly different. Furthermore, a large number of genes showed significant changes in expression at the mRNA level on treatment with prednisolone. These included structural protein genes; signalling genes and genes involved in immune response. Hopefully, analysis of this pattern of steroid-induced gene expression will provide some insight into understanding how glucocorticoids improve strength in Duchenne dystrophy, and may help in developing more effective and less toxic therapeutic approaches.

Adrenal Cortex Hormones↗
PubMed2002

Muscle MRI findings in a three-generation family affected by Bethlem myopathy.

We report clinical and muscle magnetic resonance imaging (MRI) findings in three individuals (aged 6, 26 and 73 years) from a three-generation family with Bethlem myopathy, confirmed by molecular genetic analysis which showed an exon skipping mutation in the COL6A1 gene. The clinical severity ranged from mild proximal weakness and distal laxity in the younger patients, to inability to stand or walk and severe contractures in the 76-year-old grandmother. The pattern of muscle involvement showed variable severity in parallel with the severity of motor function impairment. Although there was a marked variability in the severity of the MRI findings, it was possible to recognize a specific pattern of muscle involvement in all three patients. This consisted of involvement of the peripheral region of the vastus lateralis and hamstrings muscles with relative sparing of their central part. This was best appreciated in the third decade of life, but could also be identified both in the younger patient with minimal MRI changes and in the oldest patient, despite her more severe and diffuse muscle involvement. This report suggests that muscle MRI could be used as an additional tool to establish the pattern and the degree of muscle involvement in patients with Bethlem myopathy. Further studies in a larger cohort are needed to evaluate the specificity of these findings.

Adult↗
PubMed2002

Fracture prevalence in Duchenne muscular dystrophy.

The objective of this study was to determine the prevalence, circumstances, and outcome of fractures in males with Duchenne muscular dystrophy (DMD) attending neuromuscular clinics. Three hundred and seventy-eight males (median age 12 years, range 1 to 25 years) attending four neuromuscular centres were studied by case-note review supplemented by GP letter or by interview at the time of clinic attendance. Seventy-nine (20.9%) of these patients had experienced fractures. Forty-one percent of fractures were in patients aged 8 to 11 years and 48% in independently ambulant patients. Falling was the most common mechanism of fracture. Upper-limb fractures were most common in males using knee-ankle-foot orthoses (65%) while lower-limb fractures predominated in independently mobile and wheelchair dependent males (54% and 68% respectively). Twenty percent of ambulant males and 27% of those using orthoses lost mobility permanently as a result of the fracture. In a substantial proportion of males, the occurrence of a fracture had a significant impact on subsequent mobility.

Activities of Daily Living↗
PubMed2002

The 3'-untranslated region of the dystrophin gene - conservation and consequences of loss.

The 3'-untranslated region (3'UTR) of some vertebrate dystrophin genes shows an extraordinary degree and extent of conservation (better than that of many coding regions), a phenomenon that remains unexplained. We examine novel sequence and mutational data to explore the possible reasons for this. We show that loss of the human dystrophin 3'UTR is sufficient to cause Becker muscular dystrophy with pronounced reduction in dystrophin protein levels. The acquisition of dystrophin 3'UTR sequence from an amphibian and a cartilaginous fish allows us to refine previously identified functionally constrained regions which might account for the observed phenotype. These comprise (a) the open reading frame encoding the ancestral 'alternative' amphipathic C-terminal alpha-helix, normally removed from adult dystrophin by inclusion of a poorly conserved frameshifting penultimate exon, and (b) two highly conserved untranslated regions ('Lemaire A', 350 nucleotides and 'Lemaire D', 250 nucleotides) separated by a non-conserved 700-2000-nucleotide spacer. We consider the possibility that the 3'UTR may represent a significant target for pathogenic mutations.

3' Untranslated Regions↗
PubMed2002

Congenital muscular dystrophies.

The number of new syndromes, loci, and genes responsible for CMD forms has dramatically increased in the last few years, and it has become increasingly evident that the classification of the different forms of CMD is a difficult task. A recent classification separated the forms of CMD that have been mapped (CMD diseases) from the ones with clearly defined clinical and pathologic features that have not been mapped yet (CMD syndromes). Eight CMD forms have been mapped up to now, and the genes responsible for three of them have been identified. This review describes an update of clinical, pathologic, and genetic findings in the different CMD forms.

Brain↗
PubMed2002

[Dilated cardiomyopathy: role of clinical and instrumental evaluation of the neuromuscular system].

There are a number of cardiomyopathies secondary to a more widespread striated muscle involvement. While in some conditions the heart is affected as part of a severe myopathy (such as the dilated cardiomyopathy found in Duchenne and Becker muscular dystrophies), there are examples in which the skeletal muscle involvement is subtle. From a classification point of view, some of these cardiomyopathies are secondary to muscular dystrophies, or to metabolic disorders, or to other myopathies. From a practical diagnostic point of view, metabolic conditions predominate in infancy, whereas the dystrophic forms are more frequently found from the third decade onwards. Useful clinical clues to suggest a skeletal muscle involvement are muscle hypertrophy or wasting and contractures, in addition to weakness. Serum creatine kinase should always be studied when suspecting a form secondary to a muscular dystrophy, although a normal serum creatine kinase does not exclude a muscular dystrophy. Electromyography and muscle imaging are additional useful investigations in these patients. This article is focused on practical clinical suggestions on when to suspect and how to investigate patients with a cardiomyopathy secondary to neuromuscular disorders.

Cardiomyopathy, Dilated↗
PubMed2002

Investigating the mechanism of chromosomal deletion: characterization of 39 deletion breakpoints in introns 47 and 48 of the human dystrophin gene.

The region of the dystrophin gene containing introns 45-50 is characterized by a high rate of recombination events that give rise to large deletions causing dystrophinopathy. The nucleotide sequence of this intronic region has recently been released in GenBank. With the aim of further understanding the mechanism favoring the occurrence of these deletions, we have characterized the distribution of introns 47 and 48 deletion endpoints in 39 dystrophinopathy patients. In 14 of these patients we were able to sequence the break junction. On these sequences we were able to identify several intronic motifs that could predispose to DNA double-strand breaks. Our results, combined with other literature data, show that unequal homologous recombination is a very poorly represented event in the dystrophin gene, whereas junction features are suggestive of a model of recombination in which DNA double-strand breaks are incorrectly repaired by a nonhomologous end-joining mechanism. The correlation among recombination rate, deletion frequency, and percentage of repetitive elements is discussed.

Amino Acid Sequence↗