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Biomedical subjects

F Muntoni

Publications and source records attributed to F Muntoni.

At least 127 records · Page 7Linked to original sources
PubMed1999

Expression, regulation and localisation of dystrophin isoforms in human foetal skeletal and cardiac muscle.

We characterised the expression, localisation and developmental regulation of the three major dystrophin isoforms in human foetal skeletal and cardiac muscles and in the corresponding cultures. Gene expression studies in foetal cardiac muscle-tissue and cultures showed that the Muscle- and the Brain- but not the Purkinje-transcripts were always co-expressed. In skeletal muscle the Muscle-isoform was already present at 11.8 weeks while the Brain-isoform was detected only after 13 weeks. Myoblast cultures showed a similar sequence of isoform transcription. The Purkinje-isoform was never detected. Localisation studies showed that in cardiac muscle dystrophin was seen discontinuously at the sarcolemma from 8.5 weeks, and evenly expressed by 15 weeks. Cardiomyocyte cultures expressed desmin but not dystrophin after 7 days. Protein studies in foetal skeletal muscle suggested that dystrophin is expressed in the cytoplasm from 8.5 weeks and at the sarcolemma only after 10.5 weeks. Similar results were obtained in cultured myoblasts. This study shows that in cardiac muscle both the Muscle- and Brain-isoforms are transcribed in parallel from the very early stages of development, while in skeletal muscle transcription of the Muscle-isoform occurs first, followed by the Brain-isoform.

Bone and Bones↗
PubMed1999

Genetic heterogeneity of congenital muscular dystrophy with rigid spine syndrome.

Rigid spine syndrome is a neuromuscular disorder characterised by early rigidity of the spine due to axial muscle contractures, generally associated with muscle weakness, limb-joint contractures, and often respiratory failure. This phenotype may be associated with several muscular diseases. In cases of merosin-positive congenital muscular dystrophies (CMD) with rigid spine syndrome, we have recently identified a new locus (RSMD1) on chromosome 1p35-36. In the present study, we report the clinical, morphological and genetic analysis of other patients affected by a CMD with rigid spine syndrome from nine consanguineous families. Homozygosity mapping showed that the disease was linked to RSMD1 in one of the nine families. The other families were excluded from RSMD1, and the patients presented highly variable phenotypes suggesting the involvement of more than one gene defect in rigid spine syndrome. Nevertheless, a subgroup of patients who never walked, and had very early rigidity of the spine and scoliosis, may be considered for further genetic analysis.

Adult↗
PubMed1999

Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy.

Autosomal recessive nemaline (rod) myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive nemaline myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of nemaline myopathy. In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive nemaline myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations.

Child↗
PubMed1999

Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy.

Muscle contraction results from the force generated between the thin filament protein actin and the thick filament protein myosin, which causes the thick and thin muscle filaments to slide past each other. There are skeletal muscle, cardiac muscle, smooth muscle and non-muscle isoforms of both actin and myosin. Inherited diseases in humans have been associated with defects in cardiac actin (dilated cardiomyopathy and hypertrophic cardiomyopathy), cardiac myosin (hypertrophic cardiomyopathy) and non-muscle myosin (deafness). Here we report that mutations in the human skeletal muscle alpha-actin gene (ACTA1) are associated with two different muscle diseases, 'congenital myopathy with excess of thin myofilaments' (actin myopathy) and nemaline myopathy. Both diseases are characterized by structural abnormalities of the muscle fibres and variable degrees of muscle weakness. We have identified 15 different missense mutations resulting in 14 different amino acid changes. The missense mutations in ACTA1 are distributed throughout all six coding exons, and some involve known functional domains of actin. Approximately half of the patients died within their first year, but two female patients have survived into their thirties and have children. We identified dominant mutations in all but 1 of 14 families, with the missense mutations being single and heterozygous. The only family showing dominant inheritance comprised a 33-year-old affected mother and her two affected and two unaffected children. In another family, the clinically unaffected father is a somatic mosaic for the mutation seen in both of his affected children. We identified recessive mutations in one family in which the two affected siblings had heterozygous mutations in two different exons, one paternally and the other maternally inherited. We also identified de novo mutations in seven sporadic probands for which it was possible to analyse parental DNA.

Actins↗
PubMed1999

Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and a cardiomyopathy with conduction blocks which is life-threatening. Two modes of inheritance exist, X-linked (OMIM 310300) and autosomal dominant (EDMD-AD; OMIM 181350). EDMD-AD is clinically identical to the X-linked forms of the disease. Mutations in EMD, the gene encoding emerin, are responsible for the X-linked form. We have mapped the locus for EDMD-AD to an 8-cM interval on chromosome 1q11-q23 in a large French pedigree, and found that the EMD phenotype in four other small families was potentially linked to this locus. This region contains the lamin A/C gene (LMNA), a candidate gene encoding two proteins of the nuclear lamina, lamins A and C, produced by alternative splicing. We identified four mutations in LMNA that co-segregate with the disease phenotype in the five families: one nonsense mutation and three missense mutations. These results are the first identification of mutations in a component of the nuclear lamina as a cause of inherited muscle disorder. Together with mutations in EMD (refs 5,6), they underscore the potential importance of the nuclear envelope components in the pathogenesis of neuromuscular disorders.

Amino Acid Sequence↗
PubMed1999

Merosin-positive congenital muscular dystrophy: a large inbred family.

Large families with congenital muscular dystrophy are rare. We report a clinical, histopathological, immunocytochemical, electrophysiological, radiological and genetic study of 10 cases affected by "pure" CMD belonging to two generations of a large inbred Palestinian family. The disease showed autosomal recessive inheritance. All patients had generalised muscular weakness and hypotonia at birth without arthrogryposis. They had a relatively benign clinical course with stabilisation of the clinical picture at different ages and at variable degrees of severity. The pattern of muscle weakness and wasting was more marked in the proximal upper limb-girdle and trunk muscles. Lower limb muscles were more mildly involved. Serum CK was normal or moderately increased. All patients had normal intelligence, normal computed tomography (CT) scans of the brain and normal somatosensory evoked potentials (SEP). Electromyography (EMG) and muscle biopsy showed morphological changes compatible with muscular dystrophy. Immunocytochemistry for dystrophin, laminin alpha 2 of merosin, and for alpha, beta, gamma sarcoglycans was normal. Linkage analysis excluded all the known loci for CMD, including laminin alpha 2 on chromosome 6q2, the Fukuyama congenital muscular dystrophy locus on 9q3, the integrin alpha 7 locus on chromosome 12q13 and the recently identified locus on 1p35-36. The family we present is clinically and genetically distinct from the already mapped forms of congenital muscular dystrophy. Genetic studies are in progress to localise the gene responsible for this condition.

Adolescent↗
PubMed1999

Clinical spectrum and diagnostic difficulties of infantile ponto-cerebellar hypoplasia type 1.

We present the clinical and histopathological features and the diagnostic difficulties encountered in five children affected by a motor neuron disorder other than spinal muscular atrophy. Investigations performed suggested the diagnosis of ponto-cerebellar hypoplasia type 1 (PCH-1). Severe respiratory difficulty was present at birth in two of these children; hypotonia, arthrogryposis, microcephaly and nystagmus were present in all. Early and progressive bulbar involvement with swallowing difficulties and stridor was also a common feature in these infants. Severe cognitive delay was invariably present. Brain magnetic resonance imaging showed ponto-cerebellar hypoplasia in four children while striking atrophy of the cerebellar vermis and cerebellar hemispheres were present in the fifth child. Electrophysiological and pathological investigations of proximal muscles performed at presentation in all these children were not conclusive, while the post-mortem studies, or the study of distal muscles during life, showed a clear neurogenic picture. Genetic studies excluded involvement of the SMN gene, or of other genes located on chromosome 5q, confirming that ponto-cerebellar hypoplasia type 1 is a different entity from typical proximal spinal muscular atrophy.

Abnormalities, Multiple↗
PubMed1999

Reduced cytosolic acidification during exercise suggests defective glycolytic activity in skeletal muscle of patients with Becker muscular dystrophy. An in vivo 31P magnetic resonance spectroscopy study.

Becker muscular dystrophy is an X-linked disorder due to mutations in the dystrophin gene, resulting in reduced size and/or content of dystrophin. The functional role of this subsarcolemma protein and the biochemical mechanisms leading to muscle necrosis in Becker muscular dystrophy are still unknown. In particular, the role of a bioenergetic deficit is still controversial. In this study, we used 31p magnetic resonance spectroscopy (31p-MRS) to investigate skeletal muscle mitochondrial and glycolytic ATP production in vivo in 14 Becker muscular dystrophy patients. Skeletal muscle glycogenolytic ATP production, measured during the first minute of exercise, was similar in patients and controls. On the other hand, during later phases of exercise, skeletal muscle in Becker muscular dystrophy patients was less acidic than in controls, the cytosolic pH at the end of exercise being significantly higher in Becker muscular dystrophy patients. The rate of proton efflux from muscle fibres of Becker muscular dystrophy patients was similar to that of controls, pointing to a deficit in glycolytic lactate production as a cause of higher end-exercise cytosolic pH in patients. The maximum rate of mitochondrial ATP production was similar in muscle of Becker muscular dystrophy patients and controls. The results of this in vivo 31P-MRS study are consistent with reduced glucose availability in dystrophin-deficient muscles.

Acids↗
PubMed1999

Inherited disorders of the extracellular matrix.

Primary and secondary defects in extracellular matrix proteins emphasize the role of these proteins in neuromuscular disorders; mutations have been found in the genes for the laminin-alpha 2 chain, for all three alpha chains of collagen VI and for integrin alpha 2. Secondary alterations in protein expression occur in association with these primary defects, and in other disorders they implicate the extracellular matrix. Animal models are helping to elucidate the function of some of these proteins, to develop therapeutic strategies and to suggest candidate proteins for other neuromuscular disorders.

Animals↗
PubMed1999

Blood loss in Duchenne muscular dystrophy: vascular smooth muscle dysfunction?

Patients with Duchenne muscular dystrophy (DMD) tend to bleed more during surgery than do patients with other conditions. A retrospective analysis of blood loss after spinal surgery for scoliosis was therefore undertaken in 102 patients undergoing surgery in the senior author's unit. These included 48 patients with DMD, 26 patients with spinal muscular atrophy, and a miscellaneous group of 28 other patients most of whom had idiopathic scoliosis. For each patient the age at surgery, estimated blood volume, duration of operation, Cobb angle, and number of vertebrae fused were recorded and compared. Expression of dystrophin in skeletal muscle and the underlying gene mutation were also determined. The estimated blood loss in patients with DMD was significantly higher than that in patients with spinal muscular atrophy undergoing the same or similar procedure (P < 0.005) and was also significantly greater than that of the third group, which consisted mostly of patients with idiopathic scoliosis (P < 0.0005). Blood loss in the patient group with DMD showed a significant relationship with duration of surgery (P < 0.05). As most patients expressed no dystrophin, this did not correlate with the estimated blood loss. There was also no correlation between the estimated blood loss and the type of gene mutation found causing DMD. The authors' previous observations confirm the increased blood loss in patients with DMD who undergo scoliosis surgery. Because children with DMD lack dystrophin in all muscle types, including smooth muscle, the excessive blood loss may be because of a poor vascular smooth muscle vaso-constrictive response due to a lack of dystrophin.

Adolescent↗
PubMed1999

Feeding problems in merosin deficient congenital muscular dystrophy.

Feeding difficulties were assessed in 14 children (age range 2-14 years) with merosin deficient congenital muscular dystrophy, a disease characterised by severe muscle weakness and inability to achieve independent ambulation. Twelve of the 14 children were below the 3rd centile for weight. On questioning, all parents thought their child had difficulty chewing, 12 families modified the diet, and 13 children took at least 30 minutes to complete a meal. On examination the mouth architecture was abnormal in 13 children. On videofluoroscopy only the youngest child (2 years old), had a normal study. The others all had an abnormal oral phase (breakdown and manipulation of food and transfer to oropharynx). Nine had an abnormal pharyngeal phase, with a delayed swallow reflex. Three of these also showed pooling of food in the larynx and three showed frank aspiration. These six cases all had a history of recurrent chest infections. Six of eight children who had pH monitoring also had gastro-oesophageal reflux. As a result of the study five children had a gastrostomy, which stopped the chest infections and improved weight gain. This study shows that children with merosin deficient congenital muscular dystrophy have difficulties at all stages of feeding that progress with age. Appropriate intervention can improve weight gain and reduce chest infections. The severity of the problem has not been previously appreciated in this disease, and the study shows the importance of considering the nutritional status in any child with a primary muscle disorder.

Adolescent↗
PubMed1999

Vincristine treatment revealing asymptomatic hereditary motor sensory neuropathy type 1A.

A 5 year old boy developed severe weakness after receiving vincristine for treatment of acute lymphoblastic leukaemia. Although weakness improved after the discontinuation of vincristine, other symptoms suggestive of a neuropathy persisted. Neurophysiological and genetic analysis at age 8 years indicated that vincristine had induced symptoms of a hereditary sensory motor neuropathy type 1A, which had previously been asymptomatic; his genetically affected mother was also asymptomatic.

Antineoplastic Agents, Phytogenic↗
PubMed1998

The 5' region of intron 11 of the dystrophin gene contains target sequences for mobile elements and three overlapping ORFs.

We have characterised the 2371 bp 5' end of intron 11 of the dystrophin gene. Comparative analysis of this intronic region revealed homologies with the following sequences: regions containing mobile elements; target sites for numerous transcription factors, two resolvases, and a histone-like DNA binding protein; three eukaryotic promoters. In addition, we identified three partially overlapping ORFs, and transcription analysis confirmed that one of these is expressed, representing the first gene reported to overlap the human dystrophin gene. We have also characterised a 136 bp sequence rearranged in intron 11 in a patient affected by X-linked dilated cardiomyopathy due to a dystrophinopathy. This is a multiple copy sequence with features of a repetitive element. Its comparative analysis showed a very high homology with human genomic and EST regions, adjacent and clustered with Alu, LINE1, and THE elements. The pattern of homology suggests that it may represent a novel Alu-like, transcriptionally active sequence with a possible retrotransposable capacity. We hypothesise that the 5' region of the dystrophin intron 11, containing common target areas for the insertion of mobile elements, may have a role in the rearrangement of this novel Alu-like sequence.

Cardiomyopathy, Dilated↗
PubMed1998

Novel germline p16(INK4) allele (Asp145Cys) in a family with multiple pancreatic carcinomas. Mutations in brief no. 148. Online.

As part of a search for causative genes of familial pancreatic carcinoma, the p16 genes were sequenced in members of 21 families with a phenotype of familial pancreatic carcinoma (2 or more first degree relatives affected). One family was found in which members carried a novel p16 allele with a G to T transversion at position 451, creating a missense amino acid change at codon 145 (Asp to Cys) and possibly disrupting the donor splice site of the exon 2/3 boundary. This coding change is not a known polymorphism, and occurs at a codon position in which another missese/splicing change has been shown to be linked to familial melanoma/pancreas cancer.

Alleles↗
PubMed1998

An early onset muscular dystrophy with diaphragmatic involvement, early respiratory failure and secondary alpha2 laminin deficiency unlinked to the LAMA2 locus on 6q22.

We present four subjects from one family and one subject (with an affected sibling who had died) from a second, unrelated family, with early onset, Duchenne-like, muscular dystrophy who presented with proximal girdle weakness, calf and generalized muscle hypertrophy, selective wasting of the sternomastoid muscles, rigidity of the spine and contractures of the tendo Achilles. Intellect was normal. Serum creatine kinase was grossly elevated and the muscle biopsies showed a dystrophic picture. All five subjects have developed early respiratory failure due to severe diaphragmatic involvement; two have already died aged 4 and 7 years of age and the remaining three are dependent on night time ventilation. There has been very little deterioration over time in the skeletal muscle function, and the survivors remain ambulant, the oldest being 11 years. Immunocytochemical studies of the muscle biopsy showed a normal pattern for dystrophin and the dystrophin-associated glycoproteins, but a reduction of the laminin alpha2 chain of merosin. Magnetic resonance imaging of the brain was normal. The disease did not link to the LAMA2 locus for laminin alpha2 on chromosome 6q, so that these families seem to represent a new form of autosomal recessive muscular dystrophy with a secondary merosin deficiency. The primary protein deficiency has not yet been identified.

Age Factors↗