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A Mateddu

Publications and source records attributed to A Mateddu.

14 recordsLinked to original sources
PubMed1999

X-linked dilated cardiomyopathy and the dystrophin gene.

X-linked dilated cardiomyopathy (XLDC) represents a well known genetic disease, allelic to Duchenne and Becker muscular dystrophies and caused by dystrophin gene mutations. XLDC is a rare disease and only few families have been fully characterised. In several of them, the dystrophin mutations show a different pattern of expression in cardiac compared to skeletal muscle. In the families with the most severe cardiac phenotype, the cardiac muscle is usually unable to produce dystrophin, due to a specific effect that the mutation(s) have on the gene transcription in this tissue. The skeletal muscle escapes the dystrophic changes by maintaining dystrophin synthesis via exon skipping or alternative splicing that the heart is not able to put in place. In this paper we have reviewed the families with X-linked dilated cardiomyopathy reported so far; in addition we provided novel transcription data on two families we previously described. The aim of this review is to attempt a genotype-phenotype correlation and speculate on common pathogenic mechanisms underlying this disease.

Adolescent↗
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

Elevation of serum creatine kinase as the only manifestation of an intragenic deletion of the dystrophin gene in three unrelated families.

This study reports three children from three unrelated families, aged from 9 to 12 years, who were investigated because of the incidental finding of elevated serum creatine kinase (CK) levels and were found to have a dystrophinopathy. The molecular defect consisted of a deletion of variable extent within the central rod domain of the dystrophin gene, involving either exons 32-44 or 48-51 or 48-53. In each family we found the same deletion in at least one adult male relative aged from 40 to 77 years, who was either completely asymptomatic or had very mild muscle involvement (thin muscles and/or mild scoliosis), with normal or borderline CK levels. This study suggests once again that deletions of the central rod domain of dystrophin may be associated with elevation of serum CK as the only manifestation and that prediction of the clinical severity based solely on the molecular findings should be interpreted with caution.

Adult↗
PubMed1997

Dystrophin gene abnormalities in two patients with idiopathic dilated cardiomyopathy.

Two new cases of dilated cardiomyopathy (DC) caused by dystrophinopathy are reported. One patient, a 24 year old man, had a family history of X linked DC, while the other, a 52 year old man, had sporadic disease. Each had abnormal dystrophin immunostaining in muscle or cardiac biopsy specimens, but neither had muscle weakness. Serum creatine kinase activity was raised only in the patient with familial disease. Analysis of dystrophin gene mutations showed a deletion of exons 48-49 in the patient with familial DC and of exons 49-51 in the other. Dystrophin transcription in cardiac tissue from the patient with sporadic disease showed abundant expression, predominantly of the muscle isoform. This study, together with previous reports, suggests that some patients with DC have a dystrophinopathy that can be diagnosed using a combination of biochemical and genetic analyses.

Adult↗
PubMed1996

A point mutation in the 5' splice site of the dystrophin gene first intron responsible for X-linked dilated cardiomyopathy.

X-linked dilated cardiomyopathy (XLDC) is a familial heart disease presenting in young males as a rapidly progressive congestive heart failure, without clinical signs of skeletal myopathy. This condition has recently been linked to the dystrophin gene in some families and deletions encompassing the genomic region coding for the first muscle exon have been detected. In order to identify the defect responsible for this disease at the molecular level and to understand the reasons for the selective heart involvement, a family with a severe form of XLDC was studied. In the affected members, no deletions of the dystrophin gene were observed. Analysis of the muscle promoter, first exon and intron regions revealed the presence of a single point mutation at the first exon-intron boundary, inactivating the universally conserved 5' splice site consensus sequence of the first intron. This mutation introduced a new restriction site for MseI, which cosegregates with the disease in the analyzed family. Expression of the major dystrophin mRNA isoforms (from the muscle-, brain- and Purkinje cell-promoters) was completely abolished in the myocardium, while the brain- and Purkinje cell- (but not the muscle-) isoforms were detectable in the skeletal muscle. Immunocytochemical studies with anti-dystrophin antibodies showed that the protein was reduced in quantity but normally distributed in the skeletal muscle, while it was undetectable in the cardiac muscle. These findings indicate that expression of the muscle dystrophin isoform is critical for myocardial function and suggest that selective heart involvement in dystrophin-linked dilated cardiomyopathy is related to the absence, in the heart, of a compensatory expression of dystrophin from alternative promoters.

Adult↗
PubMed1994

Familial cardiomyopathy, mental retardation and myopathy associated with desmin-type intermediate filaments.

The clinical and morphological findings of a familial case affected by mental retardation, severe biventricular hypertrophic cardiomyopathy and vacuolar myopathy are reported. The phenotype of this patient is similar to that described by other authors, in which a lysosomal glycogen storage disease with normal acid maltase levels was suspected. However, in our case the vacuoles were stained by several antibodies directed against various sarcolemmal proteins, such as dystrophin and spectrin, and therefore, were not of lysosomal origin. Some of these vacuoles were clearly derived from the splitting of the fibres and invagination of the extracellular space; autophagic vacuoles were not observed. The accumulation of desmin-type, intermediate filaments was demonstrated on immunocytochemistry both in the skeletal and cardiac muscles. A brother of the propositus was also affected by mental retardation, severe cardiomyopathy and died suddenly at the age of 24 yr. A cardiomyopathy and mental subnormality were also present in other male cousins of the proband, while sudden death occurred in several females relatives, whose intelligence was normal. None of these latter individuals was available for further investigation. This report expands the spectrum of desmin associated myopathy and cardiomyopathy to include a familial condition with associated mental retardation.

Adult↗
PubMed1993

Muscular weakness in the mdx mouse.

mdx mice are believed to be virtually free from neuromuscular symptoms, despite the presence of a degenerative/regenerative process that involves all skeletal muscles. We analyzed both the spontaneous motility and treadmill motor activity of mdx mice aged 15 days to 6 months. Our results indicate that there is an early period, between the end of the second and up to the fifth week of life, when mdx mice experience extreme weakness. After this critical period, both spontaneous motility and endurance of mdx mice, although lower than those of controls, do not show statistically significant differences up to 6 months of age. We also carried out a detailed histological analysis of proximal and distal muscle groups in mdx mice during this early critical motility period. The occurrence of extensive necrosis followed by regeneration and involving proximal muscles before distal ones was documented in mice as young as 16-17 days of age and reached a peak at day 18. We conclude that dystrophin deficiency induces muscle degeneration and significant weakness in mdx mice, but only in an early period. Later on, during development, mdx mice adapt to the lack of this protein and do not show detectable in vivo functional muscle impairment up to 6 months of age.

Aging↗
PubMed1993

Diagnosis of DMD carrier status in a family with no known affected males.

A 30-year-old woman and her two-year-old daughter were found by chance to have moderately raised serum creatine kinase (CK) levels. Since the mother was pregnant, the authors investigated the possibility that the two females were carriers of the common Duchenne muscular dystrophy (DMD) gene. No immunohistochemical abnormality was detected in the mother, but in the daughter a clear mosaic pattern of dystrophin positive and negative fibres was found, indicating carrier status for DMD. These data indicate that a diagnosis of DMD carrier status can be made even in families without a positive history for this disorder; therefore, immunocytochemical studies, using antidystrophin antibodies, should be performed on all females with raised CK levels, including the youngest.

Child, Preschool↗
PubMed1993

Dystrophin analysis using a panel of anti-dystrophin antibodies in Duchenne and Becker muscular dystrophy.

Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene, was studied in 19 patients with Xp21 disorders and in 25 individuals with non-Xp21 muscular dystrophy. Antibodies raised to seven different regions spanning most of the protein were used for immunocytochemistry. In all patients specific dystrophin staining anomalies were detected and correlated with clinical severity and also gene deletion. In patients with Becker muscular dystrophy (BMD) the anomalies detected ranged from inter- and intra-fibre variation in labelling intensity with the same antibody or several antibodies to general reduction in staining and discontinuous staining. In vitro evidence of abnormal dystrophin breakdown was observed reanalysing the muscle of patients, with BMD and not that of non-Xp21 dystrophies, after it has been stored for several months. A number of patients with DMD showed some staining but this did not represent a diagnostic problem. Based on the data presented, it was concluded that immunocytochemistry is a powerful technique in the prognostic diagnosis of Xp21 muscular dystrophies.

Adolescent↗
PubMed1992

Variable dystrophin expression in different muscles of a Duchenne muscular dystrophy carrier.

The majority of Duchenne muscular dystrophy (DMD) female carriers show dystrophin immunostaining abnormalities, although a significant proportion of clinically non-manifesting carriers are normal following this analysis. We had the opportunity to study dystrophin immunostaining in two different muscles, the vastus lateralis and the rectus abdominis of a possible DMD carrier. While the vastus showed normal dystrophin immunostaining, pathological staining was detected in her rectus abdominis. These findings seem to indicate that dystrophin expression can vary in different muscle groups of a DMD carrier. The implications of these findings in DMD carrier detection and possible dystrophin function are discussed.

Adult↗
PubMed1991

Passive avoidance behaviour deficit in the mdx mouse.

Thirty per cent of boys with Duchenne muscular dystrophy (DMD) suffer from various degrees of mental retardation. Since dystrophin, the protein absent in muscles of boys with DMD, is produced also in the brain, it was postulated that the deficiency of brain dystrophin might account for the mental retardation found in DMD boys. The mdx mouse, a mouse model of DMD, fails to produce dystrophin in muscle and brain. This prompted us to study the cognitive function of these animals. Learning and memory processes were studied in 10 mdx females and 9 genetically matched controls using the passive avoidance test. Statistically significant differences in the retention of the passive avoidance response was detected between mdx and control mice, indicating an impairment in passive avoidance learning in mdx mice. Our data reinforce the view that brain dystrophin deficiency is correlated with cognitive dysfunction and indicate that mdx mice might be a model for the mental retardation found in DMD boys.

Animals↗