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Biomedical subjects

C Angelini

Publications and source records attributed to C Angelini.

At least 91 records · Page 5Linked to original sources
PubMed1998

Cardiac transplantation in a Duchenne muscular dystrophy carrier.

We report here for the first time the case of a symptomatic DMD carrier, who had a heart transplant for a severe dilated cardiomyopathy. Dystrophin immunohistochemistry, western blot and analysis of X-chromosome inactivation on leucocytes, and skeletal and cardiac muscle biopsies on the explanted heart were performed. The patient was a heterozygote for exons 50-52 deletion in the dystrophin gene. The number of dystrophin-deficient fibres in the heart was much higher than in skeletal muscle. On the other hand, the explanted heart showed a non-skewed pattern of X-chromosome inactivation, as in leukocytes and skeletal muscle. The adverse cardiac course may be explained by the absence of regeneration among cardiomyocytes.

Adult↗
PubMed1998

Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy.

Miyoshi myopathy (MM) is an adult onset, recessive inherited distal muscular dystrophy that we have mapped to human chromosome 2p13. We recently constructed a 3-Mb P1-derived artificial chromosome (PAC) contig spanning the MM candidate region. This clarified the order of genetic markers across the MM locus, provided five new polymorphic markers within it and narrowed the locus to approximately 2 Mb. Five skeletal muscle expressed sequence tags (ESTs) map in this region. We report that one of these is located in a novel, full-length 6.9-kb muscle cDNA, and we designate the corresponding protein 'dysferlin'. We describe nine mutations in the dysferlin gene in nine families; five are predicted to prevent dysferlin expression. Identical mutations in the dysferlin gene can produce more than one myopathy phenotype (MM, limb girdle dystrophy, distal myopathy with anterior tibial onset).

Adult↗
PubMed1998

Congenital muscular dystrophy with partial merosin deficiency and late onset epilepsy.

Merosin, the laminin alpha2 chain located on the surface of muscle fibers, has recently been shown to be absent in a subset of cases with the classical type of congenital muscular dystrophy (Cl-CMD). By immunocytochemistry and immunoblot analysis, using monoclonal antibodies to both the 80- and the 320-kDa fragments, the same protein was found to be only partially deficient in 3 of our cases. All these 3 patients were able to walk, with evidence of a mild to moderate muscle involvement, as opposed to the merosin-negative cases which are never ambulant because they are affected by severe muscular deficit. All of them also suffered from a late onset form of epilepsy, a clinical expression of brain involvement rarely described in cases with merosin-negative CMD. The 3 patients with CMD and partial merosin deficiency were investigated by brain MRI and pattern reversal visual evoked potentials (VEP) associated with electroretinography (ERG). The results were compared with those obtained by similar studies on 3 of our cases with complete merosin deficiency. In both types of patients, the neuroimaging evaluation showed supratentorial white matter changes, usually of moderate degree, irrespective of the amount of merosin detected in muscle. The VEP were normal in all the 3 cases with partial merosin deficiency, whereas they showed reduced amplitude or prolonged latency in all the 3 cases with the merosin-negative form. ERG was normal in all 6 cases. As a whole, our data indicate that leukoencephalopathy does not seem to distinguish between the two variants of Cl-CMD. On the other hand, a benign muscle involvement and normal VEP findings seem to distinguish CMD patients with partial merosin deficiency from those with complete deficiency of the same protein. Late onset epilepsy, evident in all our 3 cases with partial merosin deficiency, needs to be evaluated in a larger series of patients in order to be considered a characteristic of this variant of CMD.

Adult↗
PubMed1998

Laminin alpha2 muscular dystrophy: genotype/phenotype studies of 22 patients.

OBJECTIVE: To determine the number of primary laminin alpha2 gene mutations and to conduct genotype/phenotype correlation in a cohort of laminin alpha2-deficient congenital muscular dystrophy patients. BACKGROUND: Congenital muscular dystrophies (CMD) are a heterogeneous group of muscle disorders characterized by early onset muscular dystrophy and a variable involvement of the CNS. Laminin alpha2 deficiency has been reported in about 40 to 50% of cases of the occidental, classic type of CMD. Laminin alpha2 is a muscle specific isoform of laminin localized to the basal lamina of muscle fibers, where it is thought to interact with myofiber membrane receptor, such as integrins, and possibly dystrophin-associated glycoproteins. METHODS: Seventy-five CMD patients were tested for laminin alpha2 expression by immunofluorescence and immunoblot. The entire 10 kb laminin alpha2 coding sequence of 22 completely laminin alpha2-deficient patients was screened for causative mutations by reverse transcription (RT)-PCR/single strand conformational polymorphisms (SSCP) analysis and protein truncation test (PTT) analysis followed by automatic sequencing of patient cDNA. Clinical data from the laminin alpha2-deficient patients were collected. RESULTS: Thirty laminin alpha2-negative patients were identified (40% of CMD patients tested) and 22 of them were screened for laminin alpha2 mutations. Clinical features of laminin alpha2-deficient patients were similar, with severe floppiness at birth, delay in achievement of motor milestones, and MRI findings of white matter changes with normal intelligence. Loss-of-function mutations were identified in 95% (21/22) of the patients studied. SSCP analysis detected laminin alpha2 gene mutations in about 50% of the mutant chromosomes; PTT successfully identified 75% of the mutations. A two base pair deletion mutation at position 2,096-2,097 bp was present in 23% of the patients analyzed. CONCLUSIONS: Our data suggest that the large majority of laminin alpha2-deficient patients show laminin alpha2 gene mutations.

Base Sequence↗
PubMed1998

Muscarinic drugs affect cholinesterase activity and development of eye structures during early chick development.

During neurogenesis, markers of the cholinergic system are present in the eye and visual cortex of vertebrates. In adult vertebrates, a role for these molecules, including muscarinic acetylcholine receptors (mAChRs), in eye growth non-accommodative regulation is also known. In order to understand the biological mechanisms triggered by the cholinergic system in these events, we analysed the effects of a cholinergic agonist (10(-4) M carbachol) and an antagonist (10(-4) M atropine) of the muscarinic receptors, on early chick development. To establish if the cholinergic system also plays a role in the regulation of early neurogenetic signals, the drug treatments were made at stage 5-6 HH, during the formation of the cephalic process. Specific effects on forehead, and in particular on eye development were found; carbachol treated embryos presented huge and well pigmented eyes, significantly different from controls. The eyes of atropine-exposed embryos presented anomalies with different phenotypes ranging from strongly affected features to normal-like appearance. Generally, the eyes were smaller as compared to the controls, with a number of anomalies, also in the normal-like phenotype, including retina and lens defects. In these structures, distribution of cholinesterase activities was checked by histochemical methods, and the amount of cells undergoing nuclear disgregation was revealed by DAPI staining. We propose that the drugs affected the known nervous and pre-nervous functions of the cholinergic markers, such as cell signalling during primary induction, and regulation of cell death by ACh receptors.

Acetylcholinesterase↗
PubMed1997

RNA metabolism in myotonic dystrophy: patient muscle shows decreased insulin receptor RNA and protein consistent with abnormal insulin resistance.

Myotonic dystrophy is a dominantly inherited clinically variable multisystemic disorder, and has been found to be caused by heterozygosity for a trinucleotide repeat expansion mutation in the 3' untranslated region of a protein kinase gene (DM kinase). The mechanisms by which the expanded repeat in DNA results in a dominant biochemical defect and the varied clinical phenotype, is not known. We have recently proposed a model where disease pathogenesis may occur at the RNA level in myotonic dystrophy: the mutant DM kinase RNA with the expansion mutation may disrupt cellular RNA metabolism in some general manner, as evidenced by defects in RNA processing of the normal DM kinase gene in heterozygous patients (dominant negative RNA mutation). Here we further test this hypothesis by measuring RNA metabolism of other genes in patient muscle biopsies (nine adult onset myotonic dystrophy patients, two congenital muscular dystrophy patients, four normal controls, and four myopathic controls). We focused on the insulin receptor gene because of the documented insulin resistance of DM patients. We show that there is a significant decrease in insulin receptor RNA in both total RNA and RNA polyA+ pools relative to normal and myopathic control muscles (P < 0.002), measured relative to both dystrophin RNA and muscle sodium channel RNA. We also show reductions in insulin receptor protein. Our results reinforce the concept of a generalized RNA metabolism defect in myotonic dystrophy, and offer a possible molecular mechanism for the increased insulin resistance observed in many myotonic dystrophy patients.

Adolescent↗
PubMed1997

Mutations in the sarcoglycan genes in patients with myopathy.

BACKGROUND: Some patients with autosomal recessive limb-girdle muscular dystrophy have mutations in the genes coding for the sarcoglycan proteins (alpha-, beta-, gamma-, and delta-sarcoglycan). To determine the frequency of sarcoglycan-gene mutations and the relation between the clinical features and genotype, we studied several hundred patients with myopathy. METHODS: Antibody against alpha-sarcoglycan was used to stain muscle-biopsy specimens from 556 patients with myopathy and normal dystrophin genes (the gene frequently deleted in X-linked muscular dystrophy). Patients whose biopsy specimens showed a deficiency of alpha-sarcoglycan on immunostaining were studied for mutations of the alpha-, beta-, and gamma-sarcoglycan genes with reverse transcription of muscle RNA, analysis involving single-strand conformation polymorphisms, and sequencing. RESULTS: Levels of alpha-sarcoglycan were found to be decreased on immunostaining of muscle-biopsy specimens from 54 of the 556 patients (10 percent); in 25 of these patients no alpha-sarcoglycan was detected. Screening for sarcoglycan-gene mutations in 50 of the 54 patients revealed mutations in 29 patients (58 percent): 17 (34 percent) had mutations in the alpha-sarcoglycan gene, 8 (16 percent) in the beta-sarcoglycan gene, and 4 (8 percent) in the gamma-sarcoglycan gene. No mutations were found in 21 patients (42 percent). The prevalence of sarcoglycan-gene mutations was highest among patients with severe (Duchenne-like) muscular dystrophy that began in childhood (18 of 83 patients, or 22 percent); the prevalence among patients with proximal (limb-girdle) muscular dystrophy with a later onset was 6 percent (11 of 180 patients). CONCLUSIONS: Defects in the genes coding for the sarcoglycan proteins are limited to patients with Duchenne-like and limb-girdle muscular dystrophy with normal dystrophin and occur in 11 percent of such patients.

Adolescent↗
PubMed1997

Changes in skeletal muscle histology and metabolism in patients undergoing exercise deconditioning: effect of propionyl-L-carnitine.

To define the skeletal muscle abnormalities in patients undergoing exercise deconditioning and evaluate the metabolic effect of propionyl-L-carnitine (PLC), muscle biopsies were obtained from 28 patients with effort angina and 31 control subjects. Coronary artery disease patients received either placebo (n = 12), PLC (1.5 g i.v. followed by infusion of 1 mg/kg/min for 30 min, n = 10), or L-carnitine (1 g i.v. followed by infusion of 0.65 mg/kg/min for 30 min, n = 6) for 2 days. Exercise deconditioned patients treated with placebo showed normal muscle content of total carnitine and glycogen, and decrease in percentage of type 1 fibers (P < 0.01) and in the activity of citrate synthase (P < 0.05), succinate dehydrogenase (P < 0.05), and cytochrome oxidase (P < 0.05), as compared to controls. Both PLC and L-carnitine did not modify muscle fiber composition or enzyme activities, but significantly increased muscle levels of total carnitine by 42% and 31%, respectively (P < 0.05). Moreover, PLC significantly increased glycogen muscle content (P < 0.01), while the equimolar dose of L-carnitine did not. This effect, probably due to the anaplerotic activity of the propionic group of PLC, suggests that this drug may be effective in improving energy metabolism of muscles with impaired oxidative capacity.

Carnitine↗
PubMed1997

Long-term cyclosporine treatment in a group of severe myasthenia gravis patients.

We evaluated cyclosporine A (CsA) treatment in 9 patients (6 female and 3 male), 16-63 years old, with severe myasthenia gravis (MG) for a mean period of 2 years (range 16-36 months). All of the patients had been previously treated either with corticosteroids or by combined immunotherapy, and 5 needed periodic plasma exchanges. The reduction of plasmapheresis cycles in the 5 patients who needed periodic plasma exchange to maintain an acceptable quality of life showed an impressive cost-benefit analysis. During CsA treatment 7 of 9 patients improved their muscle strength and functional score. In all the patients except one the corticosteroid dosage was reduced and in 7 of the 9 patients the dose reduction was over 50% with subsequent reduction of the corticosteroid side effects. The findings showed that initiation of CsA treatment increased muscle strength and reduced corticosteroid dosage. The most common CsA side effects were: a serum creatinine increase that occurred in the first 6-12 months of therapy in 8 patients, other side effects like hypertrichosis and gingival hyperplasia were present in four patients. Blood pressure increase was found in only one patient. CsA treatment may be a valuable and cost effective treatment in severe MG.

Adolescent↗
PubMed1997

Genotype-phenotype correlations of DHP receptor alpha 1-subunit gene mutations causing hypokalemic periodic paralysis.

Hypokalemic periodic paralysis (hypoKPP) is an autosomal dominant or sporadic disorder characterized by periodic, reversible attacks of muscle weakness. Mutations in the skeletal muscle dihydropyridine receptor alpha 1-subunit that functions as a calcium channel (CACNL1A3) cause hypoKPP. We studied a group of 45 hypoKPP probands and demonstrated mutations in 30 of them. When compared with patients in whom CACNL1A3 mutations were not identified, those with mutations had an earlier age of onset and more often had a family history of hypoKPP. To date, three mutations have been identified. The R1239G mutation has only been found in one family. Of the 30 probands with recognized mutations, R528H accounted for 43% and R1239H was seen in 53%. Age of onset and potassium levels during attacks were lower in patients with the R1239H mutation than those with R528H. Cardiac dysrhythmias co-segregated with hypoKPP in one small kindred with the R528H mutation. No mutations were identified in exons of the gene encoding the S4 segments of domains one and three or the cytoplasmic loop between domains two and three. In addition to the 45 hypoKPP probands, an additional 11 probands with clinical variants of hypoKPP (three thyrotoxic hypoKPP and eight Andersen syndrome patients) were examined for CACNL1A3 mutations and none were found.

Adolescent↗
PubMed1997

Genetic epidemiology of muscular dystrophies resulting from sarcoglycan gene mutations.

BACKGROUND: The autosomal recessive limb-girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous muscle diseases characterised by progressive proximal limb muscle weakness. Six different loci have been mapped and pathogenetic mutations in the genes encoding the sarcoglycan complex components (alpha-, beta-, gamma-, and delta-sarcoglycan) have been documented. LGMD patients affected with primary "sarcoglycanopathies" are classified as LGMD2D, 2E, 2C, and 2F, respectively. METHODS: A geographical area in north east Italy (2,319,147 inhabitants) was selected for a genetic epidemiological study on primary sarcoglycanopathies. Within the period 1982 to 1996, all patients living in this region and diagnosed with muscular dystrophy were seen at our centre. Immunohistochemical and immunoblot screening for alpha-sarcoglycan protein deficiency was performed on all muscle biopsies from patients with a progressive muscular dystrophy of unknown aetiology and normal dystrophin. Sarcoglycan mutation analyses were conducted on all patient muscle biopsies shown to have complete or partial absence of alpha-sarcoglycan immunostaining or a decreased quantity of alpha-sarcoglycan protein on immunoblotting. RESULTS: Two hundred and four patient muscle biopsies were screened for alpha-sarcoglycan protein deficiency and 18 biopsies showed a deficiency. Pathogenetic mutations involving one gene for sarcoglycan complex components were identified in 13 patients: alpha-sarcoglycan in seven, beta-sarcoglycan in two, gamma-sarcoglycan in four, and none in the delta-sarcoglycan gene. The overall prevalence of primary sarcoglycanopathies, as of 31 December 1996, was estimated to be 5.6 x 10(-6) inhabitants. CONCLUSION: The prevalence rate estimated in this study is the first to be obtained after biochemical and molecular genetic screening for sarcoglycan defects.

Adolescent↗
PubMed1996

Myocardial involvement is very frequent among patients affected with subclinical Becker's muscular dystrophy.

BACKGROUND: Several cases of Becker's muscular dystrophy (BMD) have been reported, which showed mild or subclinical skeletal muscle involvement with an overt dilated cardiomyopathy. Here, for the first time, a group of 28 patients with BMD who had a subclinical or benign myopathy have been studied through a thorough cardiological assessment. METHODS AND RESULTS: Each patient underwent ECG and echocardiographic examinations. Molecular analyses of the dystrophin gene and protein were performed. An unexpectedly high incidence of myocardial involvement was observed among patients affected with subclinical (72%) or benign (60%) BMD. The cardiac involvement appears to develop early from the right ventricle. Both the increase in left ventricular end-diastolic volume and the reduction in the ejection fraction appeared to be age related. Severe left ventricular dilation with reduced ejection fraction, which could be complicated by life-threatening arrhythmias, may occur. Contrary to previous reports, which indicated the involvement of 5'-end mutations in cardiomyopathies as a result of dystrophin gene alterations, this study shows that despite the apparent concentration of deletions in two regions (5'-end and exons 47 through 49), no general conclusions can be drawn regarding the involvement of specific gene mutations in the development of cardiomyopathy. CONCLUSIONS: Cardiomyopathy is the main clinical feature and complication in patients affected by subclinical or mild BMD. The cardiac manifestation is characterized by early right ventricular involvement and is later associated with left ventricular impairment. In mild BMD, myocardial damage may develop because the patients, who are unaware of a possible cardiac involvement, are still able to perform strenuous muscle exercise and, through pressure or volume overload, may induce mechanical stress, which is harmful for dystrophin-deficient myocardial cells.

Adolescent↗
PubMed1996

Prediction of myotonic dystrophy clinical severity based on the number of intragenic [CTG]n trinucleotide repeats.

We carried out a genotype-phenotype correlation study, based on clinical findings in 465 patients with myotonic dystrophy (DM), in order to assess [CTG] repeat number as a predictive test of disease severity. Our analysis showed that the DM subtypes defined by strict clinical criteria fall into three different classes with a log-normal distribution. This distribution is useful in predicting the probability of specific DM phenotypes based on triplet [CTG] number. This study demonstrates that measurement of triplet expansions in patients' lymphocyte DNA is highly valuable and accurate for prognostic assessment.

Disease Progression↗
PubMed1996

alpha-Sarcoglycan (adhalin) deficiency: complete deficiency patients are 5% of childhood-onset dystrophin-normal muscular dystrophy and most partial deficiency patients do not have gene mutations.

alpha-Sarcoglycan (adhalin), a 50-kDa component of the dystrophin-associated complex of proteins, participates in the stabilization of the myofiber plasma membrane in the membrane cytoskeleton. Deficiencies of alpha-sarcoglycan cause a subset of childhood-onset muscular dystrophy (SCARMD) cases. However, secondary deficiencies of alpha-sarcoglycan are common. To begin to establish the rates of false positives (secondary deficiencies), we used immunofluorescence to screen 30 Italian dystrophin-normal muscular dystrophy patient biopsies and identified 4 patients with partial alpha-sarcoglycan deficiency and 2 patients with complete deficiency. The entire alpha-sarcoglycan gene was screened for mutations using RT-PCR and SSCP of messenger RNA isolated from muscle biopsies in each of the six patients. Aberrant SSCP conformers and novel mutations were found only in the two complete immunohistochemical deficient patients. One patient was homozygous for a R34H amino acid substitution, while the other was a compound heterozygote (R77C, D97G). These three missense mutations, with additional mutations we and others have previously described, are all localized in the extracellular domain of alpha-sarcoglycan, and most result in the loss or gain of a positively charged amino acid. These data have strong implications for structure/function maps of the alpha-sarcoglycan molecule. Our results suggest that most patients showing partial alpha-sarcoglycan deficiency exhibit this as a secondary consequence of genetically distinct disorders. In support of this, we show biochemical data indicating that secondary deficiency patients show decreased immunostaining with antibodies directed against alpha-sarcoglycan, while having nearly normal quantities of alpha-sarcoglycan protein on immunoblot. This data also suggests that approximately 5% of childhood-onset dystrophin-normal muscular dystrophy patients will show a primary alpha-sarcoglycan deficiency.

Base Sequence↗
PubMed1996

X-inactivation patterns in female Leber's hereditary optic neuropathy patients do not support a strong X-linked determinant.

Leber's hereditary optic neuropathy (LHON) accounts for about 3% of the cases of blindness in young adult males. The underlying mitochondrial pathogenesis of LHON has been well studied, with specific mitochondrial DNA (mtDNA) mutations of structural genes described and well characterized. However, enigmatic aspects of the disease are not explained by mutation data, such as the higher proportion of affected males, the later onset of the disease in females, and the presence of unaffected individuals with a high proportion of mutant mtDNA. A hypothesis which has been put forward to explain the unusual disease expression is a dual model of mtDNA and X-linked nuclear gene inheritance. If a nuclear X-linked modifier gene influences the expression of the mitochondrial-linked mutant gene then the affected females should be either homozygous for the nuclear determinant, or if heterozygous, lyonization should favor the mutant X. In order to determine if an X-linked gene predisposes to LHON phenotype we studied X-inactivation patterns in 35 females with known mtDNA mutations from 10 LHON pedigrees. Our results do not support a strong X-linked determinant in LHON cause: 2 of the 10 (20%) manifesting carriers showed skewing of X-inactivation, as did 3 of the 25 (12%) nonmanifesting carriers.

DNA, Mitochondrial↗
PubMed1996

Residual muscle cytochrome c oxidase activity accounts for submaximal exercise lactate threshold in chronic progressive external ophthalmoplegia.

The data from histological, biochemical, and mitochondrial DNA (mtDNA ) studies of muscle biopsies from 10 patients affected with chronic progressive external ophthalmoplegia (CPEO) were related to dynamic and metabolic parameters of incremental submaximal exercise. Maximum power output was reduced in all patients as compared to controls. Analysis of the venous lactate curve during exercise revealed a lactate threshold at exercise levels ranging from 40 to 50% of the predicted maximal power output. An earlier significant increase in lactate could be detected by calculating the mean delta lactate. Lactate values were inversely correlated with the cytochrome c oxidase (COX) activity of isolated muscle mitochondria. No relationship was found between lactate values and the number of ragged red fibers, or cytochrome c oxidase-negative fibers of the proportion of deleted mtDNA measured in muscle biopsy specimens. The discussion underscores the value of lactate kinetics in assessing skeletal muscle function, as well as the use of muscle COX levels to predict the effectiveness of wild-type complementation of deleted skeletal muscle mtDNA in in vivo contractile performance of CPEO subjects.

Adult↗