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Biomedical subjects

E Pegoraro

Publications and source records attributed to E Pegoraro.

At least 19 recordsLinked to original sources
PubMed2006

The glucocorticoid receptor N363S polymorphism and steroid response in Duchenne dystrophy.

BACKGROUND: Steroid administration is beneficial in Duchenne muscular dystrophy (DMD), but the response, incidence, and the severity of side effects are variable. AIMS: To investigate whether glucocorticoid receptor (GRL) gene polymorphisms may be responsible for glucocorticoid sensitivity in DMD. METHODS: Forty eight DMD patients treated either with prednisone or deflazacort were subjected to genetic analyses of the GRL gene. RESULTS: Mutation studies revealed an heterozygous A to G mutation at GRL cDNA position 1220 in three DMD patients resulting in an asparagine to serine amino acid change at amino acid position 363 (N363S). The N363S carrier DMD patients showed a trend towards a later age at loss of ambulation in comparison with non-carrier patients. CONCLUSIONS: These data suggest that the N363S GRL polymorphism may be implicated in the long term response to glucocorticoids.

Anti-Inflammatory Agents↗
PubMed2005

Secular trends in nosocomial candidaemia in non-neutropenic patients in an Italian tertiary hospital.

A retrospective study was performed in an Italian tertiary hospital to evaluate trends in candidaemia between 1992 and 2001, and to compare the characteristics of episodes of fungaemia between 1992--1997 and 1998--2001. In total, 370 episodes of candidaemia were identified, with an average incidence of 0.99 episodes/10 000 patient-days/year (range 0.49--1.29 episodes). On an annual trend basis, the overall incidence was essentially stable in surgical and medical wards, but decreased in intensive care units (ICUs) (p 0.0065). The average use of fluconazole was 37.9 g/10 000 patient-days/year (range 21.4--56.1 g), and did not change significantly during the 10-year period. Nearly two-thirds of patients were in ICUs at the onset of candidaemia, but none was neutropenic in either study period. Candida albicans remained the predominant species isolated (53.8% vs. 48.1%), followed by Candida parapsilosis, Candida glabrata and Candida tropicalis, the distribution of which did not change significantly. The 30-day crude mortality rate was essentially similar (44% vs. 35%) in both study periods. Thus the incidence of nosocomial candidaemia, although high in this institution, decreased among critically-ill patients during the 10-year period. This finding seemed to be related to an improvement in infection control practices, particularly regarding the prevention of intravascular catheter-related infections in ICUs. Although the overall use of fluconazole was considerable, no increase in azole-resistant non-albicans Candida spp. was detected.

Antifungal Agents↗
PubMed2004

LAMA2 loss-of-function mutation in a girl with a mild congenital muscular dystrophy.

The authors report a girl with autosomal recessive congenital muscular dystrophy linked to chromosome 6 (MDC1A) who carries a homozygous out-of-frame deletion in exon 56 of the LAMA2 gene but has a mild phenotype. She is still ambulant at age 13 years, shows white matter abnormalities on MRI, and traces of laminin alpha2 in her muscle biopsy with one of three antibodies used. This patient suggests that modulating factors can be associated with a less severe clinical phenotype in MDC1A.

Adolescent↗
PubMed2004

Large-scale disruption of microtubule pathways in morphologically normal human spastin muscle.

OBJECTIVE: To investigate the molecular pathways disrupted by dominant spastin mutations in apparently unaffected skeletal muscle from patients with motor neuron disease (SPG4). METHODS: The authors studied muscle of three individuals from two unrelated families affected by spastic paraplegia caused by spastin mutations. The authors compared RNA expression profiles to 7 normal and 13 pathologic muscle U95A profiles (Duchenne dystrophy, acute quadriplegic myopathy, and spinal muscular atrophy). Data were validated with U133A arrays with seven different control specimens. mRNA and protein confirmations were done for a subset of genes. RESULTS: Both nonsense and missense mutations in the spastin gene disrupted microtubule pathways in nonpathologic tissue, including microtubule dynamics, stability, exocytosis, and endocytosis. CONCLUSIONS: Normal muscle can be used to uncover biochemical perturbation in motor neuron disease. Altered microtubule metabolism in SPG4-linked hereditary spastic paraplegia patients leads to pathology of the long descending tracks of motor neurons that likely have a stringent need for efficient microtubular transport. As many inherited neurologic conditions show a systemic biochemical defect with disease limited to neurons, our data have broader implications for biochemical pathway studies of many neurologic disorders.

Adenosine Triphosphatases↗
PubMed2003

Cerebellar ataxia and coenzyme Q10 deficiency.

The authors measured coenzyme Q10 (CoQ10) concentration in muscle biopsies from 135 patients with genetically undefined cerebellar ataxia. Thirteen patients with childhood-onset ataxia and cerebellar atrophy had markedly decreased levels of CoQ10. Associated symptoms included seizures, developmental delay, mental retardation, and pyramidal signs. These findings confirm the existence of an ataxic presentation of CoQ10 deficiency, which may be responsive to CoQ10 supplementation.

Adolescent↗
PubMed2003

LGMD2E patients risk developing dilated cardiomyopathy.

Sarcoglycan gene mutations cause various limb-girdle muscular dystrophies. The sarcoglycans are expressed both in skeletal and cardiac muscle but, surprisingly, so far only a few sarcoglycanopathy patients have had documented cardiomyopathy. We studied six patients with beta-sarcoglycanopathy. Immunohistochemical and immunoblot analysis performed on skeletal muscle biopsies from five patients, showed the loss of all sarcoglycans in three cases and marked reduction in two patients. Non-invasive cardiac examinations revealed that three patients had cardiac involvement: one had a severe Duchenne-like dystrophy, lethal dilated cardiomyopathy, and shared the same mutation reported in another cardiomyopathic patient; the other two patients had limb-girdle dystrophy and moderate cardiac involvement (one of them has a novel gene mutation). Given the age profile of the patients studied, the 50% cardiac involvement found in our LGMD2E patients is likely to be a conservative estimate. Careful cardiac monitoring should be carried out in beta-sarcoglycanopathy patients who are at high risk of developing cardiomyopathy.

Adolescent↗
PubMed2003

Memory deficits and retrieval processes in ALS.

Subtle neuropsychological deficits have been described in patients affected by amyotrophic lateral sclerosis (ALS) without dementia. Overall, selective impairment in memory function has been reported, but the source of memory impairment in ALS has yet to be defined. We performed neuropsychological screening in 20 ALS patients. Semantic encoding and post-encoding cue effects on the retrieval of word lists were investigated in the ALS patients and normal controls. Severity of memory impairment was correlated to cerebral blood perfusion detected by single photon emission computed tomography (SPECT). ALS patients showed moderate impairments in frontal and memory tests. Short-term memory was normal, while serial position retrieval of word lists with normal recency effect but poor primacy effect showed long-term memory deficit. ALS patients performed better in cued encoding than in cued post-encoding recall condition. In the cued post-encoding condition, the primacy effect in word list recall improved significantly in controls, but not in ALS patients, as compared with both the free recall and cued encoding conditions. SPECT hypoperfusion was observed in frontal and temporal areas in ALS patients. ALS patients showed a long-term memory deficit which did not improve in cued post-encoding condition as it does for controls. We hypothesize abnormal retrieval processes related to frontal lobe dysfunction which entails difficulties in generating stable long-memory traces at encoding.

Aged↗
PubMed2001

A new mutation in a family with cold-aggravated myotonia disrupts Na(+) channel inactivation.

OBJECTIVE: To identify the molecular and physiologic abnormality in familial myotonia with cold sensitivity, hypertrophy, and no weakness. BACKGROUND: Sodium channel mutations were previously identified as the cause of several allelic disorders with varying combinations of myotonia and periodic paralysis. A three-generation family with dominant myotonia aggravated by cooling, but no weakness, was screened for mutations in the skeletal muscle sodium channel alpha-subunit gene (SCN4A). METHODS: Single-strand conformation polymorphism was used to screen all 24 exons of SCN4A and abnormal conformers were sequenced to confirm the presence of mutations. The functional consequence of a SCN4A mutation was explored by recording sodium currents from human embryonic kidney cells transiently transfected with an expression construct that was mutated to reproduce the genetic defect. RESULTS: A three-generation Italian family with myotonia is presented, in which a novel SCN4A mutation (leucine 266 substituted by valine, L266V) is identified. This change removes only a single methylene group from the 1,836-amino-acid protein, and is present in a region of the protein previously not known to be critical for channel function (domain I transmembrane segment 5). Electrophysiologic studies of the L266V mutation showed defects in fast inactivation, consistent with other disease-causing SCN4A mutations studied to date. Slow inactivation was not impaired. CONCLUSIONS: This novel mutation of the sodium channel indicates that a single carbon change in a transmembrane alpha-helix of domain I can alter channel inactivation and cause cold-sensitive myotonia.

Adult↗
PubMed2001

Calpain-3 and dysferlin protein screening in patients with limb-girdle dystrophy and myopathy.

BACKGROUND: Mutations in the genes encoding for calpain-3 and dysferlin are responsible for limb-girdle muscular dystrophy (LGMD) type 2A and 2B, the most common forms of autosomal recessive LGMD. OBJECTIVE: To identify calpain-3 or dysferlin deficiency in a large cohort of patients with as yet unclassified LGMD and myopathy through candidate protein analysis. METHODS: The authors' muscle biopsy database search identified 407 candidate muscle biopsies with normal dystrophin and sarcoglycan. Calpain-3 and dysferlin were studied by Western blotting and immunohistochemistry. RESULTS: Combined calpain-3 and dysferlin Western blot analysis identified calpain-3 deficiency in 66 (16%) muscle biopsies. In 31 cases (47%), the protein was absent, and in 35 (53%), it was severely reduced in amount (3 to 50% of control). Dysferlin deficiency was found in 26 (6.5%) muscle biopsies. In 9, the protein was absent (35%), and in 17 (65%), it was severely reduced in amount (traces to 20% of control). Twenty-eight percent (53/191) of patients with LGMD phenotype had calpain-3 deficiency. Sixty percent (21/35) of patients with distal myopathy had dysferlin deficiency. Dysferlin immunohistochemistry showed, in the completely dysferlin-deficient patients, absent reaction at the sarcolemma but positive nuclear membrane labeling and, in the partially dysferlin-deficient patients, scattered granular positive cytoplasmic areas and diffuse reaction in regenerating fibers. CONCLUSION: About 25% of previously unclassified dystrophy/myopathy cases are due to calpain-3 or dysferlin protein deficiency. These results suggest that immunoblot analysis may be used to define patients for calpain-3 and dysferlin gene mutation studies.

Biopsy↗
PubMed2000

A novel laminin alpha2 isoform in severe laminin alpha2 deficient congenital muscular dystrophy.

OBJECTIVES: Laminin alpha2 deficiency presents at birth with muscle weakness, hypotonia, and usually asymptomatic white matter signal on MRI. Few patients with laminin alpha2 deficiency have been described with seizures and structural brain abnormalities. The reason for the variation in the severity of the clinical phenotype in congenital muscular dystrophy (CMD) with laminin alpha2 deficiency is not known. METHODS: A patient with CMD with partial laminin alpha2 presenting with brain structural abnormalities and untreatable generalized and partial complex seizure was studied. Alternative laminin alpha2 splicing was studied by single-strand conformational polymorphism/sequencing analysis. RESULTS: A novel laminin alpha2 isoform was identified. Nonsense laminin alpha2 mutations (stop codons) were inherited from both parents; however, one of the nonsense mutations was in a region of exon 31, which is alternatively spliced. The alternatively spliced isoform excluded one of the stop codon mutations, and was thus able to produce normal laminin alpha2 corresponding to this isoform. Laminin alpha2 immunofluorescence showed that this isoform was not evenly distributed at the muscle fiber basal lamina, but preferentially localized in discrete areas. Laminin alpha5, beta1, gamma1, and nidogen showed decreased expression by immunofluorescence. CONCLUSIONS: The severity of this patient's phenotype may be due to overexpression of the exon 31-spliced laminin alpha2 isoform. Exon 31 lies in the IIIA domain of the laminin alpha2 protein, just proximal to the triple coil-coiled region. It is possible that chain assembly is impaired by this isoform, resulting in a loss of possible rescue mechanisms.

Adolescent↗
PubMed2000

Private beta- and gamma-sarcoglycan gene mutations: evidence of a founder effect in Northern Italy.

Autosomal recessive muscular dystrophies called "sarcoglycanopathies" result from mutations in the genes encoding alpha-, beta-, gamma-, or delta-sarcoglycan complex components. The present study involved six unrelated families from Northern Italy showing mutations in the beta- or gamma-sarcoglycan genes. An 8 bp duplication in the beta-sarcoglycan gene and 1 bp insertion in the gamma-sarcoglycan gene occur with high frequency in our population. These mutations have never been reported thus far in other countries. Many patients are homozygotes for a single mutation, although they derived from non-consanguineous marriages. We suggest that these alleles are "private" mutations of this geographical region. A panel of highly informative microsatellite markers that map in the beta- and gamma-sarcoglycan gene locus was used to assess the haplotypes among affected patients and control population, in order to test the presence of linkage disequilibrium. We found that the 8 bp duplication in the beta-sarcoglycan gene and the 1 bp insertion in the gamma-sarcoglycan gene are in linkage disequilibrium with neighbouring polymorphisms. The recurrence of specific sarcoglycan mutations in Northern Italy is probably due to a founder effect, combined with a relative genetic isolation.

Alleles↗
PubMed1999

Genetic localization of a new locus for recessive familial spastic paraparesis to 15q13-15.

OBJECTIVE: To characterize a new gene locus for familial spastic paraparesis (FSP). BACKGROUND: FSP is a genetically heterogeneous group of upper motor neuron syndromes. It can be inherited as an autosomal dominant, autosomal recessive, or X-linked disorder. Four loci for autosomal dominant FSP have been genetically mapped, and two genes have been shown responsible for the X-linked type. In addition, two loci for autosomal recessive type have been reported and mapped to chromosomes 8q and 16q. The gene for the 16q locus has been characterized as a mitochondrial protein. METHODS: Eight recessive FSP families from America and Europe were used for genetic linkage analysis. The known recessive loci (8q and 16q) and the X-linked loci (PLP and L1CAM genes) were screened through PCR amplification, followed by linkage analysis, single-strand conformational polymorphism, or both. RESULTS: All the families except one revealed lack of linkage to the known loci for recessive and X-linked types of FSP. One of the eight families showed data consistent with linkage to the previously characterized 8q locus. Analysis of all the families for possible linkage to other candidate loci revealed significant positive lod scores for markers in chromosome 15q. The maximum multipoint combined lod score for the non-8q families was Z = 3.14 for markers D15S1007, D15S971, D15S118, and D15S1012, at a distance of 6.41 cM from the marker D15S1007, in between D15S971 and D15S118. CONCLUSIONS: Our data suggest a new locus for recessive FSP linked to chromosome 15q, and that this may be the most common one.

Adolescent↗
PubMed1999

Prenatal diagnosis in a family affected with beta-sarcoglycan muscular dystrophy.

We present here the first prenatal diagnosis in beta-sarcoglycan muscular dystrophy. The consultand was an 11-week pregnant mother of a girl diagnosed at the age of 3 years with beta-sarcoglycan muscular dystrophy based on the identification of two nonsense mutations in her beta-sarcoglycan gene and on the absence of beta-sarcoglycan in her muscle biopsy. The direct search for these mutations in the chorionic villus DNA of the fetus showed that the fetus did not inherit her sister mutations and thus, was reported as unaffected. We suggest that direct gene mutation detection is more reliable than linkage or protein study in the prenatal diagnosis of sarcoglycanopathies.

Child, Preschool↗
PubMed1999

Myotonic dystrophy: tissue-specific effect of somatic CTG expansions on allele-specific DMAHP/SIX5 expression.

Myotonic dystrophy (DM), the most common inherited muscle disorder, is caused by a CTG expansion in the 3"-untranslated region of a protein kinase gene ( DMPK ). The complex and variable phenotype is most likely caused by a complex molecular pathogenesis, including deficiency of the DMPK protein, a trans -dominant misregulation of RNA homeostasis and haploinsufficiency of a neighboring homeobox gene [DM locus-associated homeodomain protein (DMAHP )]. Here, we study the allele-specific transcriptional activity of the DMAHP/SIX5 gene in DM patient tissues. Using a quantitative fluorescent RT-PCR assay, we tested allele-specific accumulation of DMAHP/SIX5 transcripts in both total and poly(A)+pools. In muscle biopsies, we found that transcript reductions of DMAHP/SIX5 alleles in cis with CTG expansions correlated with the extent of expansion. A patient with approximately 90 CTG repeats in muscle DNA (normal n < 37) showed a 20% reduction of allele-specific transcript levels, while four other DM patients with larger expansions showed 80% reductions. The effects of the CTG expansions on DMAHP transcription were tissue specific: autopsy tissues from a patient with 1500 repeats showed 80% reductions in muscle and liver; however, RNA from other tissues (lung, aorta, heart conduction tissue, cerebellum) showed 0-20% reductions. Our results suggest that the effect of the CTG repeat on the DMAHP/SIX5 promoter is variable and tissue-specific. Our data are consistent with abnormalities of DMAHP/SIX5 probably having a more prominent role in disease pathogenesis in muscle, liver and brain, but being less important in other tissues.

Adult↗
PubMed1999

MR imaging findings in children with merosin-deficient congenital muscular dystrophy.

BACKGROUND AND PURPOSE: Our purpose was to determine the brain MR imaging characteristics of merosin-deficient congenital muscular dystrophy in children. METHODS: We reviewed the MR imaging findings of the brain in three children with known merosin-deficient congenital muscular dystrophy to determine the presence of any cerebral or cerebellar abnormalities of development or abnormalities of the white matter. RESULTS: In all three patients, there was normal formation of the cerebrum, the cerebellum, and no evidence of neuronal migration anomalies. All three patients had abnormal white matter in the cerebrum, with sparing of the corpus callosum, internal capsule, cerebellum, and brain stem. CONCLUSION: MR imaging of the brain in children with merosin-deficient congenital muscular dystrophy reveals a consistent pattern of white matter abnormality. We postulate that disruption of the blood-brain barrier associated with merosin deficiency leads to increased water content, resulting in abnormal white matter signal intensity.

Brain↗
PubMed1998

Walker-Warburg syndrome: neurologic features and muscle membrane structure.

Walker-Warburg syndrome is an autosomal-recessive genetic disorder characterized by congenital muscular dystrophy in association with complex developmental abnormalities of the central nervous system and the eyes. Two patients with Walker-Warburg syndrome are presented to demonstrate clinical variability. Previously unreported pathologic findings involving heart, muscle, spinal cord, and gall bladder are described, and the literature is reviewed. Histopathologic studies of the muscle membrane protein network in both Walker-Warburg syndrome patients reveal a decreased immunostaining for laminin alpha2 and beta-dystroglycan. The clinical, histologic, and biochemical variability in Walker-Warburg patients may reflect heterogeneity.

Brain↗