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G Meola

Publications and source records attributed to G Meola.

At least 19 recordsLinked to original sources
PubMed2006

Increased apoptosis, Huntingtin inclusions and altered differentiation in muscle cell cultures from Huntington's disease subjects.

Mutated huntingtin (htt) is ubiquitously expressed in tissues of Huntington's disease (HD) patients. In the brain, the mutated protein leads to neuronal cell dysfunction and death, associated with formation of htt-positive inclusions. Given increasing evidence of abnormalities in HD skeletal muscle, we extensively analyzed primary muscle cell cultures from seven HD subjects (including two unaffected mutation carriers). Myoblasts from presymptomatic and symptomatic HD subjects showed cellular abnormalities in vitro, namely mitochondrial depolarization, cytochrome c release, increased caspase-3, -8, and -9 activities, and defective cell differentiation. Another notable feature was the formation of htt inclusions in differentiated myotubes. This study helps to advance current knowledge about the downstream effects of the htt mutation in human tissues. Further applications may include drug screening using this human cellular model.

Apoptosis↗
PubMed2006

Italian guidelines for molecular analysis in myotonic dystrophies.

Myotonic dystrophies, the most common form of adult muscular dystrophy, comprise at least two forms, clinically and genetically heterogeneous. Myotonic dystrophy type 1 and type 2 are both caused by unstable repetitions in untranslated gene regions: a [CTG]n expansion in the 3' region of the DMPK gene on chromosome 19q13 (DM1) and [CCTG]n tetranucleotide repeat located in the first intron of the ZNF9 gene on chromosome 3q21 (DM2). DM clinical features are caused by a gain of functions RNA mechanism in which the CUG and CCUG repeats alter nuclear functions, including alternative splicing of shared genes. Southern blot and/or polymerase chain reaction PCR-based approaches allow the detection of DM mutations in almost 100% of cases, however, the expansion size and the elevated grade of somatic instability make molecular testing for DM a diagnostic challenge. The increased use of DNA testing for DM generates many questions regarding the indications and interpretations of the test which require standardized methods, routinely available in molecular genetic laboratories. Here, we propose Guidelines for the molecular diagnosis of DM1 and DM2 approved by the Italian Ministry of Health in 2005 (Piano Nazionale Linee Guida, PNLG). Best practice for DM molecular analysis in diagnostic application, presymptomatic and prenatal testing, using direct and indirect approaches are described, with particular attention focused on ethical, legal and social issues. Overviews of materials used in the molecular diagnosis, as well as internet resources, are also included.

Genetic Testing↗
PubMed2005

Human skeletal muscle sodium channelopathies.

Ion channels are transmembrane proteins that allow ions to flow in or out of the cell. Sodium and potassium channel activation and inactivation are the basis of action potential's production and conduction. During the past 15 years, ion channels have been implicated in diseases that have come to be known as the channelopathies. Over 30 mutations of the muscle channel gene SCN4A, which encodes the muscle voltage-gated sodium channel, have been described and associated with neuromuscular disorders like hypo- and hyper-kalaemic periodic paralyses (hypoPP and hyperPP), paramyotonia congenita, sodium channel myotonias and congenital myasthenic syndrome. Different mutations within the same gene (SCN4A) cause distinct clinical disorders, while mutations in different channel genes may result in similar phenotypes. In addition, identical sodium channel mutations can result in different clinical phenotypes (hyperPP or paramyotonia) in different members of the same family, suggesting that the genetic background and perhaps other epigenetic factors may influence the clinical expression of a particular mutation. This article reviews the clinical features of the skeletal muscle sodium channel diseases and highlights the phenotypic or genetic overlap in these disorders.

Humans↗
PubMed2004

New methods for molecular diagnosis and demonstration of the (CCTG)n mutation in myotonic dystrophy type 2 (DM2).

Myotonic dystrophy types 1 and 2 are autosomal dominant, multisystemic disorders with many similarities in their clinical manifestations. Myotonic dystrophy type 1 is caused by a (CTG)n expansion in the 3' untranslated region of the DMPK gene in 19q13.3 and myotonic dystrophy type 2 by a (CCTG)n expansion in intron 1 of ZNF9 in 3q21.3. However, the clinical diagnosis of myotonic dystrophy type 2 is more complex than that of myotonic dystrophy type 1, and conventional molecular genetic methods used for diagnosing myotonic dystrophy type 1 are insufficient for myotonic dystrophy type 2. Herein we describe two in situ hybridization protocols for the myotonic dystrophy type 2 mutation detection. Chromogenic in situ hybridization was used to detect both the genomic expansion and the mutant transcripts in muscle biopsy sections. Chromogenic in situ hybridization can be used in routine myotonic dystrophy type 2 diagnostics. Fluorescence in situ hybridization on extended DNA fibers was used to directly visualize the myotonic dystrophy type 2 mutation and to estimate the repeat expansion sizes.

Adult↗
PubMed2004

Treatment in myotonia and periodic paralysis.

The myotonic disorders, including the myotonic dystrophies (myotonic dystrophy type 1, DM1; myotonic dystrophy type 2, DM2/PROMM/PDM), the muscle channelopathies or non-dystrophic myotonias (chloride, sodium, calcium and potassium channelopathies) are all characterized by myotonia and muscle weakness despite different pathophysiology involved in these disorders. Myotonia may affect the eye, facial and jaw muscles as well as the hands and legs. It may be painful and disabling. Muscle weakness may be episodical as in the paralytic attacks of the sodium and calcium channelopathies or culminate in permanent muscle weakness as in the calcium channelopathies and some sodium channelopathies associated to specific point mutations. The severity of myotonia may fluctuate in the myotonic dystrophies, but weakness is usually fixed, affecting neck flexors, facial and jaw muscles as well as proximal and distal muscles of the limbs. Despite the recent progress in molecular genetics the precise mechanisms responsible for myotonia and weakness are not fully understood and there is no standardized treatment strategy. We present a review of selected treatment trials in the myotonic disorders and the muscle channelopathies, and discuss our experience in the treatment of myotonia and muscle weakness, with reference to the limits and advantages of treatment trials in this field.

Biopsy↗
PubMed2003

Histopathological differences of myotonic dystrophy type 1 (DM1) and PROMM/DM2.

Muscle biopsy findings in DM2 have been reported to be similar to those in DM1. The authors used myosin heavy chain immunohistochemistry and enzyme histochemistry for fiber type differentiation on muscle biopsies. Their results show that DM2 patients display a subpopulation of type 2 nuclear clump and other very small fibers and, hence, preferential type 2 fiber atrophy in contrast to type 1 fiber atrophy in DM1 patients.

Adult↗
PubMed2003

Executive dysfunction and avoidant personality trait in myotonic dystrophy type 1 (DM-1) and in proximal myotonic myopathy (PROMM/DM-2).

A previous study in proximal myotonic myopathy (PROMM/DM-2) and myotonic dystrophy type 1 (DM-1) using brain positron emission tomography demonstrated a reduced cerebral blood flow in the frontal and temporal regions associated with cognitive impairment. The objective was to investigate further cognitive and behavioural aspects in a new series of patients with DM-1 and PROMM/DM-2. Nineteen patients with genetically determined PROMM/DM-2 and 21 patients with moderately severe DM-1 underwent neuropsychological testing and neuropsychiatric interviews. DM-1 and PROMM/DM-2 patients had significantly lower scores on tests of frontal lobe function compared to controls. Neuropsychiatric interviews demonstrated an avoidant trait personality disorder in both patient groups. Brain single photon emission computed tomography showed frontal and parieto-occipital hypoperfusion. The results suggest that there is a specific cognitive and behavioural profile in PROMM/DM-2 and in DM-1, and that this profile is associated with hypoperfusion in frontal and parieto-occipital regions of the brain.

Adult↗
PubMed2003

Muscle biopsy and cell cultures: potential diagnostic tools in hereditary skeletal muscle channelopathies.

Hereditary muscle channelopathies are caused by dominant mutations in the genes encoding for subunits of muscle voltage-gated ion channels. Point mutations on the human skeletal muscle Na+ channel (Nav1.4) give rise to hyperkalemic periodic paralysis, potassium aggravated myotonia, paramyotonia congenita and hypokalemic periodic paralysis type 2. Point mutations on the human skeletal muscle Ca2+ channel give rise to hypokalemic periodic paralysis and malignant hyperthermia. Point mutations in the human skeletal chloride channel CIC-1 give rise to myotonia congenita. Point mutations in the inwardly rectifying K+ channel Kir2.1 give rise to a syndrome characterized by periodic paralysis, severe cardiac arrhythmias and skeletal alterations (Andersen's syndrome). Involvement of the same ion channel can thus give rise to different phenotypes. In addition, the same mutation can lead to different phenotypes or similar phenotypes can be caused by different mutations on the same or on different channel subtypes. Bearing in mind, the complexity of this field, the growing number of potential channelopathies (such as the myotonic dystrophies), and the time and cost of the genetic procedures, before a biomolecular approach is addressed, it is mandatory to apply strict diagnostic protocols to screen the patients. In this study we propose a protocol to be applied in the diagnosis of the hereditary muscle channelopathies and we demonstrate that muscle biopsy studies and muscle cell cultures may significantly contribute towards the correct diagnosis of the channel involved. DNA-based diagnosis is now a reality for many of the channelopathies. This has obvious genetic counselling, prognostic and therapeutic implications.

Adult↗
PubMed2000

Clinical and genetic heterogeneity in myotonic dystrophies.

This review of myotonic dystrophies primarily concentrates on the clinical and genetic findings that can distinguish a novel form of myotonic dystrophy, myotonic dystrophy type 2 (DM2); proximal myotonic myopathy (PROMM); and proximal myotonic dystrophy (PDM) from myotonic dystrophy type 1 (DM1). The multisystemic nature of these disorders leads to a spectrum of symptoms and signs. Careful clinical evaluation of patients with DM2/PROMM shows that the similarities among the multisystemic myotonic disorders outweigh the differences. An important point in the comparison of the phenotypes of DM1 and DM2/PROMM is that no severe congenital type of DM2/PROMM has yet been described. Genetic linkage analyses show that myotonic dystrophies can be divided into three types: the conventional Steinert type linked to chromosome 19q13.3 (DM1); DM2/PROMM and PDM linked to chromosome 3q21.3; and families not linked to either chromosomal site. Although the diagnosis may be clinically suspected, it depends on DNA analysis.

Chromosome Mapping↗
PubMed2000

Therapy in myotonic disorders and in muscle channelopathies.

Myotonia and muscle weakness are cardinal features of myotonic disorders including the myotonic dystrophies and the non-dystrophic myotonias. Despite the recent progress in molecular genetics of these myotonic disorders, the precise mechanisms responsible for myotonia and for permanent or episodic muscle weakness are still unclear. Treatment has been mostly symptomatic, independent of the disease process involved. Moreover, there have been few randomized controlled trials of treatment for myotonic disorders and consequently no standardized treatment regimens are available. We present a review of selected treatment trials in the myotonic disorders and in muscle channelopathies, and discuss, on the basis of our experience in the myotonic disorders, the limits and advantages of treatment trials in this field. Future genotype-phenotype correlations using the patch-clamp technique are also illustrated.

Calcium Channels↗
PubMed2000

Quantitative myotonia assessment: an experimental protocol.

Severe clinical myotonia can be physically disabling and socially impairing but as yet there is no standardized treatment regimen. The aim of our study is to present a protocol to measure myotonia using quantitative muscle assessment measures. The proposed protocol addresses two main issues. Muscle strength is assessed in 8 muscles on the right and on the left using a myometer (QMA, quantitative muscle assessment) and by testing strength manually using the 5-point MRC scale (5 = normal) in 15 muscles on the right and on the left. Grip myotonia is assessed by: (a) measuring 1/2 and 3/4 relaxation times (RT) after maximum voluntary contraction (MVC) using QMA apparatus; (b) functional tests (time to open a fist 10 times, time to open and squeeze the eyes 10 times, time to climb 10 steps starting from a seated position, time to protrude the tongue 10 times, time to step onto a chair 10 times; (c) subjective measures of the severity of myotonia using an arbitrary 4-point scale (0 = absent, 4 = severe); and (d) electromyography (EMG) relaxation times after MVC. Although QMA seems to be a reliable tool to measure myotonia, there are still a number of unsolved issues. Further studies are needed to ensure the ability of QMA to quantify myotonia and to guarantee the reliability of the results for clinical research purposes.

Clinical Protocols↗
PubMed2000

Myotonic dystrophies.

This review demonstrates genetic and phenotypic heterogeneity in all of the multisystemic myotonic disorders collectively called 'myotonic dystrophies' according to the new nomenclature: myotonic dystrophy type 1, myotonic dystrophy type 2, proximal myotonic myopathy and proximal myotonic dystrophy. Only two loci have so far been assigned (19q 13.3 in myotonic dystrophy type 1, and 3q 21.3 in myotonic dystrophy type 2). Although the diagnosis of these disorders may be suspected clinically, it needs to be confirmed by DNA analysis.

Humans↗
PubMed1999

Reduced cerebral blood flow and impaired visual-spatial function in proximal myotonic myopathy.

OBJECTIVE: To compare brain involvement in myotonic dystrophy (DM) with that of proximal myotonic myopathy (PROMM). BACKGROUND: PROMM is a multisystem disease with many features in common with DM. METHODS: Twenty patients with DM (CTGF[500-700), 20 patients with PROMM, and 20 normal control subjects were studied. Neuropsychological testing was performed in 12 patients with PROMM and in 18 patients with DM; brain MRI was performed in 17 of 20 PROMM patients and 15 of 20 DM patients. Ten patients with PROMM and 11 patients with DM were subjected to H2(15)O PET. RESULTS: Two-thirds of the patients with PROMM and one-half of those with DM were impaired on visual-spatial recall, whereas one-third of the patients with PROMM and less than half of those with DM showed an impairment in visual-spatial construction. Brain MRI was normal, or showed only nonspecific white matter abnormalities in both PROMM and DM patients. PET studies in PROMM patients showed a bilateral decrease in regional cerebral blood flow (rCBF) of the orbitofrontal and medial frontal cortex, whereas DM patients had more widespread hypoperfusion that extended to the dorsolateral frontal cortex and subcortical regions. CONCLUSIONS: Impaired visual-spatial function may be present in proximal myotonic myopathy. This correlates best with a reduction in regional cerebral blood flow observed in H2(15)O PET brain scans rather than with specific structural abnormalities observed on brain MRI.

Adolescent↗