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Biomedical subjects

M Moggio

Publications and source records attributed to M Moggio.

At least 37 records · Page 2Linked to original sources
PubMed1998

Cytochrome c oxidase subunit I microdeletion in a patient with motor neuron disease.

An out-of-frame mutation of the mitochondrial DNA-encoded subunit I of cytochrome c oxidase (COX) was discovered during investigation of a severe isolated muscle COX deficiency in a patient with motor neuron-like degeneration. The mutation is a heteroplasmic 5-bp microdeletion located in the 5' end of the COI gene, leading to premature termination of the corresponding translation product. Western blot analysis, immunohistochemistry, and single-fiber polymerase chain reaction demonstrated a tight correlation between COX defect, COX I expression, and percentage of mutation. COX subunits II, III, and IV were decreased as well, suggesting a defective assembly of COX holoenzyme. The mutation was associated with a clinical phenotype unusual for a mitochondrial disorder, that is, an isolated motor neuron disease (MND) with some atypical findings, including early onset, preferential involvement of the upper motor neuron, and increased cerebrospinal fluid protein content. MND may arise from impaired scavenging and overproduction of free oxygen radicals, a by-product of oxidative phosphorylation (OXPHOS). Our observation suggests that OXPHOS impairment could play a role in the pathogenesis of some MND cases.

Adult↗
PubMed1998

Sarcoglycan deficiency in a large Italian population of myopathic patients.

Autosomal recessive limb-girdle muscular dystrophies are a heterogeneous group of genetic diseases with a wide spectrum of clinical severity and age of onset; mutations in the gene encoding the dystrophin-associated sarcoglycan proteins (alpha, beta, gamma and delta) have recently been shown to cause some cases of these myopathies (primary sarcoglycanopathies, types 2D, 2E, 2C and 2F, respectively). In this study we have examined a large population of Italian myopathic patients to determine the frequency of (alpha-, beta- and gamma-sarcoglycan deficiency and to correlate molecular defects with clinical phenotypes; to exclude the presence of primary dystrophinopathies both genetic and immunological analysis of dystrophin was performed. We report 12 patients (10 male and 2 female) with deficiency of either one or more sarcoglycan proteins. They were aged 8-56 years with onset between 4 and 30 years of age; they all presented with either mild, moderate or severe limb-girdle involvement associated with elevated blood creatine kinase levels and myopathic pattern at EMG; one was also affected with a mild dilation cardiomyopathy. All patients, except one, showed pathological muscle histological changes. Absence of all three proteins always correlates with severe forms, whereas mild protein deficiencies or isolated partial alpha-sarcoglycan deficiency correlate with either severe, moderate or mild forms.

Adolescent↗
PubMed1998

Polyneuropathy due to cobalamin deficiency in the rat.

In the present study, we investigated the peripheral nervous system (PNS) (both in terms of its ultrastructure and in terms of its function) of rats made cobalamin (Cbl)-deficient either through total gastrectomy or through prolonged feeding on a Cbl-deficient diet. In both these types of Cbl-deficient neuropathies we found: (a) ultrastructurally, intramyelin and endoneural edema, with no or minimal axonal damage in the PNS, in dorsal root ganglia, and the ventral and dorsal rootlets of the spinal cord; (b) electrophysiologically, a significant reduction in the nerve conduction velocity, consistent with that reported in (a); (c) morphometrically, a significant reduction in the density of myelinated fibers both in the sciatic nerve and in the peroneal nerve. All these pathological changes were reversed by chronic postoperative administration of Cbl into totally gastrectomized (TGX)-rats, hinting at the specificity of the damage itself in relation to the permanent Cbl-deficient status of the TGX-rats. No signs of segmental demyelination or remyelination were found. We also observed a turning of type I fibers into type II fibers in the soleus muscle of all our Cbl-deficient rats, however the Cbl deficiency had been induced. This muscular change was still present in TGX- and Cbl-treated rats, and it cannot be related to a malnutrition status, since it has been observed also in rats fed a Cbl-deficient diet. All these results demonstrate that Cbl deficiency strongly affects rat PNS within different parameters.

Animals↗
PubMed1998

Partial depletion and multiple deletions of muscle mtDNA in familial MNGIE syndrome.

OBJECTIVE: To describe the unique combination of partial depletion and multiple deletions of mitochondrial DNA (mtDNA) on muscle DNA analysis of three siblings with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). BACKGROUND: MNGIE is a relatively homogeneous autosomal recessive disorder characterized by gastrointestinal dysmobility, ophthalmoparesis, peripheral neuropathy, mitochondrial myopathy, and altered white matter signal at brain imaging. Muscle multiple mtDNA deletions have been found in about half of the described cases. METHODS: We studied three affected siblings (two were monozygotic twins) born to nonconsanguineous parents. Muscle mtDNA was investigated by quantitative Southern and Slot blot techniques and by PCR analysis. Morphologic confirmation in the muscle tissue was achieved by using in situ hybridization with a mtDNA probe complementary to an undeleted region and by DNA immunohistochemistry. RESULTS: All three patients showed ragged red (RRF) and cytochrome c oxidase-negative fibers, as well as partial deficiency of complexes I and IV. Southern and Slot blot analyses showed mtDNA depletion in all patients. Multiple mtDNA deletions were also detected by PCR analysis. In situ hybridization demonstrated an overall signal weaker than controls, with a relatively higher signal in RRF. Antibodies against DNA showed a decreased cytoplasmic network. CONCLUSIONS: The muscle histopathology and respiratory chain enzyme defects may be accounted for by the decreased mtDNA amount and by the presence of mtDNA deleted molecules; however, relative levels of mtDNA seem to correlate with life span in these patients. The combination of partial depletion and multiple deletions of mtDNA might indicate the derangement of a common genetic mechanism controlling mtDNA copy number and integrity.

Biopsy↗
PubMed1996

Asymptomatic familial hyperCKemia associated with desmin accumulation in skeletal muscle.

We describe a family, two brothers and their mother, who came to our observation because of slight to moderate hyperCKemia. The younger brother, who had the highest CK values, was only suffering from episodic myalgia, the other two members of the family were asymptomatic. Neurological examination was normal. Both brothers underwent muscle biopsy which was significant for the presence of abnormal sarcoplasmic areas of desmin accumulation. So far, desmin abnormalities have never been reported in patients with such a mild neuromuscular pattern. We discuss possible correlations between severity of clinical phenotype and degree of desmin accumulation.

Adult↗
PubMed1995

High serum creatine kinase levels associated with cylindrical spirals at muscle biopsy.

We studied the muscle biopsy from an asymptomatic patient with high serum creatine kinase values. Subsarcolemmal and intermyofibrillar granular inclusions were seen at the light microscopy level. Ultrastructural observation showed clusters of cylindrical spirals (CS). CS are nonspecific, morphological finding, so far reported only in a few cases, presenting with a wide variety of clinical phenotypes. The case we describe is peculiar because of the complete lack of clinical symptoms. The nature of the CS is unknown; we studied a possible alteration of cytoskeletal proteins using a set of different antibodies against these structures, but none of them reacted with CS. Also, since CS have been described in association with mitochondrial abnormalities, and since in our case CS were strongly positive when stained for succinate dehydrogenase, we performed specific immunohistochemical and genetic studies which ruled out any major mitochondrial alterations.

Adult↗
PubMed1995

Utrophin expression during human fetal development.

Utrophin, a protein encoded by chromosome 6 is highly homologous to the cysteine-rich domain and most of the C-terminal domain of dystrophin. In order to clarify its functional role we analyzed its expression during human fetal development. We carried out immunohistochemical analysis on muscle from normal human fetuses at different ages of gestation using an antibody directed against a specific COOH-terminal sequence of the protein. In addition, we stained serial sections with antibodies against dystrophin and alpha-bungarotoxin FITC-BTX. Our findings show that, at week 9 of gestation, utrophin is diffusely expressed in the cytoplasm. From week 12 to 22 the immunostaining is still cytoplasmic, though the reaction intensity progressively decreases. Moreover we observed a strong reaction in fetal nerve at week 18 and 22. There was no correlation between utrophin expression and progressive dystrophin membrane localization.

Amino Acid Sequence↗
PubMed1994

Anionic phospholipids calcium binding sites in Duchenne and murine X-linked muscular dystrophy.

Duchenne muscular dystrophy (DMD) and murine X-linked muscular dystrophy (mdx) are genetically homologous and both characterized by absence of dystrophin. The function of this protein is not defined nor is the pathogenesis of the severe muscle necrosis and progressive weakness found in DMD but not in mdx. Recently we found that anionic phospholipid (AP) calcium binding sites are lacking at the muscle cell surface in DMD and we correlated these data with dystrophin deficiency and muscle necrosis. In order to verify the role of AP lack in the pathogenesis of muscle necrosis in DMD we studied the ultrastructural localization of these Ca++ receptors in mdx muscle membrane showing that they are normally represented as they are in control mouse and normal human muscle. The absence of AP in DMD compared with a normal distribution in mdx suggests that these calcium binding site alterations play an important and specific role in muscle fiber necrosis.

Animals↗
PubMed1994

Mitochondrial myopathy: correlation between oxidative defect and mitochondrial DNA deletions at single fiber level.

In situ hybridization combined with immunohistochemical techniques has been applied to study patients affected by mitochondrial myopathies with large mitochondrial (mt)DNA deletions. All patients' muscle biopsies showed ragged red fibers (RRFs) and cytochrome oxidase (COX) deficiency. Two digoxigenin-labeled, polymerase chain reaction (PCR)-amplified DNAs were used as probes. One probe was designed to hybridize only with wild-type mtDNAs, while the other recognized both wild-type and deleted mtDNAs. Concomitant immunocytochemical analysis using antibodies against subunits II, III, (encoded by mtDNA) and IV (encoded by nuclear DNA) of COX was carried out. In our patients deleted mtDNAs are overexpressed in COX-negative RRFs, while wild-type mtDNAs are decreased in the same fibers. Immunohistochemistry studies show that COX IV is overexpressed in RRFs and that COX II and COX III subunits are still present. Deleted mtDNAs are spatially segregated in muscle fibers, where they interfere with the local population of normal mitochondrial genomes, causing a regional deficiency of the mitochondrial respiratory activity.

Adolescent↗
PubMed1994

Multiple sclerosis and mitochondrial myopathy: an unusual combination of diseases.

A woman with definite multiple sclerosis (MS) and mitochondrial myopathy is described. There were widespread white matter lesions on magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) abnormalities and evoked response changes. Muscle biopsy showed ragged red fibres (RRFs) and cytochrome c oxidase (CoX) deficiency. Southern blot analysis revealed a large deletion of mitochondrial DNA (mtDNA). The patient may be affected by two unrelated diseases, MS and mitochondrial myopathy, but this combination has never previously been reported.

Biopsy↗
PubMed1994

Multiple deletions of mitochondrial DNA in sporadic and atypical cases of encephalomyopathy.

Multiple deletions of mitochondrial DNA (mtDNA) were first identified in patients with mitochondrial encephalomyopathy with a clear mendelian inheritance. We found this genetic alteration in four atypical and sporadic cases of mitochondrial encephalomyopathy, characterized by RRF and partial COX deficiency. One patient was affected by essential hyperCPKemia, 1 by subacute onset flaccid tetraplegia and 2 by parkinsonism. Southern blot and PCR revealed mtDNA multiple deletions in muscle tissue of these patients. These findings indicate that these alterations are not confined to the families with mendelian transmission, but can be present in sporadic cases with heterogeneous phenotypic features.

Aged↗
PubMed1994

Clinical variability in Becker muscular dystrophy. Genetic, biochemical and immunohistochemical correlates.

We have investigated 59 Becker muscular dystrophy patients, representing 56 independent mutations, to test the hypothesis of predictability of muscle dystrophin expression and clinical phenotype based on location of dystrophin gene mutations. Partial intragenic deletions and duplications account for 82% of the independent mutations, of which 76.7% were deletions and 5.3% duplications. Mutations in which boundaries could be defined, were of in-frame type (35 out of 37, 94.6%, with two exceptions. Eighty-two percent of mutations were located at the distal part of the rod domain (exons 45-60), 9% at domain I (promoter through exon 9) and 9% at proximal and central parts of domain II. Domain I deleted patients tended to have a worse clinical phenotype, with earlier presentation, faster progression rate and lower dystrophin expression, while distal rod domain deleted patients showed a more classic Becker muscular dystrophy phenotype. Between these two groups, only the differences in the immunohistochemical patterns of dystrophin expression and disease progression rate were statistically significant. Partial clinical and biochemical heterogeneity was observed in the distal domain II patient group, due to the presence of few patients covering the extremities of clinical severity. Two asymptomatic patients had deletions located in the central (exons 41-44) and distal parts (exons 50-53) of the rod domain. Severe myalgia and cramps were often reported as early onset symptoms (18 out of 59): no correlation was found between this symptomatology and the location of the mutation. Relative levels of muscle dystrophin correlated with immunohistochemical patterns of subsarcolemma staining. Dystrophin levels (as estimated by 30 kDa antibody immuno-reactivity) correlated with age of reaching a moderate degree of muscle involvement as well as with delay in reaching that stage, a parameter of disease progression rate. Our data confirm that different Becker muscular dystrophy gene in-frame mutations have different effects on dystrophin expression and clinical severity, indicating several functional roles of the dystrophin domains.

Adolescent↗
PubMed1993

Decrease of nerve Na+,K(+)-ATPase activity in the pathogenesis of human diabetic neuropathy.

A decrease in Na+,K(+)-ATPase activity is claimed to play a central role in the pathogenesis of electrophysiological and morphological abnormalities that characterize the neuropathic complications in different animal models of diabetes mellitus. The peripheral nerves from 17 patients with either type I or type II diabetes mellitus were studied to assess the importance of changes in Na+,K(+)-ATPase activity in chronic human diabetic neuropathy. Sixteen nerves from age- and sex-matched normal individuals, and 12 nerves from non-diabetic neuropathic subjects undergoing vascular or orthopedic surgery served as negative and positive controls, respectively. All specimens were processed blind. Ouabain-sensitive ATPase activity was measured by a modified spectrophotometric coupled-enzyme assay. Standard histology, fiber teasing and electron microscopy were used to establish the normal or neuropathological patterns of surgical material. Morphometric analysis permitted calculation of fiber density in each nerve specimen and correlation of this figure with the relevant enzymatic activity. Na+,K(+)-ATPase activity was approximately 59% lower in nerves from diabetic patients than in normal controls (P < 0.01) and approximately 38% lower in nerves from non-diabetic patients with neuropathy (P < 0.01). Although nerves from both neuropathic conditions had significantly fewer fibers than those from normal individuals (diabetic -33%, and non-diabetic -22%), the decreases in Na+,K(+)-ATPase activity and fiber density were not correlated only in specimens from diabetic patients (r2 = 0.096; P = 0.22). Taken together with data from experimental animal models, these results suggest that the reduction in Na+,K(+)-ATPase activity in diabetic nerves is not an epiphenomenon secondary to fiber loss; rather, it may be an important factor in the pathogenesis and self-maintenance of human diabetic neuropathy.

Adult↗
PubMed1993

Multiple deletions of mitochondrial DNA in a patient with periodic attacks of paralysis.

In this study multiple deletions of mitochondrial genome were found in a patient presenting with periodic attacks of paralysis. Morphological studies revealed mitochondrial abnormalities along with typical histopathological features of periodic paralysis. Southern blot and PCR analysis revealed multiple mtDNA deletions. Our patient could be affected by two unrelated diseases, idiopathic periodic paralysis and presymptomatic mitochondrial myopathy. Alternatively, mtDNA alterations and oxidative deficiency might express themselves phenotypically as periodic paralytic attacks, although this correlation has never been reported.

Biopsy↗