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G P Comi

Publications and source records attributed to G P Comi.

At least 55 records · Page 3Linked to original sources
PubMed1999

Loss-of-function mutations of SURF-1 are specifically associated with Leigh syndrome with cytochrome c oxidase deficiency.

Mutations of SURF-1, a gene located on chromosome 9q34, have recently been identified in patients affected by Leigh syndrome (LS), associated with deficiency of cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain. To investigate to what extent SURF-1 is responsible for human disorders because of COX deficiency, we undertook sequence analysis of the SURF-1 gene in 46 unrelated patients. We analyzed 24 COX-defective patients classified as having typical Leigh syndrome (LS(COX)), 6 patients classified as Leigh-like (LL(COX)) cases, and 16 patients classified as non-LS(COX) cases. Frameshift, stop, and splice mutations of SURF-1 were detected in 18 of 24 (75%) of the LS(COX) cases. No mutations were found in the LL(COX) and non-LS(COX) group of patients. Rescue of the COX phenotype was observed in transfected cells from patients harboring SURF-1 mutations, but not in transfected cell lines from 2 patients in whom no mutations were detected by sequence analysis. Loss of function of SURF-1 protein is specifically associated with LS(COX), although a proportion of LS(COX) cases must be the result of abnormalities in genes other than SURF-1. SURF-1 is the first nuclear gene to be consistently mutated in a major category of respiratory chain defects. DNA analysis can now be used to accurately diagnose LS(COX), a common subtype of Leigh syndrome.

Child, Preschool↗
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

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↗
PubMed1997

The apolipoprotein E epsilon4 allele causes a faster decline of cognitive performances in Down's syndrome subjects.

The apolipoprotein E gene (APOE), located on human chromosome 19, has three common alleles (epsilon2, epsilon3, epsilon4) which encode for the three main isoforms indicated as E2, E3 and E4 respectively. Several findings indicate epsilon4 allele as an important risk factor in both sporadic and familial late-onset Alzheimer's disease (AD). Pathological changes similar to AD are seen in almost all patients with Down's syndrome (DS) aged over 35 (senile plaques, neurofibrillary tangles and neuronal loss); a proportion of these may subsequently develop dementia. Aim of this study is to evaluate the possible pathological role of epsilon4 allele as risk factor for developing AD in a DS population. ApoE epsilon4 allele frequency is not significantly different in DS cases and controls. We found a statistically significant inverse correlation between full scale IQ values and age of patients in the subgroup of DS subjects selected for the presence of at least one epsilon4 allele, while no correlation was observed in DS subjects with other ApoE genotypes. A longitudinal analysis of cognitive performances (available in 38 patients) showed a faster rate of decline in intellectual ability in those subjects carrying at least one epsilon4 allele. Our data support the hypothesis that ApoE epsilon4 allele has a contributory role in accelerating the mental deterioration of AD-type in DS patients.

Adolescent↗
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

Ryanodine receptor gene point mutation and malignant hyperthermia susceptibility.

Malignant hyperthermia (MH) is a rare clinical syndrome, triggered in susceptible subjects by a variety of anaesthetic agents and muscle relaxants, and is the commonest cause of death due to general anaesthesia. Previous studies have reported that inherited mutations in the ryanodine receptor (RYR1) gene co-segregated, in some families, with MH susceptibility; lack of linkage between MH and the RYR1 gene in some other families indicates a heterogenous genetic basis for the syndrome. The in vitro contracture test (IVCT) on muscle biopsy specimens is considered to be the most reliable test for establishing the diagnosis of MH. With the identification of RYR1 point mutations this might in turn result in non-invasive methods for the presymptomatic diagnosis of MH. In the present study we investigated four families suspected to be at risk of MH susceptibility; in all subjects histopathological examination and IVCT were performed on muscle biopsy specimens. We undertook a mutation analysis of RYR1 gene testing for the presence of five point mutations; in one pedigree a C1840-->T point mutation was detected, strictly segregating with in vitro MH susceptibility.

Adolescent↗
PubMed1995

Duplication of dystrophin gene and dissimilar clinical phenotype in the same family.

We report here three related patients with a duplication of exons 19-41 of the dystrophin gene, having dissimilar clinical phenotype and dystrophin immunohistochemistry. Two brothers aged six and three years had myalgia, proximal muscular weakness and hypertrophic calves, with 10- 20-fold increase of serum creatine kinase. Muscle biopsy showed dystrophic changes and reduced, patchy binding of dystrophin. The clinical and laboratory findings were consistent with a diagnosis of Becker muscular dystrophy with early onset. Their 14-year-old cousin had only mild hyperCKemia. His muscle biopsy was normal with only mild reduction of dystrophin immunostaining. At follow-up, he is still without symptoms and signs at age 19. All three patients had the same gene duplication and an increased dystrophin size of 507 kDa. Expression of the dystrophin-associated glycoproteins adhalin, alpha-dystroglycan, and beta-dystroglycan were normal in the three patients. An intrafamilial variability in patients carrying a partial duplication of the dystrophin gene may be related to a quantitative difference in mRNA.

Blotting, Southern↗
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

Cognitive impairment in Duchenne muscular dystrophy.

Cognitive function and dystrophin gene mutations were investigated in 50 DMD patients (mean age 11.1 yr; range 3.5-20.3). General intelligence assessment showed 31% of patients with Wechsler full intelligence quotient (FIQ) lower than 75 (normal values: 100 +/- 14), and only 24% with appropriate FIQ level. Modal distribution of Wechsler verbal, performance, and FIQs, and Raven IQs was normal. Verbal IQ was more affected than performance IQ (PIQ) only in the younger group of subjects. Low PIQ correlated with the presence of macroglossia, detected in 13 out of 50 patients. Impairment of productive language was of non-dysphasic nature and correlated with defects of short-term memory, which was also affected in non-verbal skills. DMD patients shared the same spectrum of neuropsychological defects, regardless of whether they were or were not mentally retarded. The proportion of patients with dystrophin gene deletions was 64%. No statistically significant correlations were found between genetic data and psychometric assessment. Finally, (18F)-fluorodeoxyglucose positron emission tomography studies demonstrated cerebellar hypometabolism in all the DMD patients examined and variable involvement of associative cortical areas. These findings suggest a possible role of the cerebral and cerebellar hypometabolism in the cognitive impairment of DMD.

Adolescent↗