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S Servidei

Publications and source records attributed to S Servidei.

At least 55 records · Page 3Linked to original sources
PubMed1998

Hereditary motor and sensory neuropathy with deafness, mental retardation, and absence of sensory large myelinated fibers: confirmation of a new entity.

We describe two brothers, 11 and 13 years old, respectively, with an early-onset hereditary motor and sensory neuropathy, deafness, and mental retardation. Electrophysiological studies showed marked reduction of motor and sensory conduction velocity and absence of sensory action potentials. Sural nerve biopsy, performed in both patients, showed absence of large myelinated fibers with normal density of small myelinated fibers without axonal degeneration. Signs of demyelination were found only in the younger patient. We suggest that motorsensory neuropathy associated with deafness and mental retardation with absence of large myelinated fibers on sural nerve biopsy represents a distinct clinicopathological entity, which is transmitted in families probably as an autosomal recessive trait.

Adolescent↗
PubMed1998

Functional involvement of cerebral cortex in Duchenne muscular dystrophy.

Transcranial stimulation was performed in 4 patients with Duchenne muscular dystrophy and 4 control subjects. The patients' central motor conduction time was normal. The threshold for evoking electromyographic responses using electrical anodal stimulation was the same in both groups, but the threshold for stimulation with a circular magnetic coil at the vertex was higher in the patients. This is compatible with reduced cortical excitability that may be related to the deficiency of brain synaptic dystrophin.

Adolescent↗
PubMed1998

A novel frameshift mutation 840delA and a novel polymorphism D203A in the steroidogenic acute regulatory protein gene in a Japanese patient with congenital lipoid adrenal hyperplasia. Mutations in brief no. 117. Online.

Congenital lipoid adrenal hyperplasia (CLAH) is an autosomalrecessive disorder characterized by impaired production of all steroids including glucocorticoids, mineralocorticoids and sexsteriods. It has recently been reported that mutations in the steriodogenic acute regulatory protein (StAR) gene cause CLAH. We analyzed the StAR gene in a Japanese patient with CLAH. The patient was revealed to be a compound heterozygote bearing a nonsense mutation Q258X, changing codon 258 (CAG) encoding Gln to the stop codon TAG, and a novel framshift mutation 840delA resulting from deletion of one of the three adenosines normally present in codon 238 (AAA), thus leading to a frameshift after codon 237 (Thr) in the StAR gene. The patient was also revealed to be homozygous for a novel missense point mutation D203A, changing codon 203 (GAC) encoding Asp to GCC encoding Ala in the StAR gene. To elucidate the significance of the D203A mutation, we analyzed the StAR gene sequence in twenty normal subjects, and found that all of them were homozygous for the D203A mutation, indicating that the D203A mutation is an innocent polymorphism. In conclusion, we have identified a novel frameshift mutation 840delA which seems to cause 840delA and the first polymorphism D203A in the human StAR gene.

Adrenal Hyperplasia, Congenital↗
PubMed1998

A late-onset mitochondrial myopathy is associated with a novel mitochondrial DNA (mtDNA) point mutation in the tRNA(Trp) gene.

We detected a novel pathogenic mutation, a G-->A transition at position 5521 of mitochondrial tRNA(Trp) gene, in association with familial late-onset mitochondrial myopathy. The mutation was detected in muscle but not in leukocytes from the family's proband. Morphological and biochemical studies documented a severe defect of muscle cytochrome c oxidase (COX) activity. RFLP analysis of single muscle fibers demonstrated segregation of higher percentages of mutated genomes in COX-negative ragged red fibres compared with normal fibers. A predominant impairment in synthesis of subunits I and III of complex IV due to their highest relative content of tryptophane might explain the greater susceptibility of complex IV to the pathogenic effect of this mutation. A progressive accumulation of mutated genomes in muscle can account for the late onset of symptoms observed in affected members.

Aged↗
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

Giant dystrophin deletion associated with congenital cataract and mild muscular dystrophy.

We report a patient with a large intragenic dystrophin deletion of exons 17-51 inclusive associated with congenital cataract and mild Becker muscular dystrophy. The cataract was similar to the congenital cataract described in the mdx mouse. The loss of 68% of the rod domain including hinge 2 and 3 regions did not adversely affect the correct localization of the dystrophin and the association with the dystrophin-associated glycoprotein complex. This observation may have implications for minigenes suitable for gene therapy.

Cataract↗
PubMed1997

Mitochondrial DNA deletions in oculopharyngeal muscular dystrophy.

The deletions in the mitochondrial DNA from skeletal muscle samples of two oculopharyngeal muscular dystrophy cases were studied using polymerase chain reaction techniques. The 4977 bp 'common deletion' was present in both specimens, exceeding the corresponding values of similarly aged, healthy controls. In the two samples multiple different mitochondrial DNA deletions, some case-specific and present at quite high, although not pathogenetic levels, were observed. The results suggest that mitochondrial DNA deletions, and the 'common deletion' in particular, might be a sensitive and early marker of a generalized mitochondrial suffering, due to a variety of pathological and physiological causes.

Base Sequence↗
PubMed1997

Asymptomatic dystrophinopathy.

A 4-year-old girl was referred for evaluation for a mild but persistent serum aspartate aminotransferase (AST) elevation detected incidentally during routine blood screening for a skin infection. Serum creatine kinase activity was found to be increased. Immunohistochemical study for dystrophin in her muscle biopsy showed results consistent with a carrier state for muscular dystrophy. Molecular work-up showed the proposita to be a carrier of a deletion mutation of exon 48 of the dystrophin gene. Four male relatives also had the deletion mutation, yet showed no clinical symptoms of muscular dystrophy (age range 8-58 yrs). Linkage analysis of the dystrophin gene in the family showed a spontaneous change of an STR45 allele, which could be due to either an intragenic double recombination event, or CA repeat length mutation leading to identical size alleles. To our knowledge, this is the first documentation of an asymptomatic dystrophinopathy in multiple males of advanced age. Based on molecular findings, this family would be given a diagnosis of Becker muscular dystrophy. This diagnosis implies the development of clinical symptoms, even though this family is clearly asymptomatic. This report underscores the caution which must be exercized when giving presymptomatic diagnoses based on molecular studies.

Adolescent↗
PubMed1997

Functional involvement of central nervous system in mitochondrial disorders.

Thirty-nine patients with mitochondrial diseases were studied with somatosensory and motor evoked potentials. Sixteen patients (41%) had clinical and 12 (31%) had neuroradiological evidence of central nervous system involvement. The overall incidence of electrophysiological abnormalities was 64%. Abnormal evoked potentials were also found in a significant percentage (33%) of patients with pure myopathic forms of mitochondrial diseases and in an asymptomatic carrier of MERRF mutation. Of the individual tests, somatosensory evoked potentials were abnormal in 49% of the patients and motor evoked potentials were abnormal in 46% of the patients. The outcome is that electrophysiological evidence of central nervous system involvement is present in a high percentage of patients with mitochondrial disorders, and that the threshold for central nervous system electrophysiological abnormalities is well below that for clinical and/or radiological manifestations.

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↗
PubMed1996

A novel mitochondrial DNA point mutation in the tRNA(Ile) gene is associated with progressive external ophtalmoplegia.

We report a new mutation, a T-->C transition at nt.4285 in the mitochondrial tRNA(Ile) gene, in a sporadic case of progressive external ophtalmoplegia (PEO) and ragged-red fibers (RRF). The mutation, involving a highly conserved base-pair in the anticodon stem, was detected in high percentages (91%) in muscle, but not in blood. It has never been reported in literature in normal subjects and it was not found in any of 80 controls studied in our laboratory. The absence of the mutation in leukocytes in this case with pure muscle involvement confirms the importance of performing mtDNA studies in PEO patients preferentially on muscle rather than blood, which could give false negative results. Other mutations in the tRNA(Ile) gene associated with different phenotypes have been previously reported. Thus, tRNA(Ile) gene is confirmed to be another "hot spot" region for mtDNA mutations.

Adolescent↗
PubMed1996

Partial block of glycolysis in late-onset phosphofructokinase deficiency myopathy.

A late-onset, myopathic variant of phosphofructokinase (PFK) deficiency has been previously described in two patients of Ashkenazic descent. We report here on a non-Ashkenazic woman with the onset, at the age of 48 years, of a progressive limb girdle myopathy that was not preceded by a history of exercise intolerance. Muscle biopsy findings at the age of 58 years showed deposition of amylopectin-like material in muscle fibers and the absence of histochemical PFK activity. Enzymatic PFK activity in vitro was only 4% of normal. Since the forearm ischemic exercise test induced a sub-normal production of serum lactate, the patient underwent phosphorus magnetic resonance spectroscopy (31P-MRS), a non-invasive method that allows in vivo assessment of the functional status of the glycolytic pathway and mitochondrial oxidative metabolism by measuring the high-energy phosphates and cytosolic pH. In vivo, 31P-MRS disclosed a residual glycolytic flux and a normal rate of ATP production both at rest and during exercise. These results suggest that, in some patients, muscle PFK deficiency may be partial in vivo, and more severe in vitro, possibly due to protein or mRNA instability rather than absence. The presence of these findings in a patient with the late-onset myopathic form is compatible with a distinct pathogenetic mechanism, relying on progressive polysaccharide accumulation, rather than on acute energetic shortage in muscle fibers.

Female↗
PubMed1996

Clinical heterogeneity of seronegative myasthenia gravis.

We studied 38 patients affected by seronegative myasthenia gravis (SNMG) with age at the onset of the disease ranging from 6 to 66 yr. Clinical follow-up lasted at least 2 yr. Patients' lymphocyte cultures showed in no case anti-acetylcholine receptor antibody production; HLA associations did not differ significantly from those in seropositive MG. In most cases (33 out of 38) the disease differed from seropositive MG only in the low incidence of thymic pathology. In five cases the clinical picture was characterized by prevalent involvement of ocular and bulbar muscles and by a more stable course. These last group of patients did not respond satisfactorily to immunosuppressants, but they clearly improved with plasma-exchange. Mice injected with plasma IgG from four patients (two with typical clinical picture and two with prevalent oculobulbar involvement) showed a defect of neuromuscular transmission. In our experience, SNMG is a heterogeneous disease. A humorally mediated pathogenesis appears to be operating in both groups of patients we described.

Adolescent↗
PubMed1996

A gene for familial paroxysmal dyskinesia (FPD1) maps to chromosome 2q.

Dyskinesias are hyperkinetic and involuntary movements that may result from any of a number of different genetic, infectious, and drug-induced causes. Some of the hereditary dyskinetic syndromes are characterized by paroxysmal onset of the abnormal movements. The classification of the familial paroxysmal dyskinesias (FPD) recognizes several distinct, although overlapping, phenotypes. Different forms of the disorder include attacks that are (1) induced by sudden movement (kinesiogenic); (2) spontaneous (non-kinesiogenic); and (3) induced by prolonged periods of exertion. Linkage analysis was pursued in a family segregating an autosomal dominant allele for non-kinesiogenic FPD. The disease allele was mapped to a locus on chromosome 2q31-36 (LOD score 4.64, theta = 0). Identification of distinct genetic loci for the paroxysmal dyskinesias will lead to a new genetic classification and to better understanding of these disorders.

Alleles↗
PubMed1995

Genetic homogeneity between childhood-onset and adult-onset autosomal recessive spinal muscular atrophy.

Molecular diagnosis of childhood proximal spinal muscular atrophy has been enhanced by the discovery of the survival motor neuron (SMN) gene, which is absent or truncated in 98.6% of patients. To determine whether deletion analysis of the SMN gene may also be diagnostic for adult-onset disease, we studied six patients and found deletions in all. This finding will facilitate the diagnosis of adult-onset spinal muscular atrophy, and provides evidence for genetic homogeneity between the clinically diverse adult and childhood forms of the disease.

Adult↗
PubMed1995

Analysis of peristaltic reflex in young mdx dystrophic mice.

Experiments have been carried out in isolated distal colon of young normal and mdx dystrophic mice, the animal homologous of Duchenne muscular dystrophy. Intraluminal pressure, longitudinal displacement, ejected fluid volume and changes in morphology during peristaltic events were recorded. In both male and female normal animals, pressure waves were observed to be generally regular in shape, amplitude (14.19 +/- 2.45 (SD) cm H2O), frequency (54.00 +/- 10.78 h-1) and duration (31.12 +/- 3.47 s). The propulsive activity resulted in orthograde transport of intraluminal content. Mdx mice exhibited great changes in relation to sex, since clear and more marked dysfunctions were recorded in female mice. In male mdx animals, an increase of intraluminal pressure (22%) and ejected fluid volume (38%) were recorded. In females, a remarkable significant (P < 0.001) increase (78%) of intraluminal pressure was observed. Simultaneous anterograde and retrograde propulsive activity also occurred. Localized annular constrictions in proximal, central and distal portions of colonic segment were observed. The implications of the results are discussed in terms of injury of myogenic and nervous pathways controlling mdx colonic smooth muscle.

Animals↗