Propriospinal myoclonus with life threatening tonic spasms as paraneoplastic presentation of breast cancer.
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Antibodies, Anti-Idiotypic↗
Biomedical subjects
F Cornelio
Publications and source records attributed to F Cornelio.
Sequential antibodies to potassium channels and glutamic acid decarboxylase in neuromyotonia.
A patient with thymoma-associated neuromyotonia and voltage-gated potassium channel (Kv1.2 and Kv1.6) antibodies by immunoprecipitation and rat brain immunolabeling was treated successfully with immunoadsorption and cyclophosphamide. Curiously, glutamic acid decarboxylase antibodies, absent at onset, appeared later. Stiff-person syndrome was absent, but fast blink reflex recovery suggested enhanced brainstem excitability. The range of antibodies produced in thymoma-associated neuromyotonia is richer, and the timing of antibody appearance more complex, than previously suspected.
Adult↗
Aging and vestibular system: specific tests and role of melatonin in cognitive involvement.
Balance disorders are frequent with aging. They are particularly important because they decrease social autonomy of the aged subjects and they often provoke falls. The cause is always multifactorial. There is evidence that aging affects multiple sensory inputs, as well as the muscoloskeletal system and central nervous system ability to perform sensorimotor integration. For the evaluation of decreased balance skills in elderly, a specific questionnaire has been prepared, in order to identify high risk of falling called falling risk inventory (FRI) questionnaire, and a complex psycho-sensory-motor test has been studied by means of posturography, in order to detect specific vestibular impairment. Regarding ethiopathogenesis of balance disorders in aged subjects, because the decline of behavioral and cognitive performances are due also to decline of biological rhythm control, the role of melatonin (the hormone regulating circadian rhythms, being strictly connected with cerebellar function, and it is well known that cerebellum acts in elderly both at motor and cognitive regulation. The goals of the present paper are: (i) To present a self-administered FRI questionnaire aimed at identifying possible causes of falls and quantifying falling risk in aged. (ii) To validate posturography as a specific test to investigate vestibular involvement in elderly in correlation with FRI. (iii) To present a complex behavioral test (NT) aimed at evaluating both spatial orientation and spatial memory in elderly, factors involved into the genesis of complex dizziness and unsteadiness. (iv) To evaluate the role of melatonin in cognitive involvement in dizzy, old subjects due to the functional correlations between circadian rhythms, cerebellum balance disturbances and cognitive disorders. General conclusions are: FRI correlates with falling risk. Posturography identifies specific vestibular impairments correlated to balance disorders and elderly falls. Spatial orientation is altered in about 40% of dizzy patients but no significant differences are revealed in melatonin rhythm. Spatial memory is highly altered only in subjects with inversion of circadian melatonin rhythm it is possible to hypothesize that the alteration of the normal circadian melatonin rhythm plays some role in the genesis of dizziness in a subpopulation of patients.
Accidental Falls↗
Vestibular evoked myogenic potentials in multiple sclerosis: clinical and imaging correlations.
Patients with multiple sclerosis (MS) frequently report symptoms related to vestibular disorders in the course of their disease. At present, the fundamental tests assessing vestibulospinal involvement are posturography and vestibular evoked myogenic potentials (VEMPs). While posturography cannot be performed in every subject requiring minimal stance control, VEMPs do not require any specific skill on the part of the subjects and they may be investigated in all patients able to sit. VEMPs were recorded for 40 patients (17 men, 23 women; mean age 38 years, range 17-71 years) fulfilling diagnostic criteria of clinically defined MS, by means of rarefaction clicks, recording modulation of sterno-cleido-mastoideus tonic contraction saccule-mediated modulation. VEMPs were found to be abnormal in 28 of 40 patients. In 18 of the cases the VEMPs were asymmetric, i.e., had a prolonged latency on one side. In six cases latency was increased on both sides (mean delay 4.1 ms). In four subjects VEMPs were absent on one side. Concordance with clinical findings of presence/absence of brainstem involvement was found in 55% and with MRI findings in 65% of the cases. Abnormal VEMPs indicated brainstem dysfunction in four patients (10%) with normal MRI and no specific clinical signs.
Adolescent↗
Bone mineral density and bone metabolism in Duchenne muscular dystrophy.
Very few studies on bone mineral density and bone metabolism in Duchenne muscular dystrophy (DMD) have been reported. DMD is a severe, progressive muscular disease resulting in death at a young age. No specific therapies are available, but corticosteroids induce improvement and slower progression of the disease. However, long-term steroid therapy is a serious risk factor for osteoporosis. This study was aimed at evaluating bone mineral density and calciotropic hormones in a group of children affected by DMD, with or without steroid therapy. Bone mineral density was measured by DXA scan on lumbar spine and total body. Evaluation of calcium, phosphorus, bone turnover markers and calciotropic hormones was performed. Thirty-two children affected by DMD were studied: twenty-two on long-term prednisone therapy, ten not taking corticosteroids. Bone mineral density was lower than normal for age in all patients, and even lower in the group of steroid-treated children. Trunk and lower limb bone mineral densities were more reduced than upper limb mineral density, especially in the steroid-treated subjects. A marked reduction in spine bone mineral density, hypocalciuria, low 25-hydroxyvitamin D levels, and increased bone turnover markers were observed, and even these especially in the steroid-treated group. In conclusion, decreased bone mineral density and derangement of calcium metabolism were present in DMD patients, and were worsening during corticosteroid therapy. It is thus recommended that bone and mineral metabolism be carefully evaluated in patients with DMD, so that appropriate measures could be taken, especially now that chronic corticosteroid therapy is frequently given.
25-Hydroxyvitamin D 2↗
Dystrophic phenotype of canine X-linked muscular dystrophy is mitigated by adenovirus-mediated utrophin gene transfer.
Utrophin is highly homologous and structurally similar to dystrophin, and in gene delivery experiments in mdx mice was able to functionally replace dystrophin. We performed mini-utrophin gene transfer in Golden Retriever dogs with canine muscular dystrophy (CXMD). Unlike the mouse model, the clinicopathological phenotype of CXMD is similar to that of Duchenne muscular dystrophy (DMD). We injected an adenoviral vector expressing a synthetic utrophin into tibialis anterior muscles of newborn dogs affected with CXMD and examined transgene expression by RNA and protein analysis at 10, 30 and 60 days postinjection in cyclosporin-treated and -untreated animals. Immunosuppression by cyclosporin was required to mitigate the immune response to viral and transgene antigens. RT-PCR analysis showed the presence of the exogenous transcript in the muscle of cyclosporin-treated and -untreated animals. The transgenic utrophin was efficiently expressed at the extrajunctional membrane in immunosuppressed dogs and this expression was stable for at least 60 days. We found reduced fibrosis and increased expression of dystrophin-associated proteins (DAPs) in association with muscle areas expressing the utrophin minigene, indicating that mini-utrophin can functionally compensate for lack of dystrophin in injected muscles. For this reason, utrophin transfer to dystrophin-deficient muscle appears as a promising therapeutic approach to DMD.
Adenoviridae↗
Is the CACNA1A gene involved in familial migraine with aura?
The discovery of mutations in the neural calcium channel (CACNA1A) gene in familial hemiplegic migraine (FHM), variant of migraine with aura, led to the suggestion that this gene might be involved in familial migraine with aura (FMA). We investigated whether the mutations in FHM are present in FMA patients, analyzing genomic DNA by PCR, single stranded conformation polymorphism, sequencing and restriction enzyme. No mutations were found. A known polymorphism (5682-14C>T) was found in exon 36. These findings suggest that the mutations found in FHM and the other known mutations of the CACNA1A gene are not the genetic basis of FMA. Genetic alterations in FMA patients may be localized on chromosome 19 but not in the CACNA1A exons we investigated.
Adult↗
Development of muscle pathology in canine X-linked muscular dystrophy. II. Quantitative characterization of histopathological progression during postnatal skeletal muscle development.
We have characterized the time course of muscle pathology development during the postnatal maturation of quadriceps and tibialis anterior muscle in dystrophic golden retriever dogs. We determined the percentages of degenerating, regenerating, calcium-positive, hypercontracted, albumin-positive, and C3 complement fraction-positive muscle fibers and the extent of connective tissue proliferation in animals from neonate to adult. Necrotic fibers increased from days 2 to 30, decreased at 60 days (to 0.8%) and increased in older animals to a stable level of around 2%. Hypercontracted fibers peaked at 15 days (19.1%) and declined to 3.7% in adults. Regenerating fibers were numerous at 15 and 30 days (10%), declined at 60 days to 4.7% and declined further in adults. Calcium- and albumin-positive fibers peaked at 30 days (6.5% and 13.8%, respectively) and then declined to around 3% and 5%, respectively, in older dogs. In dystrophic dogs, the extent of fibrosis was significantly greater on 15 days than in controls, but did not then increase with age. In carriers, calcium- and albumin-positive fibers always expressed dystrophin abnormally. Muscle damage occurs before completion of muscle maturation in dystrophic dogs. While necrosis and hypercontraction remain stable in adults, fiber regeneration declines to very low levels. In contrast to Duchenne muscular dystrophy, muscle fibrosis in the muscle studied does not increase with age.
Aging↗
Mild muscular dystrophy due to a nonsense mutation in the LAMA2 gene resulting in exon skipping.
Nonsense mutations outside the splicing consensus sequence have been reported to cause skipping of the nonsense-containing exon in several human diseases. We describe, for the first time, nonsense-mediated exon skipping in the laminin alpha2 (LAMA2) gene. Two siblings from a consanguineous family had altered expression of the laminin alpha2 chain and moderate clinical manifestations. In both we identified the new nonsense mutation Arg744Stop, which we expected to result in a totally non-functional polypeptide. However, analysis of the transcript revealed skipping of exon 15, containing the mutation, even though the consensus sequences for splicing at both ends of the exon and the beginning of intron 15 were unaltered. Exon skipping restored the open reading frame of the mutant transcript and resulted in a truncated protein. In cases where the genetic findings do not elucidate the phenotype, mRNA analysis is necessary to clarify the primary effect of mutations. Our findings also point to the necessity of immunochemical screening for expression of laminin alpha2 chain in atypical dystrophic adults as well as children.
Adult↗
Increased expression of beta-chemokines in muscle of patients with inflammatory myopathies.
Idiopathic inflammatory myopathies (IIM) are muscle diseases of autoimmune pathogenesis characterized by mononuclear cell infiltration within muscle tissue. Since immune cell homing and accumulation at the site of antigenic challenge is usually mediated by chemokines, we evaluated the expression of 2 beta-chemokines--monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha)--by immunohistochemistry and polymerase chain reaction in muscles of polymyositis, inclusion body myositis, and dermatomyositis patients, and related their expression to immunopathological alterations in muscle. MCP-1 and MIP-1alpha transcripts were detected by PCR in all IIM muscles, but not in controls. By immunohistochemistry, the chemokines were found in all IIM muscle sections located in infiltrating inflammatory cells and also in neighboring extracellular matrix. The extent to which extracellular matrix was filled by each chemokine differed in each disease. In view of the known ability of chemokines to bind extracellular matrix and their possible synthesis by extracellular matrix components, we suggest that chemokine storage in the extracellular matrix can act as a microenvironmental factor amplifying lymphocyte activation and migration, thereby maintaining the autoimmune attack against unknown muscle antigens.
Chemokine CCL2↗
Disruption of heart sarcoglycan complex and severe cardiomyopathy caused by beta sarcoglycan mutations.
Two young males with limb-girdle muscular dystrophy (LGMD) resulting from sarcoglycan deficiency died at 27 (patient 1) and 18 years (patient 2) of severe cardiomyopathy. Genetic analysis showed that they were compound heterozygotes for mutations in the beta sarcoglycan gene. One of these mutations, an 8 bp duplication in exon 3, was common to both patients. The second mutation in patient 2 was a 4 bp deletion at the splice donor site of intron 2, not reported previously. Patient 2 had more severe heart and skeletal muscle defects with faster deterioration; no sarcoglycans were detected in his skeletal muscle. The second mutation in patient 1, inferred because the unaffected father carries the 8 bp duplication, was not found. In patient 1, both heart and skeletal muscle were analysed and showed reduction of all sarcoglycans in both tissues and incorrect localisation of alpha and gamma sarcoglycans in heart. Therefore mutations in one sarcoglycan gene can disrupt the entire sarcoglycan complex in both skeletal and cardiac muscle. Differing expression patterns of sarcoglycan components in heart and skeletal muscle could be the result of alternatively spliced transcripts in these tissues. By sequencing an alternative transcript, highly expressed in the heart and skeletal muscle of patient 1, we found an 87 bp cryptic exon not previously reported. Although cardiomyopathy can result from mutations in alpha and gamma sarcoglycans, we show for the first time that the condition can also be caused by mutations in the beta sarcoglycan gene. This report therefore expands the phenotype of sarcoglycanopathies and suggests that cardiac function in LGMD patients with defective sarcoglycan expression should be monitored.
Adolescent↗
Partial laminin alpha2 chain deficiency in a patient with myopathy resembling inclusion body myositis.
It is becoming evident that clinical phenotypes associated with partial laminin alpha2 chain deficiency are variable. We recently observed a 29-year-old man with leukoencephalopathy and vacuolar myopathy resembling inclusion body myositis. Laminin alpha2 immunohistochemical analysis showed reduction of the protein on muscle fiber surfaces. Molecular analysis revealed two novel compound heterozygous mutations in the LAMA2 gene. This is the first report linking a mutation in the LaMA2 gene with leukoencephalopathy and inclusion body-like myositis.
Adult↗
Clinical correlations in 16 patients with total or partial laminin alpha2 deficiency characterized using antibodies against 2 fragments of the protein.
BACKGROUND: Many patients with classic congenital muscular dystrophy have been found to have partial or total deficiency of the alpha2 chain of laminin 2 (merosin). This deficiency has mostly been studied using only 1 antibody against a fragment of the protein. OBJECTIVES: To characterize the expression of laminin alpha2 in the skeletal muscle of patients with laminin alpha2 deficiency using antibodies against 2 different portions of the protein and to correlate the immunochemical findings with clinical phenotype. METHODS: We studied 4 patients with total lack of laminin alpha2 and 12 with partial laminin alpha2 deficiency with immunohistochemical techniques and Western blot analysis. We used antibodies recognizing an 80-kd fragment toward the C-terminus and a 300-kd fragment toward the amino-terminal. Patient characteristics examined were functional compromise, magnetic resonance imaging or computed tomography of the brain, electromyography, evoked potentials, and creatine kinase levels. RESULTS: In 4 patients, immunohistochemical analysis revealed no reactivity to either antibody; in 2 patients, the 300-kd fragment alone was partially expressed; in 2 patients, the 80-kd fragment alone was partially expressed; and in 8 patients, both fragments were partially expressed. Immunoblot analysis revealed bands of reduced intensity and normal molecular weight generally corresponding to the immunohistochemical findings. Absence of both fragments or of one with reduction of the other always produced a severe clinical phenotype, while a milder clinical phenotype was observed when both fragments were partially expressed. CONCLUSIONS: Extent of laminin alpha2 deficiency in most cases correlates with clinical phenotype but not with peripheral and central white matter abnormalities. Skin biopsy specimens may reveal laminin alpha2 deficiency in patients who have normal laminin alpha2 levels in muscle biopsy specimens.
Adolescent↗
Identification of three novel mutations in the major human skeletal muscle chloride channel gene (CLCN1), causing myotonia congenita.
Myotonia congenita (MC) is a genetic disease characterized by mutations in the CLCN1 gene (OMIM*118425) encoding the skeletal muscle voltage-gated chloride channel (ClC-1). Autosomal dominant and recessive forms are observed, characterized by impaired muscle relaxation after forceful contraction (myotonia), which is more pronounced after inactivity and improves with exercise. We report three novel and one known mutations of the CLCN1 gene in four unrelated MC families. In two families the mutations were missense: 803C>T (T268M) and 1272C>G (I424M) in exons 7 and 12, respectively. The third was a splice mutation in intron 5 (696+2T>A), which induced a frame shift with a stop codon in exon 6 (fs213X). In the fourth family the previously-reported missense mutation 689G>A (G230E) was found. We also report two known polymorphisms: 261C>T (T87T) and 2154T>C (D718D) in exons 2 and 17 of two MC families; also found in 14 (33%) and 28 (67%) of 42 healthy controls, respectively. These findings expand our knowledge of mutations responsible for myotonia congenita, reducing the proportion of MC patients in whom genetic alterations have not been found.
Chloride Channels↗
Development of muscle pathology in canine X-linked muscular dystrophy. I. Delayed postnatal maturation of affected and normal muscle as revealed by myosin isoform analysis and utrophin expression.
Canine X-linked muscular dystrophy (CXMD) is genetically homologous to Duchenne muscular dystrophy and shares the severe myopathy and lethal clinical development of the human disease. We used immunohistochemistry to characterize the time course of postnatal expression of adult fast, adult slow and developmental myosin in the muscle of CXMD dogs, carriers and healthy controls. We also characterized the expression of utrophin and dystrophin. This detailed immunolocalization study confirmed that postnatal muscle maturation is delayed in normal dogs compared to other animals and humans, and is only achieved at around 60 days. In CXMD dogs major derangement of myosin expression became evident from about 15 days; there was a selective loss of fibers expressing fast myosin and persistence of developmental fibers compared to controls. In carriers, the proportion of dystrophin-deficient fibers, which mainly expressed fast myosin, decreased with age. In controls and carriers utrophin was absent from muscle fiber surfaces in 2-day-old animals but present between 15 and 30 days, to mostly disappear by 60 days. In dystrophic animals, sarcolemmal expression of utrophin was more marked and persistent. That immature neonatal muscle from control dogs normally contains sarcolemmal utrophin may have implications for the success of utrophin up-regulation therapy to correct the dystrophic phenotype. The data of this study provide important baseline information for further studies on the development and progression of pathological changes in the muscle of CXMD dogs.
Aging↗
Transforming growth factor-beta1 and fibrosis in congenital muscular dystrophies.
We evaluated transforming growth factor-beta1 (TGF-beta1) expression in the muscle of four laminin alpha2-negative, four laminin alpha2-positive and seven partial laminin alpha2-deficient congenital muscular dystrophy (CMD) patients, and compared it to Duchenne muscular dystrophy (DMD) patients and controls. TGF-beta1 mRNA levels in skeletal muscle from laminin alpha2-negative and laminin alpha2-positive CMD patients were significantly greater than in controls (P < 0.05 and P < 0.005, respectively), while in partial laminin alpha2-deficient muscular dystrophy patients the amount was not significantly higher than in controls (P > 0.1). The TGF-beta1 values were lower than those found in DMD, although the extent of fibrosis was greater in CMD than in DMD and controls. Our findings suggest that TGF-beta1 is involved in CMD muscle fibrosis, but differently from what we observed in DMD muscles as it seems not to be the major player in connective tissue proliferation.
Adult↗
Oral administration of an immunodominant T-cell epitope downregulates Th1/Th2 cytokines and prevents experimental myasthenia gravis.
The mucosal administration of the native antigen or peptide fragments corresponding to immunodominant regions is effective in preventing or treating several T cell-dependent models of autoimmune disease. No data are yet available on oral tolerance with immunodominant T-cell peptides in experimental autoimmune myasthenia gravis (EAMG), an animal model of B cell-dependent disease. We report that oral administration of the T-cell epitope alpha146-162 of the Torpedo californica acetylcholine receptor (TAChR) alpha-subunit suppressed T-cell responses to AChR and ameliorated the disease in C57Bl/6 (B6) mice. Protection from EAMG was associated with reduced serum Ab's to mouse AChR and reduced AChR loss in muscle. The effect of Talpha146-162 feeding was specific; treatment with a control peptide did not affect EAMG manifestations. The protective effect induced by peptide Talpha146-162 was mediated by reduced production of IFN-gamma, IL-2, and IL-10 by TAChR-reactive cells, suggesting T-cell anergy. TGF-beta-secreting Th3 cells did not seem to be involved in tolerance induction. We therefore demonstrate that feeding a single immunodominant epitope can prevent an Ab-mediated experimental model of autoimmune disease.
Administration, Oral↗
Identification of a novel HLA class II association with DQB1*0502 in an Italian myasthenic population.
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Adult↗