Biomedical subjects

Kleopas A Kleopa

Publications and source records attributed to Kleopas A Kleopa.

18 recordsLinked to original sources

PubMed2006

Autoimmune channelopathies and related neurological disorders.

Ion channels are crucial elements in neuronal signaling and synaptic transmission, and defects in their function are known to underlie rare genetic disorders, including some forms of epilepsy. A second class of channelopathies, characterized by autoantibodies against ligand- and voltage-gated ion channels, cause a variety of defects in peripheral neuromuscular and ganglionic transmission. There is also emerging evidence for autoantibody-mediated mechanisms in subgroups of patients with central nervous system disorders, particularly those involving defects in cognition or sleep and often associated with epilepsy. In all autoimmune channelopathies, the relationship between autoantibody specificity and clinical phenotype is complex. But with this new information, autoimmune channelopathies are detected and treated with increasing success, and future research promises new insights into the mechanisms of dysfunction at neuronal synapses and the determinants of clinical phenotype.

Animals↗

PubMed2006

Neuromyotonia and limbic encephalitis sera target mature Shaker-type K+ channels: subunit specificity correlates with clinical manifestations.

Autoantibodies to Shaker-type (Kv1) K+ channels are now known to be associated with three syndromes. Peripheral nerve hyperexcitability is the chief manifestation of acquired neuromyotonia; the combination of neuromyotonia with autonomic and CNS involvement is called Morvan's syndrome (MoS); and CNS manifestations without peripheral involvement is called limbic encephalitis (LE). To determine the cellular basis of these clinical manifestations, we immunostained mouse neural tissues with sera from patients with neuromyotonia (n = 10), MoS (n = 2) or LE (n = 5), comparing with specific antibodies to relevant K+ channel subunits. Fourteen of 17 patients' sera were positive for Kv1.1, Kv1.2 or Kv1.6 antibodies by immunoprecipitation of 125I-alpha-dendrotoxin-labelled rabbit brain K+ channels. Most sera (11 out of 17) labelled juxtaparanodes of peripheral myelinated axons, co-localizing with Kv1.1 and Kv1.2. In the CNS, all sera tested (n = 12) co-localized with one or more areas of high Kv1.1, Kv1.2 or Kv1.6 channel expression: 10 out of 12 sera co-localized with Kv1.1 and Kv1.2 at spinal cord juxtaparanodes or cerebellar layers, while 3 out of 12 sera co-localized additionally (n = 2) or exclusively (n = 1) with Kv1.6 subunits in Purkinje cells, motor and hippocampal neurons. However, only sera from LE patients labelled the hippocampal areas that are enriched in excitatory, Kv1.1-positive axon terminals. All sera (17 out of 17) labelled one or more of these Kv1 subunits when expressed at the cell membrane of transfected HeLa cells, but not when they were retained in the endoplasmic reticulum. Again, LE sera labelled Kv1.1 subunits more prominently than did MoS or neuromyotonia sera, suggesting an association between higher Kv1.1 specificity and limbic manifestations. In contrast, neuromyotonia sera bound more strongly to Kv1.2 subunits than to Kv1.1 or Kv1.6. These studies support the hypothesis that antibodies to mature surface membrane-expressed Shaker-type K+ channels cause acquired neuromyotonia, MoS and LE, and suggest that future assays based on immunofluorescence of cells expressing individual Kv1 subunits will prove more sensitive than the immunoprecipitation assay. Although more than one type of antibody is often detectable in individual sera, higher affinity for certain subunits or subunit combinations may determine the range of clinical manifestations.

Adolescent↗

PubMed2006

Naturally occurring utrophin correlates with disease severity in Duchenne muscular dystrophy.

Although there is good experimental data that utrophin, the autosomal analog of dystrophin, can ameliorate the phenotype in dystrophinopathies, there is scant evidence from human data to support this hypothesis. We investigated in diagnostic muscle biopsies from 16 patients with Duchenne muscular dystrophy (DMD) the level of utrophin expression using quantitative immunoblot analysis. In 13 of 16 patients, in whom there was adequate follow-up data, utrophin expression was correlated to two clinical endpoints: age at reaching Hammersmith score of 30/40 and age at becoming wheelchair-bound. We found that utrophin expression increases with age in DMD and that there is a significant positive correlation between the quantity of utrophin at initial biopsy and time to becoming wheelchair-bound.

Age Factors↗

PubMed2006

Multifocal motor neuropathy with conduction block associated with metastatic lymphoma of the nervous system.

Peripheral neuropathies occur in 5% of patients with Non-Hodgkin Lymphoma and represent the effects of therapy, direct compression or nerve infiltration by tumor, or paraneoplastic effects. Multifocal motor neuropathy with conduction block (MMNCB) is a rare demyelinating disorder of unknown etiology characterized by progressive, distal, asymmetric weakness mostly of the upper limbs with minimal or no sensory loss. We report a patient, who developed MMNCB at the time of isolated CNS relapse from a diffuse large B-cell lymphoma. Marked neurological improvement was achieved using intravenous immunoglobulin treatment. To our knowledge, MMNCB has thus far not been described as part of the spectrum of lymphoma-related peripheral neuropathies.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Molecular genetics of X-linked Charcot-Marie-Tooth disease.

The X-linked form of Charcot-Marie-Tooth disease (CMT1X) is the second most common molecularly designated form of hereditary motor and sensory neuropathy. The clinical phenotype is characterized by progressive distal muscle atrophy and weakness, areflexia, and variable sensory abnormalities. Affected males have moderate-to-severe symptoms, whereas heterozygous females are usually mildly affected or even asymptomatic. Several patients also have manifestations of central nervous system involvement or hearing impairment. Electrophysiological and pathological studies of peripheral nerves show evidence of demyelinating neuropathy with prominent axonal degeneration. A large number of mutations in the GJB1 gene encoding the gap junction (GJ) protein connexin32 (Cx32) cause CMT1X. Cx32 is expressed by Schwann cells and oligodendrocytes, as well as by other tissues, and the GJ formed by Cx32 play an important role in the homeostasis of myelinated axons. The reported CMT1X mutations are diverse and affect both the promoter region as well as the coding region of GJB1. Many Cx32 mutants fail to form functional GJ, or form GJ with abnormal biophysical properties. Furthermore, Cx32 mutants are often retained intracellularly either in the endoplasmic reticulum or Golgi in which they could potentially have additional dominant-negative effects. Animal models of CMT1X demonstrate that loss of Cx32 in myelinating Schwann cells causes a demyelinating neuropathy. No definite phenotype-genotype correlation has yet been established for CMT1X and effective molecular based therapeutics for this disease, remain to be developed.

Amino Acid Sequence↗

PubMed2005

Reversible inflammatory and vacuolar myopathy with vitamin E deficiency in celiac disease.

We report a patient with late-onset celiac disease and neurological manifestations including myopathy, polyneuropathy, and ataxia. Laboratory investigations showed anti-gliadin antibodies and severe vitamin E deficiency. Muscle biopsy revealed inflammatory infiltrates and rimmed vacuoles, similar to those found in inclusion-body myositis. A gluten-free diet and vitamin E supplementation reversed both the clinical neurological manifestations and the abnormalities in the muscle biopsy. Anti-gliadin antibodies were no longer present. This case illustrates the spectrum of neurological complications of celiac disease and documents the occurrence of reversible pathology resembling inclusion-body myopathy in the muscle.

Aged↗

PubMed2004

A novel PMP22 mutation Ser22Phe in a family with hereditary neuropathy with liability to pressure palsies and CMT1A phenotypes.

We describe a Cypriot family in which some family members presented with episodes of pressure palsies, while other family members had a slowly progressive chronic polyneuropathy typical of the Charcot-Marie-Tooth type 1 phenotype. All family members were evaluated clinically, with nerve conduction studies, and with genetic testing. In all affected individuals there was clinical and electrophysiological evidence of diffuse demyelinating sensorimotor polyneuropathy and a novel point mutation in the PMP22 gene (Ser22Phe) was identified.

Adult↗

PubMed2004

KCNQ2 is a nodal K+ channel.

Mutations in the gene encoding the K+ channel KCNQ2 cause neonatal epilepsy and myokymia, indicating that KCNQ2 regulates the excitability of CNS neurons and motor axons, respectively. We show here that KCNQ2 channels are functional components of axon initial segments and nodes of Ranvier, colocalizing with ankyrin-G and voltage-dependent Na+ channels throughout the CNS and PNS. Retigabine, which opens KCNQ channels, diminishes axonal excitability. Linopirdine, which blocks KCNQ channels, prolongs the repolarization of the action potential in neonatal nerves. The clustering of KCNQ2 at nodes and initial segments lags that of ankyrin-G during development, and both ankyrin-G and KCNQ2 can be coimmunoprecipitated in the brain. KCNQ3 is also a component of some initial segments and nodes in the brain. The diminished activity of mutant KCNQ2 channels accounts for neonatal epilepsy and myokymia; the cellular locus of these effects may be axonal initial segments and nodes.

Amino Acid Substitution↗

PubMed2004

Unique distributions of the gap junction proteins connexin29, connexin32, and connexin47 in oligodendrocytes.

Oligodendrocytes of adult rodents express three different connexins: connexin29 (Cx29), Cx32, and Cx47. In this study, we show that Cx29 is localized to the inner membrane of small myelin sheaths, whereas Cx32 is localized on the outer membrane of large myelin sheaths; Cx29 does not colocalize with Cx32 in gap junction plaques. All oligodendrocytes appear to express Cx47, which is largely restricted to their perikarya. Cx32 and Cx47 are colocalized in many gap junction plaques on oligodendrocyte somata, particularly in gray matter. Cx45 is detected in the cerebral vasculature, but not in oligodendrocytes or myelin sheaths. This diversity of connexins in oligodendrocytes (in different populations of cells and in different subcellular compartments) likely reflects functional differences between these connexins and perhaps the oligodendrocytes themselves.

Animals↗

PubMed2004

A novel movement disorder of the lower lip.

Four patients, aged 25 to 42 years presented with acute onset of a movement disorder characterized by a tonic, sustained, lateral and outward protrusion of one half of the lower lip. The movement disorder was present at rest, while in some patients, it was also present during speech. In all cases, the abnormal lip posture could be suppressed voluntarily. Neurological examination was otherwise normal. Extensive laboratory investigation failed to reveal any causative factors for secondary focal dystonia. Treatment with oral medications and botulinum toxin was mostly ineffective. Spontaneous remissions were frequent.

Acute Disease↗

PubMed2003

Maximal voluntary ventilation in myasthenia gravis.

Assessment of respiratory muscle weakness is important at all stages of myasthenia gravis. The maximal voluntary ventilation (MVV) is an objective dynamic method for measuring the working capacity of respiratory muscles. The clinical value of this method was studied in 24 newly diagnosed patients with myasthenia gravis, classified according to Osserman criteria (grades I, IIa, and IIb). The MVV values were normal in group I, whereas a characteristic "myasthenic pattern" of decremental respiratory volumes was demonstrated during MVV in group IIa and IIb patients, with or without dyspnea. Despite some limitations and lack of specificity, MVV may be a valuable tool in the assessment of respiratory dysfunction in patients with myasthenia gravis. Muscle Nerve, 27: 715-719, 2003

Adrenal Cortex Hormones↗

PubMed2003

Compressive lumbar myelopathy presenting as segmental motor neuron disease.

Four patients presented with slowly progressive, bilateral, asymmetric weakness and muscle atrophy in the lower extremities, accompanied by cramps and fasciculations. Sensory symptoms were insignificant. There was no bladder or bowel disturbance. Upper extremities and cranial nerves were normal. Weakness was found in lumbosacral myotomes, ranging from L2 to S1. The tendon reflexes varied, and extensor plantar responses were found in one case with proximal leg involvement. Nerve conduction studies were normal, but segmental chronic and often active denervation confined to the weak myotomes in the lower extremities was found in the electromyogram. Magnetic resonance imaging showed evidence of spondylotic lumbosacral myelopathy associated with disc herniation or osteophytic arthropathy at the T11/T12 spinal level in all patients, with increased signal within the adjacent cord. This unusual purely motor presentation may result from ischemic myelopathy secondary to compression of the anterior spinal artery.

Adult↗

PubMed2002

Connexin29 is uniquely distributed within myelinating glial cells of the central and peripheral nervous systems.

Although both Schwann cells and oligodendrocytes express connexin32 (Cx32), the loss of this connexin causes demyelination only in the PNS. To determine whether oligodendrocytes might express another connexin that can function in place of Cx32, we searched for novel CNS-specific connexins using reverse transcriptase-PCR and degenerate primers. We identified Cx29, whose transcript was restricted to brain, spinal cord, and sciatic nerve. Developmental expression of Cx29 mRNA in the CNS paralleled that of other myelin-related mRNAs, including Cx32. In the CNS, Cx29 antibodies labeled the internodal and juxtaparanodal regions of small myelin sheaths, whereas Cx32 staining was restricted to large myelinated fibers. In the PNS, Cx29 expression preceded that of Cx32 and declined to lower levels than Cx32 in adulthood. In adult sciatic nerve, Cx29 was primarily localized to the innermost aspects of the myelin sheath, the paranode, the juxtaparanode, and the inner mesaxon. Cx29 displayed a striking coincidence with Kv1.2 K(+) channels, which are localized in the axonal membrane. Both Cx29 and Cx32 were found in the incisures. Cx29 expressed in N2A cells did not induce intercellular conductances but did participate in the formation of active channels when coexpressed with Cx32. Together, these data show that Cx29 and Cx32 are expressed by myelinating glial cells with distinct distributions.

Animals↗

PubMed2002

Cellular mechanisms of connexin32 mutations associated with CNS manifestations.

Both oligodendrocytes and myelinating Schwann cells express the gap junction protein connexin32 (Cx32). Mutations in the gene encoding Cx32 (GJB1) cause the X-linked form of Charcot-Marie-Tooth disease (CMTX). Although most CMTX patients do not have clinical central nervous system (CNS) manifestations, subclinical evidence of CNS dysfunction is common. We investigated the cellular effects of a subgroup of GJB1/Cx32 mutations that have been reported to cause clinical CNS dysfunction. We hypothesized that these mutants have dominant-negative effects on other connexins expressed by oligodendrocytes, specifically Cx45. We expressed these and other Cx32 mutants in communication-incompetent as well as Cx45-expressing HeLa cells, and analyzed the transfected cells by immunocytochemistry and immunoblotting. In communication-incompetent cells, the mutants associated with CNS phenotypes failed to reach the cell membrane and were instead retained in the endoplasmic reticulum (A39V, T55I) or Golgi apparatus (M93V, R164Q, R183H), although rare gap junction plaques were found in cells expressing M93V or R183H. In HeLa cells stably expressing Cx45, these Cx32 mutants showed a similar expression pattern, and did not alter the pattern of Cx45 expression. These results indicate that Cx32 mutants that are associated with a CNS phenotype do not interact with Cx45, but may instead have other toxic effects in oligodendrocytes.

Cell Communication↗

PubMed2002

Genetic disorders of neuromuscular ion channels.

Ion channels are complex proteins that span the lipid bilayer of the cell membrane, where they orchestrate the electrical signals necessary for normal function of the central nervous system, peripheral nerve, and both skeletal and cardiac muscle. The role of ion channel defects in the pathogenesis of numerous disorders, many of them neuromuscular, has become increasingly apparent over the last decade. Progress in molecular biology has allowed cloning and expression of genes that encode channel proteins, while comparable advances in biophysics, including patch-clamp electrophysiology and related techniques, have made the study of expressed proteins at the level of single channel molecules possible. Understanding the molecular basis of ion channel function and dysfunction will facilitate both the accurate classification of these disorders and the rational development of specific therapeutic interventions. This review encompasses clinical, genetic, and pathophysiological aspects of ion channels disorders, focusing mainly on those with neuromuscular manifestations.

Humans↗

PubMed2002

Diverse trafficking abnormalities of connexin32 mutants causing CMTX.

Mutations in GJB1, the gene encoding the gap junction protein connexin32 (Cx32), cause X-linked Charcot-Marie-Tooth disease (CMTX). We compared the localization of CMTX mutants that affect different domains of Cx32, by expressing them in HeLa cells. Mutants were localized to the endoplasmic reticulum (M34K, N205I, and Y211x), in the Golgi apparatus without reaching the cell membrane (M34T, V38M, A40V, R75Q, R75P, R75W, and C217x), in the Golgi apparatus but also forming rare small gap junction-like plaques (M34I, M34V, and V37M), or mainly on the cell membrane, forming gap junction-like plaques (V35M, I213V, R219C, R219H, R220G, R230C, R230L, R238H, L239I, and S281x). Selected mutants expressed in cultured rat Schwann cells showed localization similar to that in HeLa cells. Thus, many CMTX mutants have trafficking abnormalities, whereas the carboxy-terminus mutants reach the cell membrane and probably cause disease through other mechanisms.

Amino Acid Sequence↗

PubMed2002

Inherited neuropathies.

Inherited neuropathies are common and are usually caused by mutations in genes that are expressed by myelinating Schwann cells or neurons, which is the biological basis for long-standing distinction between primary demyelinating and axonal neuropathies. Neuropathies can be isolated, the primary manifestation of a more complex syndrome, or overshadowed by other aspects of the inherited disease. Increasing knowledge of the molecular-genetic causes of inherited neuropathies facilitates faster, more accurate diagnosis, and sets the stage for development of specific therapeutic interventions.

DNA Mutational Analysis↗

PubMed2002

Conus medulla-cauda compression from nerve root hypertrophy in a child with Dejerine-Sottas syndrome: improvement with laminectomy and duraplasty. Case report.

This 7-year-old boy with Dejerine-Sottas syndrome caused by a mutation in the myelin protein zero gene began to suffer rapid deterioration with increasing leg weakness, loss of the ability to ambulate, and bowel and bladder incontinence. Magnetic resonance imaging of the spine revealed nerve root hypertrophy resulting in compression of the conus medullaris and cauda equina. Decompressive surgery was successful in reversing some of his deficits.

Amino Acid Substitution↗