Kleopas A. Kleopa, M.D.
Senior Consultant Neurologist
Head of the Neuroscience Laboratory

Contact Details

email: kleopa@cing.ac.cy
Address: Section of Clinical Neurosciences
             The Cyprus Institute of Neurology and Genetics
             6 International Airport Avenue
             P.O.Box 23462
             1683 Nicosia, Cyprus
Telephone: +357 22358600
Fax:           +35722392786

CV

Selected Publications

Last updated 22.1.2009

Clinical interests

Dr. Kleopa has a broad spectrum of interests in clinical neurology with fellowship training in neuromuscular disorders and electromyography. He has special interests in myasthenia gravis, inherited and acquired peripheral neuropathies and myopathies, motor neuron disease, and other degenerative, autoimmune and metabolic neurological diseases, including inherited and acquired demyelinating disorders of the peripheral and central nervous system. He also has expertise in the electrophysiological evaluation of the peripheral nervous system and performs regularly nerve conduction studies and electromyography.  

Research Interests

Our research group in the Neuroscience Laboratory has been active both in clinical as well as basic research with emphasis on translational aspects of neuroscience. We have been involved in studies of therapeutic intervention and diagnostic methods in clinical neuromuscular disease, including the use of non-invasive respiratory support for patients with motor neuron disease (Kleopa et al., 1999) and diagnostic methods for myasthenia (Heliopoulos et al., 2003). We also participated in linkage studies for hereditary spastic paraplegia (Rainier et al., 2001) and identification of genes and mutations for hereditary neuropathy (Street et al., 2003; Kleopa et al., 2004b) and motor neuron disease (Mintchev et al., 2009), as well as in studies aiming at the development of new therapeutic and diagnostic methods in other neuromuscular disorders (Kleopa et al., 2006a).

In the past several years in research funded by the National Multiple Sclerosis Society of the USA, the Cyprus Research Promotion foundation, and the Cyprus Telethon, in collaboration with scientists at the University of Pennsylvania and Harvard Medical School, as well as other institutions, we have focused on the clinical aspects as well as cellular and molecular mechanisms of inherited peripheral neuropathies (Kleopa and Scherer, 2002), especially the X-linked form (X-linked Charcot-Marie-Tooth Disease, CMTX), which is caused by mutations in the gap junction protein conexin32 (Yum et al., 2002; Kleopa et al., 2006c). A question that has driven the creation of cellular and animal models of the disease in our lab was the mechanisms leading to the CNS phenotype associated with several of the connexin32 mutations (Kleopa et al., 2002). Additional gap junction proteins in oligodendroglia were characterized and possible interactions of mutant connexin32 with these gap junction proteins in the CNS are under investigation (Altevogt et al., 2002; Kleopa et al., 2004a). We recently published our work on the expression of Cx31.3 in human oligodendrocytes and showed that Cx32 mutants with CNS manifestations did not affect the function of this gap junction in vitro (Sargiannidou et al., 2008).

Cellular expression of Cx32 mutations. Images of HeLa cells transiently transfected to express the V140E (A) or the L143P (B) Cx32 mutants, or the wild type protein (WT Cx32) (C).  They were double labelled with a mouse monoclonal antibody against Cx32 (green, left column) and a rabbit antiserum against the Golgi marker COPII (red, middle column). Cell nuclei are visualized with DAPI (blue). Merged images are shown in the right column. In cells expressing either the V140E or the L143P mutant Cx32 immunoreactivity is concentrated intracellularly and colocalizes with the Golgi/endosomal marker COPII (arrowheads in A and B). Neither of the mutants forms any gap junctions, in contrast to the WT Cx32, which reaches the cell membrane of expressing cells and forms numerous gap junction-like plaques (arrows in C). Scale bar: 10 m (from Kleopa et al. 2006c).

The molecular architecture as well as genetic and aquired-autoimmune disorders of neuronal voltage gated ion channels has also been a main focus of our research. Especially the expression and characterization of novel potassium channels in the central and peripheral nervous system (Devaux et al., 2004), and the study of the molecular mechanisms in patients with acquired hyperexcitability of the peripheral and/or central nervous system, in the forms of neuromyotonia and limbic encephalitis (Kleopa et al., 2006b; Vincent et al., 2006; Bataller et al., 2007) has been pursuit in collaboration with scientists form the University of Oxford and University of Pennsylvania.

Binding of sera from patients with Morvan’s syndrome (MoS) or limbic encephalitis (LE) to sciatic nerve teased fibers (A&B) or to hippocampal regions (C&D). Double staining with anti-Kv1.2 (A&B) or anti-Kv1.1 (C&D) specific antibodies demonstrates the expression of Kv1.2 in peripheral myelinated axons, especially at the juxtaparanodes (arrows), the juxta-incisures (arrowheads) and juxtamesaxons (open arrowheads). While there is no specific labeling with a control serum (green) (A), the serum from a patient with MoS (B) binds to the same areas colocalizing with Kv1.2. In the hippocampal CA3 area (C), Kv1.1 is strongly expressed in the mossy fiber layer (mf) and much less in the stratum pyramidale (py), radiatum (rd) and oriens (or). The serum from a patient with LE strongly labels the mf layer colocalizing with Kv1.1. In CA1 (D), Kv1.1 is strongly expressed in the rd and less in the or layers, and the LE serum binds to the same areas colocalizing with Kv1.1. Merged images are shown in the right column including nuclear staining (blue) to demonstrate the different layers. Scale bars in A&B: 10 mm; in C&D: 50 mm (From Kleopa et al., 2006b and Vincent et al., 2006)

We have also studied the expression of ion channels in transgenic mice that lack the cell adhesion molecule TAG-1, in collaboration with Scientists at the University of Crete and the University of Athens. This work has shown that deficiency of TAG-1 results in altered expression of voltage gated potassium channels, leading to hyperexcitability and deficits in memory and learning (Savvaki et al., 2008). We currently analyze the alterations of sodium channels in the same model.

Ongoing and future research projects focus on the further study of molecular mechanisms in animal models of CMTX with the aim to develop possibilities for future therapies; on the role of gap junctions in central myelin in health and disease, especially multiple sclerosis, in collaboration with Imperial College of Medicine; and on the study of autoimmune mechanisms involving ion channels throughout the nervous system in a variety of clinical conditions including chronic pain.

Selected publications

Altevogt BM, Kleopa KA, Postma FR, Scherer SS, Paul DL (2002) Connexin29 is uniquely distributed within myelinating glial cells of the central and peripheral nervous systems. J Neurosci 22:6458-6470.
Bataller L, Kleopa KA, Wu G, Rossi JE, Rosenfeld MR, Dalmau J (2007) Autoimmune Limbic Encephalitis in 39 Patients: Immunophenotypes and Outcomes. J Neurol Neurosurg Psychiatry 78 381-385.
Devaux JJ, Kleopa KA, Cooper EC, Scherer SS (2004) KCNQ2 is a nodal K+ channel. J Neurosci 24:1236-1244.
Heliopoulos I, Patlakas G, Vadikolias K, Artemis N, Kleopa KA, Maltezos E, Piperidou C (2003) The maximal voluntary ventilation in myasthenia gravis. Muscle Nerve 27:715-719.
Kleopa KA, Scherer SS (2002) Inherited Neuropathies. Neurol Clinics North America 20:679-709.
Kleopa KA, Yum SW, Scherer SS (2002) Cellular mechanisms of connexin32 mutations associated with CNS manifestations. J Neurosci Res 68:522-534.
Kleopa KA, Sherman M., Neal B., et al (1999) Bipap improves survival and pulmonary function decline in patients with ALS. J Neurol Sci 164:82-88.
Kleopa KA, Orthmann JL, Enriquez A, Paul DL, Scherer SS (2004a) Unique distribution of gap junction proteins connexin29, connexin32, and connexin47 in oligodendrocytes. Glia 47:346-357.
Kleopa KA, Drousiotou A, Mavrikiou E, Ormiston A, Kyriakides T (2006a) Naturally occurring utrophin correlates with disease severity in Duchenne Muscular Dystrophy. Hum Mol Genet 15:1623-1628.
Kleopa KA, Elman L, Lang B, Vincent A, Scherer SS (2006b) Neuromyotonia and limbic encephalitis sera target mature Shaker-type K+ channels: subunit specificity correlates with clinical manifestations. Brain 129:1570-1584.
Kleopa KA, Georgiou DM, Nicolaou P, Koutsou P, Papathanasiou E, Kyriakides T, Christodoulou K (2004b) A novel PMP22 mutation Ser22Phe in a family with hereditary neuropathy with liability to pressure palsies and CMT1A phenotypes. Neurogenetics 5:171-175.
Kleopa KA, Zamba-Papanicolaou E, Alevra X, Nicolaou P, Georgiou D-M, Hadjisavvas A, Kyriakides T, Christodoulou K (2006c) Phenotypic and cellular expression of two novel connexin32 mutations causing CMT1X. Neurology 66:396-402.
Mintchev N, Zamba-Papanicolaou E, Kleopa KA, Christodoulou K (2009) A novel ALS2 splice-site mutation in a Cypriot Juvenile Primary Lateral Sclerosis family. Neurology 72:28-32.
Rainier S, Hedera P, Alvarado D., Zhao X., Kleopa K.A., Heiman-Patterson T., Fink JK (2001) Hereditary spastic paraplegia linked to chromosome 14q11-q21: reduction of the SPG3 locus interval from 5.3 to 2.7 cM. J Med Genet 38(11).E39.
Sargiannidou I, Ahn M, Enriquez AD, Peinado A, Reynolds R, Abrams CK, Scherer SS, Kleopa KA (2008) Human oligodendrocytes express Cx31.3: function and interactions with Cx32 mutants. Neurobiol Dis 30:221-233.
Savvaki M, Panagiotaropoulos T, Stamatakis A, Sargiannidou I, Karatzioula P, Watanabe K, Stylianopoulou F, Karagogeos D, Kleopa KA (2008) Impairment of learning and memory in TAG-1 deficient mice associated with shorter CNS internodes and disrupted juxtaparanodes. Mol Cell Neurosci 39:478-490.
Street V, Bennett C, Goldy J, Shirk A, Kleopa K, Tempel B, Lipe H, Scherer S, Bird T, Chance PF (2003) Mutation of a putative protein degradation gene LITAF/SIMPLE in Charcot-Marie-Tooth disease 1C. Neurology 60:22-26.
Vincent A, Lang B, Kleopa KA (2006) Autoimmune channelopathies and related neurological disorders. Neuron 52:123-138.
Yum SW, Kleopa KA, Shumas S, Scherer SS (2002) Diverse trafficking abnormalities of Connexin32 mutants causing CMTX. Neurobiol Dis 11:43-52.