Sometimes seen in the periodic paralyses. Click picture for larger image.
Tuesday, June 5, 2007
Funny toes and pointed ears
Sometimes seen in the periodic paralyses. Click picture for larger image.
Wednesday, May 30, 2007
Na+ Channelopathy with Heat-Induced Myotonia and Cold-Induced Paralysis
Neurology. 2000 Jun 13;54(11):2179-81.
Temperature-sensitive sodium channelopathy with heat-induced myotonia and
cold-induced paralysis.
Sugiura Y, Aoki T, Sugiyama Y, Hida C, Ogata M, Yamamoto T.
Department of Neurology, Fukushima Medical University School of Medicine,
Fukushima, Japan.
The authors report a Japanese family with dominantly inherited heat-induced myotonia and cold-induced paralysis with hypokalemia. This phenotype is associated with a novel mutation in the voltage-dependent skeletal muscle sodium channel alpha subunit (SCN4A). This Pro1158Ser mutation is localized between the fourth and fifth transmembrane segments of domain III in SCN4A and may give rise to a new function; that is, thermosensitive permeability changes of the sodium channel.
Publication Types:
Case Reports
PMID: 10851391
Temperature-sensitive sodium channelopathy with heat-induced myotonia and
cold-induced paralysis.
Sugiura Y, Aoki T, Sugiyama Y, Hida C, Ogata M, Yamamoto T.
Department of Neurology, Fukushima Medical University School of Medicine,
Fukushima, Japan.
The authors report a Japanese family with dominantly inherited heat-induced myotonia and cold-induced paralysis with hypokalemia. This phenotype is associated with a novel mutation in the voltage-dependent skeletal muscle sodium channel alpha subunit (SCN4A). This Pro1158Ser mutation is localized between the fourth and fifth transmembrane segments of domain III in SCN4A and may give rise to a new function; that is, thermosensitive permeability changes of the sodium channel.
Publication Types:
Case Reports
PMID: 10851391
Sunday, May 27, 2007
Functional and clinical characterization of KCNJ2 mutations associated with LQT7
J Clin Invest. 2002 Aug;110(3):381-8.
Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome).
Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, Ptacek LJ, Tawil R.
Division of Pediatric Cardiology, University of Utah, Salt Lake City, Utah 84112, USA.
Andersen syndrome (AS) is a rare, inherited disorder characterized by periodic paralysis, long QT (LQT) with ventricular arrhythmias, and skeletal developmental abnormalities. We recently established that AS is caused by mutations in KCNJ2, which encodes the inward rectifier K(+) channel Kir2.1.
In this report, we characterized the functional consequences of three novel and seven previously described KCNJ2 mutations using a two-microelectrode voltage-clamp technique and correlated the findings with the clinical phenotype. All mutations resulted in loss of function and dominant-negative suppression of Kir2.1 channel function. In mutation carriers, the frequency of periodic paralysis was 64% and dysmorphic features 78%. LQT was the primary cardiac manifestation, present in 71% of KCNJ2 mutation carriers, with ventricular arrhythmias present in 64%. While arrhythmias were common, none of our subjects suffered sudden cardiac death.
To gain insight into the mechanism of arrhythmia susceptibility, we simulated the effect of reduced Kir2.1 using a ventricular myocyte model. A reduction in Kir2.1 prolonged the terminal phase of the cardiac action potential, and in the setting of reduced extracellular K(+), induced Na(+)/Ca(2+) exchanger-dependent delayed afterdepolarizations and spontaneous arrhythmias. These findings suggest that the substrate for arrhythmia susceptibility in AS is distinct from the other forms of inherited LQT syndrome.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
PMID: 12163457
Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome).
Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, Ptacek LJ, Tawil R.
Division of Pediatric Cardiology, University of Utah, Salt Lake City, Utah 84112, USA.
Andersen syndrome (AS) is a rare, inherited disorder characterized by periodic paralysis, long QT (LQT) with ventricular arrhythmias, and skeletal developmental abnormalities. We recently established that AS is caused by mutations in KCNJ2, which encodes the inward rectifier K(+) channel Kir2.1.
In this report, we characterized the functional consequences of three novel and seven previously described KCNJ2 mutations using a two-microelectrode voltage-clamp technique and correlated the findings with the clinical phenotype. All mutations resulted in loss of function and dominant-negative suppression of Kir2.1 channel function. In mutation carriers, the frequency of periodic paralysis was 64% and dysmorphic features 78%. LQT was the primary cardiac manifestation, present in 71% of KCNJ2 mutation carriers, with ventricular arrhythmias present in 64%. While arrhythmias were common, none of our subjects suffered sudden cardiac death.
To gain insight into the mechanism of arrhythmia susceptibility, we simulated the effect of reduced Kir2.1 using a ventricular myocyte model. A reduction in Kir2.1 prolonged the terminal phase of the cardiac action potential, and in the setting of reduced extracellular K(+), induced Na(+)/Ca(2+) exchanger-dependent delayed afterdepolarizations and spontaneous arrhythmias. These findings suggest that the substrate for arrhythmia susceptibility in AS is distinct from the other forms of inherited LQT syndrome.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
PMID: 12163457
Tuesday, May 1, 2007
HypoKPP: a model for a clinical and research approach to
Neurotherapeutics. 2007 Apr;4(2):225-32.
Hypokalemic periodic paralysis: a model for a clinical and research approach to a rare disorder.
Fontaine B, Fournier E, Sternberg D, Vicart S, Tabti N.
Institut National de la Sante et de la Recherche Medicale (INSERM), UMR S546, Paris, France; Universite Pierre et Marie Curie Paris 6, UHR SS46, Paris, France.
Rare diseases have attracted little attention in the past from physicians and researchers. The situation has recently changed for several reasons. First, patient associations have successfully advocated their cause to institutions and governments. They were able to argue that, taken together, rare diseases affect approximately 10% of the population in developed countries. Second, almost 80% of rare diseases are of genetic origin. Advances in genetics have enabled the identification of the causative genes. Unprecedented financial support has been dedicated to research on rare diseases, as well as to the development of referral centers aimed at improving the quality of care. This expenditure of resources is justified by the experience in cystic fibrosis, which demonstrated that improved care delivered by specialized referral centers resulted in a
dramatic increase of life expectancy. Moreover, clinical referral centers offer the unique possibility of developing high quality clinical research studies, not otherwise possible because of the geographic dispersion of patients. This is the case in France where national referral centers for rare diseases were created, including one for muscle channelopathies. The aim of this center is to develop appropriate care, clinical research, and teaching on periodic paralysis and myotonia.
In this review, we plan to demonstrate how research has improved our knowledge of hypokalemic periodic paralysis and the way we evaluate, advise, and treat patients. We also advocate for the establishment of international collaborations, which are mandatory for the follow-up of cohorts and conduct of definitive therapeutic trials in rare diseases.
PMID: 17395132
Hypokalemic periodic paralysis: a model for a clinical and research approach to a rare disorder.
Fontaine B, Fournier E, Sternberg D, Vicart S, Tabti N.
Institut National de la Sante et de la Recherche Medicale (INSERM), UMR S546, Paris, France; Universite Pierre et Marie Curie Paris 6, UHR SS46, Paris, France.
Rare diseases have attracted little attention in the past from physicians and researchers. The situation has recently changed for several reasons. First, patient associations have successfully advocated their cause to institutions and governments. They were able to argue that, taken together, rare diseases affect approximately 10% of the population in developed countries. Second, almost 80% of rare diseases are of genetic origin. Advances in genetics have enabled the identification of the causative genes. Unprecedented financial support has been dedicated to research on rare diseases, as well as to the development of referral centers aimed at improving the quality of care. This expenditure of resources is justified by the experience in cystic fibrosis, which demonstrated that improved care delivered by specialized referral centers resulted in a
dramatic increase of life expectancy. Moreover, clinical referral centers offer the unique possibility of developing high quality clinical research studies, not otherwise possible because of the geographic dispersion of patients. This is the case in France where national referral centers for rare diseases were created, including one for muscle channelopathies. The aim of this center is to develop appropriate care, clinical research, and teaching on periodic paralysis and myotonia.
In this review, we plan to demonstrate how research has improved our knowledge of hypokalemic periodic paralysis and the way we evaluate, advise, and treat patients. We also advocate for the establishment of international collaborations, which are mandatory for the follow-up of cohorts and conduct of definitive therapeutic trials in rare diseases.
PMID: 17395132
Saturday, April 28, 2007
Regarding Women of a Certain Age
Outcomes in Cases of Chronic Disseminated Lyme Disease for Three Infected Physicians, Described in Their Own Essays, Published in Peer Reviewed Journals
Virginia T. Sherr, MD
13th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders
Emphasis: Pediatrics & New Research
Hartford Marriott Farmington, CT 24–-26 March 2000
In 1972, a Swedish pediatric neurologist, 46-year-old Dr. Ingrid Gamstorp, noticed generalized fatigue and paresthesias predominately in her left hand. Through the ensuing years, she developed serious balance problems, loss of fine sensation in both hands, multiple muscle pains, deep aches, weight loss, and painful feet. Colleagues dismissed her distress as being the Swedish equivalent of a “tenderfoot."
She began on a endless cycle of trips to doctors, each examining her and referring her on to another for new tests while suggesting stress as the likely cause. She became depressed and contemplated suicide. She was subjected to comments like: “You should know how it is for women of your age. You should just live with it!”
Sixteen years later, a friend noticed her blue hands and suggested Lyme disease, confirmed it with blood tests, started her on IV penicillin, then oral penicillin, then oral tetracycline and finally IV cephalosporin. These nine weeks total of antibiotics stopped the progress of her symptoms and gave her tremendous relief from the burden of being underdiagnosed, untreated and trivialized. However, neurological damage due to long-term, untreated and then partially treated infection left her disabled enough during her last nine years of work that she was forced to retire early.
She said that while the infection was important to her, it “meant a lot to Swedish child neurology, which lost its only professorship at my retirement. Never pat women on the shoulder and say, 'You know, women of your age.."
Her article is:
Lyme Borreliosis from a Patient's View-point
Scand J Infect Dis Suppl. 1991;77:15-6.
Gamstorp I.
Department of Pediatrics, University Hospital, Uppsala, Sweden.
The paper describes my own case of Lyme borreliosis, thus from the patient's point of view, stressing the clues which might have led to an earlier diagnosis. Intense antibiotic treatment is of value, also when given first some 15 years after the probable time of the infection, as, at least in my case, it stopped the progress of all symptoms and removed some of them, particularly muscle pains and skin abnormalities. Long-standing, well-established neurological symptoms, however, remain unchanged, but their previous slow, steady progress has stopped. The diagnosis is in itself valuable, as it is a relief to know what is behind the complaints.
PMID: 1947805
Virginia T. Sherr, MD
13th International Scientific Conference on Lyme Disease and Other Tick-Borne Disorders
Emphasis: Pediatrics & New Research
Hartford Marriott Farmington, CT 24–-26 March 2000
In 1972, a Swedish pediatric neurologist, 46-year-old Dr. Ingrid Gamstorp, noticed generalized fatigue and paresthesias predominately in her left hand. Through the ensuing years, she developed serious balance problems, loss of fine sensation in both hands, multiple muscle pains, deep aches, weight loss, and painful feet. Colleagues dismissed her distress as being the Swedish equivalent of a “tenderfoot."
She began on a endless cycle of trips to doctors, each examining her and referring her on to another for new tests while suggesting stress as the likely cause. She became depressed and contemplated suicide. She was subjected to comments like: “You should know how it is for women of your age. You should just live with it!”
Sixteen years later, a friend noticed her blue hands and suggested Lyme disease, confirmed it with blood tests, started her on IV penicillin, then oral penicillin, then oral tetracycline and finally IV cephalosporin. These nine weeks total of antibiotics stopped the progress of her symptoms and gave her tremendous relief from the burden of being underdiagnosed, untreated and trivialized. However, neurological damage due to long-term, untreated and then partially treated infection left her disabled enough during her last nine years of work that she was forced to retire early.
She said that while the infection was important to her, it “meant a lot to Swedish child neurology, which lost its only professorship at my retirement. Never pat women on the shoulder and say, 'You know, women of your age.."
Her article is:
Lyme Borreliosis from a Patient's View-point
Scand J Infect Dis Suppl. 1991;77:15-6.
Gamstorp I.
Department of Pediatrics, University Hospital, Uppsala, Sweden.
The paper describes my own case of Lyme borreliosis, thus from the patient's point of view, stressing the clues which might have led to an earlier diagnosis. Intense antibiotic treatment is of value, also when given first some 15 years after the probable time of the infection, as, at least in my case, it stopped the progress of all symptoms and removed some of them, particularly muscle pains and skin abnormalities. Long-standing, well-established neurological symptoms, however, remain unchanged, but their previous slow, steady progress has stopped. The diagnosis is in itself valuable, as it is a relief to know what is behind the complaints.
PMID: 1947805
Swimming-triggered aborted sudden cardiac death in a patient with ATS
Int J Cardiol. 2006 Sep 20;112(2):e45-7. Epub 2006 Jul 21.
Swimming-triggered aborted sudden cardiac death in a patient with Andersen-Tawil syndrome.
Efremidis M, Pappas LK, Sideris A, Letsas KP, Gavrielatos GD, Kardaras F.
In this report we describe the case of a 42-year-old woman who experienced an episode of near drowning during recreational swimming. A diagnosis of Andersen-Tawil syndrome was made based on the patient's dysmorphic features, characteristic T-U-wave patterns and ventricular arrhythmias. To our knowledge, this is the first report of a swimming-triggered cardiac event in a patient with Andersen-Tawil syndrome.
PMID: 16859779
Swimming-triggered aborted sudden cardiac death in a patient with Andersen-Tawil syndrome.
Efremidis M, Pappas LK, Sideris A, Letsas KP, Gavrielatos GD, Kardaras F.
In this report we describe the case of a 42-year-old woman who experienced an episode of near drowning during recreational swimming. A diagnosis of Andersen-Tawil syndrome was made based on the patient's dysmorphic features, characteristic T-U-wave patterns and ventricular arrhythmias. To our knowledge, this is the first report of a swimming-triggered cardiac event in a patient with Andersen-Tawil syndrome.
PMID: 16859779
Thursday, April 26, 2007
Progressive myopathy in hyperkalemic periodic paralysis
Arch Neurol. 1990 Sep;47(9):1013-7.
Progressive myopathy in hyperkalemic periodic paralysis.
Bradley WG, Taylor R, Rice DR, Hausmanowa-Petruzewicz I, Adelman LS, Jenkison M, Jedrzejowska H, Drac H, Pendlebury WW.
Department of Neurology, University of Vermont School of Medicine, Medical Center Hospital, Burlington 05405.
A progressive degenerative myopathy has been well described in hypokalemic periodic paralysis but is not as widely recognized in hyperkalemic periodic paralysis. We studied four families with the latter disease in which some members developed a progressive myopathy. Episodes of paralysis were prolonged, lasting for months in some cases, and in one case paralysis was sufficiently severe to require ventilatory support. The progressive myopathy tended to develop at a time when attacks of paralysis were decreasing in frequency. Muscle biopsy specimens showed variability in fiber size, internal nuclei, and fibers with vacuoles. Electron microscopy showed myofibrillary degeneration and tubular aggregates. An abnormal biopsy specimen was more common in older patients. Our experience suggests that a progressive myopathy is as common in hyperkalemic periodic paralysis as it is in the hypokalemic disorder.
PMID: 2396930
Progressive myopathy in hyperkalemic periodic paralysis.
Bradley WG, Taylor R, Rice DR, Hausmanowa-Petruzewicz I, Adelman LS, Jenkison M, Jedrzejowska H, Drac H, Pendlebury WW.
Department of Neurology, University of Vermont School of Medicine, Medical Center Hospital, Burlington 05405.
A progressive degenerative myopathy has been well described in hypokalemic periodic paralysis but is not as widely recognized in hyperkalemic periodic paralysis. We studied four families with the latter disease in which some members developed a progressive myopathy. Episodes of paralysis were prolonged, lasting for months in some cases, and in one case paralysis was sufficiently severe to require ventilatory support. The progressive myopathy tended to develop at a time when attacks of paralysis were decreasing in frequency. Muscle biopsy specimens showed variability in fiber size, internal nuclei, and fibers with vacuoles. Electron microscopy showed myofibrillary degeneration and tubular aggregates. An abnormal biopsy specimen was more common in older patients. Our experience suggests that a progressive myopathy is as common in hyperkalemic periodic paralysis as it is in the hypokalemic disorder.
PMID: 2396930
Thyrotoxic normokalemic periodic paralysis
Am J Emerg Med. 2003 Jan;21(1):71-3.
An unrecognized cause of paralysis in ED: thyrotoxic normokalemic periodic paralysis.
Wu CC, Chau T, Chang CJ, Lin SH.
Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Hypokalemic paralysis associated with hyperthyroidism (TPP) is a well-known acute electrolyte and muscle function disorder. Lesser known is normokalemic periodic paralysis associated with hyperthyroidism. We describe two cases of young men with acute muscular paralysis and bilateral impairment of sensation over the lower legs who had normal plasma potassium concentrations. They were initially misdiagnosed as having Guillain-Barre syndrome or hysterical paralysis. However, thyroid function tests showed elevated serum T(3) and T(4) and markedly depressed thyroid-stimulating hormone findings consistent with hyperthyroidism. Control of the hyperthyroidism completely abolished their periodic paralysis. Thyrotoxic normokalemic periodic paralysis (TNPP) should be kept in mind as a cause of acute muscle weakness to avoid missing a treatable and curable condition. Copyright 2003, Elsevier Science (USA). All rights
reserved.)
PMID: 12563586
An unrecognized cause of paralysis in ED: thyrotoxic normokalemic periodic paralysis.
Wu CC, Chau T, Chang CJ, Lin SH.
Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
Hypokalemic paralysis associated with hyperthyroidism (TPP) is a well-known acute electrolyte and muscle function disorder. Lesser known is normokalemic periodic paralysis associated with hyperthyroidism. We describe two cases of young men with acute muscular paralysis and bilateral impairment of sensation over the lower legs who had normal plasma potassium concentrations. They were initially misdiagnosed as having Guillain-Barre syndrome or hysterical paralysis. However, thyroid function tests showed elevated serum T(3) and T(4) and markedly depressed thyroid-stimulating hormone findings consistent with hyperthyroidism. Control of the hyperthyroidism completely abolished their periodic paralysis. Thyrotoxic normokalemic periodic paralysis (TNPP) should be kept in mind as a cause of acute muscle weakness to avoid missing a treatable and curable condition. Copyright 2003, Elsevier Science (USA). All rights
reserved.)
PMID: 12563586
Sunday, April 22, 2007
The Nondystrophic Myotonias
Neurotherapeutics. 2007 Apr;4(2):238-51.
The nondystrophic myotonias.
Heatwole CR, Moxley RT 3rd.
Department of Neurology, University of Rochester, Rochester, New York.
The nondystrophic myotonias are a heterogeneous set of rare diseases that demonstrate clinical myotonia, electrical myotonia, or both. These disorders are distinguished from myotonic dystrophy type 1 (DM-1), the more recently described proximal myotonic myopathy/myotonic dystrophy type 2 (PROMM/DM-2), and proximal myotonic dystrophy (a variant of DM-2) by characteristic clinical features, lack of abnormal nucleotide repeat expansions in the DM-1 and DM-2 genes, lack of cataracts and endocrine disturbances, and absence of significant histopathology in the muscle biopsy.
The present article reviews each of the nondystrophic myotonias by exploring the unique clinical features, electrodiagnostic findings, diagnostic criteria, gene mutations, and response to pharmacologic therapy. These diseases are divided into those with chloride channel dysfunction (the myotonia congenita disorders) and those with sodium channel dysfunction (paramyotonia congenita, potassium-aggravated myotonia, and hyperkalemic periodic paralysis with myotonia). The variants that occur in each of these conditions are commented on. The differentiating features of the nondystrophic myotonias are summarized, and their predominant clinical, electrodiagnostic, and genetic characteristics are tabulated.
For a comprehensive review of pertinent research and studies with application to diagnosis and treatment of individuals with nondystrophic myotonic disorders, the present article is best read in the context of other articles in this issue, especially those on ion channel physiology (Cannon) and pharmacology (Conte-Camerino), and on hyperkalemic periodic paralysis (Lehmann-Horn).
PMID: 17395134
The nondystrophic myotonias.
Heatwole CR, Moxley RT 3rd.
Department of Neurology, University of Rochester, Rochester, New York.
The nondystrophic myotonias are a heterogeneous set of rare diseases that demonstrate clinical myotonia, electrical myotonia, or both. These disorders are distinguished from myotonic dystrophy type 1 (DM-1), the more recently described proximal myotonic myopathy/myotonic dystrophy type 2 (PROMM/DM-2), and proximal myotonic dystrophy (a variant of DM-2) by characteristic clinical features, lack of abnormal nucleotide repeat expansions in the DM-1 and DM-2 genes, lack of cataracts and endocrine disturbances, and absence of significant histopathology in the muscle biopsy.
The present article reviews each of the nondystrophic myotonias by exploring the unique clinical features, electrodiagnostic findings, diagnostic criteria, gene mutations, and response to pharmacologic therapy. These diseases are divided into those with chloride channel dysfunction (the myotonia congenita disorders) and those with sodium channel dysfunction (paramyotonia congenita, potassium-aggravated myotonia, and hyperkalemic periodic paralysis with myotonia). The variants that occur in each of these conditions are commented on. The differentiating features of the nondystrophic myotonias are summarized, and their predominant clinical, electrodiagnostic, and genetic characteristics are tabulated.
For a comprehensive review of pertinent research and studies with application to diagnosis and treatment of individuals with nondystrophic myotonic disorders, the present article is best read in the context of other articles in this issue, especially those on ion channel physiology (Cannon) and pharmacology (Conte-Camerino), and on hyperkalemic periodic paralysis (Lehmann-Horn).
PMID: 17395134
Tuesday, April 17, 2007
HypoKPP in an African Family
Neuromuscul Disord. 2007 Apr 4; [Epub ahead of print]
Hypokalaemic periodic paralysis due to the CACNA1S R1239H mutation in a large African family.
Houinato D, Laleye A, Adjien C, Adjagba M, Sternberg D, Hilbert P, Vallat JM, Darboux RB, Funalot B, Avode DG.
UFR de Neurologie, Faculte des Sciences de la Sante, Cotonou, Benin.
Hypokalaemic periodic paralysis (HypoKPP) is a skeletal muscle channelopathy caused by mutations in calcium (CACNA1S) and sodium (SCN4A) channel subunits. A small number of causative mutations have been found in European and Asian patients, but not in African patients yet. We have identified a large Beninese family in which HypoKPP segregated over five generations and was caused by the CACNA1S R1239H mutation. We report on the clinical and histopathological spectrum of the disorder in this family. A later age at onset (15.8+/-8.8years), and particular triggering factors due to specific African life conditions seem to be characteristic of our observation.
PMID: 17418573
Hypokalaemic periodic paralysis due to the CACNA1S R1239H mutation in a large African family.
Houinato D, Laleye A, Adjien C, Adjagba M, Sternberg D, Hilbert P, Vallat JM, Darboux RB, Funalot B, Avode DG.
UFR de Neurologie, Faculte des Sciences de la Sante, Cotonou, Benin.
Hypokalaemic periodic paralysis (HypoKPP) is a skeletal muscle channelopathy caused by mutations in calcium (CACNA1S) and sodium (SCN4A) channel subunits. A small number of causative mutations have been found in European and Asian patients, but not in African patients yet. We have identified a large Beninese family in which HypoKPP segregated over five generations and was caused by the CACNA1S R1239H mutation. We report on the clinical and histopathological spectrum of the disorder in this family. A later age at onset (15.8+/-8.8years), and particular triggering factors due to specific African life conditions seem to be characteristic of our observation.
PMID: 17418573
Management and Treatment of ATS
Neurotherapeutics. 2007 Apr;4(2):233-7.
Management and Treatment of Andersen-Tawil Syndrome (ATS).
Sansone V, Tawil R.
Department of Neurology, University of Milan, IRCCS Policlinico San Donato,
Milan, Italy 20097.
Andersen-Tawil syndrome (ATS) is characterized by periodic paralysis, cardiac arrhythmias, and distinct facial and skeletal features. The majority of patients with ATS (ATS1) have point mutations in the KCNJ2 gene, which encodes the inward rectifying potassium channel known as Kir2.1. The skeletal muscle and cardiac symptoms are accounted for, in most cases, by a dominant negative effect of the mutations on potassium channel current, resulting in prolonged depolarization of the action potential. Mechanisms of disruption of channel function include abnormal trafficking and assembly of second messengers such as phosphatidylinositol 4,5-bisphosphate, abnormal gating of the channel, and incorrect folding of the Kir2.1 protein.
Less apparent is the mechanism by which these mutations account for the typical facial and skeletal abnormalities. The concomitant involvement of cardiac and skeletal muscle in ATS poses unique treatment and management challenges. Because of differences in cardiac and skeletal muscle physiology, drugs that may have a beneficial effect on cardiac function may have a detrimental effect on skeletal muscle and vice versa. We review the clinical, laboratory, and genetic features of this disorder with particular emphasis on treatment and management.
PMID: 17395133
Management and Treatment of Andersen-Tawil Syndrome (ATS).
Sansone V, Tawil R.
Department of Neurology, University of Milan, IRCCS Policlinico San Donato,
Milan, Italy 20097.
Andersen-Tawil syndrome (ATS) is characterized by periodic paralysis, cardiac arrhythmias, and distinct facial and skeletal features. The majority of patients with ATS (ATS1) have point mutations in the KCNJ2 gene, which encodes the inward rectifying potassium channel known as Kir2.1. The skeletal muscle and cardiac symptoms are accounted for, in most cases, by a dominant negative effect of the mutations on potassium channel current, resulting in prolonged depolarization of the action potential. Mechanisms of disruption of channel function include abnormal trafficking and assembly of second messengers such as phosphatidylinositol 4,5-bisphosphate, abnormal gating of the channel, and incorrect folding of the Kir2.1 protein.
Less apparent is the mechanism by which these mutations account for the typical facial and skeletal abnormalities. The concomitant involvement of cardiac and skeletal muscle in ATS poses unique treatment and management challenges. Because of differences in cardiac and skeletal muscle physiology, drugs that may have a beneficial effect on cardiac function may have a detrimental effect on skeletal muscle and vice versa. We review the clinical, laboratory, and genetic features of this disorder with particular emphasis on treatment and management.
PMID: 17395133
Monday, April 16, 2007
Genetics and Andersen-Tawil Syndrome
Andersen-Tawil Syndrome (ATS) is a less common form of Periodic Paralysis that may include flaccid paralysis or weakness, plus heart rhythm problems, fainting spells, small stature, webbed fingers or toes and blood potassium levels that usually (but not always) fall during attacks. An article titled Andersen-Tawil Syndrome, written by Drs. Rabi Tawil and Shannon Vance and published at GeneTests.org describes this condition in detail. The article includes sections on:
While about 70% of those tested for ATS have genetic mutations on KCNJ2, there remain approximately 30% of patients who have an as yet UNKNOWN mutation or mutations.
Posted by RR.
- Summary
- Diagnosis
- Clinical Description
- Prevalence
- Differential Diagnosis
- Management
- Genetic Counseling
- Molecular Genetics
- Resources
- References and
- Author Information
While about 70% of those tested for ATS have genetic mutations on KCNJ2, there remain approximately 30% of patients who have an as yet UNKNOWN mutation or mutations.
Posted by RR.
Friday, April 6, 2007
Correlating phenotype & genotype in the periodic paralyses
Neurology. 2004 Nov 9;63(9):1647-55.
Comment in: Neurology. 2004 Nov 9;63(9):E17-8.
Correlating phenotype and genotype in the periodic paralyses.
Miller TM, Dias da Silva MR, Miller HA, Kwiecinski H, Mendell JR, Tawil R, McManis P, Griggs RC, Angelini C, Servidei S, Petajan J, Dalakas MC, Ranum LP, Fu YH, Ptacek LJ.
Dept of Neurology, University of California San Francisco 94143-2922, USA.
BACKGROUND: Periodic paralyses and paramyotonia congenita are rare disorders causing disabling weakness and myotonia. Mutations in sodium, calcium, and potassium channels have been recognized as causing disease.
OBJECTIVE: To analyze the clinical phenotype of patients with and without discernible genotype and to identify other mutations in ion channel genes associated with disease.
METHODS: The authors have reviewed clinical data in patients with a diagnosis of hypokalemic periodic paralysis (56 kindreds, 71 patients), hyperkalemic periodic paralysis (47 kindreds, 99 patients), and paramyotonia congenita (24 kindreds, 56 patients). For those patients without one of the classically known mutations, the authors analyzed the entire coding region of the SCN4A, KCNE3, and KCNJ2 genes and portions of the coding region of the CACNA1S gene in order to identify new mutations.
RESULTS: Mutations were identified in approximately two thirds of kindreds with periodic paralysis or paramyotonia congenita. The authors found differences between the disorders and between those with and without identified mutations in terms of age at onset, frequency of attacks, duration of attacks, fixed proximal weakness, precipitants of attacks, myotonia, electrophysiologic studies, serum potassium levels, muscle biopsy, response to potassium administration, and response to treatment with acetazolamide.
CONCLUSIONS: Hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and paramyotonia congenita may be distinguished based on clinical data. This series of 226 patients (127 kindreds) confirms some clinical features of this disorder with notable exceptions: In this series, patients without mutations had a less typical clinical presentation including an older age at onset, no changes in diet as a precipitant, and absence of vacuolar myopathy on muscle biopsy.
PMID: 15534250
Comment in: Neurology. 2004 Nov 9;63(9):E17-8.
Correlating phenotype and genotype in the periodic paralyses.
Miller TM, Dias da Silva MR, Miller HA, Kwiecinski H, Mendell JR, Tawil R, McManis P, Griggs RC, Angelini C, Servidei S, Petajan J, Dalakas MC, Ranum LP, Fu YH, Ptacek LJ.
Dept of Neurology, University of California San Francisco 94143-2922, USA.
BACKGROUND: Periodic paralyses and paramyotonia congenita are rare disorders causing disabling weakness and myotonia. Mutations in sodium, calcium, and potassium channels have been recognized as causing disease.
OBJECTIVE: To analyze the clinical phenotype of patients with and without discernible genotype and to identify other mutations in ion channel genes associated with disease.
METHODS: The authors have reviewed clinical data in patients with a diagnosis of hypokalemic periodic paralysis (56 kindreds, 71 patients), hyperkalemic periodic paralysis (47 kindreds, 99 patients), and paramyotonia congenita (24 kindreds, 56 patients). For those patients without one of the classically known mutations, the authors analyzed the entire coding region of the SCN4A, KCNE3, and KCNJ2 genes and portions of the coding region of the CACNA1S gene in order to identify new mutations.
RESULTS: Mutations were identified in approximately two thirds of kindreds with periodic paralysis or paramyotonia congenita. The authors found differences between the disorders and between those with and without identified mutations in terms of age at onset, frequency of attacks, duration of attacks, fixed proximal weakness, precipitants of attacks, myotonia, electrophysiologic studies, serum potassium levels, muscle biopsy, response to potassium administration, and response to treatment with acetazolamide.
CONCLUSIONS: Hypokalemic periodic paralysis, hyperkalemic periodic paralysis, and paramyotonia congenita may be distinguished based on clinical data. This series of 226 patients (127 kindreds) confirms some clinical features of this disorder with notable exceptions: In this series, patients without mutations had a less typical clinical presentation including an older age at onset, no changes in diet as a precipitant, and absence of vacuolar myopathy on muscle biopsy.
PMID: 15534250
Genotype-Phenotype Correlation & Therapy in HyperKPP
Genotype-phenotype correlation and therapeutic rationale in hyperkalemic periodic paralysis.
Neurotherapeutics. 2007 Apr;4(2):216-24.
Jurkat-Rott K, Lehmann-Horn F.
Department of Applied Physiology, Ulm University, Ulm, Germany.
Familial hyperkalemic periodic paralysis (PP) is a dominantly inherited muscle disease characterized by attacks of flaccid weakness and intermittent myotonia. Some patients experience muscle stiffness that is aggravated by cold and exercise, bordering on the diagnosis of paramyotonia congenita. Hyperkalemic PP and paramyotonia congenita are allelic diseases caused by gain-of-function mutations of the skeletal muscle sodium channel, Nav1.4, which is essential for the generation of skeletal muscle action potentials. In this review, the functional and clinical consequences of the mutations and therapeutic strategies are reported and the differential diagnoses discussed.
Also, the question is addressed of whether hyperkalemic PP is truly a different entity than normokalemic PP. Additionally, the differential diagnosis of Andersen-Tawil syndrome in which hyperkalemic PP attacks may occur will be briefly introduced. Last, because hyperkalemic PP has been described to be associated with an R83H mutation of a MiRP2 potassium channel subunit, evidence refuting disease-causality in this case will be discussed.
PMID: 17395131
Neurotherapeutics. 2007 Apr;4(2):216-24.
Jurkat-Rott K, Lehmann-Horn F.
Department of Applied Physiology, Ulm University, Ulm, Germany.
Familial hyperkalemic periodic paralysis (PP) is a dominantly inherited muscle disease characterized by attacks of flaccid weakness and intermittent myotonia. Some patients experience muscle stiffness that is aggravated by cold and exercise, bordering on the diagnosis of paramyotonia congenita. Hyperkalemic PP and paramyotonia congenita are allelic diseases caused by gain-of-function mutations of the skeletal muscle sodium channel, Nav1.4, which is essential for the generation of skeletal muscle action potentials. In this review, the functional and clinical consequences of the mutations and therapeutic strategies are reported and the differential diagnoses discussed.
Also, the question is addressed of whether hyperkalemic PP is truly a different entity than normokalemic PP. Additionally, the differential diagnosis of Andersen-Tawil syndrome in which hyperkalemic PP attacks may occur will be briefly introduced. Last, because hyperkalemic PP has been described to be associated with an R83H mutation of a MiRP2 potassium channel subunit, evidence refuting disease-causality in this case will be discussed.
PMID: 17395131
Thursday, April 5, 2007
Hypokalemia and Paralysis
Hypokalemia and Paralysis; Q J Med 2001; 94: 133-139; S.-H. Lin, Y.-F. Lin and M.L. Halperin
It is not uncommon for patients to present to the emergency room with severe weakness and a markedly low plasma potassium concentration. We attempted to identify useful clues to the diagnosis of hypokalaemic periodic paralysis, because its acute treatment aims are unique.
It is not uncommon for patients to present to the emergency room with severe weakness and a markedly low plasma potassium concentration. We attempted to identify useful clues to the diagnosis of hypokalaemic periodic paralysis, because its acute treatment aims are unique.
Treatment of Hyperkalemia
From Neurology Rounds, April 2001; Vol 2; Issue 4. Authors Charles C-Y Wei and Kamel Kamel discuss the therapeutic options for treating Hyperkalemia. Controversies in the Treatment of Hyperkalemia
Wednesday, April 4, 2007
HypoKPP: Gating of the HypoPP-1 mutations
Pflugers Arch. 2007 Feb 27; [Epub ahead of print]
Gating of the HypoPP-1 mutations: I. Mutant-specific effects and cooperativity.
Kuzmenkin A, Hang C, Kuzmenkina E, Jurkat-Rott K.
Department of Applied Physiology, University of Ulm, 89081, Ulm, Germany,
karin.jurkat-rott@uni-ulm.de.
Hypokalemic periodic paralysis type 1 (HypoPP-1) is a hereditary muscular disorder caused by point mutations in the gene encoding the voltage-gated Ca(2+) channel alpha subunit (Ca(v)1.1). Despite extensive research, the results on HypoPP-1 mutations are minor and controversial, as it is difficult to analyse Ca(2+) channel activation macroscopically due to an existence of two open states. In this study, we heterologously expressed the wild-type and HypoPP-1 mutations introduced into the rabbit cardiac Ca(2+) channel (R650H, R1362H, R1362G) in HEK-293 cells. To examine the cooperative effects of the mutations on channel gating, we expressed two double mutants (R650H/R1362H, R650H/R1362G).
We performed whole-cell patch-clamp and, to obtain more information, applied a global fitting procedure whereby several current traces elicited by different potentials were simultaneously fit to the kinetic model containing four closed, two open and two inactivated states. We found that all HypoPP-1 mutations have "loss-of-function" features: D4/S4 mutations shift the equilibrium to the closed states, which results in reduced open probability, shorter openings and, therefore, in smaller currents, and the D2/S4 mutant slows the activation. In addition, HypoPP-1 histidine mutants favored the second open state O(2) with a possibly lower channel selectivity. Cooperativity between the D2/S4 and D4/S4 HypoPP-1 mutations manifested in dominant effects of the D4/S4 mutations on kinetics of the double mutants, suggesting different roles of D2/S4 and D4/S4 voltage sensors in the gating of voltage-gated calcium channels.
PMID: 17333249
Gating of the HypoPP-1 mutations: I. Mutant-specific effects and cooperativity.
Kuzmenkin A, Hang C, Kuzmenkina E, Jurkat-Rott K.
Department of Applied Physiology, University of Ulm, 89081, Ulm, Germany,
karin.jurkat-rott@uni-ulm.de.
Hypokalemic periodic paralysis type 1 (HypoPP-1) is a hereditary muscular disorder caused by point mutations in the gene encoding the voltage-gated Ca(2+) channel alpha subunit (Ca(v)1.1). Despite extensive research, the results on HypoPP-1 mutations are minor and controversial, as it is difficult to analyse Ca(2+) channel activation macroscopically due to an existence of two open states. In this study, we heterologously expressed the wild-type and HypoPP-1 mutations introduced into the rabbit cardiac Ca(2+) channel (R650H, R1362H, R1362G) in HEK-293 cells. To examine the cooperative effects of the mutations on channel gating, we expressed two double mutants (R650H/R1362H, R650H/R1362G).
We performed whole-cell patch-clamp and, to obtain more information, applied a global fitting procedure whereby several current traces elicited by different potentials were simultaneously fit to the kinetic model containing four closed, two open and two inactivated states. We found that all HypoPP-1 mutations have "loss-of-function" features: D4/S4 mutations shift the equilibrium to the closed states, which results in reduced open probability, shorter openings and, therefore, in smaller currents, and the D2/S4 mutant slows the activation. In addition, HypoPP-1 histidine mutants favored the second open state O(2) with a possibly lower channel selectivity. Cooperativity between the D2/S4 and D4/S4 HypoPP-1 mutations manifested in dominant effects of the D4/S4 mutations on kinetics of the double mutants, suggesting different roles of D2/S4 and D4/S4 voltage sensors in the gating of voltage-gated calcium channels.
PMID: 17333249
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