Hyperkalemic Periodic Paralysis Research Articles

A novel mutation in SCN4A causes severe myotonia and school-age-onset paralytic episodes

Mutations in the pore-forming subunit of the skeletal muscle sodium channel (SCN4A) are responsible for hyperkalemic periodic paralysis, paramyotonia congenita and sodium channel myotonia. These disorders are classified based on their cardinal symptoms, myotonia and/or paralysis. We report the case of a Japanese boy with a novel mutation of SCN4A, p.I693L, who exhibited severe episodic myotonia from infancy and later onset mild paralytic attack. He started to have apneic episodes with generalized hypertonia at age of 11months, then developed severe episodic myotonia since 2years of age. He presented characteristic generalized features which resembled Schwarz–Jampel syndrome. After 7years old, paralytic episodes occurred several times a year. The compound muscle action potential did not change during short and long exercise tests. Functional analysis of the mutant channel expressed in cultured cell revealed enhancement of the activation and disruption of the slow inactivation, which were consistent with myotonia and paralytic attack. The severe clinical features in his infancy may correspond to myotonia permanence, however, he subsequently experienced paralytic attacks. This case provides an example of the complexity and overlap of the clinical features of sodium channel myotonic disorders.

Management of a patient with hyperkalemic periodic paralysis requiring coronary artery bypass grafts

Hyperkalemic periodic paralysis (HPP) is an autosomal-dominant inherited muscle disease characterized by episodes of flaccid weakness and intermittent myotonia. There are no previous reports in the literature about anesthesia for cardiac surgery with cardiopulmonary bypass in this disorder. We describe perioperative anesthetic management for on-pump coronary artery bypass grafting in a 75-year-old man with a history of hyperkalemic periodic paralysis. This case report outlines our management strategy and the issues encountered during the perioperative period.

The role of diet in the prevention and management of several equine diseases

Modern feeding and housing practices of horses are typically directed at achieving a high level of athletic performance. There are some unfortunate consequences including an increased incidence of disease. Some of these diseases can be directly linked to dietary practices, while in others diet contributes as an important co-factor. Breeding practices to select for specific traits have also inadvertently resulted in the preferential selection of horses with genetic mutations within several breeds. In several of these genetic disorders specific dietary management is required for affected horses to achieve an acceptable level of performance. Diseases in which diet has a significant influence are discussed including equine metabolic syndrome, laminitis, diseases attributed to deficiency of vitamin E and/or selenium, exertional myopathies, nutritional secondary hyperparathyroidism, hyperkalaemic periodic paralysis, and the developmental orthopaedic disease complex.

Novel Insights into the Pathomechanisms of Skeletal Muscle Channelopathies

The nondystrophic myotonias and primary periodic paralyses are an important group of genetic muscle diseases characterized by dysfunction of ion channels that regulate membrane excitability. Clinical manifestations vary and include myotonia, hyperkalemic and hypokalemic periodic paralysis, progressive myopathy, and cardiac arrhythmias. The severity of myotonia ranges from severe neonatal presentation causing respiratory compromise through to mild later-onset disease. It remains unclear why the frequency of attacks of paralysis varies greatly or why many patients develop a severe permanent fixed myopathy. Recent detailed characterizations of human genetic mutations in voltage-gated muscle sodium (gene: SCN4A), chloride (gene: CLCN1), calcium (gene: CACNA1S), and inward rectifier potassium (genes: KCNJ2, KCNJ18) channels have resulted in new insights into disease mechanisms, clinical phenotypic variation, and therapeutic options.

A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis

Hypokalemic periodic paralysis (HypoPP) is an ion channelopathy of skeletal muscle characterized by attacks of muscle weakness associated with low serum K+. HypoPP results from a transient failure of muscle fiber excitability. Mutations in the genes encoding a calcium channel (CaV1.1) and a sodium channel (NaV1.4) have been identified in HypoPP families. Mutations of NaV1.4 give rise to a heterogeneous group of muscle disorders, with gain-of-function defects causing myotonia or hyperkalemic periodic paralysis. To address the question of specificity for the allele encoding the NaV1.4-R669H variant as a cause of HypoPP and to produce a model system in which to characterize functional defects of the mutant channel and susceptibility to paralysis, we generated knockin mice carrying the ortholog of the gene encoding the NaV1.4-R669H variant (referred to herein as R669H mice). Homozygous R669H mice had a robust HypoPP phenotype, with transient loss of muscle excitability and weakness in low-K+ challenge, insensitivity to high-K+ challenge, dominant inheritance, and absence of myotonia. Recovery was sensitive to the Na+/K+-ATPase pump inhibitor ouabain. Affected fibers had an anomalous inward current at hyperpolarized potentials, consistent with the proposal that a leaky gating pore in R669H channels triggers attacks, whereas a reduction in the amplitude of action potentials implies additional loss-of-function changes for the mutant NaV1.4 channels.

Na+,K+-pump stimulation improves contractility in isolated muscles of mice with hyperkalemic periodic paralysis

In patients with hyperkalemic periodic paralysis (HyperKPP), attacks of muscle weakness or paralysis are triggered by K+ ingestion or rest after exercise. Force can be restored by muscle work or treatment with β2-adrenoceptor agonists. A missense substitution corresponding to a mutation in the skeletal muscle voltage-gated Na+ channel (Nav1.4, Met1592Val) causing human HyperKPP was targeted into the mouse SCN4A gene (mutants). In soleus muscles prepared from these mutant mice, twitch, tetanic force, and endurance were markedly reduced compared with soleus from wild type (WT), reflecting impaired excitability. In mutant soleus, contractility was considerably more sensitive than WT soleus to inhibition by elevated [K+]o. In resting mutant soleus, tetrodotoxin (TTX)-suppressible 22Na uptake and [Na+]i were increased by 470 and 58%, respectively, and membrane potential was depolarized (by 16 mV, P < 0.0001) and repolarized by TTX. Na+,K+ pump–mediated 86Rb uptake was 83% larger than in WT. Salbutamol stimulated 86Rb uptake and reduced [Na+]i both in mutant and WT soleus. Stimulating Na+,K+ pumps with salbutamol restored force in mutant soleus and extensor digitorum longus (EDL). Increasing [Na+]i with monensin also restored force in soleus. In soleus, EDL, and tibialis anterior muscles of mutant mice, the content of Na+,K+ pumps was 28, 62, and 33% higher than in WT, respectively, possibly reflecting the stimulating effect of elevated [Na+]i on the synthesis of Na+,K+ pumps. The results confirm that the functional disorders of skeletal muscles in HyperKPP are secondary to increased Na+ influx and show that contractility can be restored by acute stimulation of the Na+,K+ pumps. Calcitonin gene-related peptide (CGRP) restored force in mutant soleus but caused no detectable increase in 86Rb uptake. Repeated excitation and capsaicin also restored contractility, possibly because of the release of endogenous CGRP from nerve endings in the isolated muscles. These observations may explain how mild exercise helps locally to prevent severe weakness during an attack of HyperKPP.

Development of a robust genetic test for hyperkalemic periodic paralysis (HYPP) in quarter horses

A single nucleotide substitution from cysteine to guanine in a region of the skeletal muscle sodium channel gene (SCN4A) is known to cause an equine genetic disorder known as Hyperkalemic Periodic Paralysis (HYPP). The clinical effects of this disorder range from little or no symptoms to frequent episodes of muscle tremors, weakness, and/or complete collapse. Oligonucleotide primer pairs were designed for both the wild type and mutant alleles of the SCN4A gene for use in Amplification Refractory Mutation System‐PCR (ARMS‐PCR). Genomic DNA from both whole blood and saliva swab samples were isolated from horses with wild type phenotypes for HYPP. As expected for an unaffected individual, our test showed the expected PCR product using the wild type specific primer pair, while the mutant specific primer pair did not generate a product. We then varied annealing temperatures and magnesium concentrations to optimize the PCR and found a temperature of 60°C and 3 mM magnesium to be optimal. We next plan to obtain DNA from both carrier horses and individuals expressing the full‐blown mutant phenotype. DNA isolated from HYPP animals should produce a PCR product with only the mutant specific primer pairs, and carriers for HYPP should produce a product in both wild type and mutant specific PCR reactions.

Familial hyperkalemic periodic paralysis caused by ade novomutation in the sodium channel geneSCN4A

Familial hyperkalemic periodic paralysis (HYPP) is an autosomaldominant channelopathy characterized by transient and recurrent episodes of paralysis with concomitant hyperkalemia. Mutations in the skeletal muscle voltage-gated sodium channel gene SCN4A have been reported to be responsible for this disease. Here, we report the case of a 16-year-old girl with HYPP whose mutational analysis revealed a heterozygous c.2111C>T substitution in the SCN4A gene leading to a Thr704Met mutation in the protein sequence. The parents were clinically unaffected and did not have a mutation in the SCN4A gene. A de novo SCN4A mutation for familial HYPP has not previously been reported. The patient did not respond to acetazolamide, but showed a marked improvement in paralytic symptoms upon treatment with hydrochlorothiazide. The findings in this case indicate that a de novo mutation needs to be considered when an isolated family member is found to have a HYPP phenotype.

著明な高ＣＫ血症と軽微な眼輪筋の筋強直を呈したナトリウムチャネル異常症の１例

We report on a Japanese 13-year-old male without a family history of muscle disease admitted to our hospital due to an elevated serum creatine kinase. From the age of 3 he was complaining of muscle stiffness during and after exercise. At the age of 7 he experienced muscle stiffness and weakness during long-distance running, which would continue till the next day, disappearing only after resting for a day. Upon examination, we noted that repeated eyelid contractions induced myotonia that increased in the cold. Electromyography revealed myotonic discharge in the tongue muscle. Genetic analysis revealed a mutation of Nav1.4, M1592V. Although this mutation had originally been reported in families with Hyperkalemic periodic paralysis (Hyper PP), we diagnosed as paramyotonia congenita due to the symptoms of exercise and cold-induced myotonia without an attack of generalized weakness. This case suggest that sodium channelopathy is very rare, but should be considered in the differential diagnosis of an elevation of serum creatine kinase even if coexisting myotonia is only mild.

Hormonal and pharmacological modification of plasma potassium homeostasis

Human skeletal muscles contain the largest single pool of K+ in the body (2600 mmol, 46 times the total K+ content of the extracellular space). Intense exercise may double arterial plasma K+ in one min. This is because of excitation-induced release of K+ from the working muscle cells via K+ channels. This hyperkalemia is rapidly corrected by reaccumulation of K+ into the muscle cells via Na+,K+ pumps, often leading to hypokalemia. Hyperkalemia may also arise from muscle cell damage, excessive oral or intravenous administration of K+, acidosis, renal failure, depolarization of muscle cells with succinyl choline, activation of K+ channels by fluoride poisoning, hyperkalemic periodic paralysis, malignant hyperthermia, inhibition of the Na+,K+ pumps by digitalis glycosides or treatment with nonselective beta blockers. Hyperkalemia may cause arrhythmia and can be treated with beta2 agonists, insulin or hemodialysis. Hypokalemia may be induced by the stimulation of the Na+,K+ pumps in skeletal muscles seen postexercise, or by catecholamines, beta2 agonists, pheochromocytoma, theophylline, caffeine or insulin, by sepsis, myocardial infarction, trauma, burns and heart failure. Rare causes are hypokalemic periodic paralysis, inhibition of K+ channels by barium, chloroquine or barbiturates. Hypokalemia often reflects dietary K+ deficiency, alkalosis, renal or gastrointestinal loss of K+. Hypokalemia is more likely to cause arrhythmia than hyperkalemia and can be treated by oral or intravenous administration of K+ under frequent control of electrocardiogram and plasma K+. Because of their size and high contents of K+, Na+,K+ pumps and K+ channels, the skeletal muscles play a central role in the acute, from min-to-min ongoing regulation of plasma K+. This is decisive for the maintenance of muscle contractility and heart function.

Targeted mutation of NaV1.4 causes paralysis in mouse as observed in attacks of Hyperkalemic Periodic Paralysis (HyperKPP)

The single point mutation M1592V on the skeletal muscle sodium channel, NaV1.4, causes human HyperKPP. For this specific point mutation, the onset of the paralytic attacks occurs between 5–10 years of age. In response to several known triggers, such attacks may then increase in frequency, duration and intensity until adolescence, but typically they diminish in mid‐ adulthood. By that time, fixed muscle weakness and a major shift toward type I and IIA fibers are observed in many muscles. The objective of this study was to determine if introducing a missense substitution corresponding to a human familial HyperKPP mutation (Met1592Val) into the mouse gene (mice(+/M1592V)) encoding the skeletal muscle voltage‐gated Na+ channel NaV1.4 also may predispose to paralytic attacks with changes in frequency and intensity. Paralysis of the hindlimb muscles were observed during the period of 6‐12 weeks postnatal. By 8 weeks of age, EDL muscle from mice(+/M1592V) had more than 2‐fold less type IIB and 2‐times more type IIA fibers when compared to EDL muscles of wild type mice. Finally, measurement of NaV1.4 content by immunohistochemistry showed a small decrease in protein content from 3 to 8 weeks of age followed by no further changes up to 16 weeks of age. More importantly, there was no difference in NaV1.4 protein content between wild type and mice(+/M1592V). We conclude that altered mouse NaV1.4 equivalent to the human M1592V mutation causes paralytic attacks during a postnatal window of 6–12 weeks and a shift toward type IIA fibers that is not associated with a change in NaV1.4 protein content.

Periodic Paralyses

Event Abstract Back to Event Periodic Paralyses Matthew McCoyd1* 1 Loyola University Health System, Department of Neurology, United States Learning objectives: Discuss relevant muscle physiology and ion channel properties in disease Differentiate the primary and secondary periodic paralyses Understand diagnostic and treatment options for the periodic paralyses The periodic paralyses are a heterogeneous group of disorders characterized by episodic muscle weakness. The weakness is often seen in conjunction with altered serum potassium levels (hyperkalemic and hypokalemic periodic paralysis). The physiologic basis of the weakness in these disorders is altered muscle membrane excitability due to defective membrane ion channels. These weakening conditions can be divided into primary and secondary disorders. The primary periodic paralyses are a group of inherited disorders in which mutations cause structural changes within channel proteins, specifically sodium, potassium and calcium channels, leading to aberrant depolarization and weakness. However, weakness is only one manifestation of the responsible gene defects. Symptoms can also include myotonia, stiffness and pain. The reason for variability in phenotypic expression despite genotypic similarity is not clear at this time. The goal of this discussion is to review basic muscle physiology with a focus on the relevant ion channels, review the distinguishing clinical features of the ion channel mutations, and consider diagnostic and treatment options in the disorders characterized by periodic paralysis. Conference: Paroxysmal Neurology Symposium, Chicago, United States, 7 Apr - 7 Apr, 2010. Presentation Type: Oral Presentation Topic: Abstracts Citation: McCoyd M (2010). Periodic Paralyses. Front. Neurol. Conference Abstract: Paroxysmal Neurology Symposium. doi: 10.3389/conf.fneur.2010.07.00005 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 07 Apr 2010; Published Online: 07 Apr 2010. * Correspondence: Matthew McCoyd, Loyola University Health System, Department of Neurology, Maywood, IL, United States, mmccoyd@lumc.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Matthew McCoyd Google Matthew McCoyd Google Scholar Matthew McCoyd PubMed Matthew McCoyd Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Disappearance of Episodic Weakness During Pregnancy in Hyperkalemic Periodic Paralysis From the SCNA4 Mutation T704M

Disappearance of episodic weakness during pregnancy and an increase in myotonia after delivery have not been reported in hyperkalemic periodic paralysis (hyperPP). In a 36-year-old white woman, with typical manifestations of episodic weakness of the limb muscles since age 3 years, hyperPP was diagnosed by demonstration of the T407M SCNA4 gene point mutation. At age 34 years, the index patient became pregnant for the first time. During the first trimester of her pregnancy, she noted a marked decrease in the frequency of the hyperPP attacks. During the second and third trimesters, the attacks of weakness completely disappeared and after delivery the attacks restarted with the same intensity and frequency as before pregnancy, but myotonia persisted between the attacks. Disappearance of the attacks during pregnancy was attributed to the hormonal changes. Episodic attacks of weakness in hyperPP may disappear during the second and third trimesters of pregnancy, and myotonia between the attacks may persist after delivery.

G.P.14.10 Clinical experience with acetazolamide treatment in children; good response in both sodium and chloride channelopathies

Non-dystrophic myotonic syndromes (NDM) represent a heterogeneous group of inherited skeletal muscle disorders, clinically characterized by myotonia with onset in early childhood. NDM can be distinguished in chloride channel gene (CLCN1) mutations (recessive and dominant myotonia congenita) and sodium channel gene (SCN4A) mutations (paramyotonia congenita, sodium channel myotonia and hyperkalaemic periodic paralysis). Today, treatment for NDM consist of sodium channel blockers, however potential cardiac interactions are reported.

Muscle biopsy and cell cultures: potential diagnostic tools in hereditary skeletal muscle channelopathies.

Hereditary muscle channelopathies are caused by dominant mutations in the genes encoding for subunits of muscle voltage-gated ion channels. Point mutations on the human skeletal muscle Na+ channel (Nav1.4) give rise to hyperkalemic periodic paralysis, potassium aggravated myotonia, paramyotonia congenita and hypokalemic periodic paralysis type 2. Point mutations on the human skeletal muscle Ca2+ channel give rise to hypokalemic periodic paralysis and malignant hyperthermia. Point mutations in the human skeletal chloride channel CIC-1 give rise to myotonia congenita. Point mutations in the inwardly rectifying K+ channel Kir2.1 give rise to a syndrome characterized by periodic paralysis, severe cardiac arrhythmias and skeletal alterations (Andersen's syndrome). Involvement of the same ion channel can thus give rise to different phenotypes. In addition, the same mutation can lead to different phenotypes or similar phenotypes can be caused by different mutations on the same or on different channel subtypes. Bearing in mind, the complexity of this field, the growing number of potential channelopathies (such as the myotonic dystrophies), and the time and cost of the genetic procedures, before a biomolecular approach is addressed, it is mandatory to apply strict diagnostic protocols to screen the patients. In this study we propose a protocol to be applied in the diagnosis of the hereditary muscle channelopathies and we demonstrate that muscle biopsy studies and muscle cell cultures may significantly contribute towards the correct diagnosis of the channel involved. DNA-based diagnosis is now a reality for many of the channelopathies. This has obvious genetic counselling, prognostic and therapeutic implications.

New mutation of the Na channel in the severe form of potassium‐aggravated myotonia

Myotonia manifests in several hereditary diseases, including hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita (PMC), and potassium-aggravated myotonia (PAM). These are allelic disorders originating from missense mutations in the gene that codes the skeletal muscle sodium channel, Nav1.4. Moreover, a severe form of PAM has been designated as myotonia permanens. A new mutation of Nav1.4, Q1633E, was identified in a Japanese family presenting with the PAM phenotype. The proband suffered from cyanotic attacks during infancy. The mutated amino acid residue is located on the EF-hand calcium-binding motif in the intracellular C-terminus. A functional analysis of the mutant channel using the voltage-clamp method revealed disruption of fast inactivation, a slower rate of current decay, and a depolarized shift in the voltage dependence of availability. This study has identified a new mutation of PAM with a severe phenotype and emphasizes the importance of the C-terminus for fast inactivation of the sodium channel. Muscle Nerve 39: 666-673, 2009.

Beurteilung erblicher Defekte und Dispositionen beim Pferd unter tierschutzrechtlichen Gesichtspunkten

Persons involved in equine breeding, namely veterinarians, horse breeders and breeding association judges, often lack of an apropriate consciousness about the relevance of heritability or supposed heritability of common horses diseases, which might play a distinctive role in the aetiology of numerous of these diseases. Executing animal welfare rights in equine breeding, the major concern should focus on an objective evaluation of pain, suffering and damages caused by different hereditary diseases. The basis of assessment for hygienic breeding has to be defi ned according to the actual animal welfare rights throughout guidelines, established by the state and by breeding associations. Hereditary diseases scientifi cally proven as relevant for animal welfare matters or including a potential risk of pain, suffering or damage, should be regarded as essential criterion in horse breeding. In this context following diseases have to be mentioned in particular: Osteochondritis dissecans, deep fl exor tendon contracture in the foal, navicular disease, tarsal osteoarthritis, hyperkalemic periodic paralysis, Overo-lethal-white- foal-syndrome.

Mutations in skeletal muscle

Mutations in skeletal muscle sodium channels (NaV1.4) cause periodic paralysis. Paramyotonia congenita and hyperkalemic periodic paralysis are caused by gain-of-function mutations spread widely through the protein, which increase channel activity and lead to repetitive firing or depolarization block. In contrast, mutations that cause hypokalemic (HypoPP) and normokalemic (NormoPP) periodic paralysis are localized in the outermost three gating-charge-carrying arginine residues (R1-R3) in the S4 segment in domain II, and they do not have major effects on sodium channel function as typically measured. Site-directed mutations of these residues cause gating pore current, a voltage-gated leak current through the voltage sensor (Sokolov et al., 2005); mutations of R1 and R2 cause gating pore current in the resting state, whereas mutation of R3 causes gating pore current in the activated state. Similar studies of the HypoPP mutant R2G revealed gating pore current of approximately 1% of peak current at the resting membrane potential, which was decreased by depolarization (Sokolov et al., 2007). This gating pore current was selective for Cs>K>Na and blocked by mM concentrations of divalent cations, Zn>Ba>Ca. A gating pore current of similar size was observed in the resting state for the HypoPP mutants R1H and R2H, but this current is selective for protons. In contrast to HypoPP, the mutations that cause NormoPP are in R3 (R3G/Q/W). All of these mutations cause gating pore conductance for sodium in the activated and slow-inactivated states, in which the voltage sensors are in their outward position. The common pathogenic feature of these mutations is likely to be depolarization and sodium overload, which are observed in patient biopsies. Dominant gain-of-function pathogenic effects may arise directly from excess sodium entry for R2G and R3G/Q/W and indirectly from excessive Na-H exchange for R1H and R2H.

Paramyotonia congenita (von Eulenburg) in Denmark.

Paramyotonia congenita (von Eulenburg) (PMC) is described in a Danish family in seven generations and 39 persons. PMC has not previously been described in Denmark and an epidemiological description of the family is given. The diagnostic difficulties versus hyperkalemic familial periodic paralysis with myotonia, adynamia episodica hereditaria and myotonia congenita (Thomsen) are discussed.

A STUDY OF TRANSIENT MUSCULAR WEAKNESS

Acta Neurologica ScandinavicaVolume 38, Issue 1 p. 3-19 A STUDY OF TRANSIENT MUSCULAR WEAKNESS Clinical, Biochemical, and Electromyographical Findings during Attacks of Periodic Paralysis and Adynamia Episodica Hereditaria Ingrid Gamstorp, Corresponding Author Ingrid Gamstorp Departments of Neurology and Pediatrics of the Harvard Medical School and the Neurology and Children's Medical Services and the Joseph P. Kennedy Jr. Memorial Laboratories of the Massachusetts General Hospital, Boston, Massachusetts Jerry Lewis Fellow of the Muscular Dystrophy Associations of America, Inc. Clinical and Research Fellow in Neurology and Pediatrics at Massachusetts General Hospital and Harvard Medical School.I. Gamstorp, M.D., Barnkliniken, Lasarettet, Lund, Sweden.Search for more papers by this author Ingrid Gamstorp, Corresponding Author Ingrid Gamstorp Departments of Neurology and Pediatrics of the Harvard Medical School and the Neurology and Children's Medical Services and the Joseph P. Kennedy Jr. Memorial Laboratories of the Massachusetts General Hospital, Boston, Massachusetts Jerry Lewis Fellow of the Muscular Dystrophy Associations of America, Inc. Clinical and Research Fellow in Neurology and Pediatrics at Massachusetts General Hospital and Harvard Medical School.I. Gamstorp, M.D., Barnkliniken, Lasarettet, Lund, Sweden.Search for more papers by this author First published: March 1962 https://doi.org/10.1111/j.1600-0404.1962.tb01073.xCitations: 15 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume38, Issue1March 1962Pages 3-19 RelatedInformation