[HYPP: hyperkalemic periodic paralysis in the horse]. / HYPP: hyperkaliëmische periodieke verlamming bij het paard.

Hyperkalaemic periodic paralysis(HYPP) is characterized by intermittent episodes of muscular tremor, weakness, and collapse, and is probably caused by abnormal electrolyte transport in the muscle cell membrane. During an episode of HYPP, most animals are severely hyperkalaemic. HYPP is a hereditary disease and occurs only in American Quarter horses or crossbreds. Because these horses are now being imported into the Netherlands, HYPP should be included in the differential diagnosis of horses showing signs of muscle tremor, paresis, or paralysis. The present article reviews the literature on HYPP and describes a case showing typical signs of the disease.

Phenytoin alters transcript levels of hormone-sensitive lipase in muscle from horses with hyperkalemic periodic paralysis.

In equine hyperkalemic periodic paralysis (HyperPP), there is evidence suggesting that the primary defect in the sodium channel is associated with a secondary alteration in triacylglycerol-associated fatty acid metabolism (TAFAM) in skeletal muscle. Furthermore, TAFAM may be involved in the therapeutic action of phenytoin. The effects of phenytoin treatment on the transcript levels of three key proteins in TAFAM, hormone sensitive lipase (HSL), carnitine palmitoyltransferase (CPT), and fatty acid binding protein (FABP), were examined. These transcripts were quantitated by competitive reverse transcription polymerase chain reaction in undifferentiated and differentiated primary cultures of equine skeletal muscle from control, heterozygous HyperPP, and homozygous-affected HyperPP horses. There was a 10-fold lower level of HSL transcript in both undifferentiated and differentiated cultures from homozygous-affected horses than from horses of the other genotypes. Phenytoin selectively increased the HSL transcript in homozygous-affected differentiated cultures to levels similar to those of the other genotypes. The levels of CPT and FABP transcripts were unaffected by genotype, differentiation, and phenytoin treatment. These results suggest that the primary defect in HyperPP may secondarily decrease HSL transcript levels and that the therapeutic action of phenytoin may include regulation of mRNA transcripts in skeletal muscle.

Effects of local anesthetics on Na+ channels containing the equine hyperkalemic periodic paralysis mutation.

We examined the ability of local anesthetics to correct altered inactivation properties of rat skeletal muscle Na+ channels containing the equine hyperkalemic periodic paralysis (eqHPP) mutation when expressed in Xenopus oocytes. Increased time constants of current decay in eqHPP channels compared with wild-type channels were restored by 1 mM benzocaine but were not altered by lidocaine or mexiletine. Inactivation curves, which were determined by measuring the dependence of the relative peak current amplitude after depolarization to -10 mV on conditioning prepulse voltages, could be shifted in eqHPP channels back toward that observed for wild-type (WT) channels using selected concentrations of benzocaine, lidocaine, and mexiletine. Recovery from inactivation at -80 mV (50-ms conditioning pulse) in eqHPP channels followed a monoexponential time course and was markedly accelerated compared with wild-type channels (tauWT = 10.8 +/- 0.9 ms; taueqHPP = 2.9 +/- 0.4 ms). Benzocaine slowed the time course of recovery (taueqHPP,ben = 9.6 +/- 0.4 ms at 1 mM) in a concentration-dependent manner. In contrast, the recovery from inactivation with lidocaine and mexiletine had a fast component (taufast,lid = 3.2 +/- 0.2 ms; taufast,mex = 3.1 +/- 0.2 ms), which was identical to the recovery in eqHPP channels without drug, and a slow component (tauslow,lid = 1,688 +/- 180 ms; tauslow,mex = 2,323 +/- 328 ms). The time constant of the slow component of the recovery from inactivation was independent of the drug concentration, whereas the fraction of current recovering slowly depended on drug concentrations and conditioning pulse durations. Our results show that local anesthetics are generally incapable of fully restoring normal WT behavior in inactivation-deficient eqHPP channels.

Effect of high-intensity exercise on arterial blood gas tensions and upper airway and cardiac function in clinically normal quarter horses and horses heterozygous and homozygous for hyperkalemic periodic paralysis.

OBJECTIVE: To determine the effect of exercise on arterial blood gas tensions and upper airway and cardiac function in clinically normal Quarter Horses and horses heterozygous and homozygous for hyperkalemic periodic paralysis (HYPP). ANIMALS AND PROCEDURE: 5 clinically normal Quarter Horses, and 5 heterozygous and 2 homozygous HYPP-affected horses were examined before, during, and after exercise on a high-speed treadmill. Arterial blood gas tensions, ECG, and echocardiogram were obtained prior to exercise. Upper airway endoscopy, collection of arterial blood samples, and continuous electrocardiography were performed during a high-intensity stepwise exercise test. An ECG was obtained within 1-minute after completion of the final step. RESULTS: None of the horses homozygous or heterozygous for HYPP had signs of weakness or muscle fasciculations before, during, or after exercise. Horses homozygous for HYPP had intermittent laryngospasm, dynamic pharyngeal collapse, and appreciable hypoxemia, hypercapnia, and ventricular premature contractions during exercise. Heterozygous and clinically normal horses did not have any abnormalities. Potassium concentration increased significantly above the baseline reference range during exercise in all groups of horses. CONCLUSIONS: Horses homozygous for HYPP had laryngospasm and dynamic pharyngeal collapse associated with exercise, most likely secondary to increase in potassium concentration. Upper airway dysfunction is the most likely cause of hypoxemia and hypercapnia. Cardiac arrhythmias were most likely caused by a combination of hypoxemia and hyperkalemia.

Laryngeal and pharyngeal dysfunction in horses homozygous for hyperkalemic periodic paralysis.

OBJECTIVE: Evaluate histories, clinical signs, and laboratory data of 69 horses homozygous by DNA testing for hyperkalemic periodic paralysis (HPP). DESIGN: Cohort study. SAMPLE POPULATION: 69 of 189 horses testing homozygous for HPP between October 1992 and November 1994. PROCEDURE: Questionnaires addressing signalment, training regimes, medical history, and current status of affected horses were sent to owners, trainers, or attending veterinarians. Data from completed questionnaires were tabulated and evaluated, using descriptive statistics. RESULTS: Sixty-nine (37%) of 189 questionnaires were completed and returned. Clinical episodes of muscle weakness or paralysis varied in severity and frequency from mild muscle fasciculations to recumbency and death. Sixty-three of 68 HPP-affected horses were reported to have had stridor associated with exercise, excitement, stress, or episodes of muscle paralysis. Common endoscopic findings in affected horses included pharyngeal collapse, pharyngeal edema, laryngopalatal dislocation, and laryngeal paralysis. Twelve of 27 horses receiving acetazolamide had decreases in stridor while receiving medication. CLINICAL IMPLICATIONS: Most horses testing homozygous for HPP had clinical signs associated with pharyngeal and laryngeal dysfunction. Hyperkalemic periodic paralysis should be included on a differential list for horses examined for signs of laryngeal or pharyngeal dysfunction or stridor. Treatment with acetazolamide may help to control respiratory tract signs associated with this disease.

Evidence for a single pedigree source of the hyperkalemic periodic paralysis susceptibility gene in quarter horses.

The pedigree origin of a base pair substitution in the horse muscle sodium channel gene that confers susceptibility to the muscle disease hyperkalemic periodic paralysis (HYPP) was investigated with a set of 978 Quarter Horses. The horses were chosen at random, based on a collection of blood samples taken between 1989 and 1991 to meet parentage testing requirements, primarily but not exclusively from breeding stallions. The frequency of Quarter Horses positive for the base pair substitution, all heterozygotes, was 4.4%, which corresponds to an allelic frequency of 0.02. All horses positive for the gene traced to a single previously identified stallion as first, second or third generation descendants. A higher frequency of the HYPP susceptibility trait than expected by random occurrence was found among his descendants in this study.

Laryngospasm, dysphagia, and emaciation associated with hyperkalemic periodic paralysis in a horse.

An 18-month-old Quarter Horse gelding was examined because of weight loss and dysphagia of 1 month's duration. Clinical signs included lethargy, dehydration, ptyalism, and probable aspiration pneumonia. Severe dyspnea and cyanosis were evident after mild exercise. Endoscopy revealed laryngospasm and pharyngospasm. Because clinical signs and endoscopic findings were suggestive of hyperkalemic periodic paralysis (HPP), acetazolamide treatment was instituted. Marked improvement was observed within 48 hours. The horse was determined to be homozygous for HPP. It is likely that this horse's dysphagia, with resultant weight loss and aspiration pneumonia, were clinical manifestations and consequences of HPP. Regardless of age and serum potassium concentration, HPP should be considered as a differential diagnosis for pharyngeal and laryngeal abnormalities and dysphagia in horses with Quarter Horse breeding.

Hyperkalemic periodic paralysis episode during halothane anesthesia in a horse.

A 7-month-old Quarter Horse filly was admitted for surgical repair of a right olecranon fracture. Anesthesia was achieved with xylazine hydrochloride, guaifenesin, ketamine hydrochloride, and halothane. Two and a half hours after induction of anesthesia, myotonia, muscle fasciculations, and sweating, concurrent with high serum potassium concentration and associated electrocardiographic changes consistent with hyperkalemic periodic paralysis, were observed. Treatment included intermittent positive-pressure ventilation, changing intravenous administration of fluids from lactated Ringer's solution to 0.9% NaCl solution, and administration of calcium gluconate, glycopyrrolate, dopamine, and sodium bicarbonate. Clinical signs resolved with the return of serum potassium concentrations to the reference range. The horse was confirmed to be heterozygous for hyperkalemic periodic paralysis by DNA testing.

Sodium channel inactivation is impaired in equine hyperkalemic periodic paralysis.

1. Equine hyperkalemic periodic paralysis (E-HPP) is a dominantly inherited disorder of muscle that causes recurrent episodes of stiffness (myotonia) and weakness in association with elevated serum K+. Affected horses carry a mutant allele of the skeletal muscle isoform of the Na channel alpha-subunit. To understand how this mutation may cause the disease phenotype, the functional defect in Na channel behavior was defined physiologically by recording unitary currents from cell-attached patches on normal and affected equine myotubes. 2. The presence of the mutation was confirmed in our cell line by restriction digest of polymerase chain reaction (PCR)-amplified genomic DNA. Myotubes from the affected horse were heterozygous for the point mutation that codes for a Phe to Leu substitution in S3 of domain IV. This assay provides a rapid technique to screen for the mutation in horses at risk. 3. The primary physiological defect in mutant Na channels was an impairment of inactivation. This defect was manifest as bursts of persistent activity during which the channel closed and reopened throughout a maintained depolarization. Disrupted inactivation slowed the decay of the ensemble-averaged current and produced an eightfold increase in the steady-state open probability measured at the end of a 40-ms pulse. This point mutation identifies a new region of the alpha subunit that is important for rapid inactivation of the channel. 4. The persistent Na current was produced by a distinct mode of gating. Failure of a mutant channel to inactivate was infrequent and occurred in groups of consecutive trials.(ABSTRACT TRUNCATED AT 250 WORDS)

Voltage-gated ion channelopathies: inherited disorders caused by abnormal sodium, chloride, and calcium regulation in skeletal muscle.

The pathological genetic defects in the inherited myotonias and periodic paralyses were recently elucidated using molecular genetic studies. These disorders are usually transmitted as a dominant trait from an affected parent to a child. The many clinical symptoms include cold-induced uncontrollable contraction of muscle, potassium-induced contraction and paralysis, myotonia with dramatic muscular hypertrophy, muscle stiffness, and insulin-induced paralysis (in males). Horses afflicted with the disorder can suddenly collapse, despite an impressive physique. In the past three years, these clinically defined disorders have been shown to share a common etiology: subtle defects of ion channels in the muscle-fiber membrane. Although the specific ion channel involved varies depending on the disease, most patients have single amino acid changes in the channel proteins, with both normal and mutant channels present in each muscle fiber. For each patient, we can now establish a precise molecular diagnosis in the face of overlapping clinical symptoms and begin specific pharmacological treatment based on the primary problem. These studies have also provided insight into basic muscle biology and emphasize the careful regulation of ions in muscle excitation.

[American Quarter Horses and HYPP]. / American Quarter Horses en HYPP.

Hyperkalaemic periodic paralysis is a genetic disease that affects the American Quarter Horse population and is caused by a mutation. As a result of this mutation in a gene which codes for the sodium channel in muscle cells, severe muscle weakness can appear. Reliable DNA-tests can establish whether a horse is homozygous negative, heterozygous, or homozygous positive for this mutation. Therapy and prevention are discussed.

Pathophysiology of sodium channelopathies: correlation of normal/mutant mRNA ratios with clinical phenotype in dominantly inherited periodic paralysis.

It is often suggested that polygenic or environmental factors are responsible for clinical variability between patients with identical mutations. However, most dominant diseases are caused by a change-of-function alteration in the mutant allele's protein product. All patients are heterozygous and presumably express both mutant and normal proteins from the corresponding genes. Thus, a possible molecular mechanism for clinical variability could be the difference in relative levels of mutant vs. normal mRNA in different patients with the same mutation. To investigate this hypothesis, it is necessary to have access to a series of tissue biopsies from many patients with the same mutation causing a clinically variable dominant disease. Human hyperkalemic periodic paralysis (HyperPP) has been shown to be a clinically variable disorder caused by change-of-function mutations of the skeletal muscle sodium channel protein. We recently identified a large (> 50,000) pedigree of affected Quarter Horses sharing the same causative amino acid alteration of the muscle sodium channel protein. The horses like humans show substantial clinical variability. In this report, we developed a fluorescent reverse transcription-polymerase chain reaction assay which quantifies the relative levels of normal and mutant mRNA expression of the horse adult skeletal muscle sodium channel gene in affected Quarter Horses. We found that asymptomatic horses showed more normal sodium channel mRNA, while moderately affected horses showed more mutant mRNA. The ratios of mutant/normal mRNA between these two groups are statistically different, suggesting that severity of HyperPP Quarter Horses may indeed be correlated to the ratio of mutant and normal sodium channel gene expression in skeletal muscle.

Selection of quarter horses affected with hyperkalemic periodic paralysis by show judges.

Thirty offspring of a Quarter Horse sire, affected by hyperkalemic periodic paralysis (HPP), were examined electromyographically. On the basis of the detection of or lack of spontaneous activity with high frequency myotonic or pseudomyotonic discharges, the horses were diagnosed as being affected (14 horses) or unaffected (16 horses) with HPP. The show performance of these horses was evaluated for the first 3 to 9 years of their life by use of American Quarter Horse Association records. Horses affected with HPP performed significantly (P < 0.01) better in halter classes than did unaffected horses; mean halter points for the 2 groups were 11.9 and 0.4, respectively. The mean total performance points were not significantly different. None of the offspring had a successful racing record.

Possible normokalemic variant of hyperkalemic periodic paralysis in two horses.

Hyperkalemic periodic paralysis (HPP), characterized by intermittent episodes of muscle fasciculations, profound muscle weakness, and hyperkalemia, has been described in Quarter Horses, Appaloosas, and Paints. In previous reports, the hallmark of this syndrome has been the development of hyperkalemia during each episode. Two affected horses had episodes of paralysis without associated hyperkalemia, demonstrating that normokalemia during an episode otherwise consistent with HPP does not eliminate HPP as a diagnosis. This clinical presentation appeared to be a variant of HPP.

[3H]ouabain binding in skeletal muscle from horses with hyperkalemic periodic paralysis.

Ouabain, a cardiac glycoside, binds to the Na(+)-K(+)-adenosine triphosphatase (Na+ pump) and prevents active transport of Na+ and K+ across cell membranes. We used [3H]ouabain to quantify the number and affinity of Na+ pumps in skeletal muscle from Quarter Horses with the muscular disorder hyperkalemic periodic paralysis (HYPP). [3H]Ouabain-binding properties of gluteal muscle from clinically normal and affected horses were used to determine whether altered Na+ pump number or affinity could contribute to the pathologic features of muscle in affected horses. Foals and adult horses with HYPP were compared with age-matched clinically normal horses. The number of [3H]ouabain-binding sites in adult gluteal muscle was not different between the 2 types of horses (85.7 +/- 8.9 pmol of [3H]ouabain-binding sites/g [wet muscle weight] in horses with HYPP vs 100.2 +/- 8.8 pmol/g in clinically normal adult horses). Gluteal muscles in HYPP-affected and clinically normal foals also contained a similar number of [3H]ouabain-binding sites (222.3 +/- 21.0 pmol/g vs 225.3 +/- 24.2 pmol/g, respectively). The affinity of these binding sites for ouabain was not different, between adults or foals, in clinically normal or affected horses. Our results indicate that membrane events underlying the periodic episodes of paralysis in horses with HYPP are not attributable to quantitative changes in Na+ pump number or affinity. Our data cannot exclude the possibility that the specific activity of the Na+ pump is altered in muscle from HYPP-affected horses.

Clinical syndrome and diagnosis of hyperkalaemic periodic paralysis in quarter horses.

Of the 16 horses studied, 14 belonged to a family previously shown to be susceptible to hyperkalaemic periodic paralysis (HPP), and 8 were shown to have HPP. Diagnosis of HPP by electromyographic detection of myotonic discharges or by oral administration of KCl to induce clinical signs and hyperkalaemia had similar reliability and gave the same result in 80% of cases. KCl had to be administered at doses up to 0.2 g/kg bodyweight to produce signs in some horses. KCl challenge testing was more time consuming than EMG and resulted in one fatality. Overall, electromyography and potassium challenge testing together gave the most accurate diagnosis. Horses were more likely to manifest signs of HPP if they were immature. There was no sex predisposition. The most frequent sign of HPP was muscle fasciculation. Other signs were sweating, muscle spasm, and weakness. Respiratory rate increased greatly during some attacks. Attacks of muscle fasciculation without hyperkalaemia were observed in 2 HPP-affected horses. Affected horses had a greater frequency of spontaneous clinical abnormalities, due mainly to trailering problems, traumatic abrasions and episodes of continuous muscle fasciculation. Hyperkalaemia was confirmed in only one of these instances.

Periodic paralysis in quarter horses: a sodium channel mutation disseminated by selective breeding.

We recently reported on a linkage study within a Quarter Horse lineage segregating hyperkalaemic periodic paralysis (HYPP), an autosomal dominant condition showing potassium-induced attacks of skeletal muscle paralysis. HYPP co-segregated with the equine adult skeletal muscle sodium channel alpha subunit gene, the same gene that causes human HYPP. We now describe the Phe to Leu mutation in transmembrane domain IVS3 which courses the horse disease. This represents the first application of molecular genetics to an important horse disease, and the data will provide an opportunity for control or eradication of this condition.

Effects of phenytoin in two myotonic horses with hyperkalemic periodic paralysis.

The effects of phenytoin treatment were evaluated in 2 myotonic horses with hyperkalemic periodic paralysis (HPP). Phenytoin treatment abolished the clinical signs of muscle fasciculations following oral potassium challenge and decreased or abolished repetitive firing and myotonic discharges found on electromyographic examination. In both horses, an abnormally low threshold for calcium-induced calcium release was measured in heavy sarcoplasmic reticulum fractions from skeletal muscle, and this threshold increased with phenytoin treatment. Results suggest phenytoin is useful in modifying disordered ion regulation in the sarcolemma and sarcoplasmic reticulum of skeletal muscle in equine hyperkalemic periodic paralysis.