OMIA 000785-9796 : Hyperkalemic Periodic Paralysis, HYPP in Equus caballus

Possibly relevant human trait(s) and/or gene(s) (MIM number): 170500

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Incompletely Dominant

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1992

Species-specific name: Hyperkalemic Periodic Paralysis (HYPP)

Species-specific description: HYPP in horses is an autosomal incompletely dominant disorder characterized by episodic attacks of muscle tremors, weakness and paralysis with associated increased serum potassium concentration (Rudolph et al., 1992; Animal Genetics)

While HYPP is considered a defect by the American Quarter Horse Association (AQHA), some breeders consider the muscular phenotype attractive and select for this phenotype. Thus, the AQHA refuses to register homozygous animals, but still registers heterozygotes.

{with thanks to Tatyana German and Meredith O’Connell, working under the guidance of Professor Ernie Bailey; 15 Feb 2019}

History: First described only in the mid-1980s (Cox, 1985; Steiss and Naylor, 1986).

This is the first equine disorder for which a causative mutation was identified (Rudolph et al., 1992 Nature Genetics).

In 1996 Bowling et al. (1996 Animal Genetics) reported that all horses possessing the variant were descendants of a “Stallion 1” subsequently identified as IMPRESSIVE, born in 1969. {with thanks to Tatyana German and Meredith O’Connell, working under the guidance of Professor Ernie Bailey; 15 Feb 2019}

Inheritance: Naylor et al. (1999) compared the clinical responses of heterozygotes to homozygotes for the variant causing HYPP and determined that homozygotes are more severely affected, demonstrating the partial dominant mode of inheritance. {text supplied by Professor E. Bailey and students; 20 March 2019}

Mapping: Noting that this disorder in horses is very similar to a disorder in humans which is due to mutations in the adult skeletal muscle sodium channel gene (SNC4A), Rudolph et al. (1992, Animal Genetics) isolated the orthologous horse SNC4A gene. Using a polymorphism identified in this horse gene and the observed polymorphism at the horse HYPP locus, these authors then showed complete linkage (theta = 0) between the SNC4A gene and the HYPP disorder locus in horses.

{with thanks to Tatyana German and Meredith O’Connell, working under the guidance of Professor Ernie Bailey; 15 Feb 2019}

This disorder therefore provides an excellent example of how knowledge of comparative genetics can be put to good use in elucidating the molecular basis of disorders.

Molecular basis: The molecular basis of this disorder was first reported by Rudolph et al. (1992, Nature Genetics). Having established that the horse gene for adult skeletal muscle sodium channel (SNC4A) is completely linked with this disorder (see Mapping section above), Rudolph et al. (1992, Nature Genetics) identified the causative mutation as a missense mutation causing an amino acid substitution from phenylalanine to leucine in the gene encoding the alpha chain of the adult skeletal muscle sodium channel, resulting in increased sodium permeability across the skeletal muscle cell membrane. The SIFT score for this variant is 0.01 (deleterious) (Ensembl's Variant Effect Predictor). {with thanks to Tatyana German and Meredith O’Connell, working under the guidance of Professor Ernie Bailey; 15 Feb 2019}

Clinical features: Muscle fasciculation and spasm; weakness; recumbency; episodic attacks of muscle tremors, weakness and paralysis with associated increased serum potassium concentration; pronounced muscularity; attacks follow diet changes, fasting, stressful circumstances or after consumption of alfalfa hay which is high in potassium (Steiss & Naylor 1986; Spier et al., 1990)

{with thanks to Tatyana German and Meredith O’Connell, working under the guidance of Professor Ernie Bailey; 15 Feb 2019}

Prevalence: Quarter Horse; Bowling et al. (1996) reported that all horses possessing the variant were descendants of a “Stallion 1” subsequently identified as IMPRESSIVE, born in 1969. Tryon et al.( 2009) tested subpopulations of Quarter Horses and found the variant absent among cutting horses, cow horses, reining horses and racing horses. It was present among barrel racing horses (allele frequency 0.006), western pleasure horses (allele frequency 0.013) and halter horses (allele frequency 0.299). The variant was also found among paint horses that were crosses from Quarter Horse.

{with thanks to Tatyana German and Meredith O’Connell, working under the guidance of Professor Ernie Bailey; 15 Feb 2019}

Breed: Quarter Horse.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
SCN4A sodium channel, voltage gated, type IV alpha subunit Equus caballus 11 NC_009154.3 (15432010..15478423) SCN4A Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Quarter Horse HYPP SCN4A H missense Ecab3.0 g.15474228C>G c.4248C>G p.F1416L ECA11 (NC_009154.3) g.15474228C>G; NM_001081761.1: c.4248C>G; NP_001075230.1: F1416L; Sift Score 0.01. The above information (from which the coordinate fields were populated) was provided by Tatyana German and Meredith O’Connell, working under the supervision of Professor Ernie Bailey. rs1148998534 1992 1338908

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2009 Mählmann, C.h., Steiger, A. :
[Assessment of hereditary defects and dispositions of the horse under animal welfare aspects]. Schweiz Arch Tierheilkd 151:153-8, 2009. Pubmed reference: 19333900. DOI: 10.1024/0036-7281.151.4.153.
Tryon, RC., Penedo, MC., McCue, ME., Valberg, SJ., Mickelson, JR., Famula, TR., Wagner, ML., Jackson, M., Hamilton, MJ., Nooteboom, S., Bannasch, DL. :
Evaluation of allele frequencies of inherited disease genes in subgroups of American Quarter Horses. J Am Vet Med Assoc 234:120-5, 2009. Pubmed reference: 19119976. DOI: 10.2460/javma.234.1.120.
1999 Meyer, T.S., Fedde, M.R., Cox, J.H., Erickson, H.H. :
Hyperkalaemic periodic paralysis in horses: a review [Review] Equine Veterinary Journal 31:362-367, 1999. Pubmed reference: 10505950.
Naylor, J.M., Nickel, D.D., Trimino, G., Card, C., Lightfoot, K., Adams, G. :
Hyperkalaemic periodic paralysis in homozygous and heterozygous horses: a co-dominant genetic condition Equine Veterinary Journal 31:153-159, 1999. Pubmed reference: 10213428.
van Oldruitenborgh-Oosterbaan, M.M.S. :
Hyperkalaemic periodic paralysis in the horse [Review] [Dutch] Tijdschrift voor Diergeneeskunde 124:176-181, 1999. Pubmed reference: 10188180.
1998 Maxsonsage, A., Parente, E.J., Beech, J., Lindborg, S., May, L.L., Teleis, D.C. :
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 American Journal of Veterinary Research 59:615-618, 1998. Pubmed reference: 9582966.
Reynolds, J.A., Potter, G.D., Greene, L.W., Wu, G., Carter, G.K., Martin, M.T., Peterson, T.V., Murray-Gerzik, M., Moss, G., Erkert, R.S. :
Genetic-diet interactions in the hyperkalemic periodic paralysis syndrome in quarter horses fed varying amounts of potassium: IV. Pre-cecal and post-ileal absorption of potassium and sodium Journal of Equine Veterinary Science 18:827-831, 1998.
Reynolds, J.A., Potter, G.D., Greene, L.W., Wu, G., Carter, G.K., Martin, M.T., Peterson, T.V., Murray-Gerzik, M., Moss, G., Erkert, R.S. :
Genetic-diet interactions in the hyperkalemic periodic paralysis syndrome in quarter horses fed varying amounts of potassium: III. The relationship between plasma potassium concentration and HYPP symptoms Journal of Equine Veterinary Science 18:731-735, 1998.
Reynolds, J.A., Potter, G.D., Greene, L.W., Wu, G., Carter, G.K., Martin, M.T., Peterson, T.V., Murraygerzik, M., Moss, G. :
Genetic-diet interactions in the hyperkalemic periodic paralysis syndrome in Quarter horses fed varying amounts of potassium - Part II - symptoms of HYPP Journal of Equine Veterinary Science 18:655-661, 1998.
Reynolds, J.A., Potter, G.D., Greene, L.W., Wu, G., Carter, G.K., Martin, M.T., Peterson, T.V., Murraygerzik, M., Moss, G., Erkert, R.S. :
Genetic-diet interactions in the hyperkalemic periodic paralysis syndrome in quarter horses fed varying amounts of potassium - 1 - potassium and sodium concentrations (vol 18, pg 591, 1998) Journal of Equine Veterinary Science 18:666, 1998.
Reynolds, J.A., Potter, G.D., Greene, L.W., Wu, G., Carter, G.K., Martin, M.T., Peterson, T.V., Murraygerzik, M., Moss, G., Erkert, R.S. :
Genetic-diet interactions in the hyperkalemic periodic paralysis syndrome in quarter horses fed varying amounts of potassium - I - Potassium and sodium balance, packed cell volume and plasma potassium and sodium concentrations Journal of Equine Veterinary Science 18:591-600, 1998.
Yudkowsky, M.L., Beech, J., Fletcher, J.E. :
Phenytoin alters transcript levels of hormone-sensitive lipase in muscle from horses with hyperkalemic periodic paralysis Archives of Biochemistry & Biophysics 358:264-270, 1998.
1997 Naylor, J.M. :
Hyperkalemic periodic paralysis Veterinary Clinics of North America - Equine Practice 13:129 ff., 1997.
1996 Bailey, J.E., Pablo, L., Hubbell, J.A.E. :
Hyperkalemic periodic paralysis episode during halothane anesthesia in a horse Journal of the American Veterinary Medical Association 208:1859-1865, 1996. Pubmed reference: 8675475.
Bowling, A.T., Byrns, G., Spier, S. :
Evidence for a single pedigree source of the hyperkalemic periodic paralysis susceptibility gene in quarter horses Animal Genetics 27:279-281, 1996. Pubmed reference: 8856926.
Carr, E.A., Spier, S.J., Kortz, G.D., Hoffman, E.P. :
Laryngeal and pharyngeal dysfunction in horses homozygous for hyperkalemic periodic paralysis Journal of the American Veterinary Medical Association 209:798 ff., 1996.
Guglick, M.A., Macallister, C.G., Breazile, J.E. :
Laryngospasm, dysphagia, and emaciation associated with hyperkalemic periodic paralysis in a horse Journal of the American Veterinary Medical Association 209:115-117, 1996. Pubmed reference: 8926191.
Hanna, W.J.B., Tsushima, R.G., Sah, R., Mccutcheon, L.J., Marban, E., Backx, P.H. :
The equine periodic paralysis Na+ channel mutation alters molecular transitions between the open and inactivated states Journal of Physiology 497:349-364, 1996. Pubmed reference: 8961180.
Steele, D.S., Naylor, J.M. :
Hyperkalemic periodic paralysis, plasma lactate and exercise tolerance Journal of Equine Veterinary Science 16:327-333, 1996.
Waldridge, B.M., Lin, H.C., Purohit, R.C. :
Anesthetic management of horses with hyperkalemic periodic paralysis Compendium on Continuing Education for the Practicing Veterinarian 18:1030 ff., 1996.
1995 Anon. :
Anesthetizing horses with hyperkalemic periodic paralysis Journal of Equine Veterinary Science 15:224, 1995.
Beech, J., Fletcher, J.E., Tripolitis, L., Lindborg, S., Dawso, T. :
Effect of phenytoin on skeletal muscle from quarter horses with hyperkalaemic periodic paralysis Research in Veterinary Science 58:206-211, 1995. Pubmed reference: 7659842.
Beech, J., Lindborg, S. :
Prophylactic efficacy of phenytoin, acetazolamide and hydrochlorothiazide in horses with hyperkalaemic periodic paralysis Research in Veterinary Science 59:95-101, 1995. Pubmed reference: 8525115.
Cannon, S.C., Hayward, L.J., Beech, J., Brown, R.H. :
Sodium channel inactivation is impaired in equine hyperkalemic periodic paralysis Journal of Neurophysiology 73:1892-1899, 1995. Pubmed reference: 7623088.
Church, S. :
Hyperkalaemic periodic paralysis in Australian quarter horses Australian Veterinary Journal 72:314-316, 1995. Pubmed reference: 8579565.
Moody, J.L., Parks, G., Herthel, D.J. :
Hyperkalemic periodic paralysis: The syndrome Equine Practice 17:15-18, 1995.
1994 Cornick, J.L., Seahorn, T.L., Hartsfield, S.M. :
Hyperthermia During Isoflurane Anaesthesia in a Horse with Suspected Hyperkalaemic Periodic Paralysis Equine Veterinary Journal 26:511-514, 1994. Pubmed reference: 7889930.
Naylor, J.M. :
Selection of Quarter Horses Affected with Hyperkalemic Periodic Paralysis by Show Judges Journal of the American Veterinary Medical Association 204:926-928, 1994. Pubmed reference: 8188514.
Naylor, J.M. :
Equine Hyperkalemic Periodic Paralysis - Review and Implications Canadian Veterinary Journal - Revue Veterinaire Canadienne 35:279-285, 1994.
Zeilmann, M. :
Hyperkalemic Periodic Paralysis in Horses .2. Magyar Allatorvosok Lapja 49:559-561, 1994.
1993 Cox, J.H. :
Hyperkalaemic Periodic Paralysis - Diagnosing the Disease in the Headlines Equine Veterinary Journal 25:174-177, 1993. Pubmed reference: 8508741.
Fletcher, J.E., Erwin, K., Beech, J. :
Phenytoin Increases Specific Triacylglycerol Fatty Esters in Skeletal Muscle from Horses with Hyperkalemic Periodic Paralysis Biochimica et Biophysica Acta 1168:292-298, 1993. Pubmed reference: 8323969.
Naylor, J.M., Jones, V., Berry, S.L. :
Clinical Syndrome and Diagnosis of Hyperkalaemic Periodic Paralysis in Quarter Horses Equine Veterinary Journal 25:227-232, 1993. Pubmed reference: 8508753.
Spier, S.J. :
Blood Test Available for Hyperkalemic Periodic Paralysis in Quarter Horses Journal of Equine Veterinary Science 13:140-142, 1993.
Spier, S.J., Carlson, G.P., Harrold, D., Bowling, A., Byrns, G., Bernoco, D. :
Genetic Study of Hyperkalemic Periodic Paralysis in Horses Journal of the American Veterinary Medical Association 202:933-937, 1993. Pubmed reference: 8468218.
1992 Naylor, J.M., Robinson, J.A., Bertone, J. :
Familial Incidence of Hyperkalemic Periodic Paralysis in Quarter Horses Journal of the American Veterinary Medical Association 200:340-343, 1992. Pubmed reference: 1548168.
Naylor, J.M., Robinson, J.A., Crichlow, E.C., Steiss, J.E. :
Inheritance of Myotonic Discharges in American Quarter Horses and the Relationship to Hyperkalemic Periodic Paralysis Canadian Journal of Veterinary Research - Revue Canadienne de Recherche Veterinaire 56:62-66, 1992. Pubmed reference: 1586896.
Rudolph, J.A., Spier, S.J., Byrns, G., Hoffman, E.P. :
Linkage of Hyperkalaemic Periodic Paralysis in Quarter Horses to the Horse Adult Skeletal Muscle Sodium Channel Gene Animal Genetics 23:241-250, 1992. Pubmed reference: 1323940.
Rudolph, J.A., Spier, S.J., Byrns, G., Rojas, C.V., Bernoco, D., Hoffman, E.P. :
Periodic Paralysis in Quarter Horses - A Sodium Channel Mutation Disseminated by Selective Breeding Nature Genetics 2:144-147, 1992. Pubmed reference: 1338908. DOI: 10.1038/ng1092-144.
1990 Spier, S.J., Carlson, G.P., Holliday, T.A., Cardinet, G.H., Pickar, J.G. :
Hyperkalemic periodic paralysis in horses. J Am Vet Med Assoc 197:1009-17, 1990. Pubmed reference: 2243032.
1986 Steiss, J.E., Naylor, J.M. :
Episodic muscle tremors in a quarter horse: resemblance to hyperkalemic periodic paralysis Canadian Veterinary Journal 27:332-335, 1986.
1985 Cox, J.H. :
An episodic weakness in four horses associated with intermittent serum hyperkalemia and the similarity of the disease to hyperkalemic periodic paresis in man Proceedings of the American Association of Equine Practioners 21:383-391, 1985.

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