Updated on genetic disease in quarter horses and related breeds (Proceedings)

The Big '6' Genetic Disorders

      1. HERDA

      2. PSSM*

      3. GBED*

      4. HYPP

      5. MH

      6. OLWS

Allele definitions

     • Allele – versions of a gene. Every animal has two alleles (one from each parent)

     • For diseases, there is a 'disease allele' (or gene mutation) and a 'normal allele' present in the population.

     • 'Allele frequency' is an estimate of the frequency of the disease allele in a population

HERDA

     • Hereditary Equine Regional Dermal Asthenia

     • Quarter horses and related breeds

     • Collagen problem

     • Seromas, hematomas and ulceration primarily along the dorsal aspect, some legs and other

     • Progressive skin disease: age of onset: 1.5-2 years of age

     • Skin has a hyperextensible quality

     • Mutation identified: cyclophilin B gene (PPIB) (Tyron, et al Genomics 2007)

     • Autosomal recessive

     • Heterozygotes are clinically unaffected

PSSM

     • Polysaccharide Storage Myopathy

     • EPSM – Equine Polysaccharide Storage Myopathy

     • Caused by a mutation in a gene regulating glycogen synthesis

               o Glycogen synthase 1 (GYS1) gene mutation

     • Accumulation of an abnormal glycogen in muscle cells

     • This form of glycogen cannot be used for energy

     • Leads to muscle stiffness, weakness, pain, poor performance and tying up

     • Triggering events:

          o Stress

          o Weaning

          o Onset of training

          o Prolonged rest followed by work

          o High grain (starch, sugar) diets

     • Average age of onset of clinical signs is 5 years

     • Affects a large number of breeds, but most common in:

          o Quarter horses and related breeds

          o Draft horses

     • Dominant gene

          o Only requires one copy of the gene for the horse to be affected

          › Therefore, only one parent must carry the gene

     • At least two forms of the disease in Quarter Horses

          o PSSM type 1 – most common and has a genetic test

          o Type 2 – no DNA test available yet

          o Other forms?

Diagnosis

     • Muscle biopsy – diagnosis of both forms of PSSM

          o University of California

          o University of Minnesota

     • DNA test – currently only available for PSSM type 1

          o University of Minnesota

Treatment/Prevention

     • Decrease stress

     • Keep the horses fit

          o Regular exercise

          o As much turn out time as possible

     • Strict adherence to diet

          o Low starch and sugar diet

     • No grain/molasses

     • Replace grain calories with fat sources

          o Grass hays are the best hay source

          o Vitamin E and selenium supplementation

GBED-Glycogen Branching Enzyme Deficiency

     • "Glycogen Storage Disease IV"

     • Stop codon in the glycogen branching enzyme gene (GBE1 gene)

     • Affected animals produce an abnormal, less branched glycogen that cannot be utilized for energy

     • The disease is lethal

     • Recessive gene

          o Carriers are phenotypically normal

          o Affected foals die

     • Causes abortion and neonatal mortality

     • Foals are weak from birth

          o Cannot regulate blood glucose

          o Contracted tendons

          o Muscle, liver, heart and lung problems

     • All die by a few weeks of age

     • Diagnosis:

          o Genetic (DNA) test: University of Minnesota

     • This disease is 100 % preventable

          o Identify carriers and don't breed carrier to carrier

HYPP

     • Mutation in the alpha-subunit of the muscle sodium channel gene

     • Abnormal sodium channels don't close normally, leading to potassium-inducible episodes of muscle fasciculations, contraction followed by paralysis

     • Semi-dominant trait

          o Homozygotes are more severely affected than heterozygotes, but both affected

     • Fasciculations, sweating, anxiety, respiratory noise

     • Weakness, dog-sitting, paralysis

     • Not a true seizure – horses are completely aware

     • Homozygotes exhibit dysphagia or airway narrowing

     • Both NH and HH horses can die during an episode due to complete airway closure or cardiac arrhythmias

Diagnosis and Treatment

     • DNA testing – mandatory of all Impressive descendants in AQHA

     • Management:

          o Low potassium diet (< 1-1.5 % of diet) –No alfalfa, brome, molasses...

          o Acetazolamide

          o Minimize stress

          o Small frequent feedings

          o Regular exercise

     • The AQHA has recently taken a stand to begin elimination of the trait.

     • Beginning with the 2007 foal crop, any homozygous animals can not be registered.

     • H/H horses are completely 100% avoidable

          o Never cross NH to NH

Malignant Hyperthermia

     • MH

     • Newly recognized, still a lot to learn about this disease

     • Dominant gene: Mutation in the Ryanodine Receptor 1 gene

     • Homozygous state lethal in utero?

Clinical findings

     • First cases were found under anesthesia

          o High fevers (> 104 °F)

          o Hypercontraction of muscles

          o Rapid death with rigor mortis

     • Now recognizing cases without anesthesia

          o May appear relatively normal, although heavily muscled

          o Stress seems to play a role with precipitating attacks

          o Severe, rapid myositis (tie up)

          o Persistent fevers and elevated muscle enzymes

     • Well defined and heavy muscles

Diagnosis

     • DNA test – University of California, Davis

          o Dr Monica Aleman –Neuromuscular Lab

Overo Lethal White Syndrome

  Ileocecocolic aganglionosis

    OLWS

     • All or nearly all white foals born to two frame overos or horse carrying the gene

     • Normal at birth, but colic soon after

          o Never pass meconium

          o Develop abdominal distention

          o Colic

          o No treatment: surgical resection has been unsuccessful

     • Semi-dominant gene

          o Homozygous state of frame overo

          OO

          o Heterozygotes are frame overos

          NO

     • Mutation in the endothelin b receptor gene

          o Responsible for neural crest cell migration to the skin (melanocytes) and to the gut (nerve cells)

     • 25 % of frame to frame crosses will result in lethal white foals

Note: Not all white paint foals are lethal !

     • Crosses of frame to sabino, splash, or tobiano or any other combination can produce all white foals

     • Diagnosis of carriers: DNA test, UC Davis

     • This disease is 100 % preventable

          o Never cross two carriers

Available Genetic Tests

     • Hyperkalemic Periodic Paralysis (HYPP)-1992

          o UC Davis

     • Lethal White Foal Syndrome (LWFS)- 1998

          o UC Davis

     • Glycogen storage disease IV (GBED)-2006

          o UC Davis and Univ of Minnesota

     • Hereditary Regional Dermal Asthenia (HERDA)- 2007

          o UC Davis and Cornell University

     • Polysaccharide storage myopathy (PSSM)-2008

          o Univ of Minnesota

     • Malignant Hyperthermia (MH)-2008

          o UC Davis and Univ of Minnesota

Other Breeds:

Hereditary Junctional Epidermolysis Bullosa

Saddlebred horses

     • Partial deletion of the LAMA3 gene

          o Encodes for part of the Laminin 5 basement membrane protein

          o Autosomal recessive

          o Diagnostic test – 9/175 randomly selected America Saddlebreds born in 2007 were found to be carriers.

          o Different gene than in Belgian draft horses (LAMC-2 gene), also of Laminin 5

          o Testing: Gluck Equine Research Center, University of Kentucky

Cerebellar Abiotrophy of Arabians

     • Purkinje cells, after they have been formed, die off

     • Cerebellar signs predominate

     • Autosomal recessive

     • Signs vary in severity and timing

          o May develop from birth to up to 4 months of age

     • Indirect DNA test available –Identified genetic markers associated with CA

          o Gene itself has not yet been identified

          o Available at UC Davis Veterinary Genetics

References

Tyro RC, White SD, Bannasch DL. Homozygosity mapping approach identifies a missense mutation in equine cyclophilin B (PPIB) associated with HERDA in the American Quarter Horse. Genomics 2007; 90: 93-102.

McCue ME, Valberg SJ, Jackson M, et al. Polysaccharide storage myopathy phenotype in quarter horse-related breeds is modified by the presence of an RYR1 mutation. Neuromuscul Disord 2009; 19: 37-43.

Glycogen branching enzyme (GBE1) mutation causing equine glycogen storage disease IV. Mamm Genome 2004; 15: 570-577.

Aleman M, Nieto JE, Magdesian KG. Malignant hyperthermia associated with ryanodine receptor 1 (C7360G) mutation in Quarter Horses. J Vet Intern Med 2009; 23: 329-334.

Metallinos DL, Bowling AT, Rine J. A missense mutation in the endothelin-B receptor gene is associated with Lethal White Foal Syndrome: an equine version of Hirschsprung disease. Mamm Genome 1998; 426-431.

Rudolph JA, Spier SJ, Burns G, et al. Periodic paralysis in quarter horses: a sodium channel mutation disseminated by selective breeding. Nat Genet. 1992; 2: 144-147.

Finno CJ, Spier SJ, Valberg SJ. Equine diseases caused by known genetic mutations. Vet J 2009; 179: 336-347.