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.
