Post on 31-Mar-2016
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Inherited Diseases of Domestic Cats
Leslie A. Lyons, PhD Professor
Popula5on Health & Reproduc5on School of Veterinary Medicine University of California, Davis
Lalyons@ucdavis.edu (530) 754-‐5546
Genetic Distinction of Breeds
23 of 26 breeds distinct - Persian = Exotic - Siamese = Havana Brown - Scottish Fold = British Shorthair
Questions to decipher inheritance?
Is the diagnosis accurate and consistent? Have you seen the condition before? Has it been seen in this breed before? How common is it? How many breeding animals within the breed? Has it been seen in other breeds before? Has it been seen in other species before? What is the breeding?
Hallmarks of Genetic Conditions
Bilateral presentation
Consistent presentation
“Early” onset Species specific Disease dependent
Advanced parental age?
Common Misinterpretations
Familial is not always clearly heritable due to the environmental component
Congenital is not always heritable due to the environmental component
Don’t forget random chance (idiopathic)
Cat Disease Mutations • 33 genes in cats
– 51 mutations • 37 phenotypes
• 10 genes colors / traits – 16 breed mutations
• 13 phenotypes – 1 polydactyla = AD
14 mutations offered my VGL Not SHH for Pd ? Full albino mutation
Genetic Diseases in Cat Breeds Breed Sister / Family Group Disease -‐ Gene
Abyssinian SOM, OCI, BEN, SIA… PRA (blindness) – CEP290
Abyssinian SOM, OCI, BEN, SIA… Pyruvate Kinase Def -‐ PKLR
Burmese BLM, Bombay, Singapura, Tonkinese GM2 – HEXB
Burmese BLM, Bombay, Singapura, Tonkinese Hypokalemia – To be named
Burmese BLM, Bombay, Singapura, Tonkinese Craniofacial – To be named
Korat SIA… GM1 – GLB1
Korat GM2 -‐ HEXB
Maine Coon HCM – MYBPC3 (A31P)
Maine Coon Spinal Muscular Atrophy – LIX1/LNPEP Maine Coon Polydactyla -‐ SHH
Norwegian Forest Glycogen Storage – GBE1
Persian EXO, BRI, ASH, BLM, Selkirk Rex Polycys5c Kidney – PKD1
Pixiebob Polydactyla -‐ SHH
Ragdoll HCM – MYBPC3 (R820W)
Cat Coat Color & Type Tests Trait Gene Alleles -‐ MOI Notes
Agou5 ASIP A+ > a
Brown TYRP1 B+ > b > bl
Color TYR C+ > cb = cs > c
Dense (Dilute) MLPH D+ > d
Extension (Amber) MC1R E+ > e
Gloves (Birman) KIT G+ > g
Hairless (Sphynx) KRT71 Hr > hr+ > re
Long hair FGF5 L+ > l 4 muta5ons
Polydactla SHH Pd > pd+
Rex (Devon Rex) KRT71 Hr > hr+ > re
Rex (Cornish rex) P2RY5 R+ > r
Sex AMEL, XFXY X, Y
+ Indicates the wildtype, normal allele
Hybrid Cat Breeds
Leopard Cat - Bengal
Serval - Savannah
Jungle Cat - Chaussie
F1 Bengal Cat
Female DSH
2N = 38 2N = 38
• Normal tortie/calico • Male genitalia • Normal chromosomes
– Unknown abnormality • Sterile
– Unknown cause
Tortoiseshell Males - Sterility
Feline PKD
Persian family, 1969 Exotics, Himilayan
Renal Cysts Hepatic cysts
Clinically Consistent Varies in severity Early Onset
8 months ultrasound Single Gene Autosomal Dominant
Polycystic Kidney Disease Pathology
Progressive chronic tubulointerstitial nephritis in cats with ADPKD
3 months old 3 years old
Slides courtesy of S. DiBartola
Variation in PKD
Ultrasound image of PKD
Feline AB Blood Group
• Recognized since 1915
• Anti-sera developed by Auer & Bell, early 1980’s: A, B, and AB
• A > B, not sure about AB
• Transfusion reactions
• Neonatal isoerythrolysis – B have strong anti-A
NeuGC Biosynthetic Pathway
CMP-Neu5Ac synthetase
(CMAS)
In the nucleus
In the cytoplasm
(CMAH) Key enzyme:
• humans don’t have NeuGc due to a 92 bp deletion of the gene
critical activation
Bighignoli et al., BMC Genet. 2007: 8:27
Breed Country Cats A% B% AB% Abyssinian US34 230 86.5 13.5 0 Abyssinian US33 194 79.9 20.1 0 Birman US33 216 82.4 17.6 0 British Shorthair UK42 121 39.7 58.7 1.6 British Shorthair US3 85 41.2 58.8 0 British Shorthair Germany37 33 54.5 45.5 0 Burmese Australia48 30 93 3 3 Burmese US33 25 100 0 0 Chartreux Germany50 27 77.8 18.5 3.7 Devon Rex US34 288 50.3 49.7 0 Devon Rex US33 100 57 43 0 Devon Rex* Australia48 71 45 54 1.4 Maine Coon Germany50 25 96 4 0 Persian US34 230 90.4 9.6 0 Persian US33 170 75.9 24.1 0 Persian Germany37 157 91.7 7.6 0.6 Ragdoll Italy53 36 72.2 8.3 19.4 Scottish Fold US33 27 85.2 14.8 0 Siamese US33 99 100 0 0 Siamese Italy35 26 96.2 3.8 0 Turkish Angora Turkey45 28 53.6 46.4 0 Turkish Van Turkey45 85 40 60 0
Breed Blood Type Frequencies
Pyruvate Kinase Deficiency
" Red cell disorder found in many species
" an inherited lack of the enzyme pyruvate kinase, which is used by red blood cells
" red blood cells break down too easily, resulting in low levels of these cells (hemolytic anemia)
Pyruvate Kinase Deficiency
Symptoms • Anemia • A yellowing of the whites
of the eyes (icterus) • Fatigue, lethargy • Jaundice • Pale skin (pallor)
Signs & Tests • Bilirubin in the blood • CBC • mutation in the pyruvate
kinase gene • Large red blood cells
(macrocytosis) • Levels of haptoglobin in the
blood • Osmotic fragility • Pyruvate kinase activity • Stool urobilinogen
Feline Retinal Degeneration
• Abyssinian family • Bilateral Rod-Cone
Degeneration • Clinical Consistent • Late Onset
– Slow Progression 1-2 yrs • Single Gene
– Autosomal Recessive – Complete Penetrance
• Narfstrom et al. 1983
Feline Retinal Degeneration
• Abyssinian family • Bilateral Rod-Cone
Dysplasia • Clinical Consistent • Early Onset
– Fast Progression 8 wks • Single Gene
– Autosomal Dominant – Complete Penetrance
• Keith & Ross, 1985
Feline Retinal Degeneration • Persian family • Bilateral • Clinical Consistent • Early Onset
– Fast Progression: 8-16 wks • Single Gene
– Autosomal Recessive – Complete Penetrance
• Rubin & Lipton, 1973 – Aguirre, Lyons
Persian PRA Color Fundus Examination
Affected Male
Affected Female
Unrelated Normal
Carrier
Persian PRA Angiography
Normal
Affected
Structure of the eye
Light
(Bessant et. 2001)
(PetEducation.com)
Affected
Carrier
Control
3 weeks 5 week 7 weeks 16 weeks
Figure 2. Histological morphology of retinas from PRA-affected, carrier and control cats
Persian PRA
Frequency CEP290 • 16/43 (37%) breeds, exhibiting a high allele frequency
(∼33%) in North American and European Siamese populations.
Abyssinian/Somali (USA) 16 0.070 0.005 Abyssinian (UK) 34 0.206 0.042 Abyssinian (Australia) 57 0.105 0.011 Abyssinian (Scandinavia) 130 0.196 0.038 American curl 10 0.050 0.003 American wirehair 10 0.100 0.010 Bengal 18 0.056 0.003 Balinese/Javanese 24 0.333 0.111 Colorpoint shorthair 11 0.364 0.132 Cornish Rex 20 0.025 0.001 Munchkin 15 0.033 0.001 Ocicat 18 0.083 0.007 Oriental shorthair 25 0.340 0.116 Siamese 49 0.265 0.070 Singapura 6 0.167 0.028 Tonkinese 7 0.071 0.005
N Observed hetero Expected affected
Korat – Gangliosidosis
• Autosomal Recessive • GM1 Gangliosidosis
– GALB – 17.4% carrier frequency
• GM2 Gangliosidosis – HEXB – 6.2% carrier frequency
• similar clinical & pathological characteristics
• Scott-Ritchey Research Center
GSD IV Phenotypes • autosomal recessive • Neuromuscular degeneration
– Cardiac failure • Most affected kittens are stillborn or die within
hours of birth. • A few affected kittens survive the perinatal
period – Clinical signs at 5 mos – Complete debilitation by 8-10 mos
Feline GSD IV GBE Gene
Rearrangement and 6.1 kb Deletion
2 kb 4 kb 6 kb 8 kb
Eco RI Eco RI Eco RI
A
N (CA) Rep
Burmese Hypokalemia
!
Gruffydd-Jones 1986
Non-USA Burmese cats
Autosomal recessive
Metabolism disorder causes low potassium
Seizures, generalized muscle weakness
Can be managed with supplements
Youtube – Gordon - Burmese
Burmese Head Defect
• Burmese Family – Contemporary style
• Autosomal Recessive – Carriers undetectable
• Congenital/Lethal
• Duplication of Upper Maxillary
• Proper Counseling
Burmese Head Defect
Burmese Head Defect
Feline HCM Risk Factors
" Breed and lineage history " Common environment " Male cats " Having two copies of the mutations
(homozygote) " Maybe having two of either mutation?? " Increased age, male
Feline HCM Genetics
" Most HCM in humans is Autosomal Dominant with variable penetrance
" Over a dozen genes cause HCM, including Myosin-binding protein C (MBPC3)
" Mutations in MBPC3 in Maine Coon and Ragdoll indicate high risk for HCM
Genetic Counseling for HCM
" Reduce breed or lineage risk
" Use genetic testing
" Combine with ultrasound diagnosis
" Do not breed homozygous cats or cats with severe HCM that are young