Hereditary Blood Disorders
Urs Giger, PD, Dr. med. vet., MS, FVH, DACVIM, DECVIM
University of Pennsylvania
Philadelphia, PA, USA

Hereditary disorders may affect any blood cells or plasma proteins. For many hereditary blood diseases, the biochemical basis has been elucidated; for some, the specific molecular genetic defect has recently been identified. In fact, erythrocytic pyruvate kinase deficiency was the first biochemical defect characterized in companion animals, and hemophilia B was the first molecular defect determined in domestic animals. On the other hand, the precise cause of cyclic hematopiesis in Gray Collies still needs to be discovered despite extensive research over the past 30 years. Overall the study of these hereditary blood disorders has greatly contributed to the better understanding of blood cells and protein functions.

Hereditary blood disorders may be classified into erythrocytic defects, bleeding disorders, and immunodeficiencies, although some overlap exists. Several hereditary disorders not only affect a specific function of the hematopoietic system, but also involve other organs such as bone, muscle, and hair coat, thereby forming characteristic clinical syndromes. Finally, an emerging group of genetic predispositions to infections, immune-mediated, neoplastic diseases are being recognized. Some primary immunodeficiencies (Leukocyte adhesion deficiency in Irish setters) are well defined, whereas for others only a breed predilection to a particular infection suggests a genetic basis, for instance avian tuberculosis in Bassets and leishmaniasis in Foxhounds. Similarly, breed predispositions have been recognized for certain hematologic immune-mediated diseases (immune-mediated hemolytic anemia in Cocker Spaniels) and hematopoietic cancers (lymphoma in Golden retrievers and malignant histiocytosis in Bernese Mountain dogs) without knowing the molecular basis.

With few exceptions, hereditary blood disorders are autosomal recessively inherited; hemophilia A and B in many breeds of dogs and cats and severe combined immunodeficiency in Bassets and Corgis represent the only X-chromosomal recessive traits. Each defect occurs relatively rarely, although certain breeding practices, popular sire, and founder effects may result in widespread and common occurrences. The true mutant gene frequency has rarely been determined to limit the further spread of these hereditary disorders, it is pivotal to not only recognize affected animals, but also carriers that can pass on the mutant gene. Accurate biochemical and molecular genetic screening tests have been developed for many diseases, but their application in companion animals has lagged behind.

Therapeutic options for hereditary blood diseases are limited. Animals with primary immunodeficiencies may benefit from antibiotics, albeit their response may only be partial or transient. Plasma transfusions may supplement bleeding animals with coagulopathies. Experimental allogeneic bone marrow transplantation can correct defective blood cells and gene therapy has been attempted. However, it is much more important to control further spread of the disease causing gene by screening breeding animals when tests are available. Although acquired causes, such as infections, immune disorders, intoxication, blood loss, and chronic organ failure, are the main causes for anemia, hereditary blood disorders leading to anemia are also important in clinical practice. They are particularly germane differential diagnoses in animals with Coombs' negative hemolytic anemias without apparent cause. Several hereditary erythrocytic defects have been reported in companion animals, and much new information has emerged over the past decade. In fact, some anemias have been so extensively characterized that the clinical signs to the molecular basis of the erythrocyte defect are known, thereby offering an opportunity to make a precise diagnosis in clinical practice and to prevent these disorders in future generations.

Hereditary anemias

Inherited erythrocyte defects form a large heterogeneous group of diseases. Each erythrocyte disorder is observed only rarely, although a particular defect may occur frequently within a family or breed. If the same disorder is recognized in several breeds, it is likely caused by different mutations of the same gene. The mode of inheritance is autosomal recessive, with the exception of feline porphyria which is inherited by a dominant trait. These disorders have been classified into four groups: 1) heme defects and hemoglobinopathies, 2) membrane abnormalities, 3) cytosolic enzyme deficiencies, and 4) production and maturation defects.

In contrast to the common occurrence of such hemoglobin disorders as thalassemia and sickle cell anemia in humans, no hemoglobinopathies have been documented in dogs and cats. Isolated cases of methemoglobinemia associated with methemoglobin/cytochrome b5 reductase deficiency were found among dogs of various breeds and domestic shorthair cats, but this deficiency results in polycythemia rather than anemia. Defects of heme synthesis known as porphyrias have been reported in anemic Siamese and domestic shorthair cats with pigmented and pink-fluorescent teeth and bones.

Elliptocytosis and microcytosis resulting from a deficiency of the protein band 4.1, which strengthens the interaction between spectrin and actin in the cytoskeleton, has been characterized at the molecular level in an inbred, nonanemic mongrel dog. Other presumed membrane abnormalities include: stomatocytosis in Alaskan malamutes, a Dutch breed with gastritis, and miniature Schnauzers; nonspherocytic anemia in Beagles; and increased osmotic fragility of erythrocytes in an English Springer spaniel and Abyssinian and Somali cats.

Deficiencies of the two key regulatory glycolytic enzymes result in distinctly different forms of hemolytic anemia. The classic pyruvate kinase (PK) deficiency initially reported in Basenjis is now seen in several other canine breeds and in cats. Phosphofructokinase (PFK) deficiency is frequently reported in English Springer spaniels and has also been observed in a Cocker spaniel and a mixed-breed dog.

Erythrocytic Disorders (Examples)

Erythrocyte membrane defects (hemolysis)

Elliptocytosis

Mixed breed dog

 

Stomatocytosis

Malamute (chondrodysplasia)
Miniature Schnauzers

 

Spherocytosis

Retriever

 

? Osmotic fragility

Abyssinian and Somali cats

 

Eythroenzymopathies (hemolysis)

Phosphofructokinase deficiency

English Springer Spaniel
Cocker Spaniel, mixed breed

Pyruvate kinase deficiency
(dogs w/ osteosclerosis)

Basenji, Beagle, Eskimo Toy
West Highland White Terrier
Cairn Terrier, Dachshund
Abyssinian and Somali cats

Methemoglobin reductase deficiency

Many canine breeds, cats

No hemoglobinopathies

Erythrocyte production defects (non-regenerative)

Cobalamin malabsorption
(non-regenerative anemia)

Giant Schnauzer, Beagle,
Border Collie & Austr. Shepherd

 

Macrocytosis

Miniature Poodle

 

Microcytosis

Japanese breeds (no anemia)

 

Hereditary Bleeding Disorders

Disorder

Breed

BMBT

ACT PTT

PT PIVKA

Remarks

Coagulopathies

 

 

 

 

 

Prothrombin deficiency

Cocker Spaniel, Boxer

N

upwards arrow

upwards arrow

 

Factor VII deficiency

Beagle, Malamute

N

N

upwards arrow

Colony of beagles

Factor VIII deficiency (Hemophilia A)

Many breeds, cats (x-linked)

N

upwards arrow

N

Mild to severe forms

Factor IX deficiency (Hemophilia B)

Many breeds, cats (x-linked)

N

upwards arrow

N

DNA tests for some available

Factor X deficiency

Cocker Spaniel

N

upwards arrow

N

 

Factor XI deficiency

Kerry Blue terriers, Great Pyrenese, English Springer

N

upwards arrow

N

Late posttraumatic

Factor XII deficiency

Cats

N

upwards arrow

N

No bleeding

Vitamin K dependent coagulopathy

Devon Rex

N

upwards arrow

upwards arrow

 

Von Willebrand Disease

 

 

 

 

vWD Type 1 (common) Complete vWF deficiency; <1% plasma vWF levels

Doberman, many others

upwards arrow

N

N

DNA test for Doberman, Manchester & Cairn terrier

vWD Type 2 (rare) Disproportionally low vWF activity; deficiency of high molecular weight multimers

German shorthair pointer

upwards arrow

N

N

DNA test

vWD Type 3 (severe) Complete vWF deficiency; <1% plasma vWF levels

Scottish terriers, Shelties, Chesapeake Bay retriever

upwards arrow

N

N D

NA test for Sheltie, Kooiker, Scottish terrier

 

 

 

 

 

Platelet Dysfunctions

 

 

 

 

Delta storage pool disease

Cocker spaniel

upwards arrow

N

N

High ATP/ADP ratio

Glanzmann thrombasthenia

Otterhound, Great Pyrenese

upwards arrow

N

N

GP IIb/IIIa deficiency

Chediak Higashi

Smoke Persians

upwards arrow

N

N

WBC granulation

Thrombopathies (others)

Basset hound, Spitz, Boxer, Labrador, etc., DSH cats

upwards arrow/ N

N

N

Signaling defect or unknown

N-normal, upwards arrow-prolonged

Primary or Hereditary Immunodeficiencies of Dogs and Cats

Disease

Inherit

Breeds

Defect

Characterization

DOG

Ciliary dyskinesia(Immotile cilia syndrome)

AR

Many breeds

Functional/morphologic cilia abnormalities

Rhinosinusitis, broncho pneumonia, bronchi ectasis, +/-situs inversus

Bactericidal neutrophil defect

U

Doberman

Unknown

Upper respiratory infections, ciliary dyskinesia not excluded

Cyclic hematopoiesis (Cyclic neutropenia)

AR

Gray Collie

Hematopoietic growth factors

Severe neutropenia every 12-14 days, reactive amyloidosis

Leukocyte adhesion Deficiency (CLAD)

AR

Irish Setter, Red & White Setters

CD11/18 deficiency ß chain (CD18) deficiency

Severe leukocytosis, limited pus formation, lack of neutrophil adhesion

Complement component 3 C3 deficiency)

AR

Brittany Spaniel

C3 deficiency

Pyogenic infections, phagocytosis

Selective cobalamin malabsorption

AR

G. Schnauzer, Border collie, Beagle, Aust. Shepherds

Ileal cobalamin receptor defect

Weight loss, inappetence, leukopenia with hyper- segmentation, methylmalonic aciduria

? Susceptibility to avian mycobacteriosis

U

Basset hound

RAMP deficiency?

Systemic avian tuberculosis, toxoplasmosis & neosporosis

? Susceptibility to pneumocystitis pneumonia

AR

Dachshund

Unknown

Pneumocystitis pneumonia

Pelger-Huet anomaly

AD

Australian Shepherd, foxhound

Unknown

No immunodeficiency, hyposeg. granulocytes

? Susceptibility to fungal & rickettsial infect.; pyoderma

U

German shepherd

Macrophage?, T- cell?

Severe ehrlichiosis, RMSF disseminated aspergillosis, deep pyoderma

X-SCID - X-linked severe combined immunodeficiency

XR

Basset hound, Card. Welsh Corgi

Common gamma chain of IL-2 and other cytokines

Severe bacterial/viral infections, no IgG & IgA

Severe combined immunodeficiency

AR

Jack Russell terrier

DNA-protein kinase catalytic subunit

Severe serum immunoglobulin deficiency, hypoplasia of lymphoid tissues

Selective IgA deficiency

U

Beagle, Shar Pei, German S

IgA deficiency

Respiratory & gastrointestinal infections

Thymic abnormal. & dwarfism

U

Weimaraner

Unknown

Reduced growth, thymosin responsive

Recurrent infections

U

Weimaraner

Reduced IgG

Pyoderma, abscessation, bleeding tendency

Combined immunodeficiency

U

Shar Pei

T-cell, B-cell, low IL-6 & IL-2

Skin, respiratory & GI infections

 

Amyloidosis

U

Shar Pei

Elevated IL-6

Arthritis, amyloidosis, renal failure, hepatic rupture, hypoproteinemia

 

Lethal acrodermatitis

AR

Bull Terrier

Zinc metabolism defect

Zinc deficiency, hyperkeratosis

 

? Susceptibility to parvoviral infection

U

Rottweiler Doberman

Unknown

Parvovirus infection

 

Vaccine-induced immune disturbance

U

Akitas

Unknown

Variable meningitis, polyarthritis, amyloidosis

 

CAT

 

Hypotrichosis congenital and thymic atrophy

AR

Birman

Unknown

Nude kittens, neonatal death, no thymus

 

Leukocyte granulation

U

Birman

Unknown

No immunodeficiency, acidophilic granules

 

Pelger-Huet anomaly

AD

Domestic shorthair

Unknown

No immunodeficiency, hyposegmentation

 

Chédiak-Higashi syndrome

AR

Persian

Unknown

No immunodeficiency, granules in phagocytes, bleeding tendency

 

Reactive (AA) amyloidosis

U

Abyssinian

Unknown

Reactive (AA) amyloidosis, renal failure

 

AR = autosomal recessive; U = unknown; XR = X-linked recessive; AD = autosonal dominant.

Speaker Information
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Urs Giger, PD, Dr. med. vet., MS, FVH, DACVIM, DECVIM
University of Pennsylvania
Philadelphia, PA, USA


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