What's in a name? Using signalment to guide your diagnoses (Proceedings)

Knowledge of breed predispositions and inherited disorders can direct your differential diagnoses and your diagnostic plan. For some of these diseases the genetic mutation has been identified and tests for the defect have been developed. For others, the phenotypical characteristics have been well-described but the genetic basis and mode of inheritance are unknown. This lecture is not a presentation on genetics, but rather a general discussion of several feline breeds that have recognized diseases, both common and unusual, that veterinarians should consider when presented with these patients.

Chediak-Higashi Syndrome [Persians]

This autosomal recessive disease affects both neutrophils and platelets in a variety of ways. Unlike in humans, neutropenia is not always present in cats, but the neutrophils are filled with large granules that may impair the destruction of microorganisms. Platelets are also affected, lacking granules that contain platelet agonists important for clotting. The clinical consequences of these two defects are immunodeficiency, especially recurrent bacterial infections, and prolonged bleeding times. In addition, cats may have a variety of ocular abnormalities, including light sensitivity, red-gray retinas, reduced tapetal reflection, early cataracts, and spontaneous nystagmus. Because large melanin granules form in the skin, they often have a "blue smoke" fur color. There is no treatment for the disorder, but care must be taken to manage bleeding during procedures.

Systemic amyloidosis (liver) [Siamese and Oriental breeds] (kidney) [Abyssinian]

In Siamese cats, the sequence of the Amyloid A protein is distinct from that of Abyssinians which may account for its predilection for hepatic deposition in systemic amyloidosis in Siamese and other related breeds. Cats are generally young, ranging from 10 months to 7 years [mean: 3.5 yrs]. In one study, females predominated, but males were more prevalent in another. Diagnosis is often made after acute intra-abdominal hemorrhage from ruptured hepatic parenchyma. Cats in one case series had intermittent episodes accompanied by collapse, anemia, and anorexia. Hepatomegaly may be palpable; ALT is usually elevated to a greater extent than would be expected from hypoxia secondary to anemia. On ultrasound, hepatic parenchyma had a diffuse, "heterogeneous echogenicity with highly echogenic ('sparkling') areas and hypoechoic foci." Fine needle aspirate of the liver may reveal evidence of amyloid deposition. A large, friable liver, often with subcapsular hemorrhage, is found on abdominal exploratory. Therapy with colchicine has been attempted, but prognosis is poor. Some evidence suggests that vitamin K therapy should be instituted to normalize bleeding disorders, since clotting abnormalities can be seen in human amyloidosis, but this has not been substantiated in cats. Systemic amyloidosis of Abyssinians affects the kidney and results in fatal renal disease. It is an autosomal dominant trait with incomplete penetrance. The deposition occurs in the medulla in all affected cats and in the glomeruli in 75% of cats and results in papillary necrosis and interstitial nephritis/fibrosis. Cats present between the ages of 1 to 5 years of age with chronic renal failure, but amyloid deposition first occurs between 9 – 24 months of age. However, some cats have minimal amyloid deposition and may not develop overt renal disease. Amyloid deposition can occur elsewhere but the major clinical consequence of systemic amyloidosis is chronic renal failure.

Pyruvate Kinase Deficiency [Abyssinians and Somalis]

Pyruvate kinase is essential for ATP production in the red blood cell. Without PK, important functions, such as maintenance of the RBC membrane and membrane transport, are not possible, resulting in decreased erythrocyte lifespan and hemolytic anemia. PK deficiency has been documented in Abyssinians and Somalis in the U.S., Europe and Australia with 23-31% of these breeds classified as carriers. Clinical signs are variable, depending upon the severity of the disease. In one study, the most commonly documented clinical features were lethargy, diarrhea, pale mucous membranes, inappetence, poor haircoat and weight loss. Cats may be asymptomatic or exhibit clinical signs only during times of stress. A high reticulocyte count may be apparent on the CBC, evidence that the bone marrow is replacing short-lived erythrocytes. The onset of clinical disease is usually less than 3 years of age; lifespan is variable depending upon the severity of the anemia and the frequency of the hemolytic episodes. Treatment is symptomatic, i.e., blood transfusions as necessary. Limiting stress also appears to be important. Splenectomy has been used successfully in humans and other species, including cats, but is not the first line of therapy. Culling all cats that are PK-deficient is not wise, due to the concern of creating a genetic bottleneck. Judicious use of unaffected cats for breeding programs and breeding carriers with non-carriers will help reduce the disease prevalence over time.

Increased osmotic fragility syndrome [Abyssinians and Somalis]

It is important to have this etiology as a rule-out for hemolytic anemia because Abyssinians and Somalis can also have a PK deficiency. Cats often present at a young age (2 years; range 6 mos – 5 yrs) with signs attributable to anemia, such as lethargy, anorexia, and pale mucous membranes. More chronic evidence of disease such as weight loss and poor hair coat may be apparent. Splenomegaly is a common finding which may be detected on palpation, imaging or at surgery in many of the older cats. Although the PCV can be normal in some cats, it can drop to as low as 5% during hemolytic crises. A diagnosis is made based on the presence of regenerative anemia (or macrocytosis without anemia in FeLV-negative patients), splenomegaly and a high osmotic fragility index. The red blood cells will often lyse after 24 hours in the refrigerator. The exact defect is unknown. Treatments that have been attempted include blood transfusions for hemolytic crises, prednisone, cyclophosphamide and splenectomy. The vast majority of therapies do not improve the disease. In one study, 10 cats died or were euthanized at variable times (1 month – 8 years [mean: 4.2 years]) after the first hemolytic episode, but follow-up varied for the other 8 cats that were alive so their lifespan is unknown.

Feline Mucopolysaccharidosis (MPS) [Siamese]

Although both MPS I and MPS VI have been documented in cats, MPS VI will be briefly discussed. MPS-VI is lysosomal enzyme N-acetylgalactosamine 4-sulfatase (4-sulfatase) deficiency that results in a decreased ability to break down glycosaminoglycans in bone and cartilage, though it is present in other tissues as well. Although the disease was first described in client-owned cats in the mid 70's, multiple large colonies are maintained around the world as the feline disease serves as a model for human MPS. The typical clinical signs include stunted growth, a broad head, short ears, and decreased flexibility of the cervical spine. Cloudy corneas can also be present. Over time, neurologic deficits may develop as a result of bony proliferations that compress the spine cord. Degenerative joint disease is also apparent in some animals. Some treatments may be helpful to decrease the clinical consequences, especially if instituted early as the skeletal changes cease after growth at approximately 9 months. Spinal decompression surgery, for example, may limit the development of neurologic deficits. Other exciting areas of research are bone barrow transplantation and enzyme replacement therapy. In one such study, some histopathologic features of the disease improved and the replaced enzyme was present in some tissues, but the only clinical sign that improved was corneal cloudiness in one cat.

Glycogenosis Type 4 [Norwegian Forest cats]

Many of these affected cats die at birth or within days of birth. However, the surviving cats are often normal for several months, at which time they begin to exhibit muscular abnormalities. The molecular basis for the disease is the lack of a specific glycogen-branching enzyme – specifically, alpha-1,4-D-glucan — that facilitates glycogen storage and breakdown. As a result, glycogen builds up in various tissues, including skeletal and cardiac muscle, impairing their function. Hypoglycemia can also be present if glycogen cannot be sufficiently liberated from tissues for use. The onset of signs in these previously normal kittens begins around 5-7 months. Owners will note muscle tremors or fasciculations and weakness, along with muscle atrophy, a "bunny-hopping" gait and an elevated body temperature, presumably secondary to the muscle fasciculations. A DNA test is available at the University of Pennsylvania. The prognosis is poor as there is currently no treatment. Patients either die of sudden death due to cardiac arrhythmias or are euthanized because of progression of disease.

Polycystic Kidney Disease [Persians and other Persian-related cats]

PKD is one of the most common genetic diseases in cats, affecting approximately 38% of Persians world-wide. It has also been reported in several other breeds, most recently in a 12-yr-old Chartreuse. The trait is autosomal dominant. No cat with 2 copies of the gene defect has been identified, suggesting that a homozygous condition is fatal in utero. The disease is characterized by cysts within the renal parenchyma. Hepatic and pancreatic cysts have also been documented. Confirmation of the disease is 2-fold: DNA test for a PDK1 defect and abdominal ultrasound documenting renal cysts. However, not all PKD-positive cats develop clinical signs of renal disease, despite the high prevalence rates within the breed. Removing PDK-positive cats from the breeding pool is somewhat controversial as a sudden loss (nearly 40%) of genetic diversity could create another genetic bottleneck.

Muscular dystrophy [Devon Rex and Sphynx]

A paper in 2008 described Sphynx cats and a Devon Rex, supporting previous description of Devon Rex cats in the mid-90's. Analysis of muscle biopsies revealed a decreased expression of a-dystroglycan, an important structural component of the sarcolemma during muscle contraction. Cats display some unusual clinical signs related to muscle weakness, including passive cervical ventroflexion, protrusion of the scapulae and sitting upright to support the head. The cats tire easily, may have difficulty swallowing and/or esophageal dysfunction. The CNS and the peripheral nerves are unaffected. Death in some of these patients was due presumably to asphyxiation from choking. The onset of clinical signs varies depending upon the degree of severity; signs are usually noticeable within weeks to months of birth. The disease may progress or remain stable for months. One cat euthanized at 6 years of age due to poor quality of life. Management consists primarily of upright feeding and supervision during meals.

References

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