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Introduction
Chediak-Higashi syndrome (Oculo-cutaneous albinism) is a lysosomal storage disease causing albinism in cats. To first understand this syndrome, it may help to understand the basics of storage disorders. Chediak-Higashi is inherited as an autosomal recessive disease. Mutations have been found in the CHS1 gene. The primary defect in this disease is in intracellular granules. For example, a granule that contains melanin is not made properly in skin giving the pigmentary differences. A neutrophil granule defect (an abnormality in the granules found in certain types of white blood cells that are essential for killing some bacteria, fungi, and viruses) causes the immune problems. This is one of a group of disorders called oculocutaneous albinism which means decreased pigment in the eye and skin.
Lysosomes
The main function of these microbodies is digestion. Lysosomes break down cellular waste products and debris from outside the cell into simple compounds, which are transferred out into the cytoplasm as new cell-building materials.
Like other microbodies, lysosomes are spherical organelles contained by a single layer membrane. This membrane protects the rest of the cell from the lysosomes’ harsh digestive enzymes that would otherwise damage it. Lysosomes originate in the Golgi apparatus, but the digestive enzymes are manufactured in the rough endoplasmic reticulum. Lysosomes are found in all eukaryotic cells, but are most numerous in disease-fighting cells, such as white blood cells. Some human diseases are caused by lysosome enzyme disorders. Tay-sachs disease is caused by a genetic defect that prevents the formation of an essential enzyme that breaks down a complex lipid called ganglioside. An accumulation of this lipid damages the nervous system, causes mental retardation and death in early childhood. Arthritis inflammation and pain are related to the escape of lysosome enzyme, tyrosinase (see picture below).
– Tyrosinase is a copper-containing oxidase that functions in the formation of pigments such as melanins and other polyphenolic compounds. Catalyses the rate-limiting conversions of tyrosine to DOPA, DOPA to DOPA-quinone and possibly 5,6-dihydroxyindole to indole-5,6 quinone. Chediak-Higashi syndrome is an inherited lysosomal storage disorder (tyrosinase deficiency) of the immune system that results in chronic infection, decreased pigmentation in skin and eyes, neurological disease, and early death.
Causes
This syndrome, inherited as an autosomal recessive, is characterized by leukocyte dysfunction secondary to abnormal lysosomes. It has been described in man, mink, foxes, Persian cats, Hereford and Brangus cattle, mice, and killer whales. There is an increased susceptibility to bacterial infections due to impaired WBC function, an increased tendency to bleed due to platelet granule defects, and partial oculocutaneous albinism due to abnormal melanin distribution. The beige mouse and the Aleutian mink exemplify the pigment dilution seen in the syndrome. Abnormal giant granules appear to develop after fusion of lysosomes in neutrophils, eosinophils, renal tubular cells, epithelial cells, and Kupffer’s cells of man, mink, cats, and cattle. In mice, only the WBC appear affected. Pink to magenta staining characteristics of the granules are similar in all species. Diagnosis is based on pigment dilution, presence of giant granules, and increased susceptibility to infections. Humans who have inherited the disorder have partial albinism when compared to family members. There may be a silvery sheen to their hair, light-colored eyes, jerky eye movements (nystagmus), and increased infections in their lungs, skin and mucus membranes. More serious than the pigmentation problems are the effects of this disease on the immune and nervous systems of the body. Surviving adults develop unsteady gaits (ataxia) and nerve abnormalities in the limbs (peripheral neuropathy) causing motor and sensory changes and weakness.
In cats, Chediak-Higashi syndrome is associated with a light bluish coloured coat and yellow-green iris (reflects red in photo flash) due to reduced/absent pigmentation of the tapetum (reflective layer) of the eye. Photo-sensitivity is common. The optic nerves are affected (mis-routed), causing squint or cross-eyes. Bleeding time, even after minor surgery or injury, is increased and haematomas (blood-blisters) can form in the tissues. It has been seen in some blue-smoke, yellow-eyed Persian cats. This disease was first reported in 19772where three cats with Chediak-Higashi syndrome were found in a single line of 27 Persian cats, and three additional affected cats were produced from two prospective breedings of the original line. The disorder was characterized genetically as an autosomal recessive condition. All cats in the line with the combination of yellow eye colour and “blue smoke” hair colour exhibited the disorder. Four of the five cats examined had bilateral nuclear cataracts as early in life as 3 months of age. No increased susceptibility to infectious disease was observed. A bleeding tendency was noted. Abnormally large eosinophilic, sudanophilic, peroxidase-containing granules were observed in the neutrophils of the granulocytic series of blood and bone marrow by electron and light microscopy. Granules of eosinophils and basophils were also enlarged. Light microscopic studies of hair and skin revealed enlarged melanin granules. These manifestations were similar to those in man, mink, cattle, mice, and the killer whale with Chediak-Higashi syndrome. Cats are the sixth species in which this genetic disease has been reported3.
Siamese cats have a form of oculocutaneous albinism caused by a temperature sensitive form of tyrosinase, such that pigment is only formed in the cooler parts of the body such as the ears and nose. Additionally, Siamese cats frequently have a convergent strabismus (eye squint), absence of binocular vision, and misrouted retinal ganglion cell fibres, as is seen in other breeds with oculocutaneous albinism. Similar temperature sensitive mutations are also found in humans. When such a mutation is present in humans in conjunction with a null mutation on the other chromosome, ocular albinism often results. This disorder has the ocular features of oculocutaneous albinism although patients appear to be normally pigmented. Hence, mutations of the genes involved in melanin synthesis can affect the development of the optic chiasm without affecting overall pigmentation.
Symptoms
Jerky eye movements (nystagmus), decreased vision, sensitivity to bright light (photophobia), albinism (a lighter complexion than unaffected family members), silvery sheen to hair which may be fair in color, frequent infections (skin, oral, respiratory), tremors, abnormal walking gait, seizures, numbness and muscle weakness.
Diagnosis
Blood smear that shows giant granules in the white blood cells that are positive with stains for peroxidases Giant granules are also found in cells from biopsy of skin, muscle, nervous system Blood platelet or white blood cell levels are abnormally low Physical examination may show enlarged spleen, liver or jaundice Genetic testing may show mutations in the CHS1 gene EEG may show seizures Brain MRI or CT scan may show small brain due to atrophy EMG or nerve conduction velocity testing may show delayed nerve conduction Presence of red light reflex of the eye (frequently seen in albinism) Tests show abnormal immune function
Treatment
There is no specific treatment for Chediak-Higashi syndrome. Bone marrow transplants appear to have been successful in several patients. Infections are treated with antibiotics and abscesses are surgically drained when appropriate. Antiviral drugs such as acyclovir have been tried during the terminal phase of the disease. Cyclophosphamide and prednisone have been tried.
References
1. KP Burdon et al
2. Kramer JW, Davis WC, Prieur D (1977) The Chediak-Higashi syndrome of cats. J.Lab Invest.36(5):554-62.
3. Prieur DJ, Collier LL (1987) Neutropenia in cats with the Chediak-Higashi syndrome. Can J Vet Res 51(3):407-8.