Hunter Syndrome Research Paper

Lysosomal storage diseases are rare, inherited disorders caused by the deficiency of one or more enzymes within the lysosomes of cells. Hunter Syndrome also known as mucopolysaccharidosis disorder II (MPS II), is a genetic abnormality occurring in canines and humans. It is a rare X-linked recessive metabolic storage disorder caused by the deficiency of the lysosomal enzyme iduronate-2-sulphatase, which is needed to breakdown complex sugars produced in the body, leading to progressive accumulation of glycosaminoglycans in almost all cell types, tissues, and organs. Which can affect every system in the dog’s body. The mucopolysaccharides, which aid in bone formation, as well as the skin, cornea, and cartilage, do not perform their function
properly because of the lack of lysosomal enzymes. These enzymes make sure that chemical reactions in the body proceed at the correct rate. When the enzymes are deficient, the cells do not work as they should. Improper functioning of lysosomal enzymes lead to an abnormal accumulation of complex carbohydrates in cells within many tissues, which are the skeleton, brain, joints, spinal cord, heart, liver, or spleen. Lysosomal storage diseases are difficult to diagnose and can be easily overlooked. Many storage diseases in animals are not investigated to a full diagnosis, because of their neurological features make them difficult participants for such an investigation and because there are few centers capable of providing diagnostic assistance.
Any canine can be born with Hunter syndrome, but it is more often in certain breeds. Which include the Labrador retriever, the Plott hound, the miniature poodle, the Rottweiler, the German shepherd, the miniature pinscher, the Welsh corgi, the Boston terrier, the Chesapeake Bay retriever, the miniature schnauzer, and the wirehaired dachshund. Dwarf dogs often suffer from Hunter syndrome. In severely affected dogs, the signs and symptoms are obvious.
Some puppies are born with an abnormally big forehead, and a broad mandible. Dogs usually have bowed rear legs and have difficulty walking. Some other signs are heart murmurs , chronic diarrhea, respiratory issues, skeletal deformities, liver and spleen enlargement, enlarged tongue, vision problems, degenerative joint disease, and developmental delays. MPS share many clinical features which include a chronic and progressive course, multisystem involvement, organomegaly, facial and skeletal dysmorphisms, degenerative joint disease, corneal clouding, and thickening and distortion of the heart valves. Some ways to help examine the dog and help possibly diagnose is with a radiographic examination. It can help show bony malformations in the animal that appear dysmorphic. Bony and connective tissue abnormalities usually characterize MPS, although they can be seen in other storage diseases. Magnetic Resonance Imaging or MRI have detected some lysosomal storage diseases. There are few veterinary patients that have been investigated this way, so there is little information in this area. But some veterinarians are using it and will put out data about it. Another way to diagnose is by an analysis of urine for abnormal excretion of storage products. Thin-layer chromatography is often used to separate abnormal oligosaccharides and glycopeptides in the urine. There is also the MPS spot test, that stains urine on
filter paper with toluidine blue and it will give an indication if the urine contains increased concentrations of glycosaminoglycans. A final way is through ophthalmologic examination. It is recommended because many diseases manifest with ocular pathology. “Progressive corneal opacification or cataract formation has been reported as storage products accumulate, and then the animal may become visually impaired.”
Dogs suffering from Hunter Syndrome is not good. Most die fairly young or are euthanized because of their deformities and such poor quality of life. Even though there is no cure for Hunter Syndrome, there are ways to help manage and it and live with the symptoms. There has been some research in developing therapies in animals that may help to treat human patients. There is enzyme replacement, bone marrow transplantation, and gene replacement protocols. In mildly affected dogs, early treatment with a bone marrow transplant can help sometimes. But the procedure is risky, very expensive, and needs a suitable bone marrow match. Gene therapy for lysosomal storage disorders is to provide some autologous cells with the normal cDNA to produce and secrete normal enzyme for uptake by the abnormal cells. The cross correction in MPS obviates the need to transfer the cDNA to all cells, as a small percentage of transduced cells can be therapeutic to the organ or to the animal by secreting enough of the normal enzyme for mannose-6-phosphate receptor-mediated uptake by other deficient cells. This seems simple in concept, and many human trials have been reported, but the cure of inherited metabolic diseases in humans by gene therapy has been very limited. The major difficulties are getting adequate levels of gene product in the specific cell types that are needed, maintaining expression over long periods of time, in vivo, and regulating the levels of gene expression. Gene expression needs animal models that are true orthologues of the human disease due to the defect in the homologous gene, and have the same molecular, pathological, and clinical phenotype as the human disease.
Some ways that veterinarians can help confirm a diagnosis is with a lysosomal enzyme analysis. If a lysosomal storage disease is suspected then the identification of the deficient enzyme can be assayed for the activities of lysosomal enzymes. Another way is with molecular genetic testing. The increased accessibility of molecular genetic technology has led to the investigation of the molecular basis of a lot of storage diseases. This relies on the identification of the genetic defect. Lysosomal storage diseases are very rewarding to study because they are single gene defects that are inherited in an autosomal recessive way, making heterozygote detection more desirable. MPS II is the only known X-linked MPS disorder. “The human gene encoding I2S has been mapped to Xq28. It contains nine exons spread over 24kb.” () Individuals with major deletions in the gene usually have severe MPS II. An I2S-like pseudogene, comprising copies of exons 2 and 3 and intron 7, is located about 20 kb from the active gene. “A recurring rearrangement is due to recombination between the intron region of the gene and a homologous region near exon 3 of the pseudogene, with inversion of the intervening DNA.” Large deletions of the I2S locus may extend to adjoining genes, as the neighboring DNA is gene rich. “A contiguous gene syndrome involving fragile X mental retardation genes could possibly explain the unusual phenotypes seen in some severely affected patients.” A 3 year old male Labrador Retriever was evaluated for progressive incoordination. The physical examination showed a well muscled, but thin dog, with hyperextended carpi, macrodactylia, multifocal cornea opacities of the left eye, labial mucosal thickening, and premature graying of the hair of the face and withers. The neurologic examination showed asymmetric ataxia and paresis affecting all limbs, worse on the right side and in the hind limbs, hypermetria,positional vertical and oscillatory nystagmus. The ophthalmoscope evaluation showed a small focal area of dystrophic change in the left cornea and showed an exaggerated direct pupillary light reflex followed by hippus. The electromyography, cranial computed scan, cerebrospinal fluid examination were all normal. Abdominal radiographs showed hepatomegaly. Generalized osteopenia of the axial skeleton was also noted on the spinal radiographs. Given the presence of osteopenia it suggested an inheritable metabolic disease was the cause. Urine spot tests were then used for mucopolysaccharides and they were positive. Urine electrophoretic analysis for GAG identified a moderate band of heparan sulfate and a heavy band of dermatan sulfate in the patient’s urine. After looking over all the tests a tentative diagnosis of MPS was then made. When the dog was 5 years old it showed severe asymmetric forelimb and hindlimb ataxia with falling toward the right side, hypermetria, and intention tremors. Postural reaction deficits and paresis were present in all limbs. The cranial nerve function was normal. But the dog had coarse facial features, and the tongue was very enlarged. Because of the progressive nature of the disease, the dog was euthanized. At necropsy, the dog had a focal brainstem hematoma about 1 cm in diameter located between the base of the cerebellum and the dorsal surface of the brainstem. The diagnosis of MPS due to iduronate-2-sulfatase (IDS) deficiency was confirmed biochemically. The dermal fibroblasts of the affected dog had much lower iduronate-2-sulfatase activity than did the dermal fibroblasts of two normal dogs. “IDS and betahexosaminidase activities were analyzed in hair roots obtained from two control dogs and from the dam and a sibling of the affected dog. Hair root analysis showed that the dam was a carrier of X-linked Hunter syndrome and that a phenotypically normal male littermate of the affected dog was normal.” IDS is a lysosomal enzyme that removes the sulfate group from the 2 position of L-iduronic acid, a component of acid GAG. This newly described case of canine Hunter syndrome differs from other animal models of MPS by the clinical progress was slow, which led to survival into the adult life. This is important because clinical and pathologic features of MPSI-IV are similar and do not discriminate among the enzyme deficiencies. The coarse facial features of this dog mimic MPS in humans. However, skeletal abnormalities including dystrophic bones with delayed or abnormal ossification centers were not observed in this dog.
“The enzyme results of the hair root analysis from this dog and from a parent and sibling were consistent with an X-linked inheritance.
In humans, MPS II can be expressed in a mild, intermediate, or severe form based on clinical signs with equivocally levels of enzyme in each form. The severe form occurs in children and results in skeletal deformities and neurodegeneration. The mild form occurs in adults and has a slower less debilitating course with preservation of intelligence. The clinical progression and biochemical characteristics of the enzyme defect in this dog best correlate with the intermediate form of the human disease.”
Even though lysosomal storage diseases are rare disorders, many veterinarians are unable to reach a specific diagnosis because they do not understand the disease group very well and because they do not have the testing techniques to make a diagnosis. There will be advances in the molecular genetic basis of storage diseases, that will help both humans and
animals.