[pyrnet] Literature search on chondrodysplasia

[Patric Lundberg <pyrsrgr8@yahoo.com>]

Joe,

> A reference list from a through literature search would be very
> helpful to all concerned.

Searched on Medline (1966-2000) for (canine OR dog) AND
chondrodysplasia resulted in 29 articles - the ones listed below
actually concerned us.

Certainly, the 3-4 groups that have done most of this work, Dr Sande's
included, would be aware of all of these already...

Later, Patric.

_____

Brown, R. G., G. N. Hoag, et al. (1978). “Alaskan Malamute
chondrodysplasia. V. Decreased gut zinc absorption.” Growth 42(1): 1-6.
	Experiements were conducted to determine if zinc absorption was
impaired in Alaskan Malamutes which had a genetic chondrodysplasia or
dwarfism. When the uptake of an oral dose of 65Zn from the gut in blood
was measured in whole dogs it was found that the chondrodysplastic
animals absorbed only 25 per cent the amount absorbed by their
controls. In vitro studies suggested that 65Zn was initially bound to a
protein fraction in all cases but it was later released to a
non-protein fraction in the case of normal dogs. This transfer did not
occur in the case of the chondrodysplastic dog and it suggests that the
transfer of zinc from a protein to a non-protein fraction in the
mucosal cell may be the missing step in the dog with chondrodysplasia.

Hoag, G. N., R. G. Brown, et al. (1976). “Alaskan malamute
chondrodysplasia. I. Bone composition studies.” Growth 40(1): 3-11.
	Chondrodysplastic Alaskan Malamutes exhibit concentrations of calcium,
phosphorus and magnesium in radius, ulna, and humerus bone segments
similar to those of non-chondrodysplastic dogs of similar age.
Significant differences in extractability of mineral components with 5%
EDTA were observed in specific bone segments. Although these data
suggest that a primary derangement in calcium and phosphorus was
possible the magnitude of the differences strongly suggested it
unlikely and stress or mechanical factors may account for some of the
observed differences. The possibility that chondrodysplasia provides a
model for human disorders such as fibrogenesis imperfecta ossium was
discussed. These data presented support a previous hypothesis that the
chondrodysplasia is not a vitamin D-resistant rickets syndrome.

Fezer, G. and J. Scabell (1968). “[A case of multifocal
chondrodysplasia of a dog].” Berliner Und Munchener Tierarztliche
Wochenschrift 81(24): 480-2.
	
Aroch, I., R. Ofri, et al. (1996). “Haematological, ocular and skeletal
abnormalities in a samoyed family.” Journal of Small Animal Practice
37(7): 333-9.
	Haematological, ocular and skeletal abnormalities were documented in a
samoyed male and its five offspring. Haematological abnormalities,
found in repeated tests in all the dogs, included marked eosinophilia,
eosinophilic bands and absence of Barr bodies. Two of the dogs had
bilateral buphthalmia, retinal detachments and other ocular
abnormalities. Three of the dogs had skeletal abnormalities including
chondrodysplasia (dwarfism) and brachygnathia (undershot jaw). A
similar combination of inherited skeletal and ocular disorders, without
the haematological abnormalities, has been described in samoyeds.
Acquired causes for the haematological findings, which are similar to
the inherited Pelger-Huet anomaly described in several species, have
been eliminated. Eosinophilic bands and scarcity of Barr bodies could
be a marker, or a previously unreported manifestation, of an inherited
disorder in samoyeds.

Bingel, S. A. and R. D. Sande (1994). “Chondrodysplasia in five Great
Pyrenees.” Journal of the American Veterinary Medical Association
205(6): 845-8.
	Five disproportionate, short-limbed, short-trunked (dwarf) Great
Pyrenees pups were examined. The mode of inheritance was compatible
with a simple autosomal recessive trait, and skeletal radiography
revealed flaring of the metaphyses of all long bones and the
costochondral junctions of the ribs. Vertebral bodies were poorly
ossified and short, and had a beak-like extension on the caudal
metaphyseal margin. Vertebral body end-plates were thin and concave,
and ossification was abnormal. Three of the 5 dogs were deaf, and 1 had
testicular atrophy. Ocular examinations did not reveal any
abnormalities. Histologic examination of the growth plates revealed
disorganized chondrocyte columns, and chondrocytes appeared to have
undergone degenerative changes in the zone of chondrocyte
proliferation. Transmission electron micrography of growth plate
chondrocytes revealed dilated profiles of rough endoplasmic reticulum.

Breur, G. J., C. A. Zerbe, et al. (1989). “Clinical, radiographic,
pathologic, and genetic features of osteochondrodysplasia in Scottish
deerhounds.” Journal of the American Veterinary Medical Association
195(5): 606-12.
	Clinical, radiographic, pathologic, and genetic features of a form of
osteochondrodysplasia in 5 related Scottish Deerhound pups from 2
litters were evaluated. All pups appeared to be phenotypically normal
at birth. At approximately 4 or 5 weeks, exercise intolerance and
retarded growth were observed. Kyphosis, limb deformities, and joint
laxity gradually developed. Radiography of the affected pups revealed
skeletal changes characterized by abnormalities in long bones and
vertebrae, with involvement of epiphyses, growth plates, and
metaphyses. Short long bones and vertebrae and irregular and delayed
epiphyseal ossification were most noticeable in younger pups; in older
pups, bony deformities became more prominent. In skeletally mature
dogs, osteopenia and severe deformities were seen. The histologic
changes of the growth plate were compatible with a diagnosis of
chondrodysplasia. Growth plate chondrocytes contained periodic acid
Schiff-positive, diastase-resistant cytoplasmic inclusions. A single
autosomal recessive mode of inheritance was suspected.

Minor, R. R. and C. E. Farnum (1988). “Animal models with
chondrodysplasia/osteochondrodysplasia.” Pathology and Immunopathology
Research 7(1-2): 62-7.
	
Bingel, S. A., R. D. Sande, et al. (1985). “Chondrodysplasia in the
Alaskan malamute. Characterization of proteoglycans dissociatively
extracted from dwarf growth plates.” Laboratory Investigation 53(4):
479-85.
	Proteoglycan monomers obtained from the dissociative extraction of
growth plate cartilages of chondrodysplastic and homozygous nonaffected
Alaskan malamute dogs were characterized with regard to hydrodynamic
size and glycosaminoglycan composition. Dissociative extraction
solubilized 91.7% of the uronic acid and 71.7% of the protein from
dwarf growth plates compared to 76.8% of the uronic acid and 50.2% of
the protein from normal growth plates. Dissociative density gradient
ultracentrifugation of the extracts resulted in the recovery of 84% of
the uronic acid from dwarf growth plates and 71% of the uronic acid
from normal growth plates in the D1 fraction. High-pressure liquid
chromatography of the dwarf D1 monomers revealed a single peak with a
retention time of 8.6 minutes while the normal D1 monomers eluted later
with a retention time of 8.9 minutes. After reduction of the dwarf D1
monomers, the chondroitin sulfate side chains eluted from Sepharose
CL-6B with an approximate molecular weight of 15,000 (Kav of 0.55)
while those from the normal eluted with an estimated molecular weight
of 9,500 (Kav of 0.64). High-pressure liquid chromatography analysis of
the unsaturated disaccharides from the dwarf D1 fractions revealed
increased amounts of chondroitin-6-sulfate. Analysis of the fractions
for glucosamine and galactosamine revealed that dwarf D1 and D2
fractions were enriched in galactosamine. These findings indicate that
the extracellular matrices of dwarf growth plates contain proteoglycan
monomers which may be indicative of a less mature extracellular
cartilage matrix than the cartilage matrices of age-matched normal
dogs.

Sande, R. D. and S. A. Bingel (1983). “Animal models of dwarfism.”
Veterinary Clinics of North America.  Small Animal Practice 13(1):
71-89.
	
Bingel, S. A. and R. D. Sande (1982). “Chondrodysplasia in the
Norwegian Elkhound.” American Journal of Pathology 107(2): 219-29.
	Dwarfism in the Norwegian Elkhound occurred as a result of a
generalized disturbance in endochondral ossification. Radiographic
changes included flaring and increased width of the distal metaphyses
of the radius and ulna, delayed ossification of the cuboid bones of the
carpus, and  reduction in length of the vertebral bodies. The zone of
chondrocyte proliferation was decreased in width and contained areas of
abnormal cell column formation alternated with wide areas of matrix.
Chondrocytes in all zones contained one or more inclusions bounded by a
smooth discontinuous membrane. The material within the inclusions
appeared homogeneous and stained blue-green with Movat's pentachrome
and deep blue with alcian blue-periodic acid-Schiff at pH 1.0 and 2.6.
The distribution of ruthenium red granules in the matrix frequently
revealed poor differentiation into territorial and interterritorial
zones. Twenty-four-hour urine samples were negative for glucose, and
the glycosaminoglycan excretion pattern was normal.

Terpin, T. and M. R. Roach (1981). “Chondrodysplasia in the Alaskan
Malamute: involvement of arteries, as well as bone and blood.” American
Journal of Veterinary Research 42(11): 1865-73.
	
Hoag, G. N., R. G. Brown, et al. (1976). “Alaskan malamute
chondrodysplasia. II. Urinary excretion of hydroxyproline, uronic acid
and acid mucopolysaccharides.” Growth 40(1): 13-8.
	The urinary excretion of free, total and non-dialyzable hydroxyproline
appeared to be similar in both chondrodysplastic and
non-chondrodysplastic Alaskan Malamutes of ages six and twenty-six
weeks suggesting the metabolic defect was probably not related to a
gross disturbance in collagen metabolism. Urinary hexuronic acids also
appeared to be similar in levels for both populations. A four-fold
increase in urinary mucopolysaccharide levels observed at age
twenty-six weeks in the chondrodysplastic Alaskan Malamute suggested a
deviation from normal. The magnitude and variability of deviation were
not sufficient to indicate that this condition could serve as a model
for the mucopolysaccharidosis of man but probably indicated a delayed
maturation process.

McBride-Warren, P. A., J. S. McCutcheon, et al. (1979). “Alaskan
malamute chondrodysplasia--VIII. Incorporation of [14C]glucosamine and
[3H]serine in hepatic metal-binding proteins of Canis familaris.”
Comparative Biochemistry and Physiology.  B: Comparative Biochemistry
63(4): 569-76.
	1. Hepatic proteins isolated from control kennel dogs bound small
quantities of zinc and iron and the peptide fraction contained neither
metal. 2. Zince loading of kennel dogs stimulated an hepatic uptake of
five times more zinc and three times more iron than an equivalent
copper load. The increase in metal concentration was noted in the
10,000 dalton protein. 3. Both the 12,000 and 10,000 dalton proteins
isolated from kennel dogs contained more binding sites specific for
zinc than for either copper or iron. All three proteins isolated from
Alaskan Malamutes showed a smaller affinity for zinc than copper or
iron. 4. Both copper and zinc loading stimulated an uptake of
[14C]glucosamine and [3H]serine from the peptide fraction of control
kennel dogs into the 10,000 dalton protein.

McBride-Warren, P. A., R. G. Brown, et al. (1979). “Alaskan malamute
chondrodysplasia--VII. Isolation and characterization of copper, zinc
and iron binding proteins in Canis familiaris.” Comparative
Biochemistry and Physiology.  B: Comparative Biochemistry 64(2):
187-93.
	1. Three low molecular weight (12,000, 10,000 and 7,000) metal binding
proteins have been isolated from the livers of normal and
chondrodysplastic Alaskan Malamutes. 2. Comparison studies between
kennel (mixed breed) dogs and both adult and immature Alaskan Malamutes
suggested that the disturbance in trace mineral metabolism found in the
Malamutes is almost entirely reflected in the 12,000 mol. wt species.
3. The major copper-inducible protein (10,000 mol. wt) observed in
kennel dogs was not found to be inducible in Malamutes and contained
constant ratios of both copper and zinc to protein in metal binding
proteins isolated from the livers of both normal and dwarf Malamutes.
4. The copper and zinc found in the UM2 concentrates (mol. wt greater
than 2000) of immature Malamutes showed very little affinity to the
proteins and these metals were found chiefly in a peptide fraction
which apparently serves as a reservoir from which the storage proteins
obtain the metals that they bind. 5. Regression analysis indicated a
statistically significant correlation between both copper and zinc
concentrations and the carbohydrate concentration in the proteins
investigated.

Hoag, G. N., R. G. Brown, et al. (1977). “Alaskan malamute
chondrodysplasia VI. Copper absorption studies.” Canadian Veterinary
Journal 18(12): 349-51.
	
Brown, R. G., G. N. Hoag, et al. (1977). “Alaskan malamute
chondrodysplasia IV. Concentrations of zinc, copper and iron in various
tissues.” Growth 41(3): 215-20.
	Trace mineral concentrations in various tissues of the
chondrodysplastic (dwarf) Alaskan Malamute are remarkably different as
compared to normal. The zinc level in heart tissue was depressed in
dwarf animals (26 weeks). Copper concentration in the liver is elevated
two to four fold in 26 week old dwarf animals and iron levels are
significantly elevated in kidney, liver and pancreas of these animals.
These observations suggest that the dwarf Alaskan Malamutes suffer from
a genetic defect in trace mineral metabolism. If this is the case, then
many of the skeletal lesions reported for these animals may be
attributed to disorders in either zinc or copper metabolism.

Brown, R. G., G. N. Hoag, et al. (1977). “Alaskan Malamute
chondrodysplasia III. Connective tissue of bone.” Growth 41(3): 207-14.
	The dwarf Alaskan Malamute was compared in these studies with normal
Alaskan Malamutes of the same age with regard to collagen and
mucopolysaccharide components of the bone. The hydroxyproline
concentration of bone segments was normal in most instances, whereas,
the hexosamine concentration was increased (P less than .05) in distal
segments. Alterations in amounts of collagen soluble in neutral salt,
dilute acid and 5 M guanidine hydrochloride were observed and these
were related to changes in subunits found following chromatography on
carboxymethyl (CM) cellulose. The presence of an increased
keratosulfate fraction in dwarf Alaskan Malamutes was consistent with
an apparent delayed bone ossification process. These changes in the
connective tissue moieties may account for the gross morphology with
respect to the bowed legs. The primary cause for these changes has not
yet been determined but alterations in factors related to processes of
normal development in bone are suggested. The present observations tend
to support the hypothesis that the changes in the bone are secondary to
some other primary metabolic defect.

Fletch, S. M., M. E. Smart, et al. (1973). “Clinical and pathologic
features of chondrodysplasia (dwarfism) in the Alaskan Malamute.”
Journal of the American Veterinary Medical Association 162(5): 357-61.
	
Subden, R. E., S. M. Fletch, et al. (1972). “Genetics of the Alaskan
Malmute chondrodysplasia syndrome.” Journal of Heredity 63(3): 149-52.
	
Fletch, S. M. and P. H. Pinkerton (1972). “An inherited anaemia
associated with hereditary chondrodysplasia in the Alaskan malamute.”
Canadian Veterinary Journal 13(11): 270-1.
	
Dammrich, K. (1967). “[A contribution to chondrodystrophia fetalis in
animals].” Berliner Und Munchener Tierarztliche Wochenschrift 80(6):
101-5.
_____



=====
"Sage Advice Improves with Thyme"

Patric Lundberg, PhD
patric@pyrealm.com
Department of Virology
City of Hope National Medical Center
(626)359-8111 x2612

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