Contractural arachnodactyly

From Cow
Revision as of 07:20, 29 July 2013 by WikiSysop (talk | contribs)
Congenital contractural arachnodactyly in a 1-day-old Aberdeen Angus calf. NSW Department of Primary Industries

Congenital contractural arachnodactyly (CA; CCA; "fawn calf syndrome") is a non-lethal autosomal-recessive genetic disease of newborn Aberdeen Angus and Angus-derived calves (including Murray Grey, Brangus and Black Simmental). The disease was first reported in Australia but since recognised worldwide.

Contractural arachnodactyly was transmitted in the descendants of Freestate Barbara 871 of KAF, a registered Angus cow born in Indiana, U.S.A. in 1978. The CA mutation was first introduced into Australia in commercial semen from a number of U.S. registered Angus bulls including Premier Independence KN, O'Neills Renovator, Rambo 465T of JRS, Bon View Bando 598, SAF 598 Bando 5175 and Boyd On Target 1083 and was later widely disseminated in the Australian Angus population by the Australian bred sons of these U.S. bulls, notably Te Mania Kelp K207.

Newborn calves affected by CA present with proximal limb contractures, distal limb hyperextension, joint hyperlaxity, kyphosis and sometimes scoliosis. Arachnodactyly and dolichostenomelia are also present but may be difficult to recognise unless there are normal siblings available for frame score (height) comparisons. The clinical severity of CA varies significantly between cases and diagnosis can be difficult beyond the neonatal period in milder cases. The typical newborn CA affected calf is "down on its pasterns", with marked angulation of the hindlimbs and an arched backline, hence the name "fawn calf" due to the similarity of appearance to a newborn deer. These clinical signs are however reduced in severity with post-natal growth and CA affected calves can often appear normal by four to six months of age. Severely affected CA calves (approx. 10%) are unable to stand or walk at birth and will die unless intensively nursed. As adults, CA animals are relatively tall and "rangey" animals, with lower muscle scores than their unaffected siblings. CA affected calves also have poor foot and leg conformation as adults.

CA is classified as a heritable disorder of connective tissue, specifically a disorder of the endomycium and perimycium. The defect in the muscle connective tissue results in a reduced range of elastic extension (ie reduced elasticity) of the muscle-tendon complex - from muscle contraction to muscle relaxation - manifest as proximal contractures. These contractures in CA are quite different to those seen in arthrogryposis syndromes. In CA there is no reduction of joint movement by the periarticular connective tissues of the joint ligaments and capsule, reduction in the range of joint movement in CA resulting entirely from the reduced range of extension of the muscles. The joints of newborn CA affected calves are actually hyperlax and the distal joints are hyperextensible. No neurological or neuropathological abnormality has been detected in CA affected calves[1]

Following a decade of collaboration between the Angus Society of Australia, the NSW Department of Primary Industries and the Department of Animal Sciences at the University of Illinois, U.S.A., the mutation causing CA in Angus and Angus infused cattle was identified by U.S. molecular geneticists and a laboratory DNA test for CA was developed. Since 2010 this test has been used worldwide to identify carriers of the CA mutation in the cattle population and thereby reduce the incidence of CA cases. A breeding trial in NSW, Australia between 2004 and 2008 had earlier demonstrated that the CA syndrome was transmitted as an autosomal recessive trait.

Congential contractural arachnodactyly or CCA has also been reported in man and mice. In man, CCA is usually transmitted as an autosomal dominant trait although some recessive CCA syndromes have also been reported. A significant proportion of human CCA cases are known to be caused by several different mutations of the fibrillin 2 gene, mostly in the Exon 24 region, a major glycoprotein binding zone. However, in the majority of human CCA cases, the FBN2 gene is known to be normal and these cases of the CCA phenotype must therefore be caused by mutations at one or more other loci.

The fibrillins are a group of related glycoproteins that polymerise in the extracellular space to form 10 nm fibrils that are critical in the formation of the elastic fibers of connective tissue. Fibrillin fibrils however also provide elasticity in connective tissue in their own right (ie. independent of the tropoelastin deposited on the fibrillin fibrils to form the elastic fibres). Fibrillin 2 is the dominant fibrillin protein in many embryonic mammalian connective tissues but is progressively replaced by fibrillin 1 as the dominant fibrillin during late gestation and early post-natal growth, possibly explaining the post-natal "recovery" of CA affected individuals as the abnormal fibrillin 2 fibrils become less structurally important as post-natal growth proceeds).

Recent research has indicated that a repeated pattern of molecular genetic heterogeneity is seen in the phenocopies of several connective tissue disorders, with the dominant transmitted phenocopies caused by mutations of a structural (often fibrillar) glycoprotein and the recessive phenocopies caused by mutations of other genes that encode proteins which regulate of otherwise participate in the extracellular assembly of the fibrils of this same structural protein. In the case of several diseases associated with dominant mutations of the fibrillin 1 gene such as geleophysic dysplasia, Weill-Marchesani Syndrome and isolated ectopia lentis, specific ADAMTSL proteins, distinct gene products within the ADAMTS protein superfamily, have been implicated in recessive syndromes with the same phenotypes[2].

CCA is classified as one of a number of marfanoid disorders. Marfans syndrome (MFS) itself is caused by mutations of the fibrillin 1 gene in man and in cattle. MFS is a potentially fatal heritable syndrome with post-natal onset of the same constellation of clinical signs that is seen in CCA cases at birth(including arachnodactly, dolichostenomelia, muscle hyoplasia, contractures, joint hyperlaxity and kyphosis) but with additional and much more serious manifestations such as aortic rupture, visceral rupture and rupture of the ocular zonula due to a progressively increasing fragility of the elastic connective tissues that is not seen in CCA. Interestingly, exogenous ADAMTSL6 normalises fibrillin 1 fibrillogenesis in a mouse MFS model.

There is now strong evidence that fibrillin fibrillogenesis is controlled by proteins of the ADAMTS superfamily, including the ADAMTSLs[3].

Accordingly, the ADAMTSL genes are strong candidate genes for the site of mutation in recessive CCA syndromes - including CA in Angus calves.

On this hypothesis, CCA is a disorder of fibrillin 2 fibrillogenesis caused by either a primary defect of the fibrillin 2 protein due to a dominant FBN2 mutation or, alternatively, a failure of fibrillin 2 fibrillogenesis despite normal fibrillin 2 protein, secondary to a recessive mutation in a gene encoding an ADAMTSL protein that controls extracellular fibrillin 2 fibrillogenesis[4].

The differential diagnosis of CA in calves includes other causes of non-lethal congenital contractures including the heritable congenital myopathies and a wide range of congenital arthrogryposis syndromes. The CA syndrome can however be readily distinguished from these other disorders by careful clinical examinations in the neonatal period. The presence of proximal muscle-tendon contractures with distal joint laxity and the post-natal reduction in contracture and kyphosis severity are significant in the differential diagnosis. Diagnosis can be readily confirmed by the DNA test for CA that is now available through the University of Queensland Animal Genetics Laboratory and Zoetis Animal Health Ltd.

No specific treatment is required for CA calves apart from good nursing to ensure suckling and ambulation in those cases that are recumbent after birth. To prevent dissemination of the CA mutation in the population, CA affected animals should not be used for breeding unless the progeny are to be tested and CA carriers eliminated from further breeding.

References

  1. Denholm LJ (2010) Congenital Contractural Arachnodactyly (Fawn Calf Syndrome) in Angus Calves. NSW Department of Primary Industries PrimeFact No. 1015 May 2010
  2. Le Goff, C & Cormier-Daire, V (2011) The ADAMTS(L) family and human genetic disorders. Hum Mol Genet 20(R2):R163-R167
  3. Werneck CC et al (2004) Identification of a major microfibril-associated glycoprotein-1-binding domain in fibrillin-2. J Biol Chem 279(22):23045-23051
  4. Nishimura A et al (2007) FBN2, FBN1, TGFBR1, and TGFBR2 analyses in congenital contractural arachnodactyly. Am J Med Genet A 143:694–698