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History of Research on Cerebellar Abiotrophy (CA) - viewed 23294 times PDF Print

The cerebellum (Latin for little brain) is a region of the brain that plays an important role in the integration of sensory perception, coordination and motor control. In order to coordinate motor control, there are many neural pathways linking the cerebellum with the cerebral motor cortex (which sends information to the muscles causing them to move) and the spinocerebellar tract (which provides proprioceptive feedback on the position of the body in space). The cerebellum integrates these pathways, like a train conductor, using the constant feedback on body position to fine-tune motor movements. It is the small section located at the base of the spinal column.

Initial observations by physiologists during the 18th century indicated that patients with cerebellar damage show problems with motor coordination and movement. In 1837 the Czech anatomist and physiologist, Johannes Evangelists Pukinje, also known as Jan Evangelista Purkyne (1787 – 1869) discovered Purkinje cells.  These are large neurons which are responsive cells in the nervous system that process and transmit information by electrochemical signaling. Found in the cerebellum,they have many branching dendrites, the branched projections used as conductors from other neural cells to the cell body.  He was one of the best known scientists of his time. Such was his fame that when people from outside Europe wrote letters to him, all that they needed to put as an address was “Purkyne, Europe” !.

Research into cerebellar function during the early to mid 19th century was done via lesion and ablation studies in animals. Research physiologists noted that such lesions led to animals with strange movements, awkward gait, and muscular weakness. These observations and studies led to the conclusion that the cerebellum was a motor control structure.

The neuron’s place as a primary fuctional unit of the nervous stystem was first recognized in the early 20th century through the work of the Spanish anatomist, Santiago Ramon y Cajal (1852 -1934). Caja proposed that neurons were discrete cells that commucated with each other via specialized junctions or spaces between cells. This became known as the neuron doctrine, one of the central tenets of modern neuroscience.

Motoneuron degeneration has been studied since the mid 18th century. Most research applications have been based on motor disfuction in cats and dogs. WR Gowers presented his influencial lecture on Abiotrophies in 1902. By 1940, JRM Innes, DS Russel and AJ Wilsdon had completed their study of  “Familial Cerebellar Hypoplasia and Degeneration in Hereford Calves,”  June Path Bact 1940;50: 455-461. In 1950 – Innes, JRM and  MacNaughton, WM presented their  “Inherited cortical cerebellar atrophy in Corriedale lambs in Canada identical with "daft lamb" disease in Britain”. Cornell Vet. 1950 Apr; 40(2):127–135. A major breakthrough on the existence of cerebellar degeneration in horses came over a decade later: Sponseller, Max. "Equine cerebellar hypoplasia and degeneration." Proceedings of the 13th annual convention of the American Association of Equine Practitioners, 1967, p. 123-126.

Under the name of Cerebellar Hypoplasia, Max T. Sponseller based his paper on 21 cases reported from California, Maryland, Michigan, Minnesota and Great Britain, indicating that the condition was possibly genetic and due to inbreeding. As more information was found, more research studies were published with a flurry of papers presented during the 70’s and 80s. Both England and Australia were searching the cause of sheep staggers and the similar clinical signs in Arabian horses and their derivatives. What J.R.M. Innes and Sponseller had started, was followed by publications in the Veterinary Record by Palmer AC, Blakemore WF, Cook WR, Platt H, Whitwell KE: “Cerebellar hypoplasia and degeneration in the young Arab horse: clinical and neuropathological features.”1973 Jul 21; 93(3):62-6.  PMID: 4748678.  Palmer et al published their studies on 9 cases in Great Britain from 1968-1972, with illustrations and resumes in French and German, indicating once again that this condition was genetic but not necessarily from inbreeding per se but how 'repetitive' close inbreeding occurred. As of 1974, Australia and New Zealand had sufficient cases of  a degenerative  neurological disorder to implement the exhaustive research of J.D. Baird and C.D. Mackenzie into Cerebellar Hypoplasia as it was still being called then.  Of several studies, their most in depth was published in the Australian  Veterinarian Journal: Aust Vet J. 1974 Jan;50(1):25-8. “Cerebellar hypoplasia and degeneration in part-Arab horses”. Baird JD, Mackenzie CD. PMID: 4819469 [PubMed - indexed for MEDLINE]. In fact as of the year 2000, Baird’s works were about the only available resources for Equine Cerebellar Hypoplasia or Cerebellar Abiotrophy available on line.

By 1987 Alexander de Lahunta (Cornell U.) and his test herd of Arabians confirmed the genetic inheritance. De Lahunta was involved with extensive research published on cerebellar hypoplasia in many animal breeds not just equines. His in depth paper: has free access on the internet. His earlier studies collaborated and coincided with the late well known geneticist Ann T. Bowling, whose unpublished findings of 1985 from a small test herd of CA affected Arabians established that CA was not a sex-linked mode of inheritance. 1990 saw the first reported cases and research done in Spain at the University of Cordoba by C. Riber, A Blanco and F.M. Castejon whose findings coincided with the report by Turner, et al in 1987. By this time Cerebellar Abiotrophy had been separated from Cerebellar Hypoplasia (CH) as a distinctive condition originating after the foal was born and not during uterine development as in CH.

1990 also saw the development and use of the first single nucleotide polymorphisms (SNPs) as a data base sequencing aide, distinguishing between individuals and species, genetic analysis of disease and complex traits, assessment of  linkage disequilibrium (LD), haplotype map generation, pharmacogenomics, etc. These initial sequencing machines were extremely costly, not only to build but also to run. Many improvements have been made over the last two decades with the result that the Horse Genome Project finally has been completed in 2007 enabling genetic research to surge forward.

1994 and 1995 saw two in depth publications on CA: one by Bret A. Sponseller at the University of Cornell based on his father's studies. He continued research based on the morbidity of 6% in one farm's annual foal crop of 67 foals and the following year of 8% morbidity from 36 foals from the same farm. The second study comprised a combined effort of the Universities of Ghent (Belgium), Finland and the University of Bern (Switzerland) published in German by the late H. Gerber, et al.  Included with Gerber's research team of ten were pedigree researchers and his son Vinzenz Gerber who continues today with molecular scientist Tosso Leeb (Horse Genome Project) to unravel the mysteries of CA. Gerber and Leeb are working in unison with Dr. Cecelia Penedo at the University of Davis (California) as of 2007 with the sharing of sample RNA in order to speed up the process of identification of the mutant allele due to the lack of a sufficient number of samples.

Leah S. Ruth, Melissa M. Locke  and Ann T. Bowling presented a report of a planned study at the January 2001 Plant & Animal Genome Conference to be based on tissue samples of the DNA of 30 of the original 48 family members of the mid 80s test herd. Their mtDNA research at that time to show the  matrilineal diversity for Arabian horses in the United States, using 62 tested horses, showed the existence of 34 individual mare lines acquired primarily in the mid to late 19th century from nomadic Bedouin tribes. They intended to use this information to intensify their studies on Cerebellar Abiotrophy. As of 2005 Cecelia Penedo, Leah S. Brault and Thomas R. Famula have been developing markers at UC Davis.

Caroline Hahn of the University of Edinburgh published her research in January 2006, and further studies have been done in Spain by A. Blanco published in August of the same year.

By 2007 Dr. Penedo and her assistant Leah Brault had established the locus of the defective allele on the chromosome, but still without an identification of the gene itself. The genetic basis of CA is currently under investigation at the Veterinary Genetics Laboratory of UC Davis in California. While the specific mutation that causes CA is not yet known, they have identified a group of genetic markers adjacent to gene that can be used as a surrogate test (or indirect test) for CA.  When genetic markers lie close to a gene of interest, they often are inherited along with the trait.  This CA Marker Scanning test has been available to the public as of September 2008.

Leah S. Brault specializes in mapping and identification of the gene responsible for Equine Cerebellar Abiotrophy in Arabian horses; coat color genes in horses; equine genome mapping. 

The CA test looks for a specific set of alleles that are co-inherited with CA which can be used as a diagnostic tool to identify affected foals and also animals that are potential carriers of the disease.  Breeders who wish to test their horses before breeding may use the CA test in order to avoid breeding two suspected carriers together.

Research carried out till late 2010 at the UC Davis Veterinary Genetics Laboratory (VGL) by Drs. Leah Brault and Cecilia Penedo has identified a mutation that is associated with CA.  This mutation is now part of the CA test being offered by the UC Davis VGL.  This is an important advancement, as it moves the currently available CA test from a marker based screening test to a more fully developed DNA test.

Written and compiled by Lisa Goodwin-Campiglio,© EG-C 2-IV-09

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