Genetic Advances in Neurological Disease [State of the Art Lecture]
World Small Animal Veterinary Association World Congress Proceedings, 2008
Jacques Penderis, BVSc, MVM, PhD, CVR, DECVN, MRCVS
Institute of Comparative Medicine, Faculty of Veterinary Medicine, University of Glasgow
Glasgow, UK

More spontaneously occurring genetic diseases have been described in the dog than in any other species with the exception of man, while a large number have also been recognised in the cat. In addition to these spontaneous genetic diseases, there is also the effect of selective breeding for a specific breed-conformation on general health, as well as the effect of differing genetic backgrounds on disease incidence and severity. The publication of the canine genome in 2005 has resulted in dramatic advances in the understanding of inherited diseases in dogs. In particular, the detailed pedigree information, the high number of litter siblings and the relatively short generation time make pedigree dog and cat breeds ideal models in which to study inherited diseases.

Nowhere have the advances in companion animal genetics been of greater benefit than in the field of neurology. The investigation of diseases of the nervous system is complicated by the inaccessibility of the central nervous system and the associated difficulties associated with obtaining diagnostic tissue for diagnostic confirmation. In practice this equates to the requirement for expensive and invasive investigative procedures, including advanced imaging of the brain (magnetic resonance imaging or computed tomography) and cerebrospinal fluid analysis. Furthermore, in many conditions of the nervous system, the diagnosis cannot be confirmed through standard diagnostic procedures and is often only made retrospectively following post mortem examination.

The Diagnostic Approach to Canine and Feline Neurological Disease

The diagnostic protocol in any pedigree dog or cat with neurological disease relies on an accurate clinical description of the neurological disease. In particular, classification of the neurological deficits into one or more of the regions of the nervous system, namely: forebrain, cerebellum, brainstem, spinal cord, vertebral column, peripheral nerve, neuromuscular junction and muscle. Once the disorder has been classified into one or more of these regions then the animal should be assessed to see whether 1) it represents a pedigree breed (particularly if there is a high degree of in-breeding) and 2) whether the neurological deficits fit a defined set of criteria consistent with a published genetic disorder in the breed. Where an underlying genetic defect has been described in a specific breed and the condition in a patient is consistent with the reported description, then prior to performing further investigative procedures the animal should first be assessed for the presence or absence of this genetic defect. The recent advances in our understanding of the underlying molecular basis of many canine neurological diseases mean that many conditions can now be included or excluded on the basis of a simple genetic test.

Specific Genetic Tests for Canine and Feline Neurological Disease

The development of a DNA test not only allows the rapid and accurate confirmation of the diagnosis, but a DNA test also allows the eradication of the condition from all tested dog and cat lines, while still preserving the genetic heterogeneity. One of the limitations of DNA testing is that the DNA defect responsible for a specific disease, although often situated within the same gene, is usually different in different dog breeds. This means that the DNA test used to identify a disease in one breed is unlikely to be informative if used in a different breed affected by the same disease, and a genetic test has to be developed for each breed affected by a specific neurology condition. A second limitation is where the specific genetic defect has not been identified, but a marker associated with the disease has been typed; here the test will provide a prediction of whether the animal is likely to have the disease or is likely to be a carrier. This type of test is a genetic linkage test and the accuracy of the test largely depends on the proximity of the marker to the genetic defect responsible for the disease.

Genetic tests are available for a growing number of canine and feline neurological diseases through a variety of different laboratories. Some tests are only available through one of the laboratories. Some of the laboratories are listed below (Table 1) and further information on inherited diseases in dogs can be found on: (Online Mendelian Inheritance in Man, particularly under the subheading of 'Animal Models' for each condition) and under (Online Mendelian Inheritance in Animals--although due to the larger available resources OMIM tends to be more current).

Table 1. Genetic testing laboratories.

1.  Animal Health Trust
Lanwades Park

2.  Health Gene
Health Gene Corp
3300 Highway 7
Suite 806
ON L4K 43M3

3.  Centre for Narcolepsy--Stanford University

4.  PennGen
Penn Gen Laboratories
3850 Spruce Street
PA 19104-6010

5.  Vet Gen
3728 Plaza Drive
Suite One
Ann Arbor
MI 48105

6.  CNM
Ecole Nationale Vétérinaire d'Alfort

The list of neurological diseases in which the underlying molecular defect has been described and in which a genetic test is available is constantly growing and includes:

Neurological condition

Dog breed

Institution offering test

Clinical signs

Canine GM1 gangliosidosis

Portuguese water dog


Vision deficits, lethargy, gait disturbance

Centronuclear myopathy

Labrador retriever


Exercise intolerance, muscle atrophy

Ceroid lipofuscinosis

Border terrier


Various: cerebellar and blindness


English springer spaniels

1, 4

Various: predominantly behaviour

Globoid cell leukodystrophy

Cairn terrier, West Highland white terrier

1, 2

Ataxia, tremors, weakness

Glycogenosis Type IV

Norwegian forest cat


Two forms: early neonatal death, or progressive neuromuscular weakness at 5 to 8 months of age

L-2-Hydroxyglutaric aciduria

Staffordshire bull terrier and WHWT


Various: behaviour, ataxia, seizures


Persian, DSH


Facial dysmorphism, ataxia, tremors, altered behaviour and seizures

Mucopolysaccharidosis (MPS)

Variety of breeds, including: Schipperke, miniature Pinchers, Siamese, DSH, German shepherd


Ataxia, tremors, facial dysmorphism

Muscular dystrophy

Golden retriever


Exercise intolerance, stiff gait, muscle atrophy

Myotonia congenita

Miniature schnauzer

2, 4

Exercise intolerance, muscular stiffness


Dachshund, Dobermann, Labrador retriever

2, 3


Phosphofructokinase deficiency

American cocker spaniel, English springer spaniel

2, 4, 5

Exercise intolerance, anaemia

Screening Tests for Neurological Diseases with a Suspected Genetic Basis

If the clinical signs are not specific enough to identify a likely genetic test, but the possibility does exist that the clinical signs may represent a genetic disease, then, based on the neurological localisation, a routine approach can be followed that may allow a diagnosis to be made. This is particularly true for degenerative diseases of the central nervous system due to inborn errors of metabolism (e.g., lysosomal storage diseases, organic acidurias, etc.). Many of these degenerative neurological diseases are incurable: the diagnosis only confirms what the clinical presentation has already intimated: that the clinical signs will continue to progress despite intervention, with the eventual requirement for euthanasia on humane grounds. At best the clinical signs can be managed in order to afford the dog a reasonable quality of life.

Screening for Inborn Errors of Metabolism

Screening of blood, but particularly of urine, for accumulation products indicative of inborn errors of metabolism may indicate an appropriate genetic test, or in some diseases may even be diagnostic. The screening tests are usually performed on fresh urine samples (with no preservative) and those readily available can be subdivided into:

 Urinary organic acids: these represent inborn errors of metabolism characterised by accumulation of organic acids within the bodily fluids, but particularly in the urine. The demonstration of urinary organic acid accumulation is based on the extraction of the organic acids from the urine using organic solvents and then their characterisation using gas chromatography-mass spectroscopy.

 Accumulation of urinary amino acids or decrease in urinary amino acids: the urinary amino acids are determined using the urine spot test, but are less specific and useful in neurological disease.

 Urinary carbohydrates: in particular glucose in diabetes mellitus.

 Urinary oligosaccharides: accumulation of urinary oligosaccharides that may be evident in neurological disease include 1) the accumulation of mannose-containing oligosaccharides in mannosidosis in cats, and 2) the accumulation of high-molecular weight oligosaccharides in GM1 and GM2 gangliosidosis in dogs and cats and fucosidosis in English Springer Spaniels.

 Urinary glycosaminoglycans: in particular the accumulation of dermatan sulphate is indicative of mucopolysaccharidosis (MPS) I, II, VI and VII, while the accumulation of heparin sulphate is indicative of MRS IIIA and IIIB. Detailed descriptions of tests available in MPS are available from PennGen.

Metabolic profiles on blood: pre- and post-exercise lactate and pyruvate determinations. These may give an indication of metabolic derangement related to exercise intolerance.

Enzyme Analysis of WBC's or Cultured Fibroblasts

Where the breed, signalment and clinical features are suggestive of one or more of the lysosomal storage diseases and where the underlying enzyme defect is known for those lysosomal storage diseases, then enzyme analysis can be performed against known normal control animals. Reduction in enzyme activity is indicative of that particular lysosomal storage disease. Washed WBCs or cultured skin fibroblasts are usually the most appropriate cell source, and can either be assayed fresh or fresh-frozen.

Demonstration of Accumulation Products

Dependent on the individual lysosomal storage disease, abnormal accumulations may be evident within cells, particularly macrophages, on buffy coat blood smears and biopsy samples from liver, spleen, lymph nodes or bone marrow. In some cases this may be diagnostic, e.g., in the case of sphingolipidosis.

Magnetic Resonance Imaging (MRI) Features

Characteristic MRI changes may be apparent in some canine and feline genetic diseases. In these cases the appearance is usually bilaterally symmetrical and frequently has a highly conserved pattern. An example of this would be L-2-hydroxyglutaric aciduria in the Staffordshire bull terrier or West Highland white terrier, an organic aciduria with a known genetic cause, and fucosidosis in the English springer spaniel.

Abnormalities on Muscle Biopsy

Many of the inherited neurological disorders affecting peripheral nerve and muscle may have characteristic features on muscle biopsy allowing the diagnosis to be made, including centronuclear myopathy in the Labrador retriever, and muscular dystrophy. However, muscle abnormalities are not just limited to primary diseases of muscle and peripheral nerve, as muscle abnormalities or inclusion bodies may also be evident in some diseases primarily affecting the central nervous system, e.g., Lafora's disease or canine myoclonic epilepsy.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Jacques Penderis, BVSc, MVM, PhD, CVR, DECVN, MRCVS
Institute of Comparative Medicine, Faculty of Veterinary Medicine
University of Glasgow
Glasgow, United Kingdom

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