DNA testing in neurologic diseases

Abstract

DNA testing is available for a growing number of hereditary diseases in neurology and other specialties. In addition to guiding breeding decisions, DNA tests are important tools in the diagnosis of diseases, particularly in conditions for which clinical signs are relatively nonspecific. DNA testing also can provide valuable insight into the risk of hereditary disease when decisions about treating comorbidities are being made. Advances in technology and bioinformatics will make broad screening for potential disease-causing mutations available soon. As DNA tests come into more common use, it is critical that clinicians understand the proper application and interpretation of these test results.

Keywords: Genetic mapping; Genetic markers; Genetics; Neurology.

Figure 1

Two young animals presented for progressive, spastic paraplegia illustrate the importance of considering other differential diagnoses in suspected hereditary disease. (A) A purebred English Pointer with a history of affected littermates suggested a hereditary disease but was diagnosed with Neospora caninum infection. (B) A stray cat from the streets of St. Louis came from a random breeding population, but was diagnosed with a hereditary muscular dystrophy. From O'Brien 201275 used with permission.

Figure 2

Linked marker DNA tests are useful in a family with known disease but can give false‐negative and false‐positive results as illustrated. (A) In this hypothetical pedigree of a recessive trait, males are squares and females are circles. Affected dogs are shown as filled symbols and carriers are half‐filled symbols. Parents of affected dogs are obligate carriers but genotype of normal offspring would be unknown. (B) A linked marker () will segregate with the mutant allele and can be used to identify carriers within a family with known disease. (C) The marker allele could have been present within the family before the mutation occurred () which produced the disease‐causing allele. (D) Because the marker can segregate in the breed separate from the mutant allele, false‐positive results are possible (arrow: a dog that is normal but identified as affected by linkage). (E) Because the marker is only linked to the mutant allele, recombinations (X) can break that link leading to false results (arrow: a dog that is affected but identified as a carrier).

Figure 3

Within the lysosome, tripeptidyl peptidase 1 (TPP1) and palmatoyl‐protein thioesterase 1 (PPT1) contribute to protein degradation by cleaving off different portions of a protein, the N‐terminal tripeptide chain, and a palmitoyl fatty acid, respectively. A deficiency of either enzyme blocks degradation of the protein. Thus, mutations in either gene that codes for these enzymes (TPP1 and PPT1 respectively) lead to an identical lysosomal storage disease characterized by autofluorescent inclusions in neurons of the undegraded protein. Both diseases have been reported in Dachshunds.14, 15 A DNA test would detect the mutation in 1 gene, but not the other potentially leading to a “false‐negative” result.

Figure 4

The Purkinje cells (brown in this histologic section labeled with antibodies against the calcium buffering protein calbindin) are the sole output from the complex information process that fine‐tunes movement by the cerebellar cortex. A diverse cadre of mutations can affect the function or structure of the Purkinje cell, but produce a very similar phenotype of cerebellar ataxia. (Courtesy Gayle Johnson).