Molecular diagnosis of neurologic disorders

K K Jain MD (Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.)
Originally released July 17, 2000; last updated July 11, 2019; expires July 11, 2022


Molecular diagnosis can be defined as the clinical application of molecular technologies to elucidate, diagnose, and monitor human diseases. This article introduces basic technologies and new developments for application in clinical diagnostics. These technologies are important for precise and rapid diagnosis of diseases of the nervous system such as infections, brain tumors, genetic disorders, and neurodegenerative diseases. Introduction of nanotechnology in diagnostics has further refined these procedures.

Key points


• Molecular diagnosis is the clinical application of molecular technologies to refine diagnosis.


• Many new biotechnologies have been incorporated in molecular diagnostics including biochips and nanobiotechnology.


• Next-generation sequencing is having an increasing impact on molecular diagnostics as sequencing of the human genome becomes more affordable.


• Molecular diagnostics has important applications in neurology including genetic disorders, infections, and cancer of the nervous system.


• Besides diagnosis of disease, molecular diagnostic technologies are also useful for drug discovery, monitoring of therapy by using biomarkers, and the development of personalized neurology.

Historical note and terminology

Molecular diagnosis can be defined as the clinical application of molecular technologies to elucidate, diagnose, and monitor human diseases. Basic technologies have been described in detail elsewhere (Jain 2019b). Molecular technologies incorporate the use of nucleic acids (DNA and RNA) as well as recombinant antibodies. Proteomic technologies are also applied to molecular diagnosis, justifying the term "proteodiagnostics." More than 500 molecular diagnostic systems have been developed to date. This article describes the basic principles of these technologies and their application to the diagnosis of neurologic disorders. The College of American Pathologists has used the term “molecular pathology” for molecular diagnostics, and as an extension of this, the application for neurologic disorders can be considered as “molecular neuropathology." Imaging technologies have been refined to the molecular level and the term "molecular brain imaging" is suggested.

Landmarks in the historical development of molecular diagnostics appear in Table 1. DNA was shown to carry genetic code in pneumococci (Avery 1944) even before the discovery of the double-stranded structure of the DNA (Watson and Crick 1953). DNA probes (segments of DNA labeled with radioactive markers) were used for diagnostic purposes in the 1980s, but the most important landmark in molecular diagnostics was the discovery of polymerase chain reaction (PCR) in 1985 (Mullis et al 1986). In the pre-PCR era, molecular biologists needed cumbersome and slow laboratory methods to study a few copies of a DNA sequence of interest in a clinical sample. Polymerase chain reaction, by providing unlimited copies of DNA, facilitated the applications in clinical diagnostics. Although several other technologies for amplification and detection of nucleic acids have been developed since then, PCR, with its modifications, remains the mainstay of current molecular diagnosis.

Availability of the human genome sequence will provide many opportunities for the development of molecular diagnostics. This will lead to the development of novel diagnostics as well as therapeutics for neurologic disorders and facilitate the development of personalized neurology.

Table 1. Historical Development of Molecular Diagnostics


Discovery and development


DNA shown to carry genetic code in pneumococci (Avery 1944)


Identification of the double-stranded structure of DNA (Watson and Crick 1953)


Discovery of the enzyme DNA polymerase (Kornberg 1959)


Discovery of in situ hybridization for gene location by labeled RNA probes (Gall and Pardue 1969)


Discovery of restriction enzymes that cut DNA at the site of specific sequences


Discovery of reverse transcriptase and copying of RNA into DNA (Baltimore 1970)


First recombinant DNA molecule is produced with use of ligase. The genomic age begins (Jackson et al 1972).


Southern blot test (Southern 1975)


Monoclonal antibody technology (Kohler and Milstein 1975)


Invention of the technology for DNA sequencing (Sanger 1977)


Creation of the first recombinant DNA molecule


Gene mapping by in situ hybridization becomes a standard method


DNA probes: segments of DNA labeled with radioactive markers


Demonstration of Huntington disease gene (Gusella et al 1983)


Discovery of polymerase chain reaction at Cetus Corporation (Mullis et al 1986)

1987 and 1988

Discovery of dystrophin, the protein product of the human Duchenne muscular dystrophy locus, and its characterization in muscle biopsies by immunoblotting (Hoffman et al 1988)


Development of fluorescent in situ hybridization technique (Pinkel et al 1986)


Start of Human Genome Project, National Institutes of Health, USA


Ligase chain reaction (Barany 1991)


Wedding of molecular biology and cytogenetics to create molecular cytogenetics (Lichter et al 1991)


Peptide nucleic acid, a mimic of DNA, is invented. Peptide nucleic acid arrays are useful for detection of DNA and RNA (Nielsen et al 1991).


Branched DNA technology used to quantify HIV levels


Invention of locked nucleic acid, a DNA analogue with a high affinity for complementary DNA or RNA and the ability to discriminate between correct and incorrect target sequences (Kumar et al 1998)


Antisense oligonucleotides labeled to detect RNA and tracked in their sojourn through the body by PET (Tavitian et al 1998)


Sequencing of human genome is completed. The postgenomic era begins.


Application of proteomic technologies in diagnosis: proteodiagnostics


Application of nanotechnologies in diagnosis: nanodiagnostics

This article describes the new technologies for molecular diagnostics based mostly on nucleic acids, but proteomics-based diagnostic technologies are also developing rapidly. Most of these technologies have potential applications in neurologic disorders.

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