The Role of Genetics in Neurological Disorders: From Rare Diseases to Common Conditions

Abstract

Neurological disorders result from neurological diseases affecting the brain, spinal cord and peripheral nerves and include rare genetic diseases like Huntington’s disease and spinal muscular atrophy, as well as common diseases such as Alzheimer’s, Parkinson’s disease and epilepsy. These conditions are strongly influenced by genetics, and genetics contribute to the onset, the progression of the disease, the severity of symptoms and treatment responsiveness. Genetics is relevant not only to inheritance, but also to de novo mutations, polygenic risk factors and gene environment interactions that contribute to the clinical phenotype of these disorders.

Although the many mutations and heredity patterns of neurological conditions have not been worked out completely, genetic research has come a long way to help us learn more about these conditions. Single gene mutations are invaluable particularly for rare disorders for early diagnosis and targeted interventions. For instance, predictive gene testing such as checking for the HTT gene mutation linked to Huntington's disease allows people to learn if they are at risk of the disease early on — before their symptoms develop.

On the other hand, most common neurological disorders involve genetic landscapes much more complicated, with small increases in risk due to more than one gene. Since epigenetic factors and certain environmental factors can further influence these risks, prevention is always in order. For example, people with APOE ε4 allele are more likely to develop Alzheimer’s disease but lifestyle factors such as dietary and exercise may reduce this risk. Such complexity emphasizes the necessity for complete studies, including genome wide association studies (GWAS), epigenetics, and transcriptomics to define molecular mechanisms of these multifactorial disorders.

Genetic testing has recently become one of the most important tools in neurology, allowing us to make early diagnosis with great precision and to offer a comprehensive and personalized treatment plan, based on patients' genetic profile. For instance, these genetic mutations can help physicians choose the best medicines for patients with epilepsy. Gene based therapies, including gene replacement, antisense oligonucleotides (ASOs), and gene editing (e.g., CRISPR-Cas9) are newly emerging as potential treatments for human disease and as a therapeutic for spinal muscular atrophy and Duchenne muscular dystrophy. Indeed, as these therapies become more common, these must be addressed as ethical concerns, such as issues of genetic privacy, risk of genetic discrimination, and unintended consequences of genetic manipulation.

The focus of this review is to give a brief but detailed account of the genetic components of neurological disorders, ranging from rare monogenic diseases to common multifactorial disorders. It describes key genetic discoveries and discusses developing genetic diagnostic and therapeutic strategies and the ethical implications related to these developments. The integration of genetic insights directly into clinical practice has the potential to provide a personal roadmap that could lead to individualizing the diagnostic, treatment and prevention approaches for neurological disorders and enhance patient outcomes.