Advances in molecular genetics have revolutionized the diagnosis of neurogenetic disorders. In the past, diagnosis was based on clinical features, neuroradiologic studies, and biochemical tests for gene products or the effects of its absence. All these methods have many limitations. One of the first neurologic applications of molecular diagnostics was the diagnosis of Duchenne muscular dystrophy by identification of dystrophin, the protein product of Duchenne muscular dystrophy gene. Special techniques for diagnosis are described briefly and various neurogenetic disorders that can be diagnosed by molecular methods are listed. One important advantage is that diagnosis can be made in advance of the clinical manifestations. High specificity of molecular diagnostics also enables screening of large populations for carriers.
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• Advances in the molecular biology of genetic disorders, and identification of gene mutations have enabled molecular diagnosis of these disorders.
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• Molecular diagnostics are important for screening and as adjuncts to clinical diagnosis of neurogenetic disorders.
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• Next generation sequencing, by expanding identification of rare mutation in genetically heterogenous diseases, will improve management and gene therapy of neurogenetic disorders in the era of personalized medicine.
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• Prenatal application of molecular diagnostics to in vitro fertilization procedures helps to exclude the risk of transmission of an X-linked disease.
Historical note and terminology
A neurogenetic disorder is defined as a disease caused by a defect in 1 or more genes that affect the differentiation and function of neuroectoderm and its derivatives. There are 2 types of neurogenetic disorders. Type 1 neurogenetic disorders include those resulting from malfunction of genes expressed in the neuroectoderm. Most of the classic inherited disorders belong to this category. Type 2 neurogenetic disorders are those in which neurologic manifestations are caused indirectly by the abnormal function of a gene not expressed in the nervous system. Type 2 includes metabolic diseases with neurologic manifestations as well as cerebrovascular and cranial malformations.
The field of molecular genetics has revolutionized the diagnosis of neurogenetic disorders. In the past, diagnosis was based on clinical features, neuroradiologic studies, and biochemical tests for gene products or the effects of its absence. Clinical features can be ambiguous and may take years to evolve. Radiologic findings are nonspecific. Biochemical tests are expensive and often give equivocal results. The traditional approaches had severe limitations for prenatal diagnosis and the identification of carriers. One of the first neurologic applications of molecular diagnostics was the diagnosis of Duchenne muscular dystrophy by identification of dystrophin, the protein product of Duchenne muscular dystrophy gene (23). The Huntington disease gene was mapped to the short arm of chromosome 4 using linkage analysis by polymorphic DNA markers (21), but it was not until a decade later that the Huntington disease gene was cloned and the mutation containing an unstable trinucleotide repeat was localized within a gene in the 4p16.
From an etiologic point of view, most of the neurogenetic disorders fall into the following categories:
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• Single gene disorders, autosomal, or X-linked
• Multifactorial disorders. The interaction between epigenetic/environmental factors and multiple genes
• Chromosomal abnormalities
• Unknown etiology
Both environmental factors and genetic predisposition contribute to cause birth defects. Congenital malformations of the nervous system frequently arise sporadically, making it difficult to determine whether they are genetic in origin, let alone which gene or genes may be involved. Rapid progress has been made during recent years in the localization and identification of gene mutations in specific malformations. Adult-onset genetic disorders are usually due to slow accumulation of toxic substances, slow tissue death, or inability to repair DNA damage. With new molecular genetics techniques an understanding of the molecular pathology of the disease is not essential for diagnostic or predictive tests. In adult-onset disorders it is difficult to distinguish low penetrance (low expression of an inherited gene mutation) from absence of disease state. If the individual lives long enough, this may approach 100%. However, an individual carrying the disease-related gene may never develop the manifestations of the disease.
Some neurodevelopmental genetic disorders may be caused by aberrant DNA methylation, leading to dysregulated genome function (02). Therefore, epigenetic variations have diagnostic relevance in unexplained genetic disorders.
Most of the molecular diagnosis tests are performed in clinical laboratories by specially trained personnel. Next generation sequencing is now widely available at affordable prices. The neurologists should know the basics of these tests, including the indications and advantages for decision to refer patients for such tests.