Complex Genetic Disease: Can Genetic Strategies in Alzheimer's Disease and New Genetic Mechanisms Be Applied to Epilepsy?

Summary: Strategies used in molecular genetics have changed modern neurology. The gene or genes responsible for several major neurologic diseases have now been identified using "reverse" or positional genetics. Unexpected new genetic mechanisms have been discovered in human neurologic diseases, including (a) identical mutations of the prion protein gene in Creutzfeldt-Jakob disease and fatal familial insomnia with the phenotypic expression directed by an accompanying polymorphism; (b) stable duplications of chromosome 17 in Charcot-Marie-Tooth disease (type 1 A) that involve many genes, only one of which appears to cause neuropathy; and (c) highly variable, dynamic mutations in myotonic dystrophy, fragile X syndrome, and Kennedy's syndrome that modulate variable expressivity in multiple tissues. There is growing recognition that neurologic diseases are often complex genetic diseases with multifactorial rather than simple modes of inheritance. For example, genetic association/linkage strategies have interacted with biochemistry and immunopathology studies to produce new insights into the disease mechanism of late-onset Alzheimer's disease. The role of apolipoprotein E in late-onset Alzheimer's disease is an example of how new analytical techniques of genetic disease can be applied to dissect multiple genes. Similar research strategies are suggested for the study of epilepsy as a complex disease.     

Infantile autism—fragile X: Molecular findings support genetic heterogeneity

Twenty-two members of 18 families with autism have been examined for the presence of mutations and abnormal methylation in the FMR-1 region at Xq27.3. All patients fulfilled diagnostic criteria of infantile autism. A characteristic pattern of insertion and methylation were detected after Southern blot analysis in 7 autistic individuals expressing the fragile site at Xq27.3. Normal DNA patterns were observed in 15 autistic boys cytogenetically negative for the fragile site. The results indicate a lack of involvement of the FMR-1 region in infantile autists negative for fragile X expression. © 1992 Wiley-Liss, Inc.     

Somatic RET proto-oncogene mutations in sporadic C-cell carcinoma of the thyroid

Summary. Germline mutations of the RET proto-oncogene localized on chromosome 10q11.2 are the underlying cause of hereditary medullary thyroid carcinoma. In MEN 2A and FMTC, mutations can be found in exons 10, 11, 13 or 14. MEN 2B is characterized by a specific mutation in exon 16. In a significant number of sporadic MTC somatic mutations in codon 918 (exon 16) are detectable. Some rare sporadic MTC present somatic mutations in codons 611, 634, 768 and 883. Recently, deletion-insertion of the RET proto-oncogene in exon 11 and a deletion in exon 10 has been found. RET proto-oncogene mutations are not only responsible for the development of the familial MTC, but may also play an important role in the pathogenesis of sporadic MTC. However, the prognostic relevance of these somatic events is still unclear.      

Mutation analysis of Jewish hunter patients in Israel

We have performed molecular and mutation analyses on 14 unrelated Israeli Hunter families and have identified the IDS mutation in 8 of them. Three unrelated Ashkenazi patients had the same previously reported mutation (1246 C→T). Based on the haplotypes of the mutation-bearing chromosomes, we concluded that this is a recurrent mutation. In two patients, we identified a deletion spanning exons V–VII. Three novel mutations were observed in different patients: L410P, 717del4, and 244del3. In addition, the silent mutation (562 C→T) was observed in one patient. © 1994 Wiley-Liss, Inc.     

Molecular staging of head and neck squamous carcinoma

The staging system of head and neck cancer is a Tumor-Node-Metastases system that was developed by the American Joint Committee on Cancer. The stage of the head and neck cancer defines the extent of the lesion and is determined by physical examination, radiologic studies, and pathologic examination. Accurate staging of head and neck cancer is critical since it will determine the treatment modalities used to cure the disease. Recent advances in the field of molecular genetics have allowed clinicians to detect occult cancer cells previously missed by physical examination and standard histopathologic techniques. Molecular assays are 500 times more sensitive in identifying cancer cells than standard techniques and provide more objective analyses with fewer sampling errors. Consequently, these techniques are currently being used to perform molecular staging of head and neck cancer patients. Preliminary results show that molecular staging will accurately identify those patients at significantly increased risk for recurrence of their head and neck cancer.