ABSTRACT
OBJECTIVE: To define the clinical, radiologic, and genetic features of periventricular heterotopia (PH) with Ehlers-Danlos syndrome (EDS). METHODS: Exonic sequencing and single stranded conformational polymorphism (SSCP) analysis was performed on affected individuals. Linkage analysis using microsatellite markers on the X-chromosome was performed on a single pedigree. Western blotting evaluated for loss of filamin A (FLNA) protein and Southern blotting assessed for any potential chromosome rearrangement in this region. RESULTS: The authors report two familial cases and nine additional sporadic cases of the EDS-variant form of PH, which is characterized by nodular brain heterotopia, joint hypermobility, and development of aortic dilatation in early adulthood. MRI typically demonstrated bilateral nodular PH, indistinguishable from PH due to FLNA mutations. Exonic sequencing or SSCP analyses of FLNA revealed a 2762 delG single base pair deletion in one affected female. Another affected female harbored a C116 single point mutation, resulting in an A39G change. A third affected female had a 4147 delG single base pair deletion. One pedigree with no detectable exonic mutation demonstrated positive linkage to the FLNA locus Xq28, an affected individual in this family also had no detectable FLNA protein, but no chromosomal rearrangement was detected. CONCLUSION: These results suggest that the Ehlers-Danlos variant of periventricular heterotopia (PH), in part, represents an overlapping syndrome with X-linked dominant PH due to filamin A mutations.
Subject(s)
Brain/abnormalities , Contractile Proteins/deficiency , Ehlers-Danlos Syndrome/genetics , Microfilament Proteins/deficiency , Point Mutation , Sequence Deletion , Adolescent , Adult , Amino Acid Substitution , Child , Chromosomes, Human, X/genetics , Contractile Proteins/genetics , Contractile Proteins/physiology , DNA Mutational Analysis , Ehlers-Danlos Syndrome/pathology , Epilepsy/etiology , Exons/genetics , Female , Filamins , Humans , Infant , Magnetic Resonance Imaging , Male , Microfilament Proteins/genetics , Microfilament Proteins/physiology , Microsatellite Repeats , Middle Aged , Mutation, Missense , Pedigree , Phenotype , Polymorphism, Single-Stranded ConformationalABSTRACT
Progress in DNA diagnostics has been extremely rapid. We sought to determine attitudes, awareness, and knowledge of genetic testing by physicians affiliated with the Mount Sinai Medical Center. We surveyed 363 physicians within whose fields genetic testing for various diseases and disorders exist. Physicians' awareness of and opinions regarding testing, attitudes toward counseling, knowledge of the field, and interest in further education were assessed. Three hundred forty-one (341) physicians were determined to be eligible for the study and, of these, 89 (26%) returned completed surveys. Of the respondents, 71% rated their knowledge of genetics and genetic testing as "fair" to "poor"; only 37% read articles concerning genetic testing on a regular basis. Physician awareness of currently available testing produced a bell-shaped distribution. Knowledge regarding Mendelian genetics yielded a bimodal distribution, and knowledge reflecting an understanding of the mechanics behind genetic testing produced a bell-like curve, skewed to the right. Those who identified themselves as practicing within an "academic" setting scored significantly higher on the Mendelian genetics and testing mechanics sections than those practicing in a "private" setting. Ninety-eight percent (98%) of the physicians said they would refer their patients to a genetic counselor. Although 91% of the respondents were aware of the existence of genetic counseling services, only 71% were aware of the services available at major New York medical centers. Of those aware of counseling services, 53% had referred a patient to them, and 83% of those who referred were "mostly" to "very" satisfied with the counseling. Ninety-five percent (95%) of the physicians believed that the doctor, among others, has the responsibility to counsel patients about genetic testing, yet only 51% felt that they had the time. No statistically significant preference was found concerning the methods for gaining further education or information about genetic testing. Further education for physicians is required in order for them to accurately convey the risks and benefits of genetic testing to their patients. Furthermore, awareness of the counseling services available within the New York area needs to be heightened in order to provide physicians and patients with the specific services they desire. The most efficient and effective methods for providing information and for heightening awareness need to be determined through additional research.
