This e-journal club represents the inaugural edition of a periodic journal club devoted to developmental disabilities which may or may not be accompanied by intellectual disabilities. The Journal Club will be published monthly and will contain 2-6 summaries of recent articles with occasional editorial comments, and each journal club will be devoted to a individual topic.

Journal #3, June 10th, 2012

Health benefits and reductions in bacteria from enhanced oral care

Total esophagogastric dissociation in adult neurologically impaired patients with severe gastroesophogeal reflux: an alternative approach

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Journal #2, January 13th, 2012

The first practical step in the identification of the fragile X syndrome was the observation by Martin and Bell in 1943, that a family existed with a number of members (both males and females) with sex linked intellectual disability. In the late sixties, Lub identified a marker x chromosome which was characterized by a “fragile” portion of the x chromosome that was identified in a group of males with intellectual disability in 1969. The fragile site was identified on the distal portion of the x chromosome. The most distinctive feature of the fragile X syndrome is the increased number of CGG repeats in the allele associated with the full mutation. Folic acid depleted media was used to identify the fragile site during the 1970’s and 1980’s. An international collaborative effort in 1991 led to the sequencing of the gene and the ability to diagnose fragile X by molecular means. The ‘fragile” site or FRAXA is part of the FMR1 gene (the gene is located at the xq27.3 position). During the 1970’s, post-pubertal macro-orchidism was found when many of these patients were examined. Later, other distinctive phenotypic features including a long face, large ears, social anxiety, hyperactivity and hyper laxity of the joints were noted. As mentioned above, the unique genotype associated with the fragile X syndrome includes an excess of “CGG” trinucleotide expansions. Normally the number of CGG repeats is in the range of 6-54, while the number of trinucleotide repeats in the “premutation syndrome” (see below) is in the 54-200 range and the number of repeats in the full mutation is in excess of 200. In the full mutation, the expansion of the trinucleotide repeats is in the first exon of the FMR1 gene and the FMRP protein resulting from the mutation is the abnormal protein. The FMRP down regulates the mRNA interfering with translation. The diagnosis is made by identifying the abnormal FMR1 gene and includes southern blot and PCR testing. Simply identifying the excessive CGG repeats does not correlate well with clinical symptoms, because in high functioning individuals the CGG repeats may occasionally be within the abnormally high range. Full methylation of the cytosine trinucleotide is the major determinant of whether major intellectual disability is present in the full mutation. 1.) All full mutations that are phenotypically expressesed must be fully methylated with the methyl groups attached to th cytosine nucleotides 2.) USUALLY fragile x occurs in a male after a premutation is inherited from a female and in the process of inheritance expands to a full mutation which becomes fully methylated in the process 3.) Thirty percent of females with a full mutation which is fully methylated have intellectual disability or may have shyness, anziety or learning disability.

Regarding transmissiom to her offspring by the female, the more CGG repeats in the female’s genotype, the more likely the offspring is to have a full mutation. A father with a premutation will pass that premutation to his female offspring and it usually does not expand. During the 1970’s, post-pubertal macro-orchidism was found when many of these patients were examined. Later, other distinctive phenotypic features, including a long face, large ears, social anxiety, hyperactivity and hyperlaxity of the joints were noted. The unique genotype associated with the fragile X syndrome thus starts with an excess of “CGG” triplets. The chain of events, beginning with CGG instability, not only leads to the fragile X phenotype, but is the initial genetic mechanism leading to the FRAX opathies (or premutations) with a range of CGG repeats of 54-200. The phenotypic features of the premutation syndrome will be described in the review of article three, the principal ones being the tremor- ataxia syndrome and premature menopause.

The patients with the full mutation may present with features of autism or severe intellectual disability. The majority have mild to moderate intellectual disability. The clinical correlation between the premutation and phenotypic features is not well described in the first article, which was published in 1998, however, most of the phenotypic features associated with the full mutation are. The data above concerning cytogenic features and molecular characteristics described above probably represents a more current version of such features. Therefore, the review of the first article will focus on the phenotypic characteristics of fragile X. The important points from the second article emphasize the differences between the childhood and adult phenotype, while the summary of the third article focuses on the clinical phenotype of those patients with the premutation genotype.

The Fragile X Syndrome

Clinical Report - Health Supervision for Children with Fragile X Syndrome

The FRAXOPATHIES; Definition, Overview, and Update

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Journal #1, November 14th, 2011

The first journal club will be devoted to transition of care of patients with developmental disabilities from pediatricians to internists. This topic will be important to the family practitioners as well, for whom transition to the care of an internist may not be necessary, but the achievement of medical self- advocacy, and transition to medical subspecialists whose expertise may be needed are important. Familiarity with reimbursement and insurance issues which may change when the conversion to adult care occurs is also crucial. When the transition is made, counseling needs which take into consideration the patient’s illness in relation to education and the choice of a career should be discussed with the Internist who will be assuming the responsibility for the patient’s adult care. Most important in the transition from the pediatric to adult care, is that the internist whom the disabled pediatric patient is to see be one who is familiar with the medical problems of young adults with developmental disabilities and is comfortable working with them.

Supporting the Health Care Transition from Adolescence to Adulthood in the Medical Home

The Transition from Pediatric to Adult-Oriented Care: A Challenge to the Patient with Chronic Disease

Following Catastrophic Epilepsy Patients from Childhood to Adulthood

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Clyde E Rapp Jr. MD
Associate Editor for Medicine American Academy of Developmental Medicine and Dentistry