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Genetics. Fragile X Syndrome and X Linked Disorder

Introduction

Genetic disorders are one of the health problems affected 0.5% of the population. Genetic research in this sphere concentrates on character differences and assumes that proper theory should account for how people and diseases are similar as well as different, and that personal variation is the basis for evolutionary process. In general, traditional methods of behavior genetics have included twin, adoption, and family studies, all directed to partitioning the observed variation of behavioral traits into components associated with a variety of categories of genetic and environmental influence. Environmental power in turn is divided into shared (e.g., with other family issues) and unshared types (e.g., independently distinct experience). Such work has developed a strong case for the significance of genetic factors in the complex behaviors/traits involved in normal and abnormal cognition and behavior. The aim of the paper is to investigate Fragile X-Linked Disorder and the Fragile X Syndrome, compare and contrast them. It is important to recognize that in contrast to genetic analyses of behavior, molecular genetic studies focus on locating genes on specific chromosomes and mapping them relative to other genes on that chromosome (Abrams et al) 2004. Once specific genes (X or Y) are localized they can be isolated and cloned and their function determined. Earlier molecular genetic studies relied largely on a single-gene, single-disorder approach. It is now apparent that such single-gene alterations are to be uncommon, because multiple genes generally contribute to complex behavioral traits. As a result, interest now focuses on personal genes that act in sets, each member of which contributes a part of the genetically determined difference of the trait.

Comparison and Contrast to Genetic Characteristics

The Main Genetic Characteristics of the Fragile X-Syndrome

Fragile X Syndrome can be characterized as syndromes involving cognitive deficits linked to genes on the X chromosome occur in about 1/600 live births and are believed to account for 20% to 30% of all such abnormalities. Fragile X syndrome is considered the most frequent of genetic diseases; Fragile X syndrome represents approximately 30% of all X-linked forms, is the most commonly occurring single gene form, and occurs in 1/1,250 males and 1/2,500 females. Males with Fragile X syndrome often exhibit characteristic physical features and actions; affected women show a similar but less severe phenotype. Fragile X syndrome involves a chromosome abnormality, which is characterized by a marker for an unusual type of mutation, rather than the direct cause of the deficit. It is the loss of function of a single mutated gene, located in a fragile site on the distal portion of the long arm of the X chromosome that produces Fragile X syndrome. Although Fragile X syndrome is transmitted as an X chromosome-linked trait, two phenomena associated with this syndrome remained puzzling for many years. First, 20% of male obligate carriers of the mutation are unaffected, yet transmit the trait to their grandsons (Reiss and Freund, 2004). Also, the degree to which a trait is expressed in each generation is dependent on position in the pedigree and appears to increase in successive generations. The latter phenomenon, termed “anticipation” is linked with decreased age of onset and increased severity of certain inherited diseases. The phenomenon of anticipation is uniquely associated with an unusual type of gene mutation termed triplet (or trinucleotide) repeat expansion mutations. Triplet replicate expansion mutations in different genes are now known to cause 14 different diseases involving the nervous system. The nature of the triplet repeat expansion and its consequences leads to Fragile X syndrome (Zigler, 2007).

The Main Genetic Characteristics of the X-Linked Disorder

Fragile X-Linked Disorder, characterized by an extra X chromosome, is one of the most frequent sex chromosome abnormalities seen in males, with an estimated occurrence rate in the general population of 1/1,000 males. The most common observed karyotype is the 47, XXY pattern, although mosaic and variant (i.e., XXXY) karyotypes also exist in a small fraction of cases (10%). Roughly 50% of X-Linked Disorder cases occur during maternal meiosis, with a significant fraction of these reported to show effects of maternal age. In contrast to the other syndromes previously described, to date there have not been dedicated and systematic attempts to identify genes or regions on the X chromosome, whose copy number of two in the presence of a Y chromosome contributes to the phenotype. Because of the common occurrence of this syndrome, together with discovery of the genetic mechanism of the extra X chromosome in the 1960s, Fragile X-Linked Disorder is by now a well-studied disorder, with large-scale prospective studies of developmental outcome. In Fragile X-Linked Disorder, physical features may not be apparent at birth, physical development is typically normal, and, though clinical evaluation of hypospadias and microphallus may result in early diagnosis, many persons may not be diagnosed until adolescence (Hagerman, 2001).

Differences and Similarities

It is found that the mutation associated with both the phenotype and the associated fragility of the X chromosome bearing it was found to consist of an increased number of a normally repetitive three-base sequence (the triplet CGG: cytosine, guanine, guanine) in a proximal portion of the FRM1 gene not translated into a protein product. Normal people possess 6 to 42 tandem repeats with an average of about 30 repeats. Expansion of the repeat number to > 200, termed a “full mutation, ” is invariably associated with MR in males; in some people, thousands of CGG repeats occur in this region of the FMR1 gene. Because this disorder involves the X (sex) chromosome, there are main gender differences in phenotype among people having the full mutation, with men being more severely affected than females. This results from men having only a single copy of genes on the X chromosome, whereas females receive two X chromosomes and have one mutant and one nonmutant allele when they receive the mutation. About 20% of males carrying the Fragile X- Syndrome abnormal gene are unaffected, but these “normal transmitting” males pass on the mutation, relatively unchanged in size, to all of their daughters (Goodman, 2008).

Similar to Fragile X Syndrome, X-Linked Disorder characteristics are typically noted with delayed puberty (e.g., lower testosterone production, small testes, breast enlargement, absent or diminished growth of hair, absence of voice changes). In addition to the genital abnormalities, X-Linked Disorder males tend to be taller than their cohorts with proportionately longer legs and have smaller head circumferences and slightly altered craniofacial structure. Additional features include poor weight gain through childhood; delays in gross and fine motor skills, coordination, speed, dexterity, and strength; impaired hearing thought to be associated with frequent childhood respiratory tract infections; and insulin resistance, with associated higher risk of diabetes (Goodman, 2008).

In patients with Fragile X-Syndrome one of the two X chromosomes is inactivated permanently during early embryogenesis in women. Cells receiving the inactivated chromosome express none of the genes carried on that chromosome; this process is random with regard to the maternal or paternal origin of the X chromosome. Therefore, females heterozygous for a full mutation will be mosaics. By chance, some females will have greater numbers of cells in which the nonmutant X chromosome is inactivated; others will have higher populations of cells in which the X chromosome bearing the FMR1 full mutation is inactivated. Approximately 50% to 70% of females who have the mutation show milder intellectual deficits and specific learning disabilities, with IQ in the borderline to mild MR range. In contrast, females with repeat numbers in the range of 43 to 199 may be phenotypically normal but are carriers of the Fragile X syndrome “premutation” (Goodman, 2008). This premutation can be transmitted without alteration in repeat number, but often expands to the full mutation when transmitted to the next generation. The risk of a Fragile X premutation carrier transmitting the full mutation to his or her children is dependent on gender; that is, expansion to a full mutation occurs much more frequently when the carrier is women, and is proportional to the repeat number (Zeaman and House, 2007).

Prognosis and Diagnosis

With regard to Fragile X-Syndrome diagnosis the fragile site (FRAXA) can be detected in significantly affected persons by standard cytogenetic testing, standard karyotyping does not identify unaffected carriers of the FMR1 gene. Newer molecular research employing polymerase chain reaction (PCR) technology now make it possible to genotype persons for their repeat number in the FMR1 gene (Volpe 2006). Thus, those with a family history of Fragile X Syndrome (though they may have tested negative on standard testing) should be reevaluated with the more recent DNA method to determine carrier (Reiss and Freund, 2004).

In contrast to autosomal chromosome differences such as Down syndrome, the sex chromosome disorders like X-Linked Disorder typically have a much less profound effect on cognitive development, if present, tends to be mild. However, genotypes including > 2 X chromosomes occur rarely, and, as the number of X chromosomes increases beyond 2, the likelihood of mental retardation and its severity increases. Most Fragile X Syndrome males have low average to normal intelligence, although global IQ is typically lowered due to decreased verbal abilities. Researchers report a mean Full-Scale IQ of 95.6 for these males (Verbal IQ mean of 91 and Performance IQ of 101), illustrating the characteristic weakness in verbal abilities seen in X-Linked Disorder. This cognitive phenotype also includes language deficits and significant academic difficulties. Speech and language delays as well as associated language-based learning disabilities are characteristic of -Linked Disorder. A prospective, 20-year longitudinal study of achievement indicated grade repetition in the majority, special education for 60% to 80%, and increased rates of specific learning disabilities in most -Linked Disorder males, particularly in reading, spelling, and written language. Frequently reported auditory processing difficulty and poor short-term memory impact the amount and accuracy of information acquired and underscore the specific learning impairments (Lander and Schork, 2004). Although many of these males graduate from high school, by the end of high school, they may remain as much as five years behind their peers in math and reading skills. With regard to the behavioral phenotype in -Linked Disorder, it should be underscored that much of the research on personality types prior to 1990 presented a significantly flawed characterization of X-Linked Disorder males as having increased aggressiveness, criminal behavior, and psychotic tendencies (based on studies of institutionalized people) (Reed and Reed 2006). More recent and improved studies suggest such features as low activity levels, low endurance and drive, diminished self-confidence and self-esteem, dependence on parents, emotional immaturity, shyness and reticence, passivity, low sexual activity, anxiety, and social stress. The most common presenting problems of the X-Linked Disorder males are poor peer relationships, underachievement in school, impulsivity, aggressiveness, withdrawal, apathy, and immaturity. Reports of inattention, difficulty concentrating, and decreased motivation have suggested either attention-deficit disorder or, conversely, a more basic difficulty in processing auditory information (Lubs 2006). A high-risk profile for children with sex chromosome disorders, including difficulty communicating with peers, low achievement, behavioral immaturity, and social isolation, often as a function of teasing by peers. Although sexual identity is typically male, their differences in psychosexual development place adolescent -Linked Disorder males at risk for associated problems with body image and social withdrawal (Harris, 2006).

In Fragile X-Disorder, the FMR1 gene is now known to encode a protein that appears to play a crucial role in the production of adequate amounts of proteins derived from a subset of genes expressed in the brain during fetal development. The FMR1 protein binds messenger RNAs from specific genes and can also bind to proteins on the large subunit of ribosomes. FMR1 protein is found both in the nucleus and cytoplasm. It is hypothesized that the FMR1 gene product acts as a shuttle to move specific mRNAs from the nucleus into the cytoplasm and facilitates their binding to ribosomes for translation into proteins. Thus, it can be viewed as a kind of translation factor for the expression of a family of products from different genes. It is now experimentally established that the expansion of the region beyond 200 repeats stops the production of the FMR1 protein. Full mutations cause chemical alteration of the DNA in a region of the FMR1 gene (the promoter), which prevents its transcription into messenger RNA. This type of mutation accounts for nearly all Fragile X- Syndrome patients (Tager-Flusberg, 2006). Thus, the loss of the FMR1 gene product leads to a relative deficiency of other gene products during prenatal development of the brain, which in turn results. Investigations of brain anatomy have further elucidated Fragile-X Syndrome; imaging studies have typically shown greater brain volume in Fragile-X Syndrome adults, with increased volume of the hippocampus, caudate nucleus, thalamus, and in males, the lateral ventricles. Such findings are likely associated with such behavioral characteristics as hyperarousal and problems with executive functioning (Warren, 2004).

In X-Linked Disorder, facial features in males often include a long, narrow face, prominent ears, and frequently prominent forehead and jaw; however, some of these features, in addition to macro-orchidism (enlarged testes) are frequently not observable until middle childhood or puberty. Other related features include connective tissue dysphasia, cardiac valve prolapse (heart murmur), recurrent otitis media, flat feet, and hyperextensible joints (Baron-Cohen et al 2006). Variability in growth curves is frequently observed, with leveling of height and increase in weight at adolescence. Females with either the full mutation or the premutation have few of the physical features seen in males, except for the occasional presence of prominent ears. A Physical Index has been developed to assess the number of physical features present in a person with Fragile-X Syndrome, and this has been found to correlate with the degree of involvement in the DNA and the level of FMR1 gene protein measured in the blood (Baron-Cohen et al 2007).

Sensory and/or sensory integration difficulty has been noted in many Fragile-X Syndrome children, including hypersensitivity to sound, light, or texture, tactile defensiveness, and associated feeding and sleeping problems. As mentioned previously, IQ is related to both type of mutation and gender, and ranges from borderline/low average (10%) to mild/moderate cases (60%) and severe cases (30%) (Santos, 1992). Women with the full mutation and normal IQ typically demonstrate learning disabilities, particularly in math, and often have poor attention and organizational abilities. Such associated weaknesses in sensorimotor and auditory processing may be consistent with related speech and language problems, including word retrieval, dysfluency, and perseveration/echolalia, as well as delayed development of syntactic, semantic, and pragmatic features of language. A particular interest related to the Fragile-X Syndrome cognitive phenotype is the question of cognitive decline with age: mental age in Fragile-X Syndrome appears to level off, with consequent decline in IQ. However, such reported changes in the developmental trajectory of Fragile-X Syndrome persons remain somewhat controversial because of methodological problems inherent in these studies (combining data across different intelligence tests; the occurrence of specific cognitive deficits that may be confounded with the task demands of particular IQ tests at particular ages). Because most investigations of this question involve retrospective studies, a multisite, prospective, longitudinal study is of particular interest. Of males (age 3 to 15) who were evaluated with the Stanford–Binet (fourth edition) and Vineland Adaptive Behavior Scales, declines in IQ scores were found in 75%, with 4 showing no change. Though adaptive scores were higher than IQ scores (83%), declines in adaptive scores were also noted (92%). Decreases in IQ scores appeared to follow a well-defined, negatively decelerating function, with steeper declines in DQ suggesting a slower rate of development rather than a regression of intellectual and social skills (Bishop, 2005).

Numerous genetic research studies of men have suggested poor self-control, including symptoms of short attention span and hyperactivity (though not more frequently than in other persons). Problems with social relatedness, shyness, and characteristic gaze avoidance are frequent, and such socialization problems have suggested some degree of overlap with the autistic spectrum disorders. Although a number of studies in the 1980s attempted to determine whether Fragile X- Syndrome may represent a genetic etiology of autism, most such studies were plagued with methodological weaknesses. Several studies have examined populations of autistic persons for the Fragile X chromosome or the FMR1 mutation. Overall, approximately 6% of males with autism are positive for Fragile-X Syndrome, with 15% of males with Fragile-X Syndrome fulfilling DSM-III criteria for autism, underscoring the importance of DNA studies for Fragile-X Syndrome in persons with autism of unknown etiology. At present, the evidence suggests that, although a large fraction of Fragile-X Syndrome males exhibit various combinations of autistic like behaviors and traits (i.e., rocking, hand flapping, perseveration), such behaviors often decrease in frequency or severity and have been shown to be qualitatively different from matched autistic controls (Opitz and Sutherland 2005). Thus, most Fragile-X Syndrome persons do relate to others, are attached to their caregivers, do not show the profound indifference to people that is characteristic of autism, yet most show more subtle problems of social relatedness. With regard to females, many show emotional vulnerabilities both similar to and different from males. The characteristic shyness is frequently observed in carrier females with average IQ, who have been found to have a personality pattern of internalizing disorders and withdrawal. Aside from the internalizing symptoms seen in males, some studies have indicated a higher incidence of anxiety disorders, changes of mood, and depression in adult females with the premutation, suggesting a possible biological predisposition for internalizing problems in these persons as well (Filipek, 2004).

Critical Evaluation of Treatment: Fragile X-Syndrome and X-Linked Disorder

Clinical management of patients with Fragile X-Syndrome involves the integration of medical, behavioral, and educational approaches, underscoring the need for multidisciplinary services. For the young child with tantrums, hyperactivity, and labile mood, stimulant medications have been beneficial in some, but exacerbate problems in others. Speech and language services are often needed to address such problems as perseveration, word retrieval, and dysfluency, and sensory integration and occupational therapy can be helpful in decreasing hyperarousal. People with Fragile-X Syndrome can often be educated in an inclusion setting in the regular classroom, with special education support (Ernst and Rumsey, 2005). The nature of the generalized delays, coupled with specific difficulty with auditory sequential processing, typically require targeted approaches to instruction. Techniques involving simultaneous processing strategies, for example, whole word approaches used initially in reading instruction, have been recommended. Psychological interventions would typically also be targeted toward educating parents and educational personnel about both cognitive and psychosocial characteristics for additional information regarding management) (Lehrke 2006).

Similar to X-Linked Disorder, treatment of X-Linked Disorder is more complex. Because a large proportion of X-Linked Disorder males are not diagnosed early, many come to attention because of their school-related difficulties. Thus, males exhibiting characteristic learning difficulty, together with X-Linked Disorder physical features, should be referred for genetic workup, as early diagnosis and multidisciplinary intervention plans are important for optimal outcome in these males. Treatment with testosterone has resulted in X-Linked Disorder males being less tired, having improved mood, experiencing more drive, and having an increased ability to work and concentrate. Psychological intervention is often warranted in persons because of their lowered self-esteem, social withdrawal, and adjustment difficulties (McKusick 2007). Finally, guidelines for educational management include speech and language and special education services to include emphasis on vocabulary, sentence structure, comprehension, and word finding, as well as the related reading and written language difficulties. Additional studies related to genotype have shown more frequent delays in motor and speech development in monosomic X males than the other karyotypes. In contrast, monosomic X males have been shown to be more sociable and extroverted, more even-tempered, and more emotionally stable than girls of the mosaic type (Montagu 2007).

The main difference between X-Linked Disorder and Fragile X-Syndrome is that the relative prevalence of Fragile-X Syndrome, as well as the considerable impact of this syndrome on a Fragile-X Syndrome women’s life, highlight the importance of effective interventions. Medical management of short stature and the development of secondary sexual characteristics typically involve both growth hormone and estrogen replacement therapy. Related genetic studies of psychosocial functioning of a sample of these women suggested reduction in ratings on both internalizing and externalizing scales, with specific recommendations that the comprehensive treatment of females should include educational and behavioral interventions. Estrogen replacement therapy has also become standard in medical management, with some reports that it may have positive effects on nonverbal processing speed and motor function, but with additional evidence that it may be associated with the occurrence of anorexia nervosa in some young adult females (Penrose 2008). Although most Fragile-X Syndrome women are infertile, pregnancy is possible in about 2% of cases with particular genotypes. Visuospatial deficits and accompanying learning disability need to be addressed through the use of special education services; such educational management should optimally occur before difficulties develop at school. The frequent problems with social interaction likely reflect social cognitive deficits, difficulty reading social cues, and not knowing how to interact with others, suggesting the need for intervention. Support involving both same-age girls and opportunities to meet older females as “mentors” may assist adjustment, as well as provide support to parents (Reiss and Freund, 2004).

Conclusion

The analysis of two genetic disorders shows that there are a lot of similarities between these disorders but they differ in physical and psychological manifestations. This explosion of genetic research has generated high interest in the public media as well as considerable controversy in the scientific and clinical communities, for example, refueling the nature-nurture debate and charges that such work vastly oversimplifies extremely complex social behavior. Candidate genes are ones whose map positions and functions are known and for which the function of the gene can be plausibly related to the behavior in question (e.g., genes encoding receptors for neurotransmitters through which therapeutic drugs for a psychiatric disorder are known to act). Positional cloning of the chromosomal region of interest is then undertaken with the goal of determining how mutant alleles in the gene of interest alter the function of its product, which in turn alters brain function.

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