FRAJIL X SENDROMU PDF

The fragile X mental retardation 1 gene, which codes for the fragile X mental retardation 1 protein, usually has 5 to 40 CGG repeats in the 5′ untranslated. Fragile X is the most common inherited cause of mental retardation with a prevalence of 1 in for males and 1 in to for females.

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The full mutation is the almost always the cause of fragile X syndrome FXS. The prevalence of FXS is about 1 in 4, to 1 in 7, in c general population although the prevalence varies in different regions of the world.

FXS is the most common inherited cause of intellectual disability and autism.

The understanding of the neurobiology of FXS has led to many targeted treatments, but none have cured this disorder. The treatment of the medical problems and associated behaviors remain the most useful intervention for children with FXS. In this review, we focus on the non-pharmacological and pharmacological management of medical and behavioral problems associated with FXS as well as current recommendations for follow-up and surveillance.

FXS was initially described in by Lubs and colleagues 1 and the first fragile X-linked pattern of inheritance was reported by Martin and Bell in 23. The molecular basis of FXS is characterized by the CGG full mutation and methylation of the cytosine bases, which leads to silencing of transcription and deficiency or absence of the encoded protein, Fragile X mental retardation protein FMRP. Usually, expansions occur between generations when passed on by a female with the premutation into a full mutation in the offspring 8.

Preimplantation diagnostic services and in vitro fertilization are also available 10 — Individuals with FXS present with a wide range of learning disabilities ranging from normal functioning to borderline cognition or mild to severe ID. The average Intelligence Quotient IQ of males with the full mutation is 40 Physical manifestations are subtle in infants and young boys.

Young boy with fragile X syndrome and his Go Talk device. Note prominent ears with cupping of the pinnae. The participant’s family provided informed consent for the use of this picture.

Medical problems associated with FXS include mitral valve prolapse, otitis media, seizures, strabismus, joint laxity, sleep disturbances, and gastrointestinal problems.

Boys with FXS are slightly larger than average in weight at birth. The mean birth weight from earlier studies ranges from 3, gms.

Fragile X Syndrome

The mean birth weight of boys aendromu the FXS was in the 70 th percentile, they also had a higher birth drajil than frajll siblings when this was corrected for gestational age and sex The mean birth weight in FXS was increased and the average linear growth was also above the mean for typically developed boys with the greatest increase after the second year of life.

In contrast, the weight measurements were on average below the mean until two years of age. It is suggested that in FXS there is a disturbance of early infantile growth 17 ; however, the overall proportion of infants with low birth weight was similar to that in the general population After birth, the head circumference tends to rise above the 50 th percentile and sendrmou to be larger than those without FXS.

Jacobs drajil noted fraiil in six of nine affected men, the head circumference was sendroku than the 90 th percentile 18but other studies have shown that the mean head circumference 19 — 21 and the mean birth length are not different of those of control population Hagerman and frajill found no difference in the height, weight or head circumference of girls with FXS compared with those without the full mutation Some studies reported that the height of males with FXS is greater than the 50 th percentile and height curves for FXS were higher at nearly every point in the prepubertal section of the curves, but height was lower at postpubertal ages 23 The Prader-Willi phenotype PWP can be observed in FXS and it consists of extreme obesity, sendroum, lack of satiation after meals, small genitalia, delayed puberty, sometimes short stature and stubby hands and feet 26 — Sotos-like syndrome was reported in in two boys with FXS featuring large size at birth, unusual length, large head circumference and minor facial abnormality Structural longitudinal magnetic resonance imaging MRI study of preschoolers with FXS observed generalized brain overgrowth compared to controls, evident at age two and maintained across ages 4—5 The molecular biology of FXS suggests a possible mechanism for brain growth patterns.

Harlow and colleagues have demonstrated that FMRP inhibits the generation of progenitor neurons from glia cells but enhances the glial cell number in mouse cerebral cortex, suggesting that the lack of FMRP, as seen in FXS might result in an increased proliferation of progenitor glial cells and subsequent cerebral cortical overgrowth The presence of early brain differences in young children with FXS points to aberrant early brain development in senddomu condition The results of genetic and regression analysis showed that in both boys and girls, total pubertal height gain is impaired, whereas the rate of growth during the preadolescent period is increased, compared with the growth rate of subjects without FXS.

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Fragile X Syndrome

The study demonstrates the linear effect of progressively reduced levels of FMRP on a number of physical measurements This effect is predictably less strong in females than in the sendrpmu because of sendroomu presence of the second unaffected X chromosome.

The inverse relationship of height and limb length with FMRP deficit supports a possible role of hypothalamic dysfunction in growth disturbances in FXS that may be more severe in those with the PWP sendrom This dysfunction may cause a premature increase in the pulsating secretion of high doses of estrogen, thus leading to earlier epiphyseal maturation The hypothesis of premature activation of the hypothalamic-pituitary-gonadal axis may explain the cause of growth impairment in FXS and senfromu precocious puberty in females with FXS, a few cases have been reported 35 OM is one of the most frequent medical problems associated with FXS.

An ear examination is warranted for any change of behavior and sleep patterns as well other symptoms including fever, vomiting, and headache. Children with FXS commonly develop OM complications including decreased hearing acutely and at least one-fourth develop acute sinusitis.

There is not data reported about the rates of chronic otitis. Recurrent otitis media may cause conductive hearing deficits and exacerbate the cognitive, language, and behavior problems that exist in this syndrome 38 ; therefore, the treatment of OM should be aggressive. Senddromu American Academy of Pediatrics initial recommendation for uncomplicated OM is an observation period for children 6 months to 2 years with unilateral OM without otorrhea and for children older than 2 years with bilateral OM without otorrhea; however, we recommend to consider skipping the observation period and using antibiotic therapy in children with FXS The craniofacial changes frajill FXS including a long face and collapsible Eustachian tubes predispose children to OM infections.

Signs of slight redness, mobility impairments and abnormal positioning of tympanic membrane TM such as retraction or bulging, should be carefully assessed.

A low threshold for early tympanostomy tube placement and antibiotic prophylaxis amoxicillin low dose is also advised. The potential adverse effects of antibiotics, principally allergic reaction and gastrointestinal tract consequences, such as diarrhea are important considerations for tympanostomy tubes over prophylaxis. Multiple studies provide evidence that breastfeeding for at dendromu 4 to 6 months reduces episodes of OM and recurrent OM 40 — Eliminating passive exposure to tobacco smoke could also reduce the incidence of OM in infancy.

In addition, bottles and pacifiers have been also associated with OM 44 — Typically, males have a higher prevalence when compare to females. Studies in the Fmr1 knockout KO mouse shows immature dendritic connections, increased number of long and thin spines which point to the deficiency in the normal selection or pruning of the synaptic contacts that occurs in neuronal development 56 These results demonstrate that FMRP is important in the maturation of adult dendritic spine morphology Immature dendritic connections can predispose the KO mouse to audiogenic seizures, although deficits in gamma amino butyric acid GABA inhibition are also related to the seizures in FXS 59 Similar abnormal dendritic formations are also observed in the brain of humans with FXS and may explain the higher frequency of seizures.

In addition to structural changes, the absence or deficiency of FMRP leads to increased neuronal excitability and susceptibility to seizure Other studies hypothesize that the pathophysiology of seizures in those with FXS can be related to the imbalance of the excitatory and inhibitory neurotransmitter systems 60 It is important to consider frajik many children with FXS have abnormal electroencephalogram EEG without overt seizures 62 In those with overt seizures, all types of seizures can sendromj.

frajil x sendromu

Some studies have shown a predominance of generalized seizures 64secondary generalized seizure and status epilepticus seizure Seizures in FXS may also resemble benign focal epilepsy in childhood with centro-temporal spikes 65 In general, complex partial seizures are the major type of seizure in FXS.

The observed seizures are — typically- not severe and mostly limited to childhood 66 ; however, the presence of seizures at an early age appears to be associated with developmental and behavioral morbidity that can impact brain function. The current practice is to educate parents and follow-up patients closely for any possible episodes of seizure: If seizures are suspected, then it is recommended to obtain an EEG in both the waking and sleeping states It is also important to tell families to avoid soy formulas in young children with FXS because of the recent report of soy formula intake increasing the prevalence of seizures in those with ASD and FXS Seizures are usually easily managed on monotherapy with anticonvulsants.

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Historically, most individuals with FXS have experienced good control with carbamazepine or valproic acid, with fairly limited adverse effects Carbamazepine stabilizes the inactivated state of voltage-gate sodium channels. Its action leaves the affected neuronal cells less excitable.

Testing individuals of other ancestries is not typically performed 70 — Carbamazepine has also the advantage that can be used as a mood stabilizer at a typical dosage The valproic acid mechanism of action is not fully understood, but the reduction of phosphatidylinositol 3,4,5 -trisphosphate PIP3as well as, the blockade of voltage-dependent sodium channels may protect against seizures; the increased brain levels of GABA may contribute to its mood stabilizer properties as well as its antiepileptic mechanism of action.

The most common adverse effects of valproic acid are digestive complaints diarrhea, nausea, vomiting and indigestionvision problems double vision or lazy eyehormonal disturbances increased testosterone production in females and menstrual irregularitieshair loss, memory problems, weight gain, infections, low platelet count, dizziness, drowsiness, tremor and headache 74 The FDA recommends patient testing on the Valproate VP drug label to avoid prescribing the drug to individuals with urea cycle disorders, the information is lacking about what type of genetic testing and how it should be carried out.

Newer studies correlating genotype-phenotype associations with the clinical response will be helpful to increase drug efficacy and to reduce drug-related toxicity For those who failed carbamazepine or valproic acid, lamotrigine can be used as a fairly effective second line. Phenytoin has the adverse effects of gum hypertrophy and can interfere with dental hygiene. Phenobarbital and gabapentin also should be avoided because they exacerbate behavioral problems including hyperactivity Drug-specific blood level testing, liver function studies, electrolytes, complete blood count CBC and general health monitoring should be considered for any child taking anticonvulsant medications Mitral Valve Prolapse MVP, floppy mitral valve is a valvular heart condition that is characterized by the displacement of an abnormally thickened mitral valve leaflet into the left atrium during systole Perhaps this relates to the fact that MVP is more common in adults than children and often cannot be diagnosed by just auscultation.

Careful cardiac auscultation is recommended during every annual physical examination and if a systolic murmur or the classical MVP murmur is detected a mid-systolic click, followed by a late systolic murmur heard best at the apexthen it is recommended to request a cardiology evaluation which should include an echocardiogram Individuals with MVP, particularly those without symptoms, often require no treatment Those rare cases of MVP and symptoms of arrhythmias or dysautonomia may benefit from beta-blockers.

Individuals with MVP are at higher risk of infective endocarditis, approximately three- to eightfold the risk of the general population Beforethe American Heart Association recommended prophylaxis for dental surgery and other invasive procedures that could introduce bacteria into the blood stream. Thereafter, the association determined that individuals with MVP should not receive prophylaxis routinely; prophylaxis for dental procedures should be recommended only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from infective endocarditis Surveillance cardiac evaluations are necessary for those with moderate MVP, in order to evaluate the degree of regurgitation.

In very rare instances when MVP is associated with severe mitral regurgitation, mitral valve repair or surgical replacement may be necessary.

Abnormal elastin fibers have been detected in the cardiac valves and trajil the skin of individuals with FXS so MVP is thought to be related to the connective tissue problems seen in FXS and are related to abnormalities of the elastin fibers Dilation of the aortic root is also seen in many individuals with Sendormu in both childhood and adulthood and this is also associated with abnormal elastin fibers 3558 ; Typically, this is not progressive nor have significant aneurisms been reported.

In summary, MVP carries a very low risk of complications, but in rare severe cases complications may include mitral regurgitation, infective endocarditis and congestive heart failure. Further, larger longitudinal studies that described the prevalence and MVP and its complications are necessary.

Interestingly GI problems have been described to be quite common in other connective tissue disorders, such as Ehlers-Danlos syndrome EDS and Marfan syndrome; such problems include GERD, irritable bowel syndrome, and diarrhea 87 — Even more intriguing is the association of the premutation and irritable seendromu syndrome and the fact that developmental disorders and autism are usually associated with constipation rather than diarrhea as observed in FXS General recommendations should be provided and medication management, such as, thickening agents, antacids, histamine-2 H-2 blockers and proton-pump inhibitors, should be prescribed if necessary.