Reelin central fragment supplementation improves cognitive deficits in a mouse model of Fragile X Syndrome.

Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and is characterized by autistic behaviors, childhood seizures, and deficits in learning and memory. FXS has a loss of function of the FMR1 gene that leads to a lack of Fragile X Mental Retardation Protein (FMRP) expression. FMRP is critical for synaptic plasticity, spatial learning, and memory. Reelin is a large extracellular glycoprotein essential for synaptic plasticity and numerous neurodevelopmental processes. Reduction in Reelin signaling is implicated as a contributing factor in disease etiology in several neurological disorders, including schizophrenia, and autism. However, the role of Reelin in FXS is poorly understood. We demonstrate a reduction in Reelin in Fmr1 knock-out (KO) mice, suggesting that a loss of Reelin activity may contribute to FXS. We demonstrate here that Reelin signaling enhancement via a single intracerebroventricular injection of the Reelin central fragment into Fmr1 KO mice can profoundly rescue cognitive deficits in hidden platform water maze and fear conditioning, as well as hyperactivity during the open field. Improvements in behavior were associated with rescued levels of post synaptic marker in Fmr1 KO mice when compared to controls. These data suggest that increasing Reelin signaling in FXS could offer a novel therapeutic for improving cognition in FXS.

Lovastatin, not Simvastatin, Corrects Core Phenotypes in the Fragile X Mouse Model.

The cholesterol-lowering drug lovastatin corrects neurological phenotypes in animal models of fragile X syndrome (FX), a commonly identified genetic cause of autism and intellectual disability (ID). The therapeutic efficacy of lovastatin is being tested in clinical trials for FX; however, the structurally similar drug simvastatin has been proposed as an alternative due to an increased potency and brain penetrance. Here, we perform a side-by-side comparison of the effects of lovastatin and simvastatin treatment on two core phenotypes in Fmr1-/y mice versus WT littermates: excessive hippocampal protein synthesis and susceptibility to audiogenic seizures (AGSs). We find that simvastatin does not correct excessive hippocampal protein synthesis in the Fmr1-/y hippocampus at any dose tested. In fact, simvastatin significantly increases protein synthesis in both Fmr1-/y and WT. Moreover, injection of simvastatin does not reduce AGS in the Fmr1-/y mouse, while lovastatin significantly reduces AGS incidence and severity versus vehicle-treated animals. These results show that unlike lovastatin, simvastatin does not correct core phenotypes in the Fmr1-/y mouse model.

GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Behavioral Deficits in the Fmr1 Knockout Mouse Model of Fragile X Syndrome.

Fragile X syndrome is a genetic condition resulting from FMR1 gene mutation that leads to intellectual disability, autism-like symptoms, and sensory hypersensitivity. Arbaclofen, a GABA-B agonist, has shown efficacy in some individuals with FXS but has become unavailable after unsuccessful clinical trials, prompting interest in publicly available, racemic baclofen. The present study investigated whether racemic baclofen can remediate abnormalities of neural circuit function, sensory processing, and behavior in Fmr1 knockout mice, a rodent model of fragile X syndrome. Fmr1 knockout mice showed increased baseline and auditory-evoked high-frequency gamma (30-80 Hz) power relative to C57BL/6 controls, as measured by electroencephalography. These deficits were accompanied by decreased T maze spontaneous alternation, decreased social interactions, and increased open field center time, suggestive of diminished working memory, sociability, and anxiety-like behavior, respectively. Abnormal auditory-evoked gamma oscillations, working memory, and anxiety-related behavior were normalized by treatment with baclofen, but impaired sociability was not. Improvements in working memory were evident predominantly in mice whose auditory-evoked gamma oscillations were dampened by baclofen. These findings suggest that racemic baclofen may be useful for targeting sensory and cognitive disturbances in fragile X syndrome.

Auditory and visual cortical activity during selective attention in fragile X syndrome: a cascade of processing deficiencies.

OBJECTIVE: This study examined whether attention deficits in fragile X syndrome (FXS) can be traced back to abnormalities in basic information processing. METHOD: Sixteen males with FXS and 22 age-matched control participants (mean age 29 years) performed a standard oddball task to examine selective attention in both auditory and visual modalities. Five FXS males were excluded from analysis because they performed below chance level on the auditory task. ERPs were recorded to investigate the N1, P2, N2b, and P3b components. RESULTS: N1 and N2b components were significantly enhanced in FXS males to both auditory and visual stimuli. Interestingly, in FXS males, the P3b to auditory stimuli was significantly reduced relative to visual stimuli. These modality differences in information processing corresponded to behavioral results, showing more errors on the auditory than on the visual task. CONCLUSIONS: The current findings suggest that attentional impairments in FXS at the behavioral level can be traced back to abnormalities in event-related cortical activity. These information processing abnormalities in FXS may hinder the allocation of attentional resources needed for optimal processing at higher-levels. SIGNIFICANCE: These findings demonstrate that auditory information processing in FXS males is critically impaired relative to visual information processing.

Folic acid for fragile X syndrome.

BACKGROUND: It has been argued that individuals with fragile X syndrome could have low folate levels in their bodies and that supplementing their dietary intake might remediate the adverse developmental and behavioural effects of the condition. OBJECTIVES: To review the efficacy and safety of folic acid in the treatment of people with fragile X syndrome. SEARCH STRATEGY: We searched four databases in November 2010: CENTRAL, PubMed, EMBASE and PsycINFO. SELECTION CRITERIA: Randomised controlled trials. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias using the Cochrane 'Risk of bias' tool. MAIN RESULTS: We included five trials, which were published between 1986 and 1992. Overall, they included 67 patients, all male, with ages ranging from one to 54 years. Intellectual disability in participants varied from borderline to severe and some studies included patients with an additional diagnosis of autism or autistic behaviour. Four of the studies were placebo-controlled cross-over trials and one study was a parallel design. The duration of follow-up ranged from two months to 12 months and the period on folic acid or placebo ranged from two to eight months. Doses of folic acid ranged from 10 mg to 250 mg per day, 10 mg per day being the most common. Most of the younger patients involved were also taking part in special education programmes (usually involving language and occupational therapy).We were not able to perform meta-analysis to combine results but none of the individual studies found evidence of clinical benefit with the use of folic acid medication in fragile X syndrome patients on any of the areas of interest, either psychological and learning capabilities or behaviour and social performance, as measured with standardised tools. Separate analysis of evidence for patients of different age groups, i.e. prepubertal children and postpubertal young people, found some statistically significant results, but did not show clear evidence of benefit for either group. Adverse effects of folic acid treatment were rare, not serious and transient.Studies were generally poorly reported and we classified only one study as being at low risk of bias. AUTHORS' CONCLUSIONS: The quality of available evidence is low and not suitable for drawing conclusions about the effect of folic acid on fragile X syndrome patients. It consists of few studies with small samples of patients, all of them male, with little statistical power to detect anything other than huge effects.

Onset of late posttraumatic seizure after dehydroepiandrosterone treatment.

OBJECTIVE: To describe the first reported case of a seizure in a patient using the dietary supplement DHEA in an attempt to improve ovarian oocyte production. DESIGN: Case report. SETTING: University-affiliated teaching hospital, neurologic department. PATIENT(S): A 30-year-old woman with fragile X syndrome and no history of any convulsive disorder who was receiving IVF treatment. INTERVENTION(S): Daily treatment with the dietary supplement DHEA. MAIN OUTCOME MEASURE(S): Generalized seizure. RESULT(S): After 1 month of DHEA treatment, the patient was admitted with a generalized seizure. CONCLUSION(S): A generalized seizure, associated with concurrent intake of DHEA.

Tratamiento del estreñimiento crónico grave mediante la técnica del enema anterógrado continente / Treatment of severe chronic constipation through the antegrade continent enema procedure

La técnica del enema anterógrado continente fue descrita por primera vez por Malone en 1990 para el tratamiento de la incontinencia fecal grave de origen neurogénico en niños, y posteriormente se ha utilizado con éxito también en adultos y en pacientes con estreñimiento que no responde al tratamiento médico. El procedimiento consiste en la formación de un conducto continente, generalmente una apendicostomía, que permita la cateterización intermitente para la irrigación y la limpieza rápida y controlada del colon. Presentamos el caso de un paciente de 23 años con estreñimiento grave y encopresis al que se le practicó una apendicostomía. No hubo complicaciones postoperatorias inmediatas y las irrigaciones se iniciaron con suero salino el cuarto día después de la intervención. Desde entonces, el paciente realiza deposiciones entre 1 y 3 h después del lavado, ha recuperado la continencia y ha dejado de llevar pañales (AU)

The antegrade continent enema procedure was first described in 1990 by Malone for the treatment of severe fecal neurogenic incontinence in children. Since then, this technique has been successfully carried out in adults, as well as in patients with refractory constipation. The procedure provides a continent and catheterizable channel, generally an appendicostomy, through which antegrade washouts are given to produce colonic emptying. We describe the case of a 23-year-old man with severe constipation and overflow fecal incontinence who underwent an appendicostomy. There were no immediate postoperative complications and saline washouts were started on the fourth day. Since then, the patient has had a bowel movement between 1 and 3 hours after each washout, has recovered continence, and no longer wears an absorbent pad (AU)

Language use in females with fragile X or Turner syndrome during brief initial social interactions.

Fragile X and Turner syndromes are associated with risk of atypical social function. We examined language use, including normal and atypical speech, during initial social interactions among participants engaged in a brief social role play with an unfamiliar adult. There were 27 participants with Turner syndrome, 20 with fragile X syndrome and 28 in an age-matched comparison group. Females with fragile X did not exhibit more abnormal language, but exhibited less of what is typical during initial interactions. Overall rates of dysfluencies did not differ, although females with fragile X made more phrase repetitions. Females with Turner syndrome had no language use abnormalities. Our findings suggest that language use may influence social function in females with fragile X syndrome and that such language characteristics may be observed in the context of brief encounters with an unfamiliar adult.

Fragile X syndrome.

1. Fragile X syndrome is defined by the combination of a characteristic phenotype, cognitive impairment, the presence of a fragile site (gap) detectable in folate-free culture medium on Xq27.3 called FRA X A, and transcriptional inhibition, through overmethylation, of an mRNA protein-binding gene called FMR-1. 2. It is inherited in an atypical X-linked dominant way and affects about 1 in 1000 males and 1 in 2000 females; about 1 in 700 females is a carrier. 3. A characteristic but subtle phenotype includes an elongated face and mandible, large ears, macrocephaly with bizygomatic pinching, soft skin, inconsistent mitral valve prolapse, macroorchidism, mildly shortened stature in adulthood, and characteristic behavior that may resemble autism and attention deficit disorders. Intellectual impairment in affected individuals varies from mild to severe, with a majority of affected males within the moderate range of cognitive disability. Twenty percent of males with the mutation are phenotypically and intellectually unaffected. They ae called transmitting males. 4. Female heterozygotes may be indistinguishable from the general population, or they may have subtle physical signs or both physical and intellectual impairment. 5. Sensory motor integration is the therapy of choice for the learning disabilities in children with fragile X syndrome. The benefits of folic acid supplementation are equivocal. 6. A sensitive and understanding support system for the patient and extended family is an inseparable component of appropriate management of fragile X syndrome. 7. Molecularly the mutation is characterized by varying lengths of DNA fragments consisting of the trinucleotide CGG. It is repeated about 6 to 50 times in the normal population and approximately 51 to 200 times in unaffected individuals with a so-called premuation who are at risk for expansion and transmission to offspring. Individuals with over 200 repeats are usually affected and said to have a full mutation. 8. The physician caring for a family with fragile X syndrome should work with an experienced genetics center, counselor, and a laboratory with expertise.

[Clinical heterogeneity of the autistic syndrome: a study of 60 families]. / Heterogeneidad clínica del síndrome autista: un estudio en sesenta familias.

Sixty families ascertained through a single proband, has helped to better define infantile autism as a heterogeneous group of disorders. Forty four patients showed a characteristic facio- auricular dysplasia. Twenty four of these, showed increased pyruvate and lactate and laboratory findings of metabolic acidosis i.e., anion gap above 18 mEq/L or serum bicarbonate below 21 mEq/L but only nine of these probands demonstrated reduction of plasma bicarbonate below 18 mEq/lt. Plasma amino acids in 17 probands and matched controls showed increased taurine with the rest of amino acids significantly (p less than 0.05) below the control level. Glutamate and aspartate were also significantly elevated (p less than 0.05; Student t-test). Segregation analysis in thirty four of these families which linked through at least one ancestral family name, suggested autosomal recessive inheritance (p = 0.20). Three out of eight probands who received megadoses of pyridoxine (Vitamin B6), subjectively gained in language abilities, affectivity and response to behavior modification therapy. Five autistic patients proved to have clinically defined syndromes: two with the Martin-Bell syndrome, and three girls affected respectively with the Rett syndrome, phenylketonuria and dicarboxylic aciduria.