Neurological and endocrine phenotypes of fragile X carrier women.

Women who carry fragile X mental retardation 1 (FMR1)gene premutation expansions frequently report neurological or endocrine symptoms and prior studies have predominantly focused on questionnaire report of medical issues. Premutation carrier (PMC) women (n = 33) and non-carrier controls (n = 13) were recruited and evaluated by a neurologist, neuropsychologist, and endocrinologist. Blood and skin biopsies were collected for molecular measures. Scales for movement disorders, neuropathy, cognitive function, psychiatric symptoms, sleep, and quality of life were completed. The average age of the women was 51 years (n = 46) and average CGG repeat size was 91 ± 24.9 in the FMR1 PMC women. Seventy percent of the PMC women had an abnormal neurological examination. PMC women had significantly higher scores on the Fragile X-Associated Tremor Ataxia Syndrome (FXTAS) rating scale, more neuropathy, and difficulty with tandem gait compared to controls. Central sensitivity syndromes, a neuroticism profile on the NEO Personality Profile, and sleep disorders were also prevalent. Discrepancies between subject report and examination findings were also seen. This pilot study suggests that women with the FMR1 premutation may have a phenotype that overlaps with that seen in FXTAS. Additional research with larger sample sizes is warranted to better delineate the clinical features.

Update on Kleefstra Syndrome.

Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric feature.

Clinical involvement in daughters of men with fragile X-associated tremor ataxia syndrome.

Women with the fragile X mental retardation 1 (FMR1) premutation often have concerns about neurological and medical problems, as they become older and if their fathers experience fragile X-associated tremor/ataxia syndrome (FXTAS). We therefore determined the prevalence of these problems in 110 daughters of men with FXTAS [mean age of 44.8 years (SD 8.2)]. We compared them with 43 female controls with normal FMR1 alleles [mean age of 43.8 years (SD 8.1)] and 36 premutation carrier daughters of parents with the premutation, but without FXTAS [mean age of 43.5 years (SD 7.7)]. Overall, daughters of men with FXTAS have a higher prevalence of neurological symptoms including tremor, balance problems, memory problems, and dizziness, menopausal symptoms, and psychiatric involvement including sleep problems and anxiety when compared with non-carrier female controls. Reported balance problems and menopausal symptoms were significantly higher in daughters of men with FXTAS than in carrier daughters of parents without FXTAS, suggesting the potential influence of background gene effects. Therefore, neurological, psychological and gynecological surveillance should be warranted to better provide appropriate counseling, management and care for daughters of men with FXTAS. Biological markers of additional gene effects that predispose individuals with the premutation to FXTAS need to be developed.

A comparative study of the performance of individuals with fragile X syndrome and Fmr1 knockout mice on Hebb-Williams mazes.

Fragile X syndrome (FXS) is the most prevalent form of heritable mental retardation. It arises from a mutation in the FMR1 gene on the X chromosome that interferes with expression of fragile X mental retardation protein (FMRP) and leads to a wide range of behavioural and cognitive deficits. Previous studies have shown a deficit in basic visual perceptual processing as well as spatial abilities in FXS. How such a deficit may impact spatial navigation remains unknown. The current study extended previous research by evaluating spatial learning and memory using both virtual and physical versions of Hebb-Williams mazes, which allows for testing of humans and animals under comparable conditions. We compared the performance of individuals affected by FXS to typically developing individuals of equivalent mental age as well as the performance of Fmr1 knockout mice to wild-type control mice on the same maze problems. In human participants, performance of the comparison group improved across trials, showing expected significant decreases in both errors and latency. In contrast, the performance of the fragile X group remained at similar levels across trials. Although wild-type control mice made significantly fewer errors than the Fmr1 knockout mice, latencies were not statistically different between the groups. These findings suggest that affected humans and mice show similar spatial learning deficits attributable to the lack of FMRP. The implications of these data are discussed including the notion that Hebb-Williams mazes may represent a useful tool to examine the impact of pharmacological interventions on mitigating or reversing the symptoms associated with FXS.

A pilot open label, single dose trial of fenobam in adults with fragile X syndrome.

OBJECTIVE: A pilot open label, single dose trial of fenobam, an mGluR5 antagonist, was conducted to provide an initial evaluation of safety and pharmacokinetics in adult males and females with fragile X syndrome (FXS). METHODS: Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50-150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect screening was obtained at baseline and numerous time points for 6 h after dosing. Outcome measures included prepulse inhibition (PPI) and a continuous performance test (CPT) obtained before and after dosing to explore the effects of fenobam on core phenotypic measures of sensory gating, attention and inhibition. RESULTS: There were no significant adverse reactions to fenobam administration. Pharmacokinetic analysis showed that fenobam concentrations were dose dependent but variable, with mean (SEM) peak values of 39.7 (18.4) ng/ml at 180 min after the 150 mg dose. PPI met a response criterion of an improvement of at least 20% over baseline in 6 of 12 individuals (4/6 males and 2/6 females). The CPT did not display improvement with treatment due to ceiling effects. CONCLUSIONS: Clinically significant adverse effects were not identified in this study of single dose fenobam across the range of dosages utilised. The positive effects seen in animal models of FXS treated with fenobam or other mGluR5 antagonists, the apparent lack of clinically significant adverse effects, and the potential beneficial clinical effects seen in this pilot trial support further study of the compound in adults with FXS.

A comparative neuropsychological test battery differentiates cognitive signatures of Fragile X and Down syndrome.

BACKGROUND: Standardised neuropsychological and cognitive measures present some limitations in their applicability and generalisability to individuals with intellectual disability (ID). Alternative approaches to defining the cognitive signatures of various forms of ID are needed to advance our understanding of the profiles of strengths and weaknesses as well as the affected brain areas. AIM: To evaluate the utility and feasibility of six non-verbal comparative neuropsychological (CN) tasks administered in a modified version of the Wisconsin General Test Apparatus (WGTA) to confirm and extend our knowledge of unique cognitive signatures of Fragile X syndrome (FXS) and Down syndrome (DS). METHOD: A test battery of CN tasks adapted from the animal literature was administered in a modified WGTA. Tasks were selected that have established or emerging brain-behaviour relationships in the domains of visual-perceptual, visual-spatial, working memory and inhibition. RESULTS: Despite the fact that these tasks revealed cognitive signatures for the two ID groups, only some hypotheses were supported. Results suggest that whereas individuals with DS were relatively impaired on visual-perceptual and visual-spatial reversal learning tasks they showed strengths in egocentric spatial learning and object discrimination tasks. Individuals with FXS were relatively impaired on object discrimination learning and reversal tasks, which was attributable to side preferences. In contrast, these same individuals exhibited strengths in egocentric spatial learning and reversal tasks as well as on an object recognition memory task. Both ID groups demonstrated relatively poor performance for a visual-spatial working memory task. CONCLUSION: Performance on the modified WGTA tasks differentiated cognitive signatures between two of the most common forms of ID. Results are discussed in the context of the literature on the cognitive and neurobiological features of FXS and DS.

FMR1 CGG repeat length predicts motor dysfunction in premutation carriers.

BACKGROUND: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently described, underrecognized neurodegenerative disorder of aging fragile X mental retardation 1 (FMR1) premutation carriers, particularly men. Core motor features are action tremor, gait ataxia, and parkinsonism. Carriers have expanded CGG repeats (55 to 200); larger expansions cause fragile X syndrome, the most common heritable cause of mental retardation and autism. This study determines whether CGG repeat length correlates with severity and type of motor dysfunction in premutation carriers. METHODS: Persons aged >or=50 years with a family history of fragile X syndrome underwent structured videotaping. Movement disorder neurologists, blinded to carrier status, scored the tapes using modified standardized rating scales. CGG repeat length analyses for women incorporated the activation ratio, which measures the percentage of normal active chromosome X alleles. RESULTS: Male carriers (n = 54) had significantly worse total motor scores, especially in tremor and ataxia, than age-matched male noncarriers (n = 51). There was a trend toward a difference between women carriers (n = 82) and noncarriers (n = 39). In men, increasing CGG repeat correlated with greater impairment in all motor signs. In women, when activation ratio was considered, increasing CGG correlated with greater ataxia. CONCLUSIONS: CGG repeat size is significantly associated with overall motor impairment in premutation carriers. Whereas this association is most pronounced for men and covers overall motor impairment-tremor, ataxia, and parkinsonism-the association exists for ataxia among women carriers. This is the first report of a significant correlation between the premutation status and a motor feature of fragile X-associated tremor/ataxia syndrome in women.

Amyloid mediates the association of apolipoprotein E e4 allele to cognitive function in older people.

BACKGROUND: The neurobiological changes underlying the association of the apolipoprotein E (APOE) e4 allele with level of cognition are poorly understood. OBJECTIVE: To test the hypothesis that amyloid load can account for (mediate) the association of the APOE e4 allele with level of cognition assessed proximate to death. METHODS: There were 44 subjects with clinically diagnosed Alzheimer's disease and 50 without dementia, who had participated in the Religious Orders Study. They underwent determination of APOE allele status, had comprehensive cognitive testing in the last year of life, and brain autopsy at death. The percentage area of cortex occupied by amyloid beta and the density of tau positive neurofibrillary tangles were quantified from six brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multiple regression analyses were used to examine whether amyloid load could account for the effect of allele status on level of cognition, controlling for age, sex, and education. RESULTS: Possession of at least one APOE e4 allele was associated with lower level of cognitive function proximate to death (p = 0.04). The effect of the e4 allele was reduced by nearly 60% and was no longer significant after controlling for the effect of amyloid load, whereas there was a robust inverse association between amyloid and cognition (p = 0.001). Because prior work had suggested that neurofibrillary tangles could account for the association of amyloid on cognition, we next examined whether amyloid could account for the effect of allele status on tangles. In a series of regression analyses, e4 was associated with density of tangles (p = 0.002), but the effect of the e4 allele was reduced by more than 50% and was no longer significant after controlling for the effect of amyloid load. CONCLUSION: These findings are consistent with a sequence of events whereby the e4 allele works through amyloid deposition and subsequent tangle formation to cause cognitive impairment.

Initial diagnoses given to persons with the fragile X associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a newly described disorder that occurs in premutation carriers of the fragile X mental retardation 1 (FMR1) gene. Fifty-six patients with FXTAS were given 98 prior diagnoses: most were in the categories of parkinsonism, tremor, ataxia, dementia, or stroke. Data from this study and others were used to develop guidelines for FMR1 diagnostic testing for FXTAS.

The apolipoprotein E epsilon4 allele increases the odds of chronic cerebral infarction [corrected] detected at autopsy in older persons.

BACKGROUND AND PURPOSE: Studies investigating the relation of the apolipoprotein E (apoE) epsilon4 allele to clinical stroke and to vascular changes on magnetic resonance imaging have been conflicting. Little data are available regarding the relation of apoE epsilon4 to cerebral infarctions documented on postmortem examination. METHODS: We studied the apoE epsilon4 allele in 214 deceased members of the Religious Orders Study, a longitudinal clinical-pathologic study of aging and Alzheimer disease. The apoE genotype was determined using DNA from lymphocytes. Brains were removed a median of 5 hours (interquartile range, 5.5) after death. At postmortem examination, age, location, and size of macroscopic chronic cerebral infarctions were recorded from 1-cm coronal slabs after paraformaldehyde fixation. We also examined 20-microm paraffin-embedded sections of midfrontal and calcarine cortex for amyloid angiopathy on a scale of 1 to 4. RESULTS: Subjects included 96 males and 118 females with a mean age at death of 86 years (SD, 7). Sixty-five subjects (30.4%) had at least 1 apoE epsilon4 allele and 76 (35.5%) exhibited cerebral infarctions. More than 74% of the subjects exhibited amyloid angiopathy with a mean score of 1.4+/-1.2. After controlling for age and sex, apoE epsilon4 increased the odds of cerebral infarction by 2.3-fold (95% CI, 1.2 to 4.2). apoE epsilon4 increased the odds of cortical 3.2-fold (95% CI, 1.3 to 7.7) and subcortical infarctions 2.3-fold (95% CI, 1.2 to 4.5). The effect was unchanged after accounting for amyloid angiopathy. CONCLUSIONS: apoE epsilon4 increases the odds of chronic cerebral infarction detected at autopsy in older persons.

Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome.

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.

Aging in individuals with the FMR1 mutation.

Individuals with fragile X mental retardation 1 (FMR1) premutation (55 to 200 CGG repeats) are typically unaffected by fragile X syndrome. However, a subgroup of older males with the premutation have developed a neurological syndrome, which usually begins between 50 and 70 years and is associated with a progressive intention tremor and/or ataxia manifested by balance problems, frequent falling, and Parkinsonian symptoms, such as masked facies, intermittent resting tremor, and mild rigidity. This finding has been termed the fragile X-associated tremor/ataxia syndrome (FXTAS) and has brought focus to the aging process in individuals with the FMR1 mutation. The premutation is associated with elevated messenger RNA levels leading to the formation of intranuclear inclusions in neurons and astrocytes associated with FXTAS. This review is a summary of our experience with FXTAS in male carriers of the premutation.

Apolipoprotein E epsilon4 allele, AD pathology, and the clinical expression of Alzheimer's disease.

OBJECTIVE: To test the hypothesis that the APOE epsilon4 allele is associated with the clinical manifestations of AD through an association with the pathologic hallmarks of disease. METHODS: Participants were older Catholic nuns, priests, and brothers who agreed to annual neurologic and neuropsychological evaluation for AD and other common neurologic conditions and brain autopsy at the time of death. There were 77 persons without dementia and 51 with probable AD; 38 participants had one or more epsilon4 alleles. RESULTS: In logistic regression analyses, controlling for age, sex, and education, the epsilon4 allele was strongly associated with the likelihood of clinical AD (odds = 3.46, 95% CI = 1.44 to 8.33). However, controlling for the effect of AD pathology, the association of the epsilon allele with clinical AD was reduced by >50% and was no longer significant (odds = 1.58, 95% CI = 0.56 to 4.43). Similarly, in linear regression analyses, controlling for age, sex, and education, the epsilon4 allele was strongly associated with level of cognitive function proximate to death (regression coefficient = -0.477, p = 0.005). However, after controlling for the effect of AD pathology, the association of the epsilon4 allele with level of cognition was reduced by >80% and was no longer significant (regression coefficient = -0.093). Similar results were found in analyses using separate measures of neuritic plaques, diffuse plaques, and neurofibrillary tangles, and in analyses of five different cognitive systems (episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability). CONCLUSIONS: The APOE epsilon4 allele appears to be associated with the clinical manifestations of AD through an association with the pathologic hallmarks of AD rather than another mechanism.

The apolipoprotein E epsilon 2 allele and decline in episodic memory.

OBJECTIVES: The apolipoprotein E (apoE) epsilon 4 allele is related to decline in multiple cognitive domains, especially episodic memory, but the effect of the epsilon 2 allele on change in different forms of cognitive function has been difficult to establish. METHODS: Participants are from the Religious Orders Study. At baseline, they were at least 65 years old and free of clinical evidence of dementia. For up to eight years, they underwent annual clinical evaluations that included detailed cognitive function assessment from which previously established summary measures of episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability were derived. Growth curve models were used to assess change in each measure and its relation to apoE genotype, controlling for age, sex, education, and baseline level of cognition. Follow up data were available in 669 persons (98% of those eligible). We treated those with the epsilon 3/3 genotype as the reference group (n=425), which was contrasted with epsilon 2 ( epsilon 2/2, epsilon 2/3; n=86), and epsilon 4 ( epsilon 3/4, epsilon 4/4; n=158) subgroups. RESULTS: Rate of episodic memory change in the three subgroups significantly differed, with an average annual increase of 0.016 units in the epsilon 2 subgroup and annual decreases of 0.022 units in those with epsilon 3/3 and of 0.073 units in the epsilon 4 subgroup. The epsilon 2 subgroup did not differ from those with epsilon 3/3 in rate of decline in other cognitive systems. The epsilon 4 subgroup declined more rapidly than those with epsilon 3/3 in semantic memory and perceptual speed but not in working memory or visuospatial ability. CONCLUSION: Possession of one or more apoE epsilon 2 alleles is associated with reduced decline in episodic memory in older persons.

Genetic variation analysis in parkinson disease patients with and without hallucinations: case-control study.

BACKGROUND: Visual hallucinations in Parkinson disease (PD) occur in approximately one third of patients treated long-term with dopaminergic medications. In Alzheimer disease, hallucinations and psychosis have been linked to increased representations of B2/B2 homozyogotes for the dopamine receptor gene DRD1 and 1/1 or 2/2 homozygotes for DRD3. In addition, a previous study of PD patients with and without hallucinations did not show differences in D2 and D3 polymorphisms, although careful case-control matching was not performed. Another study linked the apolipoprotein E4 (APOE4) allele to hallucinations in PD. OBJECTIVE: To determine whether the frequency of dopamine receptor genetic variants and APOE alleles in patients with PD with and without chronic visual hallucinations resembles the pattern previously documented in patients with Alzheimer disease. METHODS: We conducted a case-control study of 44 patients with PD and chronic hallucinations and 44 patients with PD who had never hallucinated. Cases and controls were matched for current age and medications. DNA was isolated from blood samples and assayed for DRD1, DRD2, DRD3, DRD4, and APOE polymorphisms. Receptor polymorphisms were genotyped by polymerase chain reaction. Genotypes in hallucinators and nonhallucinators were compared using Mantel-Haenszel tests stratified by pair, and allele frequencies were compared using Wilcoxon signed rank tests within pairs. RESULTS: Neither D1 receptor genotypes (P =.37) nor allele frequencies (P =.38) differed, and there was no predominance of B2/B2 homozygotes in the hallucinators. For D3, there was a higher frequency of allele 2 (P =.047), but there was no significant difference between frequencies of homozygotes vs heterozygotes (P =.39) as reported in Alzheimer disease. D4 receptor distribution of long and short alleles did not differ between the 2 patient groups, and there were too few C alleles (3 of 86) to compare D2 allele genotypes or frequencies. For APOE, 12 cases and 12 controls carried E4 alleles (P>.99). CONCLUSIONS: With careful case-control matching, visual hallucinations in PD are not associated with the pattern seen for patients with Alzheimer disease and visual hallucinations. Furthermore, there was no association between hallucinations and APOE. Similar methods using larger sample sizes might be adapted to test whether specific dopaminergic receptor genetic variants are associated with visual hallucinations in PD. Based on our data, the DRD3 allele 2 may merit further study.

Bruising and the ketogenic diet: evidence for diet-induced changes in platelet function.

Excessive bruising is a symptom noted by parents of some children treated with the ketogenic diet for epilepsy control, although this side effect is not reported in the literature. We evaluated our cohort of current and past diet-treated patients for symptoms of bruising or bleeding through chart review and prospective screening at clinic follow-up visits. A significant increase in bruising or other minor bleeding was reported and/or observed in 16 of 51 patients (31.4%). There were no differences in sex distribution or number of anticonvulsants used between patients with bruising/bleeding and those without this symptom, although the group with bruising/bleeding was significantly younger. No specific anticonvulsant was associated with bruising/bleeding. Six patients with diet-induced bruising/bleeding underwent an investigation for bleeding diathesis. Five of these patients had prolonged bleeding times and all had diminished responsiveness to various platelet aggregating agents, with no evidence of a release defect. The abnormalities all normalized in the 1 patient tested after ceasing the diet. No patients had serious hemorrhage. One patient had mild von Willebrand disease, which had been asymptomatic before diet initiation. Some patients were Stimate responsive, suggesting a treatment for more severe bouts of symptoms. These data suggest that a ketogenic diet-related bleeding tendency occurs in about one third of treated patients owing to preexisting factors defining susceptibility in combination with diet-induced depression of platelet responsiveness, possibly related to changes in platelet membrane lipid composition and/or concentration and resultant effects on function of membrane-embedded proteins. Patients on the diet undergoing anticoagulation or surgery should be evaluated carefully for symptoms of bleeding tendency.

Carnitine levels and the ketogenic diet.

PURPOSE: To determine the long-term effect of the ketogenic diet (KD) on carnitine levels and whether carnitine depletion is a significant cause of clinical complications during KD initiation or treatment. METHODS: Carnitine levels at 0, 1, 6, 12, and 24 months of diet treatment, carnitine antiepileptic drug (AED) history, lowest blood glucose and time to achieve ketosis during diet initiation, and diet complications were analyzed for 38 consecutive patients who initiated the KD from May 1997 to March 2000. Carnitine levels at follow-up were analyzed for eight patients started on the diet before to May 1997. RESULTS: Total carnitine (TC) at diet initiation correlated negatively with the number of AEDs at diet initiation but not with number of past AEDs, lowest blood glucose, or time to ketosis. TC decreased in the first months of diet treatment and then stabilized or increased slightly with long term treatment. Only 19% of patients were supplemented with carnitine for low TC. No patient showed clinical signs of carnitine deficiency. CONCLUSIONS: Multiple AED exposure lowers TC, but actual TC deficiency in patients initiating the KD is not common, and TC levels do not appear to predict hypoglycemia or problems achieving ketosis. Mild carnitine depletion may occur early in KD treatment and occasionally TC decreases out of the normal range, without clinical symptoms. TC stabilizes or increases back toward baseline with long-term treatment, and most patients do not require carnitine supplementation.

Prenatal testing for late infantile neuronal ceroid lipofuscinosis.

Classic late infantile neuronal ceroid lipofuscinosis (LINCL) is a neurodegenerative disease in which autofluorescent "curvilinear" storage bodies accumulate in tissues from affected patients. Recently, the LINCL gene (CLN2) has been found to code for a pepstatin-insensitive lysosomal protease whose activity is deficient in LINCL specimens. We report the first 2 cases of successful prenatal testing for LINCL by using DNA and enzyme-based methods on amniocytes, and describe a new private mutation in one of the families analyzed. These approaches allow definitive prenatal diagnosis and represent a significant improvement over previous pathological methods.

Cognitive and visual processing skills and their relationship to mutation size in full and premutation female fragile X carriers.

BACKGROUND: The fragile X gene contains an unstable trinucleotide (CGG) repeat that expands as it is passed from female carriers to the affected offspring. Obligate female carriers may have a premutation or full mutation genotype. METHODS: In this study, fragile X premutation and full mutation female carriers were compared on three tasks of visual processing and cognitive skills. RESULTS: In each case, there were significant differences between premutation and full mutation carriers on a number of the subtests or the full test scores. Specifically, full mutation female carriers performed more poorly in visual-motor processing and analysis-synthesis on the Woodcock-Johnson Psycho-Educational Battery-Revised, The Developmental Test of Visual Motor Integration, and on five of the seven subtests of the Test of Visual-Perceptual Skills. Regression analyses revealed significant negative correlations between mutation size and cognitive ability. CONCLUSIONS: These findings have implications in educational planning decisions for full mutation carriers who may present with specific cognitive deficits.