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.

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.

Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome.

OBJECTIVES: To assess changes in regional brain volumes associated with the fragile X-associated tremor/ataxia syndrome (FXTAS) and the molecular correlates of these changes. METHODS: We administered molecular, MRI, and neurocognitive tests to 36 male premutation carriers (ages 51 to 79), 25 affected and 11 unaffected with FXTAS, and to 21 control subjects of similar age and education. RESULTS: We found differences among the three groups in whole brain, cerebrum, cerebellum, ventricular volume, and whole-brain white matter hyperintensity, with the affected group showing significantly more pathology than the control and unaffected groups. Brainstem volume was significantly smaller in the unaffected group vs controls but did not differ from the affected group. Within the premutation sample, CGG repeat length correlated with reductions in IQ and cerebellar volume and increased ventricular volume and whole-brain white matter hyperintensity. CONCLUSIONS: The current findings, coupled with recent evidence linking the degree of neuropathology (numbers of intranuclear inclusions) to the size of the premutation allele, provide evidence that the neurodegenerative phenotype in the fragile X-associated tremor/ataxia syndrome is a consequence of the CGG repeat expansion.

Prevalence of FMR1 repeat expansions in movement disorders. A systematic review.

We reviewed prevalence rates of fragile X mental retardation gene (FMR1) repeat expansions in movement disorder populations. Inclusion criteria included published epidemiological studies from systematic searches of Medline, Pubmed, Cochrane Databases and Web Science. Thirteen cross-sectional studies were carried out between 2003 and 2005. Subjects with ataxia showed higher than expected rates while those with essential tremor and parkinsonism showed lower rates. The heterogeneous design of the studies, inclusion criteria and mean age of subjects may have led to underestimation of FMR1 repeat expansion prevalence rates.

Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers, principally males, of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS include progressive intention tremor and gait ataxia, accompanied by characteristic white matter abnormalities on MRI. The neuropathological hallmark of FXTAS is an intranuclear inclusion, present in both neurons and astrocytes throughout the CNS. Prior to the current work, the nature of the associations between inclusion loads and molecular measures (e.g. CGG repeat) was not defined. Post-mortem brain and spinal cord tissue has been examined for gross and microscopic pathology in a series of 11 FXTAS cases (males, age 67-87 years at the time of death). Quantitative counts of inclusion numbers were performed in various brain regions in both neurons and astrocytes. Inclusion counts were compared with specific molecular (CGG repeat, FMR1 mRNA level) and clinical (age of onset, age of death) parameters. In the current series, the three most prominent neuropathological characteristics are (i) significant cerebral and cerebellar white matter disease, (ii) associated astrocytic pathology with dramatically enlarged inclusion-bearing astrocytes prominent in cerebral white matter and (iii) the presence of intranuclear inclusions in both brain and spinal cord. The pattern of white matter pathology is distinct from that associated with hypertensive vascular disease and other diseases of white matter. Spongiosis was present in the middle cerebellar peduncles in seven of the eight cases in which those tissues were available for study. There is inclusion formation in cranial nerve nucleus XII and in autonomic neurons of the spinal cord. The most striking finding is the highly significant association between the number of CGG repeats and the numbers of intranuclear inclusions in both neurons and astrocytes, indicating that the CGG repeat is a powerful predictor of neurological involvement in males, both clinically (age of death) and neuropathologically (number of inclusions).

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.

PRNP H187R mutation associated with neuropsychiatric disorders in childhood and dementia.

Described is a large family with an autosomal dominant dementia associated with an H187R mutation in the prion protein gene (PRNP). Clinical features include neuropsychiatric disturbances in childhood and adolescence, dementia in young adulthood with frontotemporal manifestations, and long disease duration. Neuropathology revealed atrophy and mild gliosis, whereas prion protein analysis revealed an abnormal conformer with unusual sensitivity to protease digestion. Mutations in PRNP may cause neuropsychiatric disorders that predate dementia by many years.

Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation.

We describe five female carriers of the FMR1 premutation who presented with symptoms of tremor and ataxia and who received a diagnosis of definite or probable fragile-X-associated tremor/ataxia syndrome (FXTAS). Unlike their male counterparts with FXTAS, none of the women had dementia. Females had not been reported in previous studies of FXTAS, suggesting that they may be relatively protected from this disorder. Brain tissue was available from one of the five subjects, a women who died at age 85 years; microscopic examination revealed intranuclear neuronal and astrocytic inclusions, in accord with the findings previously reported in males with FXTAS. The work-up of families with the FMR1 mutation should include questions regarding neurological symptoms in both older male and female carriers, with the expectation that females may also manifest the symptoms of FXTAS, although more subtly and less often than their male counterparts.

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.

Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers.

A neurological syndrome involving progressive action tremor with ataxia, cognitive decline and generalized brain atrophy has been described recently in some adult males with pre-mutation alleles of the fragile X syndrome (FXS) fragile X mental retardation gene (FMR1). Neurohistological studies have now been performed on the brains of four elderly premutation carriers, not reported previously, who displayed the neurological phenotype. Eosinophilic, intranuclear inclusions were present in both neuronal and astrocytic nuclei of the cortex in all four individuals. Systematic analysis of the brains of two of these carriers demonstrated the presence of the intranuclear inclusions throughout the cerebrum and brainstem, being most numerous in the hippocampal formation. The cerebellum displayed marked dropout of Purkinje cells, Purkinje axonal torpedoes and Bergmann gliosis. Intranuclear inclusions were absent from Purkinje cells, although they were present in a small number of neurones in the dentate nucleus and diffusely in cerebellar astrocytes. The presence of inclusions in the brains of all four FXS carriers with the neurological findings provides further support for a unique clinical entity associated with pre-mutation FMR1 alleles. The origin of the inclusions is unknown, although elevated FMR1 mRNA levels in these pre-mutation carriers may lead to the neuropathological changes.

Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X.

The authors report five elderly men with the fragile X premutation who had a progressive action tremor associated with executive function deficits and generalized brain atrophy. These individuals had elevated fragile X mental retardation 1 gene (FMR1) messenger RNA and normal or borderline levels of FMR1 protein. The authors propose that elevations of FMR1 messenger RNA may be causative for a neurodegenerative syndrome in a subgroup of elderly men with the FMR1 premutation.

Bell's palsy in an older patient with uncontrolled hypertension due to medication nonadherence.

OBJECTIVE: To describe and inform pharmacists of a rarely reported occurrence of facial palsy in an elderly patient with uncontrolled hypertension resulting from nonadherence to blood pressure medications. CASE SUMMARY: A 62-year-old Hispanic woman presented to the hypertension clinic with left facial weakness, mild eyelid lag, and auricular pain for two days. The patient self-discontinued fosinopril and minoxidil six days and two days prior to developing these symptoms, respectively. A diagnosis of idiopathic peripheral VII cranial nerve lesion was made after ruling out other possible causes. Corticosteroids were not initiated because of this patient's labile hypertension. Palliative therapy was initiated and the left facial paralysis continuously improved during the six months after discharge. DISCUSSION: Patients have rarely presented with facial paralysis as the initial feature of severe hypertension. The relationship between facial paralysis and hypertension has been reported in a small number of cases, including several reports of recurrence of paralysis during acute exacerbations of hypertension. A variety of physiologic theories to explain the relationship between facial paralysis and hypertension have been published, including small hemorrhages into the facial canal which have been confirmed by two autopsies. However, the true etiology remains unknown. CONCLUSIONS: The possible relationship between facial paralysis and uncontrolled hypertension has not been reported in pharmacy literature and has been reported only twice in subspecialty medical journals since 1990. Pharmacists should be aware of the complications of hypertension and should question patients about signs and symptoms at each visit. While Bell's palsy complicating hypertension does not appear to be a serious complication, pharmacists must appreciate that the patient should be immediately evaluated to rule out a more serious neurologic event.

Chromosome 17 and hereditary dementia: linkage studies in three non-Alzheimer families and kindreds with late-onset FAD.

Several previous families with differing clinical and pathologic characteristics have demonstrated linkage to the 17q21-22 region. We have performed a linkage analysis with chromosome 17 markers on three families showing autosomal dominant inheritance of non-Alzheimer dementia and 60 kindreds with late-onset familial Alzheimer's disease (FAD). Family A shows unequivocal evidence of linkage with a maximum lod score of 5.0 for marker D17S934 (theta = 0.001). This family has an unusual syndrome of a schizophrenia-like psychosis beginning in the fifth or sixth decade followed by severe dementia with an average disease duration of 13.8 years. Neuropathology from five autopsies in this family has shown marked neurofibrillary tangle formation (NFT), degeneration of the amygdala, and no amyloid plaques. This confirms the presence of a gene associated with dementia on 17q and extends the related phenotype to include schizophrenia-like symptoms and classic NFT pathology. A second family with early aphasia progressing to dementia and cortical-basal ganglion-like degeneration also has suggestive evidence for linkage to 17q. A third family with very early-onset dementia (mean, 31 years) and nonspecific pathology can be excluded from the 17q region and emphasizes additional genetic heterogeneity in non-Alzheimer hereditary dementia. Finally, we also present evidence against linkage to D17S579 in the set of 60 families with late-onset FAD, providing further evidence that the chromosome 17 gene is unlikely to be involved in the pathogenesis of typical AD.

Platelet mitochondrial respiratory chain function in Parkinson's disease.

Reports on mitochondrial respiratory chain (MRC) complex I (CI) dysfunction in the substantia nigra in Parkinson's disease (PD) support the oxidative stress hypothesis in the neuropathogenesis of PD. Studies in peripheral tissue have found variable decreased CI and occasionally other complex activity suggestive of systemic impairment of MRC function in PD; however, MRC activity may be influenced by numerous variables. We conducted spectrophotometric measurements of MRC function in platelet mitochondrial preparations in 13 individuals with PD and 9 age-matched controls (CON) and have identified additional variables that may affect MRC activity. Mean CI, CIII, CIV, and citrate synthase (CS) activities were similar between PD and CON. CIII and CIV, specific and CS-corrected, activities were significantly positively correlated with CI in combined and individual group data, with the exception of CIII CS-corrected and CIV specific activities in CON and PD, respectively. CIII and CS specific activities were negatively correlated with age in CON, but varied randomly in PD. In PD, CIII specific activity was 1.4-fold higher in those with a history of environmental risk factors for PD and CIV specific activity was lower in those with a positive family history of PD [8.34 +/- 0.74 (n = 4) vs. 12.4 +/- 1.1 (SEM) min-1 mg-1; p = 0.046]. Group heterogeneity, variables affecting enzyme activity, and intrinsic properties of cells may thus contribute to conflicting data in studies of MRC function in platelets and other tissues.

A noncanonical tertiary conformation of a human mitochondrial transfer RNA.

Transfer RNAs possess highly conserved secondary structures, and crystallographic studies suggest a common, L-shaped tertiary conformation in which the anticodon and acceptor stems are disposed at approximately right angles to one another. However, many animal mitochondrial tRNAs possess unusual secondary structures, and little is known regarding their tertiary conformations, in particular, the relative orientations of their acceptor and anticodon stems. To address this issue, we have constructed heteroduplex RNA molecules corresponding to human mitochondrial and cytoplasmic lysyl tRNAs in which the acceptor and anticodon stems of each tRNA have been extended by approximately 70 base pairs. The rotational decay times of the two "extended" tRNA(Lys) species were compared to the decay times of a linear RNA control and to an extended yeast cytoplasmic tRNA(Phe) species whose interstem angle had been reported previously. Whereas the apparent interstem angle of the human cytoplasmic tRNA(Lys) species is essentially identical to that of the yeast tRNA(Phe) heteroduplex, with both conforming to the canonical L-shape, the angle for the mitochondrial tRNA(Lys) construct is much larger (approximately 140 degrees). Thus, the universal L-shape may not be applicable to noncanonical mitochondrial tRNAs, a finding of significance for both tRNA evolution and mitochondrial disease.