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.

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.

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.

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.