James A. Brunberg

Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates.

We present a series of 26 patients, all >50 years of age, who are carriers of the fragile X premutation and are affected by a multisystem, progressive neurological disorder. The two main clinical features of this new syndrome are cerebellar ataxia and/or intention tremor, which were chosen as clinical inclusion criteria for this series. Other documented symptoms were short-term memory loss, executive function deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower limb proximal muscle weakness, and autonomic dysfunction. Symmetrical regions of increased T2 signal intensity in the middle cerebellar peduncles and adjacent cerebellar white matter are thought to be highly sensitive for this neurologic condition, and their presence is the radiological inclusion criterion for this series. Molecular findings include elevated mRNA and low-normal or mildly decreased levels of fragile X mental retardation 1 protein. The clinical presentation of these patients, coupled with a specific lesion visible on magnetic resonance imaging and with neuropathological findings, affords a more complete delineation of this fragile X premutation-associated tremor/ataxia syndrome and distinguishes it from other movement disorders.

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.

Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines.

Fragile X‐associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder with core features of action tremor and cerebellar gait ataxia. Frequent associated findings include parkinsonism, executive function deficits and dementia, neuropathy, and dysautonomia. Magnetic Resonance Imaging studies in FXTAS demonstrate increased T2 signal intensity in the middle cerebellar peduncles (MCP sign) in the majority of patients. Similar signal alterations are seen in deep and subependymal cerebral white matter, as is general cortical and subcortical atrophy. The major neuropathological feature of FXTAS is the presence of intranuclear, neuronal, and astrocytic, inclusions in broad distribution throughout the brain and brainstem. FXTAS is caused by moderate expansions (55–200 repeats; premutation range) of a CGG trinucleotide in the fragile X mental retardation 1 (FMR1) gene, the same gene which causes fragile X syndrome when in the full mutation range (200 or greater CGG repeats). The pathogenic mechanism is related to overexpression and toxicity of the FMR1 mRNA per se. Although only recently discovered, and hence currently under‐diagnosed, FXTAS is likely to be one of the most common single‐gene disorders leading to neurodegeneration in males. In this report, we review information available on the clinical, radiological, and pathological features, and prevalence and management of FXTAS. We also provide guidelines for the practitioner to assist with identifying appropriate patients for DNA testing for FXTAS, as well as recommendations for genetic counseling once a diagnosis of FXTAS is made.

Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS)

Background: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder occurring in male and rare female carriers of a premutation expansion (55 to 200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Methods: Volumetric MRI studies, clinical staging, cognitive testing, and molecular analysis were conducted in 15 female premutation carriers affected by FXTAS (age 59.5 ± 10.3 years), 20 unaffected female carriers (43.3 ± 11.2 years), 11 genetically normal female controls (51.0 ± 10.3 years), 36 affected male carriers (65.0 ± 5.6 years), 25 unaffected male carriers (53.5 ± 12.5 years), and 39 male controls (58.0 ± 15.0 years). Female and male carriers with FXTAS were matched on duration of disease. Results: We found less pronounced reductions of cerebellar volume and a lower incidence of involvement (symmetric high T2 signal) of the middle cerebellar peduncles (MCP sign) in females affected by FXTAS (13%) compared with affected males (58%). We found reduced brain volumes and increased white matter disease associated with the presence of FXTAS in females compared with female controls. We also observed significant associations between reduced cerebellar volume and both increased severity of FXTAS symptoms and increased length of the CGG repeat expansion in male premutation carriers, but not in females. Conclusions: Females affected by fragile X-associated tremor/ataxia syndrome (FXTAS) demonstrated milder brain changes than affected males, although they showed a similar pattern of radiologic findings consistent with brain atrophy and white matter disease. FXTAS should be considered (by ordering fragile X DNA testing) in females who present with late-onset ataxia, action tremor, or neuropathy, particularly in those with a family history of mental retardation, autism, or premature ovarian failure.

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.

Hippocampus and amygdala in schizophrenia: assessment of the relationship of neuroanatomy to psychopathology

The hippocampus and amygdala are believed to be involved in the pathology of schizophrenia. In this study, we attempted to replicate the reported bilateral volume reduction of the hippocampus and amygdala and to study the relationship of the volumes of these structures to the symptoms of schizophrenia. The hippocampus-amygdala complex (HAC) was manually traced on 3-mm coronal T(1)-weighted MRIs, resampled into 1-mm coronal slices, from 20 male patients with schizophrenia and 20 age-matched male controls. The complex was divided into three parts: anterior one-third representing the amygdala and middle and posterior thirds representing the anterior and posterior halves of the hippocampus. Positive and negative symptoms and severity of hallucinations and thought disorder (conceptual disorganization) were quantified using the Brief Psychiatric Rating Scale (BPRS). None of the above structures, controlled for brain volume, differed significantly in patients compared with normal controls. When the relationship between volumes and symptoms was examined, the left HAC was found to inversely correlate with thought disorder and negative symptoms. Specifically, significant inverse correlations were found between (i) left amygdala and thought disorder, (ii) left hippocampus and negative symptoms, and (iii) left anterior and posterior hippocampus volumes and positive and negative symptoms, respectively. Our findings further support the role of the HAC in the pathophysiology of schizophrenia and suggest unique associations between individual structures and specific symptoms of the illness.

ACR Appropriateness Criteria® on Low Back Pain

Acute low back pain with or without radiculopathy is one of the most common health problems in the United States, with high annual costs of evaluation and treatment, not including lost productivity. Multiple reports show that uncomplicated acute low back pain or radiculopathy is a benign, self-limited condition that does not warrant any imaging studies. Guidelines for recognition of patients with more complicated status can be used to identify those who require further evaluation for suspicion of more serious problems and contribute to appropriate imaging utilization.

Psychological symptoms correlate with reduced hippocampal volume in fragile X premutation carriers

Fragile X‐associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder occurring in male and occasional female carriers of a premutation expansion (55–200 CGG repeats) of the fragile X mental retardation 1 gene (FMR1). This study assessed the relationship between hippocampal volume and psychological symptoms in carriers, both with and without FXTAS, and controls. Volumetric MRI measures, clinical staging, cognitive testing, molecular analysis, and measures of psychological symptoms were performed for female premutation carriers both with FXTAS (n = 16, age: 57.50 ± 12.46) and without FXTAS (n = 17, age: 44.94 ± 11.23), in genetically normal female controls (n = 8, age: 50.63 ± 11.43), male carriers with FXTAS (n = 34, age: 66.44 ± 6.77) and without FXTAS (n = 21, age: 52.38 ± 12.11), and genetically normal male controls (n = 30, age: 57.20 ± 14.12). We examined the relationship between psychological symptom severity and hippocampal volume, as well as correlations with molecular data. We found a significant negative correlation between total hippocampal volume and anxiety in female carriers, with and without FXTAS. This finding was mainly driven by the significant negative correlation between right hippocampal volume and anxiety. Other anxiety‐related subscales also correlated with the right hippocampus in females. In male carriers with and without FXTAS, only paranoid ideation negatively correlated with hippocampal volume. Female premutation carriers demonstrated a negative association between hippocampal volume and the severity of anxiety‐related psychological symptoms. Though the presentation of FXTAS symptoms is less common in females, anxiety‐related problems are common both prior to and after the onset of FXTAS, and may be related to hippocampal changes.

Clinical and Neuropathologic Findings in a Woman With the FMR1 Premutation and Multiple Sclerosis

BACKGROUND Multiple sclerosis (MS) and fragile X-associated tremor/ataxia syndrome (FXTAS) have overlapping clinical signs and symptoms. OBJECTIVES To present a case with evidence of both MS and FXTAS and to discuss the relationship of both disorders. DESIGN Case report. SETTING Fragile X Research and Treatment Center at the University of California, Davis, Medical Center. Patient Woman with the FMR1 premutation who died of MS at the age of 52 years. MAIN OUTCOME MEASURES Magnetic resonance imaging, physical examination, and neuropathologic examination results. RESULTS Magnetic resonance imaging, physical examination, and autopsy neuropathologic examination revealed diagnostic features of MS and FXTAS. CONCLUSION The molecular mechanism of RNA toxicity, including the elevation of alphaB-crystallin levels observed in FXTAS, may lead to enhanced predisposition to autoimmune diseases.

Neuropathy as a presenting feature in fragile X-associated tremor/ataxia syndrome.

Peripheral neuropathy is common among patients with fragile X‐associated tremor ataxia syndrome (FXTAS). Four patients with FXTAS are described with neuropathy as the presenting feature, two having received a prior diagnosis of Charcot‐Marie‐Tooth (CMT) disease. A fifth is described with neuropathy as the only clinical feature. A functional connection between FXTAS and neuropathy has been suggested by the presence of lamin A/C in the intranuclear, neuronal and astrocytic inclusions of FXTAS, since mutations in lamin A/C are known to give rise to an axonal form of CMT.