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The fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder caused by CGG trinucleotide repeat expansions in the fragile X mental retardation 1 (FMR1) gene. The neuropathological hallmark of FXTAS is the presence of ubiquitin-positive intranuclear inclusions in neurons and in astroglia. Intranuclear inclusions have also been reported in the neurons of male CGG KI mice carrying an expanded CGG trinucleotide repeat and used to model FXTAS, but no study has been carried out quantifying inclusions in female CGG KI mice heterozygous for the fragile X premutation. We used histologic and immunocytochemical methods to determine the pathological features of intranuclear inclusions in astroglia and neurons. In female CGG KI mice, ubiquitin-positive intranuclear inclusions were found in neurons and astroglia throughout the brain in cortical and subcortical regions. These inclusions increased in number and became larger with advanced age and increasing CGG repeat length, supporting hypotheses that these pathologic features are progressive across the lifespan. The number of inclusions in neurons was reduced by similar to 25% in female CGG KI mice compared to male CGG KI mice, but not so low as the 50% predicted. These data emphasize the need to evaluate the neurocognitive and pathological features in female carriers of the fragile X premutation with and without FXTAS symptomatology is warranted, as this population shows similar neuropathological features present in male FXTAS patients. (C) 2012 Elsevier B.V. All rights reserved.

Examples of white matter hyperintensities (wmh) on magnetic resonance images in a basis pontis are presented in two male carriers, each of whom carry a small CGG expansion fragile X mental retardation (FMR1) allele. One carried a premutation (PM) allele of 85 CGG repeats and the other, a gray zone (GZ) allele of 47 repeats. Both were originally diagnosed with idiopathic Parkinson's disease (iPD). Similar changes are also shown in one PM carrier of 99 repeats affected with mild tremor and imbalance, who was ascertained through a fragile X syndrome family. These examples draw attention to the occurrence of wmh in a basis pontis in the carriers of small CGG expansions presenting with tremor and ataxia. Moreover, the presence of this change in GZ, as well as PM, allele carriers originally diagnosed with iPD supports our earlier suggestion that both these alleles may contribute to the neurodegenerative changes in this disorder which, in the examples presented, have been reflected by wmh, most prominent in the cerebellar peduncles and/or pontine area.

Item does not contain fulltext Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder generally presenting with intention tremor and gait ataxia, but with a growing list of co-morbid medical conditions including hypothyroidism, hypertension, peripheral neuropathy, and cognitive decline. The pathological hallmark of FXTAS is the presence of intranuclear inclusions in both neurons and astroglia. However, it is unknown to what extent such inclusions are present outside the central nervous system (CNS). To address this issue, we surveyed non-CNS organs in ten human cases with FXTAS and in a CGG repeat knock-in (CGG KI) mouse model known to possess neuronal and astroglial inclusions. We find inclusions in multiple tissues from FXTAS cases and CGG KI mice, including pancreas, thyroid, adrenal gland, gastrointestinal, pituitary gland, pineal gland, heart, and mitral valve, as well as throughout the associated autonomic ganglia. Inclusions were observed in the testes, epididymis, and kidney of FXTAS cases, but were not observed in mice. These observations demonstrate extensive involvement of the peripheral nervous system and systemic organs. The finding of intranuclear inclusions in non-CNS somatic organ systems, throughout the PNS, and in the enteric nervous system of both FXTAS cases as well as CGG KI mice suggests that these tissues may serve as potential sites to evaluate early intervention strategies or be used as diagnostic factors.

Fragile X premutation conditions are associated with a significant degree of psychopathology and thus are of interest to the psychiatrist. Remarkable advances at the molecular level have enhanced our understanding of fragile X premutation disorders.The authors review the genetic, molecular, neuroimaging, and clinical (systemic, neurologic, and psychiatric) manifestations of the premutation carrier state (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene.The search for the psychiatric clinical manifestations of fragile X-associated conditions was accomplished by PubMed for clinical papers published between 1970 and 2008 with the following search terms: Fragile X syndrome, depression, psychosis, anxiety, and dementia.Articles addressing psychiatric symptoms in premutation carriers based on review of the abstracts were reviewed. As the majority of the literature on this topic is based on case reports and small case series, these were included in the database.Reported clinical manifestations of psychiatric illness in premutation carriers include an apparently significant rate of cognitive, mood, anxiety, and other psychiatric disorders. Fragile X premutation-associated conditions are part of the clinical differential diagnosis of several psychiatric syndromes, particularly in pedigrees with known fragile X syndrome cases.Fragile X-associated psychiatric manifestations serve as a useful model for a molecular genesis of neuropsychiatric illness. Because of the multigenerational expression of fragile X-associated neuropsychiatric illness, there is a prominent role for genetic testing and genetic counseling of patients and their relatives. Genetic testing is confirmatory of the FMR1 premutation and is an essential component of the clinical evaluation. Psychopharmacologic and psychotherapeutic treatment of fragile X-associated psychiatric illnesses may improve patient function and assist in adaptation to the burden of a genetic neuropsychiatric illness.

We present a case of a giant sellar and suprasellar skull base-invasive metastasis from a medullary carcinoma of the thyroid gland. Radiographic features were similar to atypical/malignant meningioma or pituitary macroadenoma. Intracranial metastases from medullary thyroid carcinoma are very rare. Unusual features of our case are discussed.

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.

Congenital central nervous system (CNS) tumors are uncommon, accounting for 1% of all childhood brain tumors. They present clinically either at birth or within the first 3 months. Glioblastoma (GBM) only rarely occurs congenitally and has not been fully characterized. We examined clinicopathologic features and genetic alterations of six congenital GBMs. Tumors were seen by neuroimaging as large, complex cerebral hemispheric masses. All showed classic GBM histopathology, including diffuse infiltration, dense cellularity, GFAP‐positivity, high mitotic activity, endothelial proliferation and pseudopalisading necrosis. Neurosurgical procedures and adjuvant therapies varied. Survivals ranged from 4 days to 7.5 years; two of the three long‐term survivors received chemotherapy, whereas the three short‐term survivors did not. Paraffin‐embedded tissue sections were used for FISH analysis of EGFR, chromosomes 9p21 (p16/CDKN2A) and 10q ( PTEN/DMBT1); sequencing of PTEN and TP53; and immunohistochemistry for EGFR and p53. We uncovered 10q deletions in two cases. No EGFR amplifications, 9p21 deletions, or mutations of TP53 or PTEN were noted; however, nuclear p53 immunoreactivity was strong in 5/6 cases. Tumors were either minimally immunoreactive (n = 3) or negative (n = 3) for EGFR. We conclude that congenital GBMs show highly variable survivals. They are genetically distinct from their adult counterparts and show a low frequency of known genetic alterations. Nonetheless, the strong nuclear expression of p53 in these and other pediatric GBMs could indicate that p53 dysregulation is important to tumorigenesis.

We describe the medical course, neuropathology and testicular pathology in 2 men who died with fragile X associated tremor/ataxia syndrome. Fragile X associated tremor/ataxia syndrome, which is a recently described, late onset neurodegenerative disorder, affects up to a third of males and occasionally females older than age 50 years who are carriers of premutation alleles (55 to 200 CGG repeats) of the fragile X mental retardation 1 gene FMR1. Clinical manifestations of premutation status are distinct from those of the full mutation, which is the cause of the fragile X syndrome.Standard pathological techniques were used to examine the brain, pituitary gland and testicular tissues of 2 males who had fragile X associated tremor/ataxia syndrome.The clinical course of the 2 cases included impotence before the onset of neurological symptoms of tremor and ataxia. Neuropathological findings included eosinophilic intranuclear inclusions in neurons and astrocytes throughout the central nervous system, and in the anterior and posterior pituitary gland of 1 of the 2 men. Inclusions were also seen in the Leydig and myoid cells in the testicles of these 2 men with fragile X associated tremor/ataxia syndrome.Fragile X associated tremor/ataxia syndrome inclusions are formed in tissues outside of the central nervous system. Involvement of the testicles and the pituitary gland may lead to neuroendocrine dysfunction, including testosterone deficiency. These noncentral nervous system components of fragile X associated tremor/ataxia syndrome require further study.

Premutation alleles of the fragile X mental retardation 1 (FMR1) gene give rise to a late-onset movement disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), characterized by progressive intention tremor and gait ataxia, with associated dementia and global brain atrophy. The natural history of FXTAS is largely unknown. To address this issue, a family-based, retrospective, longitudinal study was conducted with a cohort of 55 male premutation carriers. Analysis of the progression of the major motor signs of FXTAS, tremor and ataxia, shows that tremor usually occurs first, with median onset at approximately 60 years of age. From the onset of the initial motor sign, median delay of onset of ataxia was 2 years; onset of falls, 6 years; dependence on a walking aid, 15 years; and death, 21 years. Preliminary data on life expectancy are variable, with a range from 5 to 25 years.

A patient presented with severe suboccipital headaches. Noncontrast CT was obtained and a densely calcified mass was found at the right cerebellomedullary angle cistern (figure 1). This lesion was followed clinically and with serial imaging. Follow-up MRI of the brain performed 8 months later demonstrated slightly increased mass effect and edema on the adjacent medulla and gross total surgical resection was performed. Final pathologic diagnosis was calcifying pseudoneoplasm of the neuraxis (CAPNON) (figure 2).

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).

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by premutation expansions (55-200 CGG repeats) in the fragile X mental retardation 1 (FMR1) gene. The pathologic hallmark of FXTAS is the ubiquitin-positive intranuclear inclusion found in neurons and astrocytes in broad distribution throughout the brain. The pathogenesis of FXTAS is likely to involve an RNA toxic gain-of-function mechanism, and the FMR1 mRNA has recently been identified within the inclusions. However, little is known about the proteins that mediate the abnormal cellular response to the expanded CGG repeat allele. As one approach to identify the protein mediators, we have endeavoured to define the protein complement of the inclusion itself. Fluorescence-activated flow-based methods have been developed for the efficient purification of inclusions from the post-mortem brain tissue of FXTAS patients. Mass spectrometric analysis of the entire protein complement of the isolated inclusions, combined with immunohistochemical analysis of both isolated nuclei and tissue sections, has been used to identify inclusion-associated proteins. More than 20 inclusion-associated proteins have been identified on the basis of combined immunohistochemical and mass spectrometric analysis, including a number of neurofilaments and lamin A/C. There is no dominant protein species in the inclusions, and ubiquitinated proteins represent only a minor component; thus, inclusion formation is not likely to reflect a breakdown in proteasomal degradation of nuclear proteins. The list of proteins includes at least two RNA binding proteins, heterogeneous nuclear ribonucleoprotein A2 and muscle blind-like protein 1, which are possible mediators of the RNA gain-of-function in FXTAS.

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.

Fragile X associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder that affects individuals with premutation alleles of the fragile X mental retardation ( FMR1 ) gene. The clinical features of FXTAS include intention tremor, ataxia, parkinsonism, peripheral neuropathy, autonomic dysfunction and cognitive impairment.1 Such symptoms are accompanied by characteristic MRI focal areas of increased T2 signal in the middle cerebellar peduncles (MCP).1 In this report, we describe two female patients with FXTAS who were initially diagnosed with multiple sclerosis (MS) and treated accordingly but who also met diagnostic criteria for FXTAS. Their clinical features and MRI appearance are compared with other female FXTAS cases previously reported without a diagnosis of MS. A recent report of a female who died of MS and who also had FXTAS inclusions suggests that these two disorders can occur together.2 ### Patient No 1 Case 1 is a 48-year-old female premutation carrier with a history of MS which began at the age of 33 years. Initially, her handwriting quality declined, and she subsequently became ataxic. A combination of weakness, clumsiness and ataxia forced her to use a wheelchair beginning in her late thirties. During that same period, she was diagnosed with MS following a CSF study which showed elevated IgG (9.8 mg/dl; reference range 0.5–6.1 mg/dl) without oligoclonal bands or myelin basic protein. Her course was consistent with relapsing–remitting MS with early secondary progression, and she was treated …

Case Reports Neurosarcoidosis and Delirium J AMES A. B OURGEOIS , O.D., M.D., R ICHARD J. M ADDOCK , M.D. L ORI R OGERS , M.D., C LAUDIA M. G RECO , M.D. R AJESH S. M ANGRULKAR , M.D., S ANJAY S AINT , M.D., M.P.H. S arcoidosis is a systemic inflammatory disease with characteristic noncaseating granulomas. There may be involvement of multiple organ systems, including the lungs, lymph nodes, liver, skin, muscles, bones, and eyes. 1 Involvement of the nervous system (neurosarcoidosis) is seen in less than 10% of cases; psychiatric symptoms in- frequently herald disease onset. 1–3 Case Report Ms. A, a 39-year-old African American woman, came to a psychiatric hospital with incoherent speech, auditory hal- lucinations, and distractibility that had begun months ear- lier and worsened over 2 weeks. She had increased her long-term cocaine use and had unintentionally lost 70 kg in the last year. She was also a regular user of alcohol. She had no previous history of psychosis. After admission, she received oral risperidone, 2 mg b.i.d., without improve- ment. Four days later, she fell and suffered a right peri- orbital hematoma. For 2 days, she was nonverbal and re- fused food and drink. Ms. A was then sent to a university medical center, where computed tomography (CT) revealed a low-density area in her right frontal white matter. Subsequent magnetic resonance imaging (MRI) revealed a right frontal lobe en- hancing mass of 1.5 cm in diameter with surrounding Received March 12, 2004; revision received April 27, 2004; accepted June 15, 2004. From the Department of Psychiatry and Behavioral Sci- ences and the Department of Pathology/Neuropathology, University of California–Davis Medical Center; the Department of Veterans Affairs Health Services Research and Development Center of Excellence and the Department of Internal Medicine, University of Michigan, Ann Arbor. Address correspondence and reprint requests to Dr. Bourgeois, Depart- ment of Psychiatry and Behavioral Sciences, University of California– Davis Medical Center, 2230 Stockton Blvd., Sacramento, CA 95817; james.bourgeois@ucdmc.ucdavis.edu (e-mail). Copyright ᭧ 2005 The Academy of Psychosomatic Medicine. edema, multiple small enhancing lesions, and areas of edema within both cerebral hemispheres and posterior fossa structures and diffuse meningeal enhancement in both cerebral hemispheres, the cerebellum, and the brain- stem (Figure 1). Ms. A was admitted to the neurology service, and a psychiatric consultation was obtained. Psychiatric exami- nation findings included delusions; auditory hallucinations; thought disorganization; disorientation to person, place, and time; and stereotypical movements. Her risperidone dosage was increased to 1.5 mg q.i.d. CSF analysis re- vealed a glucose level of 27 mg/dl, a protein level of 166 mg/dl, 12 WBC/mm 3 , 1 RBC/mm 3 , and a negative Gram’s stain. Chest radiography and a CT showed bilateral hilar adenopathy and nodular pulmonary infiltrates. Intravenous dexamethasone and acyclovir were started for possible herpes simplex encephalitis. Tests for angio- tensin-converting enzyme, antinuclear antibody, human immunodeficiency virus, hepatitis B surface antigen, hep- atitis C antibody, and urinary histoplasmosis antigen were normal, as were VDRL results. A test for tuberculin-puri- fied protein derivative without controls was nonreactive. Polymerase chain reaction on CSF for mycobacterium tu- berculosis and herpes simplex virus types 1 and 2 were negative. Acyclovir was then discontinued. Tests for CSF cryptococcal antigen titer and acid-fast bacillus smear were negative, as were tests for CSF my- cobacterium, bacterial, and fungal cultures. Rifampin, ethambutol, isoniazid, pyrazinamide, and vitamin B6 were started for possible CNS tuberculosis. Psychiatry re-eval- uation on the eighth hospital day revealed full alertness and intact orientation but continued blunted affect and auditory hallucinations. Ms. A scored 14 on the Folstein Mini-Men- tal State Exam (MMSE). Her risperidone dosage was de- creased to 2 mg b.i.d. An open brain biopsy of the frontal lobe mass showed pale white, rubbery soft tissue that histologically revealed noncaseating granulomas with multinucleated giant cells Psychosomatics 46:2, March-April 2005 http://psy.psychiatryonline.org

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder associated with premutation alleles of the fragile X mental retardation 1 (FMR1) gene. Approximately 40% of older male premutation carriers, and a smaller proportion of females, are affected by FXTAS; due to the lower penetrance the characterization of the disorder in females is much less detailed. Core clinical features of FXTAS include intention tremor, cerebellar gait ataxia and frequently parkinsonism, autonomic dysfunction and cognitive deficits progressing to dementia in up to 50% of males. In this study, we report the clinical, molecular and neuropathological findings of eight female premutation carriers. Significantly, four of these women had dementia; of the four, three had FXTAS plus dementia. Post-mortem examination showed the presence of intranuclear inclusions in all eight cases, which included one asymptomatic premutation carrier who died from cancer. Among the four subjects with dementia, three had sufficient number of cortical amyloid plaques and neurofibrillary tangles to make Alzheimer's disease a highly likely cause of dementia and a fourth case had dementia with cortical Lewy bodies. Dementia appears to be more common than originally reported in females with FXTAS. Although further studies are required, our observation suggests that in a portion of FXTAS cases there is Alzheimer pathology and perhaps a synergistic effect on the progression of the disease may occur.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder among carriers of premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. The clinical features of FXTAS, as well as various forms of clinical involvement in carriers without FXTAS, are thought to arise through a direct toxic gain of function of high levels of FMR1 mRNA containing the expanded CGG repeat. Here we report a cellular endophenotype involving increased stress response (HSP27, HSP70 and CRYAB) and altered lamin A/C expression/organization in cultured skin fibroblasts from 11 male carriers of premutation alleles of the FMR1 gene, including six patients with FXTAS and five premutation carriers with no clinical evidence of FXTAS, compared with six controls. A similar abnormal cellular phenotype was found in CNS tissue from 10 patients with FXTAS. Finally, there is an analogous abnormal cellular distribution of lamin A/C isoforms in knock-in mice bearing the expanded CGG repeat in the murine Fmr1 gene. These alterations are evident even in mouse embryonic fibroblasts, raising the possibility that, in humans, the expanded-repeat mRNA triggers pathogenic mechanisms early in development, thus providing a molecular basis for the neurodevelopmental abnormalities observed in some children and clinical symptoms in some adults who are carriers of premutation FMR1 alleles. Cellular dysregulation in fibroblasts represents a novel and highly advantageous model for investigating disease pathogenesis in premutation carriers and for quantifying and monitoring disease progression. Fibroblast studies may also prove useful in screening and testing the efficacy of therapeutic interventions.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder caused by CGG trinucleotide repeat expansions in the fragile X mental retardation 1 (FMR1) gene. The neuropathological hallmark of the disease is the presence of ubiquitin-positive intranuclear inclusions in neurons and in astrocytes. Ubiquitin-positive intranuclear inclusions have also been found in the neurons of transgenic mice model carrying an expanded CGG(98) trinucleotide repeat of human origin but have not previously been described in glial cells. Therefore, we used immunocytochemical methods to determine the pathological features of nuclear and/or cytoplasmic inclusions in astrocytes, Bergmann glia, and neurons, as well as relationships between inclusion patterns, age, and repeat length in CGG knock-in (KI) mice in comparison with wild-type mice. In CGG KI mice, ubiquitin-positive intranuclear inclusions were found in neurons (e.g., pyramidal cells, GABAergic neurons) throughout the brain in cortical and subcortical brain regions; these inclusions increased in number and size with advanced age. Ubiquitin-positive intranuclear inclusions were also present in protoplasmic astrocytes, including Bergmann glia in the cerebellum. The morphology of intranuclear inclusions in CGG KI mice was compared to that of typical inclusions in human neurons and astrocytes in postmortem FXTAS brain tissue. This new finding of previously unreported pathology in astrocytes of CGG KI mice now provides an important mouse model to study astrocyte pathology in human FXTAS. (C) 2010 Elsevier B.V. All rights reserved.

In 2002, a syndrome of tremor, ataxia, cognitive decline, and the presence of unique ubiquitin staining intranuclear inclusions in the brain was discovered in premutation males carrying an expansion of between 55 and 200 CGG trinucleotide repeats on the FMR1 gene. This clinical syndrome is now known as fragile X-associated tremor/ataxia (FXTAS) and has been found in both male and female carriers of the expanded premutation allele. The goal of this chapter is to summarize what is known about the anatomical pathology associated with the fragile X premutation and particularly in those individuals with FXTAS. Neuropathology in FXTAS was initially found in the central nervous system, but recent evidence has demonstrated pathological features, including intranuclear inclusions, in the peripheral nervous system, the enteric nervous system, and the neuroendocrine system. The precise cellular dysfunctions that underlie these pathologic features are currently under intense investigation with the goal of prevention and treatment of this devastating disorder.

Multiplesclerosis(MS), the most common demyelinating disease of the central nervous system (CNS), affects more than 350 000 people in the United States and an estimated 2 million people worldwide; CNS demyelination and varying degrees of axonal injury and inflammation are essential features in established cases. The consistent presence of axonal dysfunction has furthered an understanding of sustained disability and regenerative failure in those with MS.1 Premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are common (1 per 100-300 females and 1 per 300-800 males); toxic effects caused by the excess amount of premutation FMR1 messenger RNA (mRNA) leads to the adult-onset neurologic disorder fragile X–associated tremor/ataxia syndrome (FXTAS).2 The penetrance of FXTAS in male carriers throughout 50 years, ascertained through families with a fragile X syndrome proband, is approximately 40%; its penetrance in female carriers is lower (approximately 5%-10%).2,3 The pathologic features of FXTAS include intranuclear inclusions in neurons and astrocytes throughout the brain and brainstem, astrocyte activation, axonal retraction bulbs, axonal loss, and myelin loss.4,5 The inclusions contain αB-crystallin, MBP, lamin A/C isoforms, and numerous other proteins.5 The toxic effects of FMR1 mRNA also result in the disruption of nuclear lamin A/C architecture and formation of perinuclear αB-crystallin aggregates in cultured neural cells.6

The role of stem cells in the origin, growth patterns, and infiltration of glioblastoma multiforme is a subject of intense investigation. One possibility is that glioblastoma may arise from transformed stem cells in the ventricular zone. To explore this hypothesis, we examined the distribution of two stem cell markers, activating transcription factor 5 (ATF5) and CD133, in an autopsy brain specimen from an individual with glioblastoma multiforme. A 41-year-old male with a right posterior temporal glioblastoma had undergone surgery, radiation, and chemotherapy. The brain was harvested within several hours after death. After formalin fixation, sectioning, and mapping of tumor location in the gross specimen, histologic specimens were prepared from tumor-bearing and grossly normal hemispheres. Fluorescence immunohistochemistry and colorimetric staining were performed for ATF5 and CD133. Both markers co-localized to the ependymal and subependymal zones on the side of the tumor, but not in the normal hemisphere or more rostrally in the affected hemisphere. ATF5 staining was especially robust within the diseased hemisphere in histologically normal ependyma. To our knowledge, this is the first in situ demonstration of stem cell markers in whole human brain. These preliminary results support the hypothesis that some glioblastomas may arise from the neurogenic zone of the lateral ventricle. The robust staining for ATF5 and CD133 in histologically normal ventricular zone suggests that an increase in periventricular stem cell activity occurred in this patient on the side of the tumor, either as a localized response to brain injury or as an integral component of oncogenesis and tumor recurrence.

Objective This is the first case report of a comprehensive neuropsychologic examination of an older man with the fragile X-associated tremor-ataxia syndrome (FXTAS). Background FXTAS, a newly identified phenotype affecting older male carriers of the fragile X premutation allele, is a progressive disorder marked by gait ataxia, action tremor, peripheral neuropathy, executive cognitive deficits, generalized brain atrophy, and neuronal and astrocytic intranuclear inclusion bodies throughout the brain. The patient previously had undergone neurologic evaluation, molecular analysis, and magnetic resonance imaging. Method The patient was administered a neuropsychologic examination, assessing motor and somatosensory functioning, visual and spatial functioning, speech and language, attention, executive abilities, learning and memory, and reasoning. Results The patient showed a pattern of cognitive impairment characterized by essentially normal speech and language, moderately impaired control of attention, and moderate to severe deficits in working memory, executive functioning, and both declarative and procedural learning. Visual and spatial abilities were relatively unimpaired, and verbal reasoning was only mildly deficient. Conclusions The findings suggest that a cognitive disorder, with especially marked executive cognitive function and memory deficits, accompanies FXTAS. The findings in FXTAS are compared with those in several other neurodegenerative disorders.

This case study describes a 65-year-old man initially diagnosed with an atypical rapidly progressive dementia who subsequently participated in a research project at the MIND Institute at the University of California-Davis, where he was diagnosed with a recently identified neurodegenerative syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS). He was a carrier of the fragile X premutation and in later life developed tremor, gait ataxia, parkinsonism, and cognitive deficits that progressed very rapidly. This case study provides a detailed description of the individual's history, presenting symptoms, neuropsychological test results, and postmortem neuropathological analysis. Pathological findings showed diagnostic features of both FXTAS and Alzheimer's disease, which might help to explain the rapid progression of his dementia.

Background Currently, there is no adequate animal model to study the detailed molecular biochemistry of fragile X syndrome, the leading heritable form of mental impairment. In this study, we sought to establish the use of immature neural cells derived from adult tissues as a novel model of fragile X syndrome that could be used to more fully understand the pathology of this neurogenetic disease. Methods By modifying published methods for the harvest of neural progenitor cells from the post-mortem human brain, neural cells were successfully harvested and grown from post-mortem brain tissue of a 25-year-old adult male with fragile X syndrome, and from brain tissue of a patient with no neurological disease. Results The cultured fragile X cells displayed many of the characteristics of neural progenitor cells, including nestin and CD133 expression, as well as the biochemical hallmarks of fragile X syndrome, including CGG repeat expansion and a lack of FMRP expression. Conclusion The successful production of neural cells from an individual with fragile X syndrome opens a new avenue for the scientific study of the molecular basis of this disorder, as well as an approach for studying the efficacy of new therapeutic agents.

Paraneoplastic limbic encephalitis (PLE) is an unusual disorder that is characterized by the association of clinical limbic system abnormalities with neoplasia, usually malignancy. It has rarely been reported in children and then manifests during the teenage years. Diagnosis is often delayed, especially when the tumor has not been recognized. In adults, the diagnosis can be revealed by the presence of antineuronal antibodies. We describe an unusual case of behavioral disturbance leading rapidly to coma in a 14-year-old girl with CSF pleocytosis who was found 10 weeks later to have an immature ovarian teratoma. Although her symptoms eventually improved slightly after tumor excision, she died while in rehabilitation. PLE is an important diagnosis to consider in the teenage girl with symptoms of a progressive limbic disorder and CSF pleocytosis, and whose brain MR imaging demonstrates no abnormality or mild T2-weighted temporal lobe signal abnormality. When this constellation of findings presents in a teenage girl, the possibility of an underlying ovarian teratoma should be considered.

ContextPremutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are frequent in the general population, with estimated prevalences of 1 per 259 females and 1 per 813 males. Several articles have recently described the presence of late-onset neurological symptoms in male carriers of premutation (FMR1) alleles. The main clinical features described in this newly identified syndrome are cerebellar ataxia and intention tremor. Additional documented symptoms include short-term memory loss, executive functional deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower-limb proximal muscle weakness, and autonomic dysfunction.ObjectiveTo study the penetrance of the fragile X–associated tremor/ataxia syndrome (FXTAS) among premutation carriers.Design, Setting, and ParticipantsFamily-based study of 192 individuals (premutation carriers and controls) whose families belong to the Northern or Southern California Fragile X Associations. Data were collected (March 2002-April 2003) through a survey and a standardized neurological examination, which was videotaped and subsequently scored in a blinded fashion.Main Outcome MeasuresPenetrance of intention tremor and ataxia among adult carriers (aged ≥50 years) of premutation expansions of the FMR1 gene.ResultsData from the survey of 192 individuals demonstrated an age-related penetrance of the combination of reported intention tremor and gait ataxia in male carriers (17%, 38%, 47%, and 75% [lower-bound estimates] for participants aged 50-59, 60-69, 70-79, and ≥80 years, respectively). The male carrier group had an age-adjusted 13-fold increased risk (95% confidence interval, 3.9-25.4; P = .003) of combined intention tremor and gait ataxia when compared with male controls. The clinical examination data from 93 individuals demonstrated that male carriers experienced more difficulties on each of 3 standardized neurological rating scales compared with controls (P

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 syndrome is a neurodevelopmental disorder that is not known to have any progressive neurological sequelae in adulthood. However, a neurological condition involving intention tremor, ataxia, and cognitive decline has recently been identified among older male carriers of premutation alleles of the FMR1 gene. This condition is clinically distinct from fragile X syndrome and arises through a different molecular mechanism involving the same gene (FMR1). Characteristic findings on magnetic resonance imaging include cerebral and cerebellar volume loss and altered signal intensities of the middle cerebellar peduncles. A striking feature of this fragile X-associated tremor/ataxia syndrome is the presence of ubiquitin-positive neuronal and astroglial intranuclear inclusions. Unlike the CAG repeat expansion diseases, which lead to altered protein products, there is no known protein abnormality among FMR1 premutation carriers. Thus, inclusion formation may reflect a gain-of-function effect of the FMR1 mRNA or the CGG repeat itself. Finally, since this syndrome may represent one of the more common single-gene causes of tremor, ataxia, and dementia among older males, FMR1 DNA testing should be considered when evaluating adult patients with tremor/ataxia.

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.

Rett syndrome (RTT) is an X-linked, dominant neurodevelopmental disorder caused by mutations in MECP2, encoding the methyl-CpG-binding protein 2 (MeCP2). A major paradox in the pathogenesis of RTT is how mutations in ubiquitously transcribed MECP2 result in a phenotype specific to the central nervous system (CNS) during postnatal development. To address this question, we have used a novel approach for quantitating the level and distribution of wild-type and mutant MeCP2 in situ by immunofluorescence and laser scanning cytometry. Surprisingly, cellular heterogeneity in MeCP2 expression level was observed in normal brain with a subpopulation of cells exhibiting high expression (MeCP2(hi)) and the remainder exhibiting low expression (MeCP2(lo)). MeCP2 expression was significantly higher in CNS compared with non-CNS tissues of human and mouse by automated quantitation of MeCP2 on multiple tissue arrays. Quantitative localization of MeCP2 expression phenotypes in normal human brain showed a mosaic, but distinct, distribution pattern, with MeCP2(hi) neurons highest in layer IV of the cerebrum and MeCP2(lo )neurons highest in the granular layer of the cerebellum. In female RTT brains, MECP2 mutant-expressing cells were identified as cells negative for the MeCP2 C-terminal epitope. MECP2 mutant-expressing cells were randomly localized in Rett cerebrum and cerebellum and showed normal MeCP2 expression with N-terminal-specific anti-MeCP2. These results demonstrate a CNS-specific cellular phenotype of MeCP2 high expression and suggest that MECP2 mutations in RTT are only manifested in MeCP2(hi) cells. In addition, our results demonstrate the power of laser scanning cytometry in examining complex cellular phenotypes in disease pathogenesis.

Objective: To determine the frequency of calpain III mutations in a heterogeneous limb–girdle muscular dystrophy (LGMD) population. Background: Mutations of the calpain III gene have been shown to cause a subset of autosomal recessive LGMDs. Patient populations studied to date have been primarily of French and Spanish origin, in which calpain III may cause 30% of autosomal recessive MDs. The incidence of calpain III mutations in non–French/Spanish MD patients has not been studied thoroughly. No sensitive and specific biopsy screening methods for detecting patients with abnormal calpain III protein are available. Thus, detection of patients relies on direct detection of gene mutations. Methods: The authors studied the calpain III gene in 107 MD patient muscle biopsies exhibiting normal dystrophin. Muscle biopsy RNA was produced for each patient, and the entire calpain III complementary DNA was screened for mutations by reverse-transcriptase PCR/single-strand conformation polymorphism using three different conditions. Results: The authors identified nine patients (eight unrelated) with causative mutations. Six of the seven distinct mutations identified are novel mutations and have not been described previously. Conclusion: The results suggest that approximately 9.2% of patients in the heterogeneous population with an LGMD diagnosis will show mutations of the calpain III gene. Interestingly, two patients were heterozygous for a single mutation at the DNA level, whereas only the mutant allele was observed at the RNA level. This suggests that there are undetectable, nondeletion mutations that ablate expression of the calpain III gene.

Some patients with autosomal recessive limb-girdle muscular dystrophy have mutations in the genes coding for the sarcoglycan proteins (alpha-, beta-, gamma-, and delta-sarcoglycan). To determine the frequency of sarcoglycan-gene mutations and the relation between the clinical features and genotype, we studied several hundred patients with myopathy.Antibody against alpha-sarcoglycan was used to stain muscle-biopsy specimens from 556 patients with myopathy and normal dystrophin genes (the gene frequently deleted in X-linked muscular dystrophy). Patients whose biopsy specimens showed a deficiency of alpha-sarcoglycan on immunostaining were studied for mutations of the alpha-, beta-, and gamma-sarcoglycan genes with reverse transcription of muscle RNA, analysis involving single-strand conformation polymorphisms, and sequencing.Levels of alpha-sarcoglycan were found to be decreased on immunostaining of muscle-biopsy specimens from 54 of the 556 patients (10 percent); in 25 of these patients no alpha-sarcoglycan was detected. Screening for sarcoglycan-gene mutations in 50 of the 54 patients revealed mutations in 29 patients (58 percent): 17 (34 percent) had mutations in the alpha-sarcoglycan gene, 8 (16 percent) in the beta-sarcoglycan gene, and 4 (8 percent) in the gamma-sarcoglycan gene. No mutations were found in 21 patients (42 percent). The prevalence of sarcoglycan-gene mutations was highest among patients with severe (Duchenne-like) muscular dystrophy that began in childhood (18 of 83 patients, or 22 percent); the prevalence among patients with proximal (limb-girdle) muscular dystrophy with a later onset was 6 percent (11 of 180 patients).Defects in the genes coding for the sarcoglycan proteins are limited to patients with Duchenne-like and limb-girdle muscular dystrophy with normal dystrophin and occur in 11 percent of such patients.

Background Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, and is the most common single-gene disorder known to be associated with autism. Despite recent advances in functional neuroimaging and our understanding of the molecular pathogenesis, only limited neuropathologic information on FXS is available. Methods Neuropathologic examinations were performed on post-mortem brain tissue from three older men (aged 57, 64 and 78 years) who had received a clinical or genetic diagnosis of FXS. In each case, physical and cognitive features were typical of FXS, and one man was also diagnosed with autism. Guided by reports of clinical and neuroimaging abnormalities of the limbic system and cerebellum of individuals with FXS, the current analysis focused on neuropathologic features present in the hippocampus and the cerebellar vermis. Results Histologic and immunologic staining revealed abnormalities in both the hippocampus and cerebellar vermis. Focal thickening of hippocampal CA1 and irregularities in the appearance of the dentate gyrus were identified. All lobules of the cerebellar vermis and the lateral cortex of the posterior lobe of the cerebellum had decreased numbers of Purkinje cells, which were occasionally misplaced, and often lacked proper orientation. There were mild, albeit excessive, undulations of the internal granular cell layer, with patchy foliar white matter axonal and astrocytic abnormalities. Quantitative analysis documented panfoliar atrophy of both the anterior and posterior lobes of the vermis, with preferential atrophy of the posterior lobule (VI to VII) compared with age-matched normal controls. Conclusions Significant morphologic changes in the hippocampus and cerebellum in three adult men with FXS were identified. This pattern of pathologic features supports the idea that primary defects in neuronal migration, neurogenesis and aging may underlie the neuropathology reported in FXS.

A term male infant is described with an isolated disorder of peripheral myelination. At necropsy, the great majority of medium-to-large axons were unmyelinated. Electron microscopy showed normal axons and redundant lamination of basement membrane, suggestive of early onion bulb pathology. Immunohistochemistry of peripheral nerve showed deficiency of the myelin proteins P2 and P0, myelin basic protein, and myelin-associated glycoprotein. Arrest of peripheral myelination at the promyelin stage appears to be the origin of myelin deficiency.

Fragile X syndrome is generally considered to be a non-progressive neurodevelopmental disorder in which carriers of premutation alleles (~55 to 200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene are largely unaffected. However, we have recently identified a new syndrome among male carriers, characterised by tremor and/or ataxia, cognitive deficits, parkinsonism, and autonomic dysfunction.1,5,6,8,10 Neuroradiological findings include moderate to severe cortical atrophy (cerebral and cerebellar cortical volume loss) and characteristic hyperintensities on T2-weighted MR imaging of the deep cerebellar white matter and middle cerebellar peduncles.2,8 The disorder, termed fragile X associated tremor/ataxia syndrome,8 has been observed thus far almost exclusively in older adult male premutation carriers of more than 50 years of age. Eosinophilic intranuclear inclusions are broadly distributed in both neurones and astrocytes throughout the cerebrum and brain stem of all persons with fragile X associated tremor/ataxia syndrome (FXTAS) examined to date (8/8),5,7 with the greatest numbers of neuronal inclusions found in the hippocampus. No inclusions were detected in the Purkinje cells, although axonal degeneration and Purkinje cell loss were prominent findings in the cerebellum.5 Premutation carriers generally have elevated FMR1 mRNA levels, suggesting that FXTAS could result from a toxic gain of function of the FMR1 mRNA.5,6,8 To determine whether inclusion formation and clinical involvement are associated with allelic mosaicism, we defined the size of the CGG expansion and the relative expression levels of the FMR1 gene in various regions of the brain of a male premutation carrier who died with neurological symptoms consistent with FXTAS, and whose neural cells possessed numerous intranuclear inclusions. Analysis of multiple brain regions was undertaken to demonstrate that premutation alleles were directly associated with inclusion formation, and that full mutation alleles, even if present at …

The fragile X premutation has recently been reported to be associated with a neurodegenerative syndrome, chiefly characterized by intention tremor, gait ataxia, and executive cognitive deficits in men older than 50 years. Essential tremor is a frequent cause of tremor in elderly patients and in some cases is associated with impaired tandem gait and cognitive deficits.To describe 2 fragile X carriers whose clinical presentation mimicked essential tremor.The 2 patients described herein underwent neurologic examinations by experienced movement disorders neurologists, magnetic resonance imaging, and fragile X gene, messenger RNA, and protein analyses. One underwent detailed neuropsychological testing.Patients were studied at 2 large university movement disorders clinics.Both patients were white men older than 50 years who had been diagnosed as having essential tremor and then found to be fragile X carriers.Besides disabling intention tremor, the 2 patients had impaired tandem, generalized brain atrophy, and unusual bilateral T2 middle cerebellar hyperintensities on magnetic resonance imaging. The patient who underwent neuropsychological testing had frontal executive deficits. Both patients had elevated fragile X mental retardation gene 1 messenger RNA and reduced fragile X mental retardation 1 protein levels.The fragile X carrier state may underlie the clinical findings in some older men diagnosed as having essential tremor.

The myopathy caused by zidovudine (AZT) appears to be common but is incompletely characterized, particularly regarding prognosis. Twenty patients with HIV infection developed a necrotizing myopathy while taking AZT for 9 to 30 months. Ten presented with myalgia and 17 with proximal muscle weakness. Serum CK was elevated in all (two to 11 times normal), and EMG suggested active myopathy in all but two. There were scattered granular degenerating fibers, with scant or no inflammation, in a pattern consistent with a toxic myopathy in all 18 patients biopsied. Three patients with an HIV-related inflammatory myopathy were distinguished by histologic differences. After stopping AZT (n = 15), myalgia promptly resolved (10 of 10). Strength improved more slowly with 12 of 15 regaining normal or nearly normal strength, but three have persistent weakness. CK returned to normal in 12 of 15, and follow-up EMG (n = 11) documented reduced fibrillation density in all 11 patients. These findings underscore the need for early diagnosis of this reversible myopathy.

We present 7 HIV-infected patients with a unique, subacute, progressive polyradiculopathy. All had AIDS, sacral sensory loss, acute urinary retention, and progression to flaccid paraparesis in days to weeks. Cytomegalovirus was cultured from spinal fluid of 4 patients, and postmortem examination on the 1st 5 patients disclosed an inflammatory polyradiculopathy with cytomegalic inclusions. The inclusion-bearing cells were immunocytochemically positive for cytomegalovirus. Two patients who received early anti-cytomegalovirus treatment with ganciclovir improved. Thus, early recognition and treatment with ganciclovir may be effective in this otherwise fatal condition.

Spontaneous regression of metastatic neoplasia is rare. A review of previously reported spontaneous regressions of testicular cancer indicates that in no case has such a patient had a prior, concurrent, or subsequent contralateral tumor. The case presented is unusual because it is the first instance of bilateral sequential testicular cancer in which spontaneous regression of metastases from one of the tumors has been noted. Together with a previous report of a spontaneous regression of testicular cancer which occurred only after a second orchiectomy, the present case suggests the possibility of hormonal modulation of tumor growth.

Two continuous human glioma derived cell lines, LI and DF, were established in our laboratory. Both cell lines showed cytological features and in vitro behavior similar to those of the respective original neoplasms. These two lines were characterized for their main biological properties including in vitro and in vivo growth rate, clonogenic ability and tumorigenicity in nude mice. The plating efficiencies were generally high both during exponential and stationary growth phases and a high tumorigenicity was observed. All injected nude mice developed tumors. The two lines were tested for chemosensitivity to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and cis-Diamminedichloroplatinum II (DDP). Heterogeneity in biological features and in drug sensitivity was observed. Exposure of the two lines to BCNU and DDP showed that the glioblastoma (LI) was less sensitive than the anaplastic astrocytoma (DF). For both lines BCNU was more effective on cells in plateau than in exponential phase, while the killing effect of DDP was not phase-dependent.

• We report the first published case (to our knowledge) of histopathologically documented acquired immunodeficiency syndrome-related cytomegalovirus (CMV) myelitis in which antiviral drug therapy was administered. Despite sensitivity of the patient's CMV isolate to therapy with both ganciclovir and foscarnet, use of neither of these agents halted progression of central nervous system CMV disease. Higher doses of these drugs or combination therapy may be required to treat acquired immunodeficiency syndrome-related CMV myelitis effectively.

• An unusual myopathy characterized by selective loss of thick filaments and widespread formation of rod bodies is described in two men, both seropositive for human immunodeficiency virus. We were unable to find any previous reports documenting this combination of morphological abnormalities, which we believe may be related to human immunodeficiency virus infection. Both patients responded to treatment: one, to steroid therapy; the other, to plasmapheresis.

Six cell lines were derived from pleural effusions of two lung cancer patients and established in vitro in our laboratory. Cell line AE1 was obtained from a small cell lung cancer (SCLC) before the patient had received any chemotherapy; the other lines (AE2 and AE3) were established from tumour recurrences in the same patient after therapy. Cell lines DG1 and DG2 were derived from specimens of an untreated non-small cell lung cancer (NSCLC), while cell line DG3 originated from pleural effusions recurring in the same patient after therapy. The results of the present study show that: (a) the SCLC lines AE1, AE2 and AE3 are heterogeneous in their biological characteristics and in their chemosensitivity patterns. In particular lines AE2 and AE3 are less responsive to cis-Platinum (DDP) and Adriamycin (ADM) than line AE1, so that they may reflect resistant subpopulations existing within the original tumour, selected following therapy with these drugs. In contrast, however, line AE1 proved more resistant to Vepesid (VP16) than lines AE2 and AE3. (b) The three NSCLC lines are similar in various biological features as well as in their chemosensitivity to DDP and Vinblastine (VBL).

Excerpt To the editor: Although involvement of the meninges is a well-known complication of carcinoma and lymphoma, such involvement in Hodgkin's disease is not. In April 1977, excision of a left i...

Lack of the fragile X mental retardation protein leads to Fragile X syndrome (FXS) while increased levels of FMR1 mRNA, as those observed in premutation carriers can lead to Fragile X- associated tremor ataxia syndrome (FXTAS). Until recently, FXTAS had been observed only in carriers of an FMR1 premutation (55–200 CGG repeats); however the disorder has now been described in individuals carriers of an intermediate allele (45–54 CGG repeats) as well as in a subject with a full mutation with mosaicism. Here, we report on molecular and clinical data of a male FMR1 mosaic individual with full and premutation alleles. Molecular analysis of FMR1 and FMRP expression in this subject is consistent with a FXS phenotype. We observed reduced expression of FMRP in both peripheral blood and brain leading to the FXS diagnosis. In addition, a dramatic 90% depletion of both FMR1 mRNA and FMRP levels was observed in the blood, as normally observed in FXS cases, and an even greater depletion in the brain. A clinical report of this patient, at age 71, described neurodegenerative signs of parkinsonism that were likely, in retrospect, part of a FXTAS scenario as post-mortem examination shows the presence of intranuclear inclusions, the hallmark pathology of FXTAS. The findings presented in this study indicate co-morbidity for both FXS and FXTAS in this individual carrying both full and premutation FMR1 alleles. In addition, based on symptoms and pathological and molecular evidence, this report suggests the need to redefine the diagnostic criteria of FXTAS.