A mutation in myotilin causes spheroid body myopathy.

BACKGROUND: Spheroid body myopathy (SBM) is a rare, autosomal dominant, neuromuscular disorder, which has only been previously reported in a single large kindred. Identification of the mutated gene in this disorder may provide insight regarding abnormal neuromuscular function. METHODS: The authors completed a detailed clinical evaluation on an extensive kindred diagnosed with SBM. Genome-wide linkage analysis was performed to localize the disease gene to a specific chromosomal region. Further marker genotyping and screening of a positional, functional candidate gene were completed to detect the disease-causing mutation. Pathologic analysis of muscle biopsy was performed on three individuals. Biochemical studies were performed on one muscle biopsy specimen from an affected individual. RESULTS: Linkage to chromosome 5q23-5q31 was detected with a lod score of 2.9. Genotyping of additional markers in a larger sample of family members produced a maximum lod score of 6.1 and narrowed the critical interval to 12.2 cM. Screening of the candidate gene titin immunoglobulin domain protein (TTID, also known as MYOT) detected a cytosine-to-thymine mutation in exon 2 of all clinically affected family members. Similar pathologic changes were present in all muscle biopsy specimens. Immunohistologic and biochemical analysis revealed that the TTID protein, also known as myotilin, is a component of the insoluble protein aggregate. CONCLUSIONS: A novel mutation in the TTID gene results in the clinical and pathologic phenotype termed "spheroid body myopathy." Mutations in this gene also cause limb-girdle muscular dystrophy 1A and are associated with myofibrillar myopathy.

Intense p53 staining is a valuable prognostic indicator for poor prognosis in medulloblastoma/central nervous system primitive neuroectodermal tumors.

UNLABELLED: Intense p53 immunostaining may predict for a poor prognosis in central nervous system primitive neuroectodermal tumor of childhood. BACKGROUND: Medulloblastoma is a common childhood primary brain tumor. Potential prognostic indicators for patients with local disease are age, extent of resection, and gender. However, none of these are well established. Immunohistologic staining is a potentially useful means to identify high-risk patients. The purpose of this clinical pathologic study was to investigate the prognostic significance of GFAP, synaptophysin, Ki-67, and p53 immunostaining in medulloblastoma/central nervous system primitive neuroectodermal tumors (CNS PNETs.) MATERIALS AND METHODS: The records of 40 patients with CNS PNETs were reviewed. Their surgical specimens were immunostained for p53, glial fibrillary acidic protein (GFAP), synaptophysin, and Ki-67. The p53 specimens were scored blindly for the intensity of staining of nuclei (intense vs weak) and the quantity of cells stained. The Ki-67, GFAP, and synaptophysin specimens were analyzed for quantity of cells stained. RESULTS: Ten patients' specimens stained intensely for the p53 protein. Eleven had weakly staining nuclei. Nineteen specimens had no staining. The patients with specimens that stained intensely had a statistically significant decreased disease free survival (P = 0.03). Mere presence or quantity of p53 nuclear staining did not correlate with disease free survival. Immunohistochemical staining for Ki-67, GFAP, and synaptophysin did not correlate with disease free survival. Clinical parameters of age, gender, and extent of resection also did not approach statistical significance for disease free survival. CONCLUSION: Intense nuclear staining for p53 was the only variable in this clinical pathologic study that reached statistical significance for disease free survival. This suggests that intense staining for p53 may be the most important prognostic indicator for non-metastatic CNS PNETs. p53 Immunostaining with antibodies against p53 in CNS PNETs should be studied in a multi-institutional setting with larger numbers of patients.

Recurrence in pituitary adenomas in childhood and adolescence.

Pediatric pituitary adenomas are thought to behave more aggressively than their adult counterparts, and the ability to predict the degree of such behavior remains elusive. Proliferation marker Ki-67 and tumor suppressor gene p53 mutations have been used in adults to assist in the evaluation of invasiveness and recurrence; however, their use in childhood and adolescence remains anecdotal. Our study evaluates the proliferative potential in pituitary adenomas of five patients and its relationship with recurrence or persistence of endocrinologic or clinical abnormalities. For such assessment, tissues were stained with monoclonal antibodies BP53-12 forp53 tumor suppressor gene mutation and MIB-1, which binds to cell cycle-specific nuclear antigen Ki-67. In our series, one patient with recurrent adenoma demonstrated the highest (50%) p53 immunoreactivity. Ki-67-stained nuclei ranged from 0 to 2%, failing to identify the recurrent tumor. Therefore, p53 immunoreactivity, rather than Ki-67 nuclear stain, may be useful for identification of recurrent pituitary adenomas in childhood and adolescence.

Genetic evidence that Shp-2 tyrosine phosphatase is a signal enhancer of the epidermal growth factor receptor in mammals.

By using both genetic and biochemical approaches, we have investigated the physiological role of Shp-2, a cytoplasmic tyrosine phosphatase with two Src homology 2 domains, in signaling pathways downstream of epidermal growth factor receptor (EGF-R). In previous studies, a targeted deletion mutation in the SH2-N domain of Shp-2 was introduced into the murine Shp-2 locus, which resulted in embryonic lethality of homozygous mutant (Shp-2(-/-)) mice at midgestation. By aggregating Shp-2(-/-) embryonic stem cells with wild-type embryos, we created Shp-2(-/-)/wild-type chimeric animals. Most chimeras had open eyelids at birth and abnormal skin development, a phenotype characteristic of mice with mutations in EGF-R signaling components. In genetic crosses, a heterozygous Shp-2 mutation dominantly enhanced the phenotype of a weak mutant allele of EGF-R (wa-2), resulting in distinctive growth retardation, developmental defects in the skin, lung, and intestine, and perinatal mortality that are reminiscent of EGF-R knockout mice. Biochemical analysis revealed that signal propagation proximal to the EGF-R upon EGF stimulation was significantly attenuated in wa-2 fibroblast cells, which was exacerbated by the additional Shp-2 mutation. Thus, we provide biological evidence here that protein-tyrosine phosphatase Shp-2 acts to enhance information flow from the EGF-R in mouse growth and development.

Presurgical evaluation and surgical outcome of temporal lobe epilepsy.

The authors analyzed 22 patients younger than 18 years of age with temporal lobe epilepsy (TLE) treated surgically. Patients underwent a comprehensive presurgical evaluation, including video-electroencephalogram. Fifty-five percent had a history of febrile seizures. Eighty-two percent had auraes and most exhibited oroalimentary and gestural automatisms. Contralateral dystonic posturing was present in 36% and postictal dysphasia in 54% of patients with left-sided resections. Cranial magnetic resonance imaging (MRI) was abnormal in 59% of patients. MRI revealed changes consistent with mesial temporal sclerosis in 8 (47%) of 17 patients without lesions. Fluorodeoxyglucose-positron emission tomography (PET) scans revealed ipsilateral temporal hypometabolism (PET-TH) in 12 (85.7%) of 14 patients. The intracarotid amobarbital procedure revealed impaired memory of the epileptogenic side in 59% of patients. Seventeen patients underwent en-bloc resections and five lesionectomies and resection of the epileptogenic area. There was no surgical morbidity or mortality. Forty-three percent had hippocampal sclerosis, 28.5% gliosis, 14% low-grade tumors, 9.5% cavernous angiomas, and 5% had no pathologic findings. Follow-up (6 months to 12 years) was available for 21 patients; 76% became seizure free, 19% had rare seizures, and 5% had a worthwhile improvement. TLE can be safely treated surgically in younger patients with excellent results. The clinical manifestations were similar to adult patients. PET-TH was present even at a younger age, suggesting that the focal functional deficits appear early in patients with medically refractory TLE, which may help in the early identification of these patients.

Neuro-ophthalmic, radiographic, and pathologic manifestations of adult-onset Alexander disease.

A 61-year-old woman had a 3-year history of imbalance. Eye movement studies revealed square-wave jerks, gaze paretic nystagmus, rebound nystagmus, impaired smooth pursuit, impaired optokinetic nystagmus, and abnormal fixation suppression of vestibular nystagmus. A brain magnetic resonance imaging study showed extensive areas of increased signal from the middle cerebellar peduncles and dentate nuclei, which enhanced with gadolinium. Histopathological analysis of a needle biopsy specimen of the left cerebellar peduncle revealed diffuse gliosis in the presence of symmetrically distributed areas of demyelination. There were associated Rosenthal fibers. Clinicopathologic correlation supported a diagnosis of Alexander disease. An adult patient with a history of progressive imbalance, ocular motility abnormalities consistent with cerebellar and/or brainstem dysfunction, and diffuse, symmetric hyperintense magnetic resonance imaging signals in brainstem and cerebellar white matter should suggest a diagnosis of adult-onset Alexander disease.

Biased suppression of hematopoiesis and multiple developmental defects in chimeric mice containing Shp-2 mutant cells.

Shp-2 is a cytoplasmic tyrosine phosphatase that contains two Src homology 2 (SH2) domains at the N terminus. Biochemical data suggests that Shp-2 acts downstream of a variety of receptor and cytoplasmic tyrosine kinases. A targeted deletion mutation in the N-terminal SH2 (SH2-N) domain results in embryonic lethality of homozygous mutant mice at midgestation. In vitro embryonic stem (ES) cell differentiation assays suggest that Shp-2 might play an important role in hematopoiesis. By aggregating homozygous mutant (Shp-2(-/-)) ES cells and wild-type (WT) embryos, we created Shp-2(-/-)-WT chimeric animals. We report here an essential role of Shp-2 in the control of blood cell development. Despite the widespread contribution of mutant cells to various tissues, no Shp-2(-/-) progenitors for erythroid or myeloid cells were detected in the fetal liver and bone marrow of chimeric animals by using the in vitro CFU assay. Furthermore, hematopoiesis was defective in Shp-2(-/-) yolk sacs. In addition, the Shp-2 mutation caused multiple developmental defects in chimeric mice, characterized by short hind legs, aberrant limb features, split lumbar vertebrae, abnormal rib patterning, and pathological changes in the lungs, intestines, and skin. These results demonstrate a functional involvement of Shp-2 in the differentiation of multiple tissue-specific cells and in body organization. More importantly, the requirement for Shp-2 is more stringent in hematopoiesis than in other systems.

FDG-PET and MRI in temporal lobe epilepsy: relationship to febrile seizures, hippocampal sclerosis and outcome.

OBJECTIVE: To correlate the volumetric head magnetic resonance imaging (MRI) and fluorodeoxyglucose-positron emission tomography (FDG-PET) scan findings with the history, intracarotid amobarbital procedure, pathology, and outcome in patients with medically refractory temporal lobe epilepsy. MATERIAL AND METHODS: Thirty-eight patients with temporal lobe epilepsy treated surgically following a comprehensive presurgical evaluation. Follow-up ranged from 12 to 44 months. RESULTS: Volumetric MRI showed ipsilateral hippocampal atrophy in 29 (76%), and PET scan showed ipsilateral temporal hypometabolism (PET-TH) in 31 (81.5%) of patients. Eighty-three percent of those patients with hippocampal sclerosis on MRI (MRI-HS) had ipsilateral PET-TH. Sixty-six percent of patients with MRI-HS had a history of prolonged febrile convulsions or a childhood febrile illness accompanied by convulsions, and 77% of patients with MRI-HS had pathologically proven hippocampal sclerosis (HS). Ninety percent became seizure free or had rare seizures. CONCLUSION: FDG-PET scans and head MRIs were complementary; 95% of patients had either MRI-HS or temporal hypometabolism. MRI-HS correlated with a history of febrile seizures and pathologically demonstrated hippocampal sclerosis. Ninety-three percent of patients had focal functional deficits on the epileptogenic side. Concordance between PET temporal hypometabolism and MRI-HS correlated with better outcome.

Primary intravascular lymphomatosis associated with Mycobacterium marinum.

Intravascular lymphomatosis (i.v.l.) is a rare condition in which neoplastic cells preferentially infiltrate blood vessels of the central nervous system. Nonspecific symptoms associated with i.v.l. include dementia, seizures, and multifocal cerebrovascular events. i.v.l. was discovered at autopsy of a patient whose neurological deficits were predated by a particularly aggressive form of Mycobacterium marinum soft-tissue infection. It is speculated that i.v.l. may have had an occult effect on the patient's cell-mediated immunity that predisposed him to this normally innocuous mycobacteria.

The jugular foramen: a review of anatomy, masses, and imaging characteristics.

A variety of lesions may occur in the jugular foramen, arising from the structures normally found within the jugular foramen or from contiguous structures. The most common jugular foramen lesions are nontumoral pseudolesions (eg, asymmetrically enlarged jugular foramen, high or protruding jugular bulb) and tumors (eg, paraganglioma, metastasis). In nontumoral pseudolesions, computed tomography (CT) demonstrates smooth, intact margins of the jugular foramen. Turbulent or slow flow in a high or protruding jugular bulb can result in loss of the flow void and contrast enhancement at magnetic resonance (MR) imaging, thereby mimicking real disease. Use of flow-sensitive techniques or MR angiography will help clarify confusing cases. In cerebral venous thrombosis, CT findings are often normal. At conventional MR imaging, flow-related enhancement and in-plane, turbulent, or slow flow can cause loss of the flow void and thus mimic thrombosis. Consequently, phase-contrast MR venography is the imaging modality of choice in the assessment of cerebral venous thrombosis. Most tumoral lesions of the jugular foramen manifest at CT as areas of infiltrative bone destruction, although schwannoma and meningioma cause smooth enlargement of the jugular foramen. In addition, most of these tumors have low to intermediate signal intensity on T1-weighted MR images and intermediate to high signal intensity on T2-weighted MR images and enhance strongly after the administration of contrast material. Careful analysis of these imaging features and correlation with clinical manifestations can allow a more specific diagnosis.

Spheroid body myopathy revisited.

Having reported spheroid body myopathy from Indiana (IN) inherited in an autosomal-dominant fashion several years ago, we now describe additional findings from the Oregon branch--briefly recorded earlier--and confirm earlier studies in another clinically affected IN member of this kinship demonstrating identical spheroid bodies within the myopathic muscle specimens. The spheroid bodies also contained increased amounts of desmin, alpha-B crystallin, and ubiquitin within muscle fibers. Our studies now have established that spheroid body myopathy is a member of the growing family of desminopathic neuromuscular conditions.

Flow cytometric DNA analysis of pediatric intracranial ependymomas.

OBJECTIVE: To examine the clinicopathologic features and perform flow cytometric DNA analysis of pediatric intracranial ependymomas to determine whether any of these parameters were predictors of clinical outcome. METHODS: Flow cytometric DNA analysis was performed on 17 paraffin-embedded tumors from patients aged 7 months to 16 years. RESULTS: Seven cases were aneuploid, while the remaining 10 were diploid. Proliferative fractions varied from 1% to 17%. CONCLUSIONS: No correlation between histologic features such as mitotic activity, cellularity, pleomorphism, vascular proliferation, and length of survival was observed. However, the presence of a diploid DNA stemline, elevated proliferative fraction, or young age were associated with a poor clinical outcome and shortened survival times (P < 0.05). Additional studies of larger patient groups with extended follow-up are necessary to confirm these findings.

Neuropathy and vasculopathy in colonic strictures from children with cystic fibrosis.

Colonic strictures are rare in patients who have cystic fibrosis, but recently have developed in those who have been treated with delayed-release high-dose pancreatic enzyme supplements. Colonic strictures from eight such pediatric patients showed neural abnormalities consisting of ganglion cell hyperplasia and ectopia, and intermyenteric plexus hyperplasia. Cholinergic and adrenergic stains of mucosal nerve fibers were more prominent in histological sections of the cystic fibrosis strictures than in sections from colons of children without cystic fibrosis. The mean grade of staining with acetylcholinesterase in the lamina propria of the strictured cystic fibrosis colons was 2.38 +/- 1.25, compared with .93 +/- .93 (P < .055) in bowels from children without cystic fibrosis. The mean grade for tyrosine hydroxylase staining in the lamina propria was 2 +/- .97 in the strictures and was .79 +/- .81 (P < .05) in the bowels of children who did not have cystic fibrosis. Vasoactive intestinal peptide staining in bowels from children with cystic fibrosis with and without stricture did not differ significantly from that of children without cystic fibrosis. Vasculopathy consisting of fibrointimal hyperplasia in submucosal veins and mesenteric arteries was found only in colonic strictures owing to cystic fibrosis. Colonic strictures in patients with cystic fibrosis who received high-dose pancreatic enzyme supplements contain ganglion cell abnormalities, and mucosal cholinergic and adrenergic activity may be increased in these strictures. The stricture vasculopathy may be drug-related and/or related to increased catecholamine activity.

Hypoxic-ischemic encephalopathy in areas of primary myelination: a neuroimaging and PET study.

The stage of regional structural and biochemical development of the central nervous system appears as a critical factor determining the distribution of hypoxic-ischemic lesions during the perinatal period. We describe the brain lesions in 12 patients who suffered hypoxia-ischemia during the perinatal period. The gestational age ranged from 35 to 42 weeks and the age at death from 2 to 16 weeks. There is one patient alive at age 18 years and a second patient at age 1 year. The cerebral cortical damage is mainly restricted to areas of primary myelination and adjacent subcortical white matter. In addition, there is thalamic, basal ganglia, brainstem, and spinal cord damage. It is postulated that selective damage occurs in those areas which at the moment of the hypoxic-ischemic insult had achieved higher rates of oxygen-glucose utilization. This hypothesis is supported by studies utilizing positron emission tomography which indicates that glucose utilization in the normal human neonatal brain follows a phylogenetic order. Regions that achieved higher levels of glucose consumption are those that suffered the brunt of the damage in our term neonates.

Malignant fibrous histiocytoma in a 9-year-old girl.

A case of malignant fibrous histiocytoma in the left temporoparietal region of a 9-year-old girl is reported. The tumor was cystic with a mural nodule. Microscopically, the tumor focally infiltrated the leptomeninges sparing the dura mater, and was composed of glial fibrillary acidic protein-negative cells suspended in a rich meshwork of reticulin fibers. Electron microscopy showed the presence of extensive thin processes on the cell's surface and lysosomal-like inclusions in the cytoplasm. No basal lamina was present around the cells. The clinical and pathologic features of this case were compared with those of previous cases described in the world literature.

Intermittent diplopia and strabismus caused by ocular neuromyotonia.

PURPOSE: Two cases illustrate the symptoms, signs, etiologies, and treatment of ocular neuromyotonia (ONM). METHODS: The histories, neuroradiologic tests, and/or biopsy revealed the etiologies of ONM in both patients. Clinical observations, videotaping, and electronic eye movement recordings documented the eye movements. RESULTS: A 72-year-old man with chronic arachnoiditis following myelography with thorium dioxide (Thorotrast) developed intermittent diplopia and a partial right third nerve palsy. Left gaze induced spasm of the right medial rectus. Right gaze produced right lateral rectus spasm. A 66-year-old woman, who had radiation treatment for a pituitary tumor and acromegaly, had intermittent spasm of the left medial rectus muscle and left esotropia. The episodes occurred spontaneously and were induced by right gaze. A left internuclear ophthalmoplegia was also found. Carbamazepine (Tegretol) abolished the ONM in both patients. CONCLUSIONS: Although ONM is an unusual cause of intermittent diplopia and strabismus, its distinctive clinical features identify it. Injury to the peripheral cranial nerves probably leads to segmental demyelination, axonal hyperexcitability, and a self-perpetuating, reverberating circuit, which causes spasms of the extraocular muscles.

Gliofibroma: CT and MRI.

We describe CT and MRI appearances in two children with pathologically proven gliofibromas, in the cerebrum and cerebellum. A striking finding was lack of high signal on T2-weighted MRI.