Adult-onset MLD: a gene mutation with isolated polyneuropathy.

A 22-year-old man presented with recurrent ulnar mononeuropathies and diffusely slow nerve conduction velocities. Arylsulfatase A (ASA) activity from leukocytes and fibroblasts was reduced, and urinary sulfatides were increased. Sural nerve biopsy revealed a reduction in myelinated fibers and Schwann cell inclusions. Results of studies of CNS integrity, including cranial MRI, evoked potentials, and neuropsychologic tests, were normal. Molecular genetic analyses revealed a novel homozygous missense mutation (Thr286Pro) in the ASA gene.

Correlation of tumor p53 and PCNA with response and survival of glioblastoma in patients treated with an ECOG protocol of pre-irradiation chemotherapy.

BACKGROUND: The ability to predict treatment responsiveness and survival of patients with glioblastoma multiforme, the most malignant and most common primary brain tumor, would be a valuable asset. Tumor and proliferation markers such as p53 and PCNA have been immunohistochemically defined and have been useful in other tumors in determining prognosis. Therefore, the authors studied the correlation of responsiveness to treatment, time to progression and survival with p53 and PCNA labeling indices in a pre-irradiation chemotherapy study of the glioblastoma multiforme. METHODS: Immunohistopathology for labeling indices for p53 and PCNA using formalin-fixed, paraffin-embedded tissue from the glioblastomas of 23 patients entered into a phase II ECOG trial of pre-irradiation chemotherapy were defined using the streptavidin-peroxidase technique with AEC chromogen. The labeling indices were correlated with response to treatment time to progression and overall survival. Most patients received three cycles of BCNU for three days over three months and cisplatin monthly for three days over three months prior to external beam irradiation. RESULTS: There were no significant differences in treatment response, time to progression or overall survival in glioblastoma, patients with positive p53 labeling index (> 5%) versus a negative p53 labeling index (< or = 5%) or positive PCNA labeling (> 10%) versus a negative labeling index (< or = 10%) or any combination of P53 and PCNA labeling indices. CONCLUSIONS: Using this protocol of pre-irradiation chemotherapy, p53 and PCNA labeling indices in the glioblastoma multiforme did not predict treatment benefit.

Autosomal dominant Emery-Dreifuss dystrophy due to mutations in rod domain of the lamin A/C gene.

BACKGROUND: Autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD-AD) is a disorder characterized clinically by humeropelvic weakness, contractures, and cardiomyopathy, and genetically by mutations in the lamin A/C gene on 1q21.2-q21.3. Of the 14 lamin A/C gene mutations reported thus far, the four involving the rod domain have been associated with isolated cardiomyopathy and conduction-system disease. This is the first report of rod domain mutations in patients with the full EDMD-AD phenotype. METHODS: Clinical, pathologic, and genetic data are provided on two families with EDMD-AD. RESULTS: In both families, the full clinical spectrum of EDMD-AD was demonstrated. For the proband in family 1, sequence analysis detected a mutation within exon 2 of the lamin A/C gene. The missense mutation was due to a A448C base substitution causing a Thr150Pro amino acid change. For the proband of family 2, sequence analysis detected an in-frame 3-bp deletion (AAG 778-780 or 781-783) removing one of two adjacent lysine residues (K 260 or 261) of exon 4. Both mutations were in the central rod domain of the lamin A/C gene. CONCLUSIONS: Mutations in the rod domain of the lamin A/C gene may cause the full clinical spectrum of EDMD-AD.

Broad immunocytochemical localization of the formylpeptide receptor in human organs, tissues, and cells.

The formylpeptide receptor (FPR), previously found only on polymorphonuclear leukocytes and monocytes/macrophages, responds to both synthetic N-formyl oligopeptides and those produced by bacteria. The cDNA for human FPR has been cloned and a rabbit polyclonal antiserum directed against a synthetic 11-amino-acid peptide corresponding to the deduced carboxy-terminus has been produced. We have now extensively characterized and used the antibody to detect FPR on normal human tissues and cell types. The receptor antigen is present on some epithelial cells, especially those with a secretory function, and on some endocrine cells, e.g., follicular cells of the thyroid and cortical cells of the adrenal. Liver hepatocytes and Kupffer cells are positive. Smooth muscle and endothelial cells are also generally positive. In the brain and spinal cord, the neurons of the motor, sensory, and cerebellar systems, and those of the parasympathetic and sympathetic systems stain positively. These data suggest that the putative endogenous agonist for FPR or an antigenically similar receptor reacts with cellular targets in the neuromuscular, vascular, endocrine, and immune systems.

The generation of encephalitogenic T cell lines from experimental allergic encephalomyelitis-resistant strains of mice.

While only a few strains of mice are susceptible to the primary induction or passive transfer of experimental allergic encephalomyelitis (EAE), the basis of EAE resistance remains unclear. In the present studies, we have defined two approaches that allow for the generation of encephalitogenic, myelin basic protein-reactive, T cell lines from EAE-resistant strains of mice. The first approach, based on the putative relevance of apoptosis to autoimmune disease, involves repeat antigenic stimulation of recently initiated T cell lines. The second approach involves the initiation of lymph node cultures in the absence of exogenous splenocytes as antigenic-presenting cells and the use of a higher antigen concentration. Both approaches lead to the generation of encephalitogenic T cell lines from EAE-resistant mouse strains and will be useful for identifying factors relevant to the pathogenesis of EAE.

Autosomal dominant centronuclear myopathy: report of a new family with clinical features simulating facioscapulohumeral syndrome.

The centronuclear myopathies are a clinically and genetically heterogeneous group of disorders which share similar histological features on muscle biopsy. The familial cases have been classified genetically as X-linked or autosomal in inheritance. The autosomal forms usually have a later onset and milder course as compared to the X-linked form. Thirteen families with autosomal dominant centronuclear myopathy have been previously described. We describe an additional family with unique clinical features which initially suggested a facioscapulohumeral syndrome.

Morphologic evidence for a preferential storage of tissue plasminogen activator (t-PA) in perivascular axons of the rat uvea.

The uveal layer is thought to hold the largest stores of tissue plasminogen activator (t-PA) within the eye. However, the uveal cell types that contain and could release t-PA to contiguous tissues and fluids have not been clearly identified. In the present study the general distribution pattern of t-PA antigen in fresh rat iris and choroid tissue was determined by immunofluorescence in preliminary light microscopic (LM) cryosections. Transmission electron microscopic (TEM) immunogold localization was then used to detect specific cellular and subcellular sites of t-PA antigen. The primary antibody was rabbit anti-mouse t-PA IgG. The immunofluorescence in preliminary LM cryosections of both tissues was most intense over discrete linear and cross-sectioned structures that resembled the contours of axon bundles. This impression was strengthened when silver impregnation highlighted similar structures in separate sections of the same tissue samples. TEM immunogold labeling of thin sections then confirmed that the t-PA antigen was confined to the axoplasm of both myelinated and unmyelinated perivascular nerve fibers in both the iris and choroid. Gold particles were not observed over axonal membranes, myelin sheaths, Schwann cells, retinal pigment epithelium or vascular endothelial cells. Ultrathin TEM cryosections of the iris showed a localization of some particles over structures that resembled tubules and vesicles within the axoplasm, but not over mitochondria. The axonal location of t-PA was shown by the co-localization of t-PA with an antibody against rat neurofilaments. The typical axon morphology that enclosed the t-PA particle markers in all TEM sections also indicated an axonal location. Separate TEM sections were processed with conventional fixatives and stains to highlight the typical uveal axon morphology, which also confirmed the identity of perivascular axons as the sites of t-PA localization. Affinity of the primary antibody for rat t-PA was shown by an inhibition ELISA against rat uveal tissue extracts and by the inhibition of t-PA activity in aqueous humor. An amidolytic assay was used to quantify t-PA activity. Possible explanations for the preferential immunolocalization of t-PA antigen to the axoplasm of uveal nerve terminals and the need for additional functional studies to confirm a putative neural t-PA synthesis are discussed.

Childhood-onset spinocerebellar syndrome associated with massive polyglucosan body deposition.

INTRODUCTION: Polyglucosan body disease (PBD) is a progressive neurological disorder beginning in adult life and associated pathologically with widespread accumulation of polyglucosan bodies (PB) in neuronal and astrocytic processes. We report the unique clinicopathological findings in an early onset spinocerebellar syndrome associated with massive PB deposition. PATIENT & METHODS: A 14-month-old male developed a slowly progressive neurological disorder characterized by distally predominant weakness and sensory loss, urinary bladder incontinence, and cerebellar signs. He died at age 62 years from pneumonia. We report the clinical and autopsy findings. RESULTS: The autopsy findings were remarkable for diffuse cortical and cerebellar atrophy, diffuse neuronal loss and gliosis, and massive accumulations of PB within neuronal and astrocytic processes. CONCLUSION: PBD may begin in childhood.

Selective atrophy of type 1 muscle fibers in McArdle's disease.

McArdle's disease is a metabolic myopathy of glycogen utilization caused by an absence or deficiency of myophosphorylase. The muscle biopsy features include increased deposition of subsarcolemmal glycogen and absent phosphorylase histochemical staining of myofibers. We report the clinical and unique pathologic findings in three cases of McArdle's disease with prominent type 1 fiber atrophy.

A lectin and synaptophysin study of developing brain.

Lectins which bind to carbohydrate residues of glycoconjugates can be used as histochemical markers of these substances. A battery of lectins including peanut agglutinin, ricinus communis, wheat germ agglutinin, soybean agglutinin, concanavalin ensiformis, Ulex europaeus, and Dolichos biflorus as well as synaptophysin was used on paraffin-embedded human fetal and infant brains of varying gestation (20 weeks to term) to determine whether there were changes in the pattern of glycoconjugate staining. The findings indicate that lectin binding of several of these markers changes with gestation as does synaptophysin.

Clinical variability in adult-onset acid maltase deficiency: report of affected sibs and review of the literature.

Acid maltase deficiency (AMD) is a rare cause of muscle disease in adult patients. The present report of 2 sibs and review of 36 previously reported cases illustrates the vast clinical variability in adult-onset AMD. This is 1 of only 3 reports to document tongue weakness and enlargement in an adult with AMD. The presenting signs and symptoms usually include progressive limb weakness, restrictive lung disease, or both. Consistent supportive abnormalities include a modest elevation in serum CK, a reduction in the forced vital capacity, and abnormal spontaneous activity (that is, myotonic discharges or fibrillations) in resting muscles during needle electromyography. The clinical spectrum is also extended to include distal limb weakness, scapular winging, asymmetric muscle weakness, and tongue involvement.

Möbius sequence: further in vivo support for the subclavian artery supply disruption sequence.

Möbius sequence consists of a congenital bilateral facial nerve palsy and external ophthalmoplegia often associated with malformations of the limbs and orofacial structures. The pathogenesis of the sequence is a subject of debate. However, a new hypothesis proposes that Möbius sequence results from an interruption of embryonic blood supply (subclavian artery supply disruption sequence). Here we present an infant with bilateral facial nerve palsy (VII), external ophthalmoplegia (IV, VI), paresis of cranial nerves V, IX, X, XI, and XII, absence of the pectoralis major muscle (Poland anomaly), terminal transverse limb defects, and absence of the right diaphragm. Also, he was found to have discrete foci of brainstem calcifications in the region of the dorsal respiratory group on both CT scan and the histologic sections with microscopic evidence of diffuse brainstem "injury." The anomalies and histopathology noted in this infant imply that vascular insufficiency prior to the sixth week of gestation involving the proximal sixth intersegmental artery may result in the manifestations presented in this report and lend further support for the existence of a subclavian artery supply disruption sequence.

Muscle biopsy and the clinical course of infantile spinal muscular atrophy.

Eight infants with severe early infantile spinal muscular atrophy diagnosed by clinical presentation and muscle biopsy were studied. The extent of alterations in muscle histology, histochemistry, and ultrastructure did not reflect the relative severity of the clinical presentation or the course of the illness. In seven biopsies, ultrastructural studies demonstrated empty sleeves of basal lamina projecting from the surface of small myofibers. We conclude that severe infantile spinal muscular atrophy often results in myofiber atrophy similar to that found in other motor neuron diseases, and it is not solely a hypotrophic process. Muscle biopsy findings are important because they help to establish the diagnosis, but they do not help predict the severity of disease among infants with this condition.

Juvenile Leigh's encephalomyelopathy with peripheral neuropathy, myopathy, and cardiomyopathy.

A child with typical histopathologic changes of Leigh's subacute necrotizing encephalomyelopathy presented with a chronic demyelinating neuropathy. During her 11-year course, she developed an unusual myopathy and cardiomyopathy in addition to many of the previously described manifestations of Leigh's disease. Despite an extensive evaluation, the biochemical basis of her condition was never identified. This case demonstrates another unique constellation of clinical alterations associated with subacute necrotizing encephalomyelopathy, and that chronic demyelinating neuropathy can be an important initial presentation of the disease.

An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis.

Uncertainty regarding pathogenic mechanisms has been a major impediment to effective prevention and treatment for human neurologic diseases such as multiple sclerosis, tropical spastic paraparesis, and AIDS demyelinating disease. Here, we implicate lymphotoxin (LT) (tumor necrosis factor beta [TNF-beta]) and TNF-alpha in experimental allergic encephalomyelitis (EAE), a murine model of an autoimmune demyelinating disease. In this communication, we report that treatment of recipient mice with an antibody that neutralizes LT and TNF-alpha prevents transfer of clone-mediated EAE. LNC-8, a myelin basic protein-specific T cell line, produces high levels of LT and TNF-alpha after activation by concanavalin A, antibody to the CD-3 epsilon component of the T cell receptor, or myelin basic protein presented in the context of syngeneic spleen cells. LNC-8 cells transfer clinical signs of EAE. When LNC-8 recipient mice were also treated with TN3.19.12, a monoclonal antibody that neutralizes LT and TNF-alpha, the severity of the transferred EAE was reduced, while control antibodies did not alter the disease. The effect of anti-LT/TNF-alpha treatment was long lived and has been sustained for 5 mo. These findings suggest that LT and TNF-alpha and the T cells that produce them play an important role in EAE.

Primary lateral sclerosis in a child.

Primary lateral sclerosis (PLS), previously undescribed in children, is characterized by a spastic motor deterioration and pathologic demonstration of corticospinal tract degeneration. We report an infant who, before 12 months of age, developed a progressive motor disease characterized by generalized spasticity. He died at 47 months, and neuropathologic examination revealed only corticospinal tract degeneration. We conclude that this child had typical clinical and pathologic findings for PLS.

Morphometry of blood vessels in the cortex and germinal plate of premature neonates.

Germinal plate hemorrhage with intraventricular rupture has been a leading cause of morbidity and mortality among premature neonates. Because germinal plate hemorrhage decreases with increasing gestational age, germinal plate vessel size and/or structure may be an important etiologic factor. Electron micrographs of the cortical and germinal plate blood vessels from 13 premature infants ranging in age from 19-37 weeks gestation were studied; vessel, lumena, and endothelial areas were measured using a digitizing tablet. In infants between 25-32 weeks gestation, the germinal plate vessel and lumenal areas were significantly greater than the areas of cortical vessel and lumena. This finding suggests that one of the factors involved in germinal plate hemorrhage is described by LaPlace's law which states that the larger the vessel diameter, the greater the pressure on the vessel wall.

Polymyositis with tubular aggregates.

We report a patient with classic idiopathic polymyositis who had tubular aggregates on muscle biopsy. Tubular aggregates are distinctly rare in polymyositis although seen in a variety of other muscle disorders including myopathies associated with muscle cramping. Our patient did not have muscle cramps or severe myalgia. Moreover, the patient's disease responded to steroids, indicating that tubular aggregates were not a marker for steroid resistance. The function of the tubular aggregates in this disease is not clear.