Congenital muscular dystrophy, cardiomyopathy, and peripheral neuropathy due to merosin deficiency: Peripheral nerve histology of cauda equina

AbstractPeripheral neuropathy, white matter abnormalities, and cardiomyopathy are associated findings with merosin-deficient congenital muscular dystrophy. Although characterization of the neuropathy with nerve conduction studies has been well documented, limited research has been able to correlate histopathology with nerve biopsy in humans. Our understanding of the mechanism, described as a demyelinating neuropathy, is mainly derived from mouse model studies. We report a 23-year-old male who succumbed to respiratory failure and ultimately cardiac arrhythmia in the setting of an uncharacterized end stage progressive muscular disease complicated by cardiomyopathy and severe scoliosis. Autopsy revealed extensive muscular atrophy and replacement by fibroadipose tissue throughout the skeletal muscle and myocardium. Immunohistochemical analysis of the muscle biopsy showed a complete loss of merosin. Thus, the cause for both his muscular disease and demyelinating neuropathy was established with the diagnosis of merosin-deficient muscular dystrophy. Nerve biopsy obtained from the cauda equina showed clear evidence of segmental demyelination and remyelination, providing a better understanding of the proximal peripheral nerve histopathological changes in this disease entity

Amino acid substitutions within the heptad repeat domain 1 of murine coronavirus spike protein restrict viral antigen spread in the central nervous system.

Targeted recombination was carried out to select mouse hepatitis viruses (MHVs) in a defined genetic background, containing an MHV-JHM spike gene encoding either three heptad repeat 1 (HR1) substitutions (Q1067H, Q1094H, and L1114R) or L1114R alone. The recombinant virus, which expresses spike with the three substitutions, was nonfusogenic at neutral pH. Its replication was significantly inhibited by lysosomotropic agents, and it was highly neuroattenuated in vivo. In contrast, the recombinant expressing spike with L1114R alone mediated cell-to-cell fusion at neutral pH and replicated efficiently despite the presence of lysosomotropic agents; however, it still caused only subclinical morbidity and no mortality in animals. Thus, both recombinant viruses were highly attenuated and expressed viral antigen which was restricted to the olfactory bulbs and was markedly absent from other regions of the brains at 5 days postinfection. These data demonstrate that amino acid substitutions, in particular L1114R, within HR1 of the JHM spike reduced the ability of MHV to spread in the central nervous system. Furthermore, the requirements for low pH for fusion and viral entry are not prerequisites for the highly attenuated phenotype

Pathology Case Study: Mental Status Changes and a Severe Occipital Headache

This is a case study presented by the University of Pittsburgh Department of Pathology in which a 32-year-old man with symptoms of an upper respiratory infection presented himself to the hospital with mental status changes and a severe occipital headache of two days duration. Visitors are given both the microscopic description and radiology results, including images, and are given the opportunity to diagnose the patient. This is an excellent resource for students in the health sciences to familiarize themselves with using patient history and laboratory results to diagnose disease. It is also a helpful site for educators to use to introduce or test student learning in neuropathology

Coronavirus Neurovirulence Correlates with the Ability of the Virus To Induce Proinflammatory Cytokine Signals from Astrocytes and Microglia

The molecular and cellular basis of coronavirus neurovirulence is poorly understood. Since neurovirulence may be determined at the early stages of infection of the central nervous system (CNS), we hypothesize that it may depend on the ability of the virus to induce proinflammatory signals from brain cells for the recruitment of blood-derived inflammatory cells. To test this hypothesis, we studied the interaction between coronaviruses (mouse hepatitis virus) of different neurovirulences with primary cell cultures of brain immune cells (astrocytes and microglia) and mouse tissues. We found that the level of neurovirulence of the virus correlates with its differential ability to induce proinflammatory cytokines (interleukin 12 [IL-12] p40, tumor necrosis factor alpha, IL-6, IL-15, and IL-1β) in astrocytes and microglia and in mouse brains and spinal cords. These findings suggest that coronavirus neurovirulence may depend on a novel discriminatory ability of astrocytes and microglia to induce a proinflammatory response in the CNS

Mouse hepatitis virus type-2 infection in mice: An experimental model system of acute meningitis and hepatitis

Infection with mouse hepatitis virus (MHV) strain A59 produces acute hepatitis, encephalitis, and chronic demyelination in mice. However, little is known about a closely related strain, MHV-2, which is only weakly neurotropic. To better understand the molecular basis of neurotropism of MHVs, we compared the pathogenesis and genomic sequence of MHV-2 with that of MHV-A59. Intracerebral injection of MHV-2 into 4-week-old C57B1/6 mice produces acute meningitis and hepatitis without encephalitis or chronic inflammatory demyelination. Sequence comparison between MHV-2 and MHV-A59 reveals 94-98% sequence identity of the replicase gene, 83-95% sequence identity of genes 2a, 3, 5b, 6, and 7, and marked difference in the sequence of genes, 2b, 4, and 5a. This information provides the basis for further studies exploring the mechanism of viral neurotropism and virus-induced demyelination. © 2001 Academic Press

Pathology Case Study: Leg Weakness and Numbness

The University of Pittsburgh School of Medicine's Department of Pathology has compiled a series of case studies to help both students and instructors. In this particular study, a 48 year-old man is admitted to the hospital with âa three week history of back pain, progressive right leg weakness and bilateral lower leg numbness.â A detailed patient history and account of the attending doctorâs examination is provided in the âPatient Historyâ section. MRI and CT images of the patient, as well as gross and microscopic descriptions of the condition are included as well. Clicking on the âFinal Diagnosisâ provides a thorough explanation of the diagnosis and treatment