Amyotrophic lateral sclerosis microgenomics.
Explore the source record for details and available documents.
Amyotrophic Lateral Sclerosis↗
Biomedical subjects
John Ravits
Publications and source records attributed to John Ravits.
Sporadic amyotrophic lateral sclerosis: a hypothesis of persistent (non-lytic) enteroviral infection.
Because of recently reported reverse transcriptase polymerase chain reaction evidence of enterovirus in sporadic amyotrophic lateral sclerosis (SALS) and because of newly available anti-enteroviral drugs binding enteroviral capsids, it is reasonable to re-formulate an enteroviral hypothesis of SALS using recent advances in molecular virology. Viral persistence is non-lytic and non-cytopathic infection that evades host's immune surveillance. Enteroviruses are known to cause persistent as well as lytic infection both in vitro and in vivo. Both virion as well as host factors modulate between persistent and lytic infection. Apoptosis, or programmed cell death, is a process of active non-necrotic cell death. It has complex interplay with viruses and may be either promoted or opposed by them. Apoptosis is a major factor in motor neuron death in SALS. Viral tropism is the process by which viruses select and propagate to target cells. It is controlled by capsid conformation and surface receptors on host cells. Enteroviruses have a region on their capsids known as the canyon which docks on such receptors. Docking induces conformational changes of the capsid and genome release. Poliovirus, tropic for motor neurons, docks on the poliovirus receptor, about which much is known. The virus penetrates the motor system focally after crossing either the blood-muscle or the blood-brain barriers. It propagates bidirectionally along axons and synapses to contiguous motor neurons, upper as well as lower, which sequester infection and create avenues for spread over long distances. If chronic and persistent rather than acute and lytic, such viruses trafficking in a finite system of non-dividing cells and inducing apoptosis would cause cell death that summates linearly rather than exponentially. Taken together, these explain signature clinical features of SALS - focal onset weakness, contiguous or regional spread of weakness, confinement to upper and lower motor neurons, and linear rates of progression. The hypothesis predicts the following testable investigations: 1) viral detection may be possible by applying amplification technology to optimally acquired nervous tissue processed by laser microdissection; 2) genetic susceptibility factors such as cell surface receptor polymorphisms may combine with sporadic exposure and chance penetration of the motor system in SALS; 3) a transgenic animal model might be created by inserting such genetic factors into an animal host and inoculating intramuscularly rather than intracerebrally biochemical fractions of SALS motor neurons at vulnerable periods in the developmental life cycle of the transgenic host; and 4) continual long-term administration of anti-enteroviral agents called capsid-binding compounds which stabilize capsids and prevent genome release might be efficacious.
Amyotrophic Lateral Sclerosis↗
Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes.
OBJECTIVE: Since the discovery of mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) ten years ago, testing for SOD1 gene mutations has become a part of the investigation of patients with suspected motor neuron disease. We searched for novel SOD1 mutations and for clinical characteristics of patients with these mutations. METHODS: Analysis was made of patient files at the Neurogenetic DNA Diagnostic Laboratory at Massachusetts General Hospital. We also scrutinized available medical records and examined patients with the different SOD1 mutations. RESULTS: One hundred and forty eight (148) of 2045 amyotrophic lateral sclerosis (ALS) patients carried a disease-associated mutation in the SOD1 gene. The most prevalent was the A4V missense mutation, found in 41% of those patients. Sixteen novel exonic mutations (L8V, F20C, Q22L, H48R, T54R, S591, V87A, T88deltaTAD, A89T, V97M, S105deltaSL, V118L, D124G, G141X, G147R, 11515) were found, bringing the total number of SOD1 gene mutations in ALS to 105. CONCLUSIONS: Mutations in the SOD1 gene are found both in sporadic and familial ALS cases without any definite predilection for any part of the gene. A common structural denominator for the 16 novel mutations or previously reported mutations is not obvious. Similarly, the nature of the putative acquired toxic function of mutant SOD1 remains unresolved. We conclude that patients with SOD1 mutations may infrequently show symptoms and signs unrelated to the motor systems, sometimes obscuring the diagnosis of ALS.
Adult↗