Biomedical subjects

Michael E Shy

Publications and source records attributed to Michael E Shy.

26 records · Page 2Linked to original sources

PubMed2003

Schwann cell expression of PLP1 but not DM20 is necessary to prevent neuropathy.

Proteolipid protein (PLP1) and its alternatively spliced isoform, DM20, are the major myelin proteins in the CNS, but are also expressed in the PNS. The proteins have an identical sequence except for 35 amino acids in PLP1 (the PLP1-specific domain) not present in DM20. Mutations of PLP1/DM20 cause Pelizaeus-Merzbacher Disease (PMD), a leukodystrophy, and in some instances, a peripheral neuropathy. To identify which mutations cause neuropathy, we have evaluated a cohort of patients with PMD and PLP1 mutations for the presence of neuropathy. As shown previously, all patients with PLP1 null mutations had peripheral neuropathy. We also identified 4 new PLP1 point mutations that cause both PMD and peripheral neuropathy, three of which truncate PLP1 expression within the PLP1-specific domain, but do not alter DM20. The fourth, a splicing mutation, alters both PLP1 and DM20, and is probably a null mutation. Six PLP1 point mutations predicted to produce proteins with an intact PLP1-specific domain do not cause peripheral neuropathy. Sixty-one individuals with PLP1 duplications also had normal peripheral nerve function. These data demonstrate that expression of PLP1 but not DMSO is necessary to prevent neuropathy, and suggest that the 35 amino acid PLP1-specific domain plays an important role in normal peripheral nerve function.

Adolescent↗

PubMed2003

Asymmetric flaccid paralysis: a neuromuscular presentation of West Nile virus infection.

The neuromuscular aspects of West Nile virus (WNV) infection have not been characterized in detail. We have studied a group of six patients with proven WNV infection. All cases presented with acute, severe, asymmetric, or monolimb weakness, with minimal or no sensory disturbance after a mild flu-like prodrome. Four cases also had facial weakness. Three of our cases had no encephalitic signs or symptoms despite cerebrospinal fluid pleocytosis. Electrophysiological studies showed severe denervation in paralyzed limb muscles, suggesting either motor neuron or multiple ventral nerve root damage. This localization is supported further by the finding of abnormal signal intensity confined to the anterior horns on a lumbar spine magnetic resonance imaging. Muscle biopsies from three patients showed scattered necrotic fibers, implicating mild direct or indirect muscle damage from the WNV infection. In summary, we describe a group of patients with acute segmental flaccid paralysis with minimal or no encephalitic or sensory signs. We have localized the abnormality to either the spinal motor neurons or their ventral nerve roots. It will be important for physicians to consider WNV infection in patients with acute asymmetric paralysis with or without encephalitic symptoms.

Acute Disease↗

PubMed2003

Motor unit number estimate of distal and proximal muscles in Charcot-Marie-Tooth disease.

In order to determine the utility of motor unit number estimation (MUNE) in assessing axonal loss in chronic inherited neuropathies, we determined MUNEs in 54 patients with Charcot-Marie-Tooth (CMT) disease (29 patients with CMT-1A, 13 with CMT-X, and 12 with CMT-2) by using spike-triggered averaging (STA) of the ulnar-innervated abductor digiti minimi/hypothenar muscles (ADM) and the musculo-cutaneous innervated biceps/brachialis (BB) muscles. MUNEs were analyzed in relationship to the corresponding compound muscle action potential (CMAP) amplitudes as well as to clinical strength. Proximal muscles, which appeared strong clinically, had evidence of chronic denervation/reinnervation, although to a lesser extent than weak distal hand muscles, supporting the concept that axonal loss in CMT occurs in a length-dependent fashion. The reduction in ADM-MUNE strongly correlated with clinical weakness in the hand. Both the ADM-MUNE and BB-MUNE were abnormal more often than CMAP amplitude, probably reflecting extensive motor unit reconfiguration and enlargement that maintains CMAP amplitude despite severe motor unit loss. This study suggests that MUNE can assess motor unit loss in CMT and may better reflect axonal loss than CMAP amplitude. The STA technique of MUNE may be useful in longitudinal studies of proximal and distal motor unit changes in CMT.

Action Potentials↗

PubMed2002

Hereditary neuropathy with liability to pressure palsy: the electrophysiology fits the name.

BACKGROUND: Studies of patients with hereditary neuropathy with liability to pressure palsies (HNPP) have shown accentuated distal slowing along with nonuniform conduction abnormalities at segments liable to compression, suggesting a distal myelinopathy as an underlying pathophysiological mechanism. METHODS: We evaluated 12 patients with HNPP by standard nerve conduction studies and by conduction to more proximal muscles in the arm and leg. Three CMT1A patients and six healthy subjects also were evaluated as controls. RESULTS: Median and peroneal motor nerves in all HNPP patients showed prolonged distal motor latencies (DML) (mean +/- SE, 5.9 +/- 0.41 and 8.63 +/- 0.58 milliseconds), but the ulnar and tibial DML were minimally prolonged or normal (mean +/- SE, 3.87 +/- 0.16 and 5.66 +/- 0.24 milliseconds). DML to forearm flexor (median and ulnar nerves) or anterior tibial muscles (peroneal nerve) were also normal. CONCLUSION: Accentuated distal slowing is found primarily in median and peroneal nerve segments liable to pressure palsies or repetitive trauma. However, the ulnar and tibial nerves, which are less liable to compression, have minimal changes. In addition, distal latencies to more proximal muscles in the arm and leg do not have distal slowing. These findings do not support a distal myelinopathy as a determinant of the conduction abnormalities in HNPP.

Adolescent↗

PubMed2002

Increased survival and function of SOD1 mice after glial cell-derived neurotrophic factor gene therapy.

Amyotrophic lateral sclerosis (ALS) is caused by a progressive degeneration of motor neurons. The cause of sporadic ALS is not known, but 1-2% of all cases are familial and caused by mutations in the copper-zinc superoxide dismutase (SOD1) gene. Transgenic SOD1 mice serve as a transgenic mouse model for these cases. Glial cell-derived neurotrophic factor (GDNF) has a potent trophic effect on motor neurons. Clinical trials in which growth factors have been systemically administered to ALS patients have not been effective, owing in part to the short half-life of these factors and their low concentrations at target sites. Gene transfer of therapeutic factors to motor neurons and/or their target cells, such as muscle, may overcome these problems. Previously, we and others have shown that intramuscularly administered adenovirus vector (AVR) results in foreign gene expression not only in muscle cells, but also in relevant motor neurons in the spinal cord, because of retrograde axonal transport. In this study we utilized an AVR to introduce GDNF into muscles of neonatal SOD1 mice. We showed that AVR-mediated GDNF expression delayed the onset of disease by 7 +/- 8 days (mean +/- SD), prolonged survival by 17 +/- 10 days, and delayed the decline in motor functions (as determined on a rotating rod) by 7-14 days. These results demonstrate that gene delivery to muscle and motor neurons has the potential to treat devastating neurodegenerative diseases such as ALS.

Adenoviridae↗

PubMed2002

Transient central nervous system white matter abnormality in X-linked Charcot-Marie-Tooth disease.

X-linked Charcot-Marie-Tooth disease (CMTX) is a hereditary demyelinating neuropathy caused by mutations in the connexin 32 (Cx32) gene. Cx32 is widely expressed in brain and peripheral nerve, yet clinical manifestations of CMTX mainly arise from peripheral neuropathy. We have evaluated two male patients with CMTX who on separate occasions developed transient ataxia, dysarthria, and weakness within 3 days of returning from ski trips at altitudes above 8,000 feet. Magnetic resonance imaging studies in both patients showed nonenhancing, confluent, and symmetrical white matter abnormalities that were more pronounced posteriorly and that resolved over several months. Magnetic transfer images in one patient demonstrated increased magnetization transfer ratios distinct from that seen in demyelination or edema. Both patients returned to their normal baseline within 2 to 3 weeks. These cases suggest that CMTX patients are at risk for developing an acute, transient, neurological syndrome when they travel to places at high altitudes and return to sea level. Cx32 mutations may cause central nervous system dysfunction by reducing the number of functioning gap junctions between oligodendrocytes and astrocytes, making both cells more susceptible to abnormalities of intercellular exchange of ions and small molecules in situations of metabolic stress.

Adolescent↗

PubMed2002

Hereditary motor and sensory neuropathies: a biological perspective.

Mutations in genes expressed in Schwann cells and the axons they ensheath cause the hereditary motor and sensory neuropathies known as Charcot-Marie-Tooth (CMT) disease. At present, mutations in ten different genes have been identified, chromosomal localisation of many other distinct inherited neuropathies has been mapped, and new genetic causes for inherited neuropathies continue to be discovered. How to keep track of these mutations is a challenge for any neurologist, partly because the mutations are commonly presented as an expanding list to be memorised without a biological context of how the encoded proteins behave in the cell. A further challenge for investigators studying diseases of the peripheral nervous system is the increasing complexity of myelination, axonal function, and interactions between Schwann cells and axons. To address these concerns, we present the mutated genes causing these inherited neuropathies in the context of the cell biology of the Schwann cell and axon, and we begin to develop a model of how the various genes may interact in the pathogenesis of CMT disease.

Amino Acid Sequence↗

PubMed2002

Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation.

Axonal degeneration contributes to clinical disability in the acquired demyelinating disease multiple sclerosis. Axonal degeneration occurs during acute attacks, associated with inflammation, and during the chronic progressive phase of the disease in which inflammation is not prominent. To explore the importance of interactions between oligodendrocytes and axons in the CNS, we analysed the brains of rodents and humans with a null mutation in the gene encoding the major CNS myelin protein, proteolipid protein (PLP1, previously PLP). Histological analyses of the CNS of Plp1 null mice and of autopsy material from patients with null PLP1 mutations were performed to evaluate axonal and myelin integrity. In vivo proton magnetic resonance spectroscopy (MRS) of PLP1 null patients was conducted to measure levels of N-acetyl aspartate (NAA), a marker of axonal integrity. Length-dependent axonal degeneration without demyelination was identified in the CNS of Plp1 null mice. Proton MRS of PLP1-deficient patients showed reduced NAA levels, consistent with axonal loss. Analysis of patients' brain tissue also demonstrated a length-dependent pattern of axonal loss without significant demyelination. Therefore, axonal degeneration occurs in humans as well as mice lacking the major myelin protein PLP1. This degeneration is length-dependent, similar to that found in the PNS of patients with the inherited demyelinating neuropathy, CMT1A, but is not associated with significant demyelination. Disruption of PLP1-mediated axonal--glial interactions thus probably causes this axonal degeneration. A similar mechanism may be responsible for axonal degeneration and clinical disability that occur in patients with multiple sclerosis.

Adult↗