7
Journal of the Peripheral Nervous System 6:60–66 (2001) © 2001 Peripheral Nerve Society, Inc. 60 Blackwell Science Publishers Neuropathy Abstracts Abstracts of selected articles recently published in the medical literature MICROVASCULITIS IN NON-DIABETIC LUMBOSACRAL RADICULOPLEXUS NEUROPATHY (LSRPN): SIMILARITY TO THE DIABETIC VARIETY (DLSRPN) Dyck PJB, Engelstad J, Norell J, Dyck PJ. Journal of Neu- ropathology and Experimental Neurology 59: 525–538, 2000. Reprinted with permission from the American Associ- ation of Neuropathologists, Inc. Diabetic lumbosacral radiculoplexus neuropathy (DLSRPN) has been shown to be due to ischemic injury from microvas- culitis. The present study tests whether ischemic injury and microvasculitis are the pathologic cause of non-diabetic lum- bosacral radiculoplexus neuropathy (LSRPN), and whether the pathologic alterations are different between LSRPN and DLSRPN. We studied distal cutaneous nerve biopsies of 47 patients with LSRPN and compared findings with those of 14 age-matched healthy controls and 33 DLSRPN patients. In both disease conditions, we found evidence of ischemic injury (multifocal fiber degeneration and loss, perineurial de- generation and scarring, characteristic fiber alterations, neo- vascularization, and injury neuroma) that we attribute to micro- vasculitis (mural and perivascular mononuclear inflammation of microvessels, inflammatory separation, fragmentation and destruction of mural smooth muscle, and previous micro- scopic bleeding [hemosiderin]). Teased nerve fibers in LSRPN showed significantly increased frequencies of axonal degen- eration, segmental demyelination, and empty nerve strands. The segmental demyelination appeared to be clustered on fi- bers with axonal dystrophy. The nerves with abnormal fre- quencies of demyelination were significantly associated with nerves showing multifocal fiber loss. We reached the follow- ing conclusions: 1) LSRPN is a serious condition with much morbidity that mirrors DLSRPN. 2) Ischemic injury from mi- crovasculitis appears to be the cause of LSRPN. 3) Axonal degeneration and segmental demyelination appear to be linked and due to ischemia. 4) The pathologic alterations in LSRPN and DLSRPN are indistinguishable, raising the ques- tion whether these 2 conditions have a common underlying mechanism, and whether diabetes mellitus contributes to the pathology or is a risk factor in DLSRPN. 5) Both LSRPN and DLSRPN are potentially treatable conditions. GIANT AXONAL NEUROPATHY LOCUS REFINEMENT TO A , 590 KB CRITICAL INTERVAL Cavalier L, BenHamida C, Amouri R, Belal S, Bomont P, Lagarde N, Gressin L, Callen D, Demir E, Topaloglu H, Landrieu P, Ioos C, BenHamida M, Koenig M, Hentati F. European Journal of Human Genetics 8: 527–534, 2000. Reprinted with permission from Nature Publishing Group. Giant axonal neuropathy (GAN) is a rare autosomal re- cessive neurodegenerative disorder, characterised clinically by the development of chronic distal polyneuropathy during childhood, mental retardation, kinky or curly hair, skeletal ab- normalities and, ultrastructurally, by axons in the central and peripheral nervous systems distended by masses of tightly woven neurofilaments. We recently localised the CAN locus in 16q24.1 to a 5-cM interval between the D16S507 and D16S511 markers by homozygosity mapping in three con- sanguineous Tunisian families. We have now established a contig-based physical map of the region comprising YACs and BACs where we have placed four genes, ten ESTs, three STSs and two additional microsatellite markers, and where we have identified six new SSCP polymorphisms and six new microsatellite markers. Using these markers, we have refined the position of our previous flanking recombi- nants. We also identified a shared haplotype between two Tunisian families and a small region of homozygosity in a Turkish family with distant consanguinity, both suggesting the occurrence of historic recombinations and supporting the conclusions based on the phase-known recombinations. Taken together, these results allow us to establish a tran- scription map of the region, and to narrow down the GAN position to a , 590 kb critical interval, an important step to- ward the identification of the defective gene. INDUCTION OF ENDOTHELIN-1 EXPRESSION BY GLUCOSE: AN EFFECT OF PROTEIN KINASE C ACTIVATION Park JY, Takahara N, Gabriele A, Chou E, Naruse K, Suzuma K, Yamauchi T, Ha SW, Meier M, Rhodes CJ, King GL. Diabetes 49: 1239–1248, 2000. Reprinted with permis- sion from the American Diabetes Association. Enhanced actions or levels of endothelin-1 (ET-1), a potent vasoconstrictor, have been associated with decreased blood flow in the retina and peripheral nerves of diabetic animals and may be related to the development of pathologies in these tissues. Hyperglycemia has been postulated to increase ET-1 secretion in endothelial cells. We have characterized the mechanism by which elevation of glucose is increasing ET-1 mRNA expression in capillary bovine retinal endothelial cells (BREC) and bovine retinal pericytes (BRPC). Elevation of glu- cose, but not mannitol, from 5.5 to 25 mmol/l for 3 days in- creased membranous protein kinase C (PKC) activities and

Acute Deterioration Of Charcot-Marie-Tooth Disease IA (CMT IA) Following 2 MG Of Vincristine Chemotherapy

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Page 1: Acute Deterioration Of Charcot-Marie-Tooth Disease IA (CMT IA) Following 2 MG Of Vincristine Chemotherapy

Journal of the Peripheral Nervous System 6:60–66 (2001)

© 2001 Peripheral Nerve Society, Inc.

60

Blackwell Science Publishers

Neuropathy Abstracts

Abstracts of selected articles recently published in the medical literature

MICROVASCULITIS IN NON-DIABETIC LUMBOSACRAL RADICULOPLEXUS NEUROPATHY (LSRPN): SIMILARITY TO THE DIABETIC VARIETY (DLSRPN)

Dyck PJB, Engelstad J, Norell J, Dyck PJ.

Journal of Neu-ropathology and Experimental Neurology 59: 525–538,2000. Reprinted with permission from the American Associ-ation of Neuropathologists, Inc.

Diabetic lumbosacral radiculoplexus neuropathy (DLSRPN)has been shown to be due to ischemic injury from microvas-culitis. The present study tests whether ischemic injury andmicrovasculitis are the pathologic cause of non-diabetic lum-bosacral radiculoplexus neuropathy (LSRPN), and whetherthe pathologic alterations are different between LSRPN andDLSRPN. We studied distal cutaneous nerve biopsies of 47patients with LSRPN and compared findings with those of14 age-matched healthy controls and 33 DLSRPN patients.In both disease conditions, we found evidence of ischemicinjury (multifocal fiber degeneration and loss, perineurial de-generation and scarring, characteristic fiber alterations, neo-vascularization, and injury neuroma) that we attribute to micro-vasculitis (mural and perivascular mononuclear inflammationof microvessels, inflammatory separation, fragmentation anddestruction of mural smooth muscle, and previous micro-scopic bleeding [hemosiderin]). Teased nerve fibers in LSRPNshowed significantly increased frequencies of axonal degen-eration, segmental demyelination, and empty nerve strands.The segmental demyelination appeared to be clustered on fi-bers with axonal dystrophy. The nerves with abnormal fre-quencies of demyelination were significantly associated withnerves showing multifocal fiber loss. We reached the follow-ing conclusions: 1) LSRPN is a serious condition with muchmorbidity that mirrors DLSRPN. 2) Ischemic injury from mi-crovasculitis appears to be the cause of LSRPN. 3) Axonaldegeneration and segmental demyelination appear to belinked and due to ischemia. 4) The pathologic alterations inLSRPN and DLSRPN are indistinguishable, raising the ques-tion whether these 2 conditions have a common underlyingmechanism, and whether diabetes mellitus contributes tothe pathology or is a risk factor in DLSRPN. 5) Both LSRPNand DLSRPN are potentially treatable conditions.

GIANT AXONAL NEUROPATHY LOCUS REFINEMENT TO A

,

590 KB CRITICAL INTERVAL

Cavalier L, BenHamida C, Amouri R, Belal S, Bomont P,Lagarde N, Gressin L, Callen D, Demir E, Topaloglu H,Landrieu P, Ioos C, BenHamida M, Koenig M, Hentati F.

European Journal of Human Genetics 8: 527–534, 2000.Reprinted with permission from Nature Publishing Group.

Giant axonal neuropathy (GAN) is a rare autosomal re-cessive neurodegenerative disorder, characterised clinicallyby the development of chronic distal polyneuropathy duringchildhood, mental retardation, kinky or curly hair, skeletal ab-normalities and, ultrastructurally, by axons in the central andperipheral nervous systems distended by masses of tightlywoven neurofilaments. We recently localised the CAN locusin 16q24.1 to a 5-cM interval between the D16S507 andD16S511 markers by homozygosity mapping in three con-sanguineous Tunisian families. We have now established acontig-based physical map of the region comprising YACsand BACs where we have placed four genes, ten ESTs,three STSs and two additional microsatellite markers, andwhere we have identified six new SSCP polymorphisms andsix new microsatellite markers. Using these markers, wehave refined the position of our previous flanking recombi-nants. We also identified a shared haplotype between twoTunisian families and a small region of homozygosity in aTurkish family with distant consanguinity, both suggestingthe occurrence of historic recombinations and supportingthe conclusions based on the phase-known recombinations.Taken together, these results allow us to establish a tran-scription map of the region, and to narrow down the GANposition to a

,

590 kb critical interval, an important step to-ward the identification of the defective gene.

INDUCTION OF ENDOTHELIN-1 EXPRESSION BY GLUCOSE: AN EFFECT OF PROTEIN KINASE C ACTIVATION

Park JY, Takahara N, Gabriele A, Chou E, Naruse K,Suzuma K, Yamauchi T, Ha SW, Meier M, Rhodes CJ, KingGL.

Diabetes 49: 1239–1248, 2000. Reprinted with permis-sion from the American Diabetes Association.

Enhanced actions or levels of endothelin-1 (ET-1), a potentvasoconstrictor, have been associated with decreased bloodflow in the retina and peripheral nerves of diabetic animalsand may be related to the development of pathologies inthese tissues. Hyperglycemia has been postulated to increaseET-1 secretion in endothelial cells. We have characterized themechanism by which elevation of glucose is increasing ET-1mRNA expression in capillary bovine retinal endothelial cells(BREC) and bovine retinal pericytes (BRPC). Elevation of glu-cose, but not mannitol, from 5.5 to 25 mmol/l for 3 days in-creased membranous protein kinase C (PKC) activities and

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Neuropathy Abstracts Journal of the Peripheral Nervous System 6:60–66 (2001)

61

ET-1 mRNA in parallel levels by 2-fold in BREC and BRPC.These effects were reversed by decreasing glucose levels to5.5 mmol/l for an additional 2 days. Glucose-induced ET-1overexpression was inhibited by a general PKC inhibitor,GF109203X, and a mitogen-activated protein kinase kinase in-hibitor, PD98059, but not by wortmannin, a phosphatidylinosi-tol 3-kinase inhibitor. By immunoblot analysis, PKC-beta 2 and-delta isoforms in BREC were significantly increased relativeto other isoforms in the membranous fractions when glucoselevel was increased. Overexpression of PKC-beta 1 and -deltaisoforms but not PKC-zeta isoform by adenovirus vectors con-taining the respective cDNA enhanced in parallel PKC activi-ties, proteins, and basal and glucose-induced ET-1 mRNAexpression by at least 2-fold. These results showed that en-hanced ET-1 expression induced by hyperglycemia in diabetesis partly due to activation of PKC-beta and -delta isoforms,suggesting that inhibition of these PKC isoforms may preventearly changes in diabetic retinopathy and neuropathy.

INTRACELLULAR TRANSPORT, ASSEMBLY, AND DEGRADATION OF WILD-TYPE AND DISEASE-LINKED MUTANT GAP JUNCTION PROTEINS

Vanslyke JK, Deschenes SM, Musil LS.

Molecular Biologyof the Cell 11: 1933–1946, 2000. Reprinted with permissionfrom the American Society of Cell Biology.

More than 130 different mutations in the gap junctionintegral plasma membrane protein connexin32 (Cx32) havebeen linked to the human peripheral neuropathy X-linkedCharcot-Marie-Tooth disease (CMTX). How these variousmutants are processed by the cell and the mechanism(s) bywhich they cause CMTX are unknown. To address these is-sues, we have studied the intracellular transport, assembly,and degradation of three CMTX-linked Cx32 mutants stablyexpressed in PC12 cells. Each mutant had a distinct fate:E208K Cx32 appeared to be retained in the endoplasmicreticulum (ER), whereas both the E186K and R142W mu-tants were transported to perinuclear compartments fromwhich they trafficked either to lysosomes (R142W Cx32) orback to the ER (E186K Cx32). Despite these differences,each mutant was soluble in nonionic detergent but unable toassemble into homomeric connexons. Degradation of bothmutant and wild-type connexins was rapid (t(1/2)

,

3 h) andtook place at least in part in the ER by a process sensitive toproteasome inhibitors. The mutants studied are thereforeunlikely to cause disease by accumulating in degradation-resistant aggregates but instead are efficiently cleared fromthe cell by quality control processes that prevent abnormalconnexin molecules from traversing the secretory pathway.

DISTRIBUTION OF PACLITAXEL WITHIN THE NERVOUS SYSTEM OF THE RAT AFTER REPEATED INTRAVENOUS ADMINISTRATION

Cavaletti G, Cavalletti E, Oggioni N, Sottani C, Minoia C,D’Incalci M, Zucchetti M, Marmiroli P, Tredici G.

Neurotox-icology 21: 389–393, 2000. Reprinted with permission fromIntox Press, Inc.

The distribution of paclitaxel (Taxol(R)) within the centraland peripheral nervous system after repeated administration

of this antineoplastic agent is still largely unknown. In thisstudy we determined for the first time paclitaxel tissue con-centration in the brain, spinal cord, dorsal root ganglia (DRG)and sciatic nerve using an experimental paradigm in the ratwhich reproduces the features of paclitaxel peripheral neuro-toxicity in humans. Pathological confirmation of the onset ofpaclitaxel-induced peripheral neurotoxicity was performed.In order to achieve reliable results even with low concentra-tions of paclitaxel, a newly reported analytical method (high-performance liquid chromatography with tandem mass spec-trometry) was used. We demonstrated that paclitaxel haseasy access to the DRG, where it accumulates, while thelowest concentrations of the drug were measured in thebrain. The intermediate concentrations of paclitaxel observedin the sciatic nerve and spinal cord may be due to paclitaxeltransport along the centrifugal and centripetal branches ofthe DRG neuron axons.

NEUROLOGICAL DYSFUNCTION AND AXONAL DEGENERATION IN CHARCOT-MARIE-TOOTH DISEASE TYPE 1A

Krajewski KM, Lewis RA, Fuerst DR, Turansky C, HindererSR, Garbern J, Kamholz J, Shy ME.

Brain 123: 1516–1527,2000. Reprinted with permission from Oxford University Press.

Charcot-Marie-Tooth disease type 1A (CMT1A), the mostfrequent form of GAIT, is caused by a 1.5 Mb duplication onthe short arm of chromosome 17. Patients with CMT1A typi-cally have slowed nerve conduction velocities (NCVs), re-duced compound motor and sensory nerve action potentials(CMAPs and SNAPs), distal weakness, sensory loss and de-creased reflexes. In order to understand further the molecu-lar pathogenesis of CMT1A, as well as to determine whichfeatures correlate with neurological dysfunction and mightthus be amenable to treatment, we evaluated the clinicaland electrophysiological phenotype in 42 patients with CMT1A.In these patients, muscle weakness, CMAP amplitudes andregeneration, motor unit number estimates correlated withclinical disability, while motor NCV did not. In addition, lossof joint position sense and reduction in SNAP amplitudesalso correlated with clinical disability, while sensory NCV didnot. Taken together, these data strongly support the hypoth-esis that neurological dysfunction and clinical disability inCMT1A are caused by loss or damage to large calibre motorand sensory axons. Therapeutic approaches to amelioratedisability in CMT1A, as in amyotrophic lateral sclerosis andother neurodegenerative diseases, should thus be directedtowards preventing axonal degeneration and/or promotingaxonal regeneration.

THE COURSE AND PROGNOSTIC FACTORS OF FAMILIAL AMYLOID POLYNEUROPATHY AFTER LIVER TRANSPLANTATION

Adams D, Samuel D, Goulon-Goeau C, Nakazato M,Costa PMP, Feray C, Plante V, Ducot B, Ichai P, Lacroix C,Metral S, Bismuth H, Said G.

Brain 123: 1495–1504, 2000.Reprinted with permission from Oxford University Press.

Familial amyloid polyneuropathy (FAP) associated withmutations of the transthyretin (TTR) gene is the most com-

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62

mon type of FAP, a devastating disease causing death within10 years after the first symptoms. Because most of the amy-loidogenic mutated TTR is secreted by the liver, transplanta-tion is widely used to treat these patients, but long-termquantitative evaluation of the effects of liver transplantationon the progression of the neuropathy are not available. Wehave treated 45 patients with symptomatic TTR-FAP, includ-ing 43 with the Met30 TTR gene mutation, and report on theresults of periodic evaluation of markers of neuropathy in 25of them, who have been followed for more than 2 years afterliver transplantation (mean follow-up 3 years). The overallsurvival rates at 1 and 5 years were 82 and 60%, respec-tively. Urinary incontinence and a low Norris score at livertransplantation were associated with poorer outcome. Themotor score stabilized in seven of 11 patients (64%) withmild sensorimotor neuropathy (walking unaided) and in twoof the eight patients (25%) with severe sensorimotor deficit(walking with aid) at liver transplantation. In five other pa-tients, deterioration of motor deficit occurred only within thefirst year after liver transplantation, but was progressive afterthis interval in two patients. None of the six patients withpure sensory neuropathy developed motor loss and superfi-cial sensory loss remained unchanged. Two years after livertransplantation, the rate of myelinated axon loss in nerve bi-opsy specimens was markedly lower in seven transplantedpatients (0.9/mm(2) of endoneurial area/month) than in non-transplanted patients (70/nm(2) of endoneurial area/month).Symptoms of dysautonomia and quantitated cardiocircula-tory autonomic tests remained unchanged. In all patients,serum mutated TTR decreased to 2.5% of pre-liver trans-plantation values and remained at this level during follow-up.We presently recommend liver transplantation in FAP pa-tients at onset of first symptoms and exclusion of thosewith a Norris score below 55 and/or with urinary inconti-nence.

FOCAL AMYOTROPHY IN NEUROFIBROMATOSIS 2

Trivedi R, Byrne J, Huson SM, Donaghy M.

Journal of Neu-rology Neurosurgery and Psychiatry 69: 257–261, 2000.Reprinted with permission from the British Medical JournalPublishing Group.

Neurofibromatosis type 2 (NF2) is an autosomal domi-nant disorder characterised by bilateral vestibular schwanno-mas and other CNS tumours including meningiomas and spi-nal schwannomas. Occasionally, peripheral neuropathy occursin these patients but this is the first report of focal amyotro-phy. Clinical, electrophysiological, and imaging data fromfour NF2 patients seen at a specialist neurofibromatosisclinic over a 4 year period are described in whom symptom-atic focal amyotrophy preceded the diagnosis of NF2. Twopresented with wasting and weakness of a single musclegroup, several years before NF2 was diagnosed. In one pa-tient a mononeuritis multiplex was the presenting feature ofNF2, and in one patient focal wasting and weakness devel-oped after the diagnosis of NF2 was made. In none of thefour cases could a focal peripheral nerve or root neurofi-broma be identified despite extensive imaging with MRI,and the limitations of neuroimaging for identifying a struc-tural cause in patients with NF2 with a focal peripheral nerve

lesion is discussed. It is likely that NF2 may affect peripheralnerve structures in a manner distinct from a compressiveschwannoma.

ACUTE DETERIORATION OF CHARCOT-MARIE-TOOTH DISEASE IA (CMT IA) FOLLOWING 2 MG OF VINCRISTINE CHEMOTHERAPY

Hildebrandt G, Holler E, Woenkhaus M, Quarch G,Reichle A, Schalke B, Andreesen R.

Annals of Oncology 11:743–747, 2000. Reprinted with permission from Kluwer Aca-demic Publishers.

Background: Severe up to life-threatening neuropathyhas been observed in patients with hereditary neuropathiesreceiving vincristine. Case report: A 52-year-old femalepainter suffering from high-grade non-Hodgkin’s lymphoma(stage IVB) was treated with a total of 4 mg of vincristineduring two courses of CHOP chemotherapy (cyclophospha-mide, vincristine, adriamycin, prednisone). At onset of treat-ment no neurological problems were reported. There wasgood lymphoma response to chemotherapy. At the sametime, however, the patient gradually developed dysphagia,dysarthria, muscular weakness of both lower and upper ex-tremities, areflexia, paraesthesia of the fingertips and bilat-eral sensory impairment of feet and lower legs. These symp-toms continually worsened over a period of seven weeksuntil she was unable to walk or to perform her work. Electro-physiological studies showed peripheral axonal and demyeli-native sensorimotor neuropathy in correlation to histologicalfindings. Molecular analysis revealed 17p11.2 duplication typ-ical for Charcot-Marie-Tooth disease IA. While continuingchemotherapy without the use of vincristine the patient’sneurologic symptoms slowly recovered within six months.Conclusion: Prior to administration of vincristine family andpatient history as well as physical examination should beperformed carefully to look for underlying hereditary neu-ropathy. For those patients with a clinical history or symp-toms suggestive for CMT nerve conduction velocity studiesand on an individual base even molecular genetic analysisare necessary to prevent serious neurologic complications.

CHILDHOOD CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY: CLINICAL COURSE AND LONG-TERM OUTCOME

Ryan MM, Grattan-Smith PJ, Procopis PG, Morgan G, Ou-vrier RA.

Neuromuscular Disorders 10: 398–406, 2000. Re-printed with permission from Pergamon-Elsevier Science, Ltd.

We reviewed the clinical history, electrophysiologic andpathologic findings, and response to therapy of 16 childrenwith chronic inflammatory demyelinating polyneuropathy.The majority presented with lower limb weakness. Sensoryloss was uncommon. The illness was monophasic in sevenchildren, relapsing in six, and three had a slowly progressivecourse. All patients were treated with immunosuppressiveagents. In 11, the initial treatment was prednisolone. All hadat least a short-term response but five went on to develop arelapsing course. Intravenous immunoglobulin was the initialtreatment in four patients. Three responded rapidly, with treat-ment being stopped after a maximum of 5 months. In resis-

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tant chronic inflammatory demyelinating neuropathy, in addi-tion to prednisolone and immunoglobulin, plasma exchange,azathioprine, cyclosporine, methotrexate, cyclophosphamideand pulse methylprednisolone were tried at different timesin different patients. On serial neurophysiologic testing slow-ing of nerve conduction persisted for long periods after clini-cal recovery. Follow-up was for an average of 10 years. Whenlast seen 14 patients were asymptomatic, two having mildresidual deficits. Childhood chronic inflammatory demyeli-nating neuropathy responds to conventional treatment andgenerally has a favourable long-term outcome.

CERAMIDE INITIATES NF KAPPA B-MEDIATED CASPASE ACTIVATION IN NEURONAL APOPTOSIS

Gill JS, Windebank AJ.

Neurobiology of Disease 7: 448–461,2000. Reprinted with permission from Academic Press, Inc.

The objective of the present study was to evaluate therole of ceramide in mediating apoptosis of dorsal root gan-glion neurons induced by either nerve growth factor with-drawal or treatment with the chemotherapeutic agents sur-amin and cisplatin. Measurement of ceramide accumulationby mass spectrometry and the diacylglycerol kinase assayrevealed elevation of intracellular ceramide only in suramintreated cultures. Ceramide-mediated neuronal cell deathwas inhibited by the caspase inhibitor zVAD.fmk. In theseexperimental models, ceramide accumulation mediated acti-vation and nuclear translocation of the transcription factorNF kappa B and cyclin D1 protein expression. Specific inhibi-tion of NF kappa B using a molecular decoy strategy resultedin increased cell viability accompanied by diminished caspaseactivity and cyclin D1 expression. Inhibition of NF kappa Bdid not alter intracellular ceramide levels. Our study suggeststhat ceramide generation occurs upstream of NF kappa B ac-tivation, cell cycle reentry, and caspase activation in the neu-ronal death pathway.

SUCCESSFUL GENERATION OF PERIPHERAL NEUROPATHY WITH ONION-BULB FORMATION IN THE MACROPHAGE SCAVENGER RECEPTOR CLASS A KNOCKOUT MOUSE TREATED WITH ISONIAZID

Naba I, Yoshikawa H, Sakoda S, Itabe H, Suzuki H, Ko-dama T, Yanagihara T.

Neuroscience Letters 290: 5–8, 2000.Reprinted with permission from Elsevier Science Ireland Ltd.

We previously reported successful generation of manyonion-bulbs (OBs) and formation of oxidized phosphatidyl-choline after compression injury to the peripheral nerve ofmice deficient of macrophage scavenger receptor class A(MSR-A). In the present study, we employed chemical injurywith isoniazid to the peripheral nerve of the MSR-A knockoutmice to investigate the role of the MSR-A in toxic neuropa-thy. Peripheral neuropathy has not previously been gener-ated with isoniazid in mice. In the present study, we alsonoted little histological change after isoniazid administrationnot only to control littermates but also to the A/J strain miceknown to be slow acetylators. Surprisingly, however, wewere successful in generating peripheral neuropathy withisoniazid in the MSR-A knockout mice. Histologically, thepredominant feature was the presence of many thinly mye-

linated fibers with some OBs, which have not been observedin rats with isoniazid neuropathy. Deficiency of the MSR-Aappears to have played an important role in generation of pe-ripheral neuropathy with isoniazid in mice.

ANTI-SULFATIDE IGM ANTIBODIES IN PERIPHERAL NEUROPATHY

Carpo M, Meucci N, Allaria S, Marmiroli P, Monaco S,Toscano A, Simonetti S, Scarlato G, Nobile-Orazio E.

Journal of the Neurological Sciences 176: 144–150, 2000.Reprinted with permission from Elsevier Science BV.

Anti-sulfatide IgM antibodies have been recently asso-ciated with neuropathy but the clinical and electrophysio-logical correlations of this reactivity remains unclear. We re-viewed the clinical and electrophysiological features of patientswith high anti-sulfatide titers detected in our laboratory from1991 to 1998. Of the 564 patients with different neurologicaldiagnosis tested by enzyme-linked immunosorbent assay(ELISA), 11 had high anti-sulfatide IgM titers (

.

1/8000), 26had titers of 1/8000 while 78 had titers of 1/4000. All pa-tients with high anti-sulfatide IgM titers had a chronic, dys-immune, mostly sensorimotor neuropathy that in seven wasassociated with IgM monoclonal gammopathy. In most ofthese patients electrophysiological and morphological stud-ies were consistent with a predominantly demyelinatingneuropathy frequently associated with prominent axonalloss. Antibody titers of 1/8000, though always associatedwith neuropathy, did not correlate with a particular form orcause of neuropathy, while lower titers were equally distrib-uted in patients with different neurological disorders. Ourstudy indicates that high anti-sulfatide IgM titers (

.

1/8000)are highly predictive for a chronic, dysimmune, mostly demy-elinating neuropathy often associated with IgM monoclonalgammopathy, and may therefore have potential diagnosticrelevance.

EVALUATION OF ALPHA 1-ADRENOCEPTOR ANTAGONIST ON DIABETES-INDUCED CHANGES IN PERIPHERAL NERVE FUNCTION, METABOLISM, AND ANTIOXIDATIVE DEFENSE

Obrosova IG, Van Huysen C, Fathallah L, Cao XH,Stevens MJ, Greene DA.

FASEB Journal 14: 1548–1558, 2000.Reprinted with permission from the Federation of AmericanSociety for Experimental Biology.

The role for nerve blood flow (NBF) vs. other factors inmotor nerve conduction (MNC) slowing in short-term diabe-tes was assessed by evaluating alpha(1)-adrenoceptor an-tagonist prazosin on NBF, MNC, as well as metabolic imbal-ances and oxidative stress in the neural tissue. Control anddiabetic rats were treated with or without prazosin (5 mg.kg(

2

1).d(

2

1) for 3 wk). NBF was measured by hydrogen clear-ance. Both endoneurial vascular conductance and MNC ve-locity were decreased in diabetic rats vs. controls, and thisdecrease was prevented by prazosin. Free NAD(

1

):NADH ra-tios in mitochondrial cristae, matrix, and cytosol assessed bymetabolite indicator method, as well as phosphocreatinelevels and phosphocreatine/creatine ratios, were decreasedin diabetic rats, and this reduction was ameliorated by pra-

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zosin. Neither diabetes-induced accumulation of two majorglycation agents, glucose and fructose, as well as sorbitoland total malondialdehyde plus 4-hydroxyalkenals nor deple-tion of myo-inositol, GSH, and taurine or decrease in (Na/K)-ATP-ase activity were affected by prazosin. In conclusion,decreased NBF, but not metabolic imbalances or oxidativestress in the neural tissue, is a key mechanism of MNCslowing in short-term diabetes. Further experiments areneeded to estimate whether preservation of NBF is suffi-cient for prevention of nerve dysfunction and morphologicalabnormalities in long-standing diabetes or whether theaforementioned metabolic imbalances closely associatedwith impaired neurotropism are of greater importance in ad-vanced than in early diabetic neuropathy.

ENHANCED B7 COSTIMULATORY MOLECULE EXPRESSION IN INFLAMMATORY HUMAN SURAL NERVE BIOPSIES

Kiefer R, Dangond F, Mueller M, Toyka KV, Hafler DA, Har-tung HP.

Journal of Neurology Neurosurgery and Psychiatry69: 362–368, 2000. Reprinted with permission from the Brit-ish Medical Journal Publishing Group.

Objectives-To define the role of the costimulatory mole-cules B7-1 and B7-2 in inflammatory disorders of the periph-eral nervous system. B7 molecules are essential for effectiveantigen presentation and may determine the differentiationof T cells into a Th-1 or Th-2 phenotype, thus modulating im-mune response and disease course. Methods-Forty ninesural nerve biopsies from patients with neuroborreliosis,Guillain-Barre syndrome (GBS), chronic inflammatory demy-elinating polyneuropathy (CIDP), CIDP variants and heredi-tary neuropathies, and those with no detectable abnormalitywere investigated. The expression of B7-1 and B7-2 mRNAand protein was investigated by polymerase chain reaction(PCR) and immunocytochemistry. Results-B7-1 mRNA wasstrongly upregulated in both cases of neuroborreliosis, intwo cases of GBS and one case of variant CIDP. Moderate tolow levels were detected in the remaining GBS and CIDP bi-opsies and were rarely found in a noninflammatory controlgroup consisting of hereditary neuropathy and normalnerves. At the immunocytochemical level, strong expressionof B7-1 protein was found in both neuroborreliosis cases,and moderate or low expression in six of eight GBS casesand seven of 17 CIDP cases investigated, whereas only oneof five non-inflammatory control nerves showed staining,which was very weak. In neuroborreliosis, B7-1 protein wasfound very pronounced in epineurial infiltrates, whereas inCBS and CIDP, labelling was predominantly endoneurial andlocalised to putative macrophages. B7-2 mRNA and proteinwere expressed only at low levels in neuroborreliosis and se-lected autoimmune neuropathy cases, and were essentiallyabsent from noninflammatory controls. Conclusions-B7 mol-ecules are expressed in the peripheral nervous system andregulated during disease, and their presence in macrophagesunderlines the putative function of endoneurial macrophagesas local antigen presenting cells in the immunopathology ofperipheral nerve. B7-1 rather than B7-2 is preferentially up-regulated, possibly promoting the induction of a Th-1-typeT cell response within the nerve.

N-MYC DOWNSTREAM-REGULATED GENE 1 IS MUTATED IN HEREDITARY MOTOR AND SENSORY NEUROPATHY-LOM

Kalaydjieva L, Gresham D, Gooding R, Heather L, Baas F,de Jonge R, Blechschmidt K, Angelicheva D, Chandler D,Worsley P, Rosenthal A, King RHM, Thomas PK.

AmericanJournal of Human Genetics 67: 47–58, 2000. Reprinted withpermission from University Chicago Press.

Hereditary motor and sensory neuropathies, to whichCharcot-Marie-Tooth (CMT) disease belongs, are a commoncause of disability in adulthood. Growing awareness that ax-onal loss, rather than demyelination per se, is responsible forthe neurological deficit in demyelinating CMT disease hasfocused research on the mechanisms of early development,cell differentiation, and cell-cell interactions in the peripheralnervous system. Autosomal recessive peripheral neuropa-thies are relatively rare but are clinically more severe thanautosomal dominant forms of CMT, and understanding theirmolecular basis may provide a new perspective on thesemechanisms. Here we report the identification of the generesponsible for hereditary motor and sensory neuropathy-Lom (HMSNL). HMSNL shows features of Schwann-cell dys-function and a concomitant early axonal involvement, sug-gesting that impaired axon-glia interactions play a major rolein its pathogenesis. The gene was previously mapped to8q24.3, where conserved disease haplotypes suggested ge-netic homogeneity and a single founder mutation. We havereduced the HMSNL interval to 200 kb and have character-ized it by means of large-scale genomic sequencing. Se-quence analysis of two genes located in the critical regionidentified the founder HMSNL mutation: a premature-termi-nation codon at position 148 of the N-myc downstream-reg-ulated gene 1 (NDRG1). NDRG1 is ubiquitously expressedand has been proposed to play a role in growth arrest andcell differentiation, possibly as a signaling protein shuttlingbetween the cytoplasm and the nucleus. We have studiedexpression in peripheral nerve and have detected particularlyhigh levels in the Schwann cell. Taken together, these find-ings point to NDRG1 having a role in the peripheral nervoussystem, possibly in the Schwann-cell signaling necessary foraxonal survival.

EXPRESSION OF THE CO-STIMULATORY MOLECULE BB-1, THE LIGANDS CTLA-4 AND CD28 AND THEIR MRNAS IN CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY

Murata K, Dalakas MC.

Brain 123: 1660–1666, 2000. Reprintedwith permission from Oxford University Press.

To examine whether the Schwann cells in patients withautoimmune neuropathies have the potential to behave asprofessional antigen-presenting cells, we investigated theexpression of the co-stimulatory molecules BB-1, B7-1 (CD80),B7-2 (CD86) and their counter-receptors CD28 or CTLA-4(CD152) at the protein and mRNA levels in sural nerve biop-sies of patients with chronic inflammatory demyelinatingpolyneuropathy (CIDP), CIDP associated with human immu-nodeficiency virus infection (HIV-CIDP), IgM paraproteinaemicneuropathy and normal or non-immune axonal neuropathy. Insingle-and double-labelling experiments, we used the S-100

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antigen as a pan-Schwann cell marker, myelin-associated gly-coprotein as a marker for myelinating Schwann cells and thefibrillary acidic protein as a marker for unmyelinating Schwanncells. The expression of the B7 family of molecules was lim-ited to BB-1 and was observed only on the Schwann cells.There was constitutive expression of BB-1 on unmyelinatingSchwann cells in all nerves studied. However, in CIDP andHIV-CIDP, but not the other diseases, there was prominentupregulation of BB-1 on the myelinating Schwann cells. Theendoneurial T cells in the proximity of BB-1-positive Schwanncells expressed the CD28 or CTLA-4 counterreceptors. Re-verse transcription-polymerase chain reaction confirmed thatthese ligands were upregulated only in CIDP. Because themyelinating BB-1-positive Schwann cells expressed HLA-DRantigen, the findings indicate that, in CIDP, Schwann cellspossess the necessary markers to function as antigen-pre-senting cells.

GENDER AND PERIPHERAL NEUROPATHY IN CHRONIC ALCOHOLISM: A CLINICAL-ELECTRONEUROGRAPHIC STUDY

Ammendola A, Gemini D, Iannaccone S, Argenzio F, Cic-cone G, Ammendola E, Serio L, Ugolini G, Bravaccio F.

Alcohol and Alcoholism 35: 368-371, 2000. Reprinted withpermission from Oxford University Press.

In some alcohol-related pathologies of chronic alcohol-ism women are more vulnerable than men. A consecutivesample of 62 chronic alcoholics was studied, 18 females and44 males, aged between 28 and 69 years to assess the inci-dence and distribution of peripheral neuropathy with regardto gender. All patients underwent clinical and neurologicalobservations, laboratory tests, and electroneurography. Totallifetime dose of ethanol (TLDE) and other risk factors forneuropathy (disease duration, age, nutritional status) werecalculated and correlated to sural nerve sensory-evoked po-tential (SEP) amplitude. In 42 patients (67.7%), we observedthe presence of clinical and/or infraclinical neuropathy, mostlyaxonal, in 29 males (65.9%) and 13 females (72.2%). Inwomen, compared to men, TLDE and disease duration weresignificantly inversely correlated to sural nerve SEP ampli-tude, i.e in women, SEP amplitude is significantly reduced inrelation to TLDE and disease duration increase. These dataindicate a higher sensitivity of females towards the toxic ef-fects of ethanol, other than malnutrition, on peripheral nervefibres.

IDENTIFICATION OF TWO NEW PMP22 MOUSE MUTANTS USING LARGE-SCALE MUTAGENESIS AND A NOVEL RAPID MAPPING STRATEGY

Isaacs AM, Davies KE, Hunter AJ, Nolan PM, Vizor L,Peters J, Gale DG, Kelsell DP, Latham ID, Chase JM,Fisher EMC, Bouzyk MM, Potter A, Masih M, Walsh FS,Sims MA, Doncaster KE, Parsons CA, Martin J, BrownSDM, Rastan S, Spurr NK, Gray IC.

Human Molecular Genet-ics 9: 1865–1871, 2000. Reprinted with permission fromOxford University Press.

Mouse mutants have a key role in discerning mamma-lian gene function and modelling human disease; however,

at present mutants exist for only 1–2% of all mouse genes.In order to address this phenotype gap, we have embarkedon a genome-wide, phenotype-driven, large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis screen for dominant muta-tions of clinical and pharmacological interest in the mouse.Here we describe the identification of two similar neurologi-cal phenotypes and determination of the underlying muta-tions using a novel rapid mapping strategy incorporatingspeed back-crosses and high throughput genotyping. Twomutant mice were identified with marked resting tremor andfurther characterized using the SHIRPA behavioural andfunctional assessment protocol. Back-cross animals weregenerated using in vitro fertilization and genome scans per-formed utilizing DNA pools derived from multiple mutantmice. Both mutants were mapped to a region on chromo-some 11 containing the peripheral myelin protein 22 gene(Pmp22). Sequence analysis revealed novel point mutationsin Pmp22 in both lines. The first mutation, H12R, alters thesame amino acid as in the severe human peripheral neu-ropathy Dejerine Sottas syndrome and Y153TER in the othermutant truncates the Pmp22 protein by seven amino acids.Histological analysis of both lines revealed hypomyelinationof peripheral nerves. This is the first report of the generationof a clinically relevant neurological mutant and its rapid ge-netic characterization from a large-scale mutagenesis screenfor dominant phenotypes in the mouse, and validates theuse of large-scale screens to generate desired clinical phe-notypes in mice.

PHASE II EVALUATION OF THALIDOMIDE IN PATIENTS WITH METASTATIC BREAST CANCER

Baidas SM, Winer EP, Fleming GF, Harris L, Pluda JM,Crawford JG, Yamauchi H, Isaacs C, Hanfelt J, Tefft M,Flockhart D, Johnson MD, Hawkins MJ, Lippman ME,Hayes DF.

Journal of Clinical Oncology 18: 2710–2717, 2000.Reprinted with permission from Lippincott Williams &Wilkins.

Purpose: To determine the efficacy, safety, pharmacoki-netics, and effect on serum angiogenic growth factors oftwo dose levels of thalidomide in patients with metastaticbreast cancer. Patients and Methods: Twenty-eight patientswith progressive metastatic breast cancer were randomizedto receive either daily 200 mg of thalidomide or 800 mg tobe escalated to 1,200 mg. Fourteen heavily pretreated pa-tients were assigned to each dose level. Each cycle con-sisted of 8 weeks of treatment. Pharmacokinetics andgrowth factor serum levels were evaluated. Results: No pa-tient had a true partial or complete response. On the 800-mgarm, 13 patients had progressive disease at or before 8weeks of treatment and one refused to continue treatment.The dose was reduced because of somnolence to 600 mgfor five patients and to 400 mg for two and was increasedfor one to 1,000 mg and for four to 1,200 mg. On the 200-mgarm, 12 patients had progressive disease at or before 8weeks and two had stable disease at 8 weeks, of whom onewas removed from study at week 11 because of grade 3neuropathy and the other had progressive disease at week16. Dose-limiting toxicities included somnolence and neur-opathy. Adverse events that did not require dose or schedule

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modifications included constipation, fatigue, dry mouth, diz-ziness, nausea, anorexia, arrhythmia, headaches, skin rash,hypotension, and neutropenia. Evaluation of circulating an-giogenic factors and pharmacokinetic studies failed to pro-vide insight into the reason for the lack of efficacy. Conclu-

sion: Single-agent thalidomide has little or no activity inpatients with heavily pretreated breast cancer. Further stud-ies that include different patient populations and/or combina-tions with other agents might be performed at the lowerdose levels.