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We report a case of POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M protein and Skin changes) with unusual clinical features. A 62-year-old woman presented a severe polyneuropathy with dysphonia and vegetative symptoms, including bradycardia and sphincterial disorders. The clinical examination showed facial hyperpigmentation, cachexia, anasarca and splenomegaly. She also presented restrictive cardiomyopathy and endocrine disturbances. Nerve conduction studies revealed a severe demyelinating sensorimotor neuropathy. Cerebrospinal fluid analysis showed an elevated protein level. We detected a biclonal gammapathy (Ig G and Ig A with lambda light chain) and lytic pelvic bone lesions. Later, she developed a severe ventilatory failure due to a bilateral phrenic nerve paralysis leading to a mechanical ventilation. Steroids followed by localized radiotherapy partially improved the respiratory status and stabilized the neuropathy. Phrenic nerve paralysis, restrictive cardiomyopathy, vegetative symptoms and cranial nerve palsy are exceptional in POEMS syndrome. Moreover, this case emphasizes the importance of radiological investigations since the discover of plasmocytoma may improve the prognosis of POEMS syndrome.

Aims The aim of this study is to assess the long-term cardiac prognosis of adults with mitochondrial diseases. Methods and results Between January 2000 and May 2014, we retrospectively included in this study 260 consecutive patients (60% women) ≥18 years (interquartile range 31–54), with genetically proven mitochondrial diseases, including 109 with mitochondrial DNA (mtDNA) single large-scale deletions, 64 with the m.3243A>G mutation in MT-TL1 , 51 with other mtDNA point mutations, and 36 patients with nuclear gene mutations. Cardiac involvement was present at baseline in 81 patients (30%). Single and multiple variable analyses were performed in search of predictors of major adverse cardiac events (MACEs), and hazard ratios (HRs) and 95% confidence intervals (CI) were calculated. Over a median follow-up of 7 years (3.6–11.7), 27 patients (10%) suffered a MACE, defined as sudden death, death due to heart failure (HF), resuscitated cardiac arrest, third-degree atrioventricular block, sinus node dysfunction, cardiac transplantation, or hospitalization for management of HF. Patients with single large-scale mtDNA deletions or m.3243A>G mutations had the highest incidence of MACE. By multiple variable analysis, intraventricular conduction block (HR = 16.9; 95% CI: 7.2–39.4), diabetes (HR = 7.0; 95% CI: 2.9–16.7), premature ventricular complexes (HR = 3.6; 95% CI: 1.4–9.2), and left ventricular (LV) hypertrophy (HR = 2.5; 95% CI: 1.1–5.8) were independent predictors of MACEs. In patients with zero, one, and two or more risk factors, the incidences of MACE were 1.7, 15 and 42%, respectively. Conclusion Patients with mitochondrial diseases are at high risk of MACE, independently predicted by intraventricular conduction block, diabetes, ventricular prematurity, and LV hypertrophy.

Resume Propos . -L'utilisation des interferons (IFN) en neurologie se limite actuellement a la prise en charge therapeutique de la sclerose en plaques. Dans cette affection, seuls les IFN beta sont utilises. Actualites et points forts . -Les progres concernent essentiellement les formes remittentes de la maladie. Les IFN beta constituent danscette indication le traitement de premiere intention lorsque la prescription d'un traitement de fond parait justifie. De nombreux arguments ont demontre l'interet d'un traitement precoce. De facon globale et dans cette indication, les IFN beta diminuent d'environ un tiers la frequency des poussees ainsi que le risque de progression du handicap neurologique. Dans les formes secondairement progressives, l'indication d'un traitement par IFN beta est discutee en raison de resultats plus mitiges. Les IFN beta diminuent egalement l'evolution des lesions a l'imagerie par resonance magnetique. La dose prescrite varie d'un IFN beta a l'autre. Si un effet dose existe probablement sur certains parametres cliniques, il est difficile d'affirmer formellement que cette effet dose a une importance sur l'evolution du handicap a moyen et a long terme. Les effets secondaires sont en regle moderes malgre la survenue frequente d'un syndrome pseudogrippal en debut de traitement. Perspectives et projets . -Au vu des donnees recentes, il est possible que certains patients puissent beneficier d'un traitement par IFNbeta des la premiere poussee. En cas d'echec therapeutique, outre la prescription de certains immunosuppresseurs, des espoirs sont fondes sur des combinaisons therapeutiques incluant un IFN beta. Les IFN ont ete egalement proposes avec des resultats peu convaincants dans d'autres indications notamment dans les polyradiculonevrites chroniques inflammatoires.

Introduction Les gammapathies monoclonales ont ete associees a de nombreuses pathologies, en particulier renales ou neurologiques. Au sein des myopathies acquises, la myopathie a bâtonnets ou l’amylose musculaire sont deux entites rares associees aux gammapathies monoclonales, dont le traitement permet une amelioration fonctionnelle. Nous decrivons une nouvelle pathologie musculaire encore jamais rapportee, associee avec une gammapathie monoclonale. Patients et methodes Trois patients, suivis dans 2 centres hospitaliers universitaires differents, ont ete etudies prospectivement. Les caracteristiques cliniques, electrophysiologiques, histologiques ainsi que l’evolution ont ete colligees. Resultats Deux femmes et un homme âges de 48 a 60 ans ont ete analyses. Tous les patients presentaient un deficit moteur d’installation sub-aigue ( Conclusion Nous rapportons une myopathie originale associee a une gammapathie monoclonale definie par une myosite vacuolaire avec deficit moteur proximal et axial avec rigidite musculaire.

Background Charcot-Marie-Tooth type 1A disease (CMT1A) is a rare orphan inherited neuropathy caused by an autosomal dominant duplication of a gene encoding for the structural myelin protein PMP22, which induces abnormal Schwann cell differentiation and dysmyelination, eventually leading to axonal suffering then loss and muscle wasting. We favour the idea that diseases can be more efficiently treated when targeting multiple disease-relevant pathways. In CMT1A patients, we therefore tested the potential of PXT3003, a low-dose combination of three already approved compounds (baclofen, naltrexone and sorbitol). Our study conceptually builds on preclinical experiments highlighting a pleiotropic mechanism of action that includes downregulation of PMP22. The primary objective was to assess safety and tolerability of PXT3003. The secondary objective aimed at an exploratory analysis of efficacy of PXT3003 in CMT1A, to be used for designing next clinical development stages (Phase 2b/3). Methods 80 adult patients with mild-to-moderate CMT1A received in double-blind for 1 year Placebo or one of the three increasing doses of PXT3003 tested, in four equal groups. Safety and tolerability were assessed with the incidence of related adverse events. Efficacy was assessed using the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and the Overall Neuropathy Limitations Scale (ONLS) as main endpoints, as well as various clinical and electrophysiological outcomes. Results This trial confirmed the safety and tolerability of PXT3003. The highest dose (HD) showed consistent evidence of improvement beyond stabilization. CMTNS and ONLS, with a significant improvement of respectively of 8% (0.4% - 16.2%) and 12.1% (2% - 23.2%) in the HD group versus the pool of all other groups, appear to be the most sensitive clinical endpoints to treatment despite their quasi-stability over one year under Placebo. Patients who did not deteriorate over one year were significantly more frequent in the HD group. Conclusions These results confirm that PXT3003 deserves further investigation in adults and could greatly benefit CMT1A-diagnosed children, usually less affected than adults. Trial registration EudraCT Number: 2010-023097-40. ClinicalTrials.gov Identifier: NCT01401257. The Committee for Orphan Medicinal Products issued in February 2014 a positive opinion on the application for orphan designation for PXT3003 (EMA/OD/193/13). Electronic supplementary material The online version of this article (doi:10.1186/s13023-014-0199-0) contains supplementary material, which is available to authorized users.

To the Editor: de Seze et al.1 provide an important addition to our understanding of Sjogren syndrome (SS) and primary progressive multiple sclerosis (PPMS), but several aspects of the report need comment. Two of the ten patients with SS and PPMS should have been excluded. Patient 7 was age 64, and according to the European classification criteria used in this study,2 the Schirmer test is not applicable over age 60. Without this test, the patient would not meet criteria for SS. Patient 9 had “possible PPMS,” with normal brain and spine MRI and normal CSF. Patients with only “possible PPMS” are excluded from most studies of PPMS, and should have been excluded here too. To my knowledge, the autonomic testing employed by the European criteria has not been evaluated in patients with MS or other myelopathies. Using different autonomic tests, the same authors have reported autonomic dysfunction in 56% of MS patients,3 so an abnormal Schirmer test in 28% and abnormal scintigraphy in 40% of PPMS patients is not unexpected. Many autoimmune disorders are associated with SS (so-called secondary SS). Importantly, the European criteria for secondary SS is different from that for primary SS, presumably …

The main aetiologies of acute myelopathy (AM) are: multiple sclerosis, systemic disease (SD), spinal cord infarct (SCI), parainfectious myelopathy (PIM) and delayed radiation myelopathy (DRM). Although a large amount of data have been published for each individual aetiology, comparison studies are scarce. The aim of this study was to assess the various aetiological and outcome profiles of AM. We studied 79 cases: 34 (43%) in multiple sclerosis; 13 (16.5%) in SD; 11 (14%) in SCI; five (6%) in PIM; and three (4%) in DRM. Myelopathies were of unknown origin in 13 (16.5%) patients. We evaluated clinical, spinal cord and brain MRI, CSF and evoked potentials data at admission, MRI outcome at 6 months and clinical outcome at 12 months. A statistical comparison of clinical, laboratory and outcome data was only performed between multiple sclerosis, SD and SCI patients due to the small number of cases in the other groups. A motor deficit was more frequent in SD and SCI than in multiple sclerosis where initial symptoms were predominantly sensory (P < 0.001). Spinal cord MRI showed lateral or posterior lesions of less than two vertebral levels in multiple sclerosis, in contrast to SD and SCI, where lesions involved more vertebral levels and were centromedullar (P < 0.001). Brain MRI was most frequently abnormal in multiple sclerosis (68%), but was also abnormal in 31% of SD patients (P < 0.05). Oligoclonal bands in CSF were more frequent in multiple sclerosis than in SD (P < 0.001) and were never found in SCI. Clinical outcome at 12 months was good in 88% of multiple sclerosis cases, and poor or fair in 91% of SCI and 77% of SD. Aetiologies of AM may be differentiated on the basis of clinical, spinal cord and brain MRI, CSF and outcome data, and allow a probable diagnosis to be made in previously undetermined cases. These findings may have therapeutic implications for cases with a questionable diagnosis.

Autonomic nervous system disturbances such as pupillary abnormalities have rarely been evaluated in multiple sclerosis (MS). However, pupillary impairment is not uncommon in MS and its origin is still unclear. The aim of this study was to investigate pupillary disturbances in MS and to try to correlate pupillary defects with spinal cord and brainstem magnetic resonance imaging (MRI) findings. We prospectively studied 45 MS patients and 30 normal subjects.The pupillary contraction latency and the amplitude of contraction were recorded by pupillometry. We also determined afferent and efferent pathway defects by comparing the direct and consensual pupillary reflexes. We evaluated brainstem and spinal cord demyelinating lesions and spinal cord cross-sectional area on MRI. At least one pupillometric parameters were significantly impaired in 60% of patients and in none of the controls. We did not find any correlation between pupillary defect and demyelinating lesions on MRI. The most frequent abnormality was efferent pathway shift and this was correlated with spinal cord atrophy (P0.02). These results confirm that the autonomic nervous system, and especially pupillary function, is frequently impaired in MS. The parasympathetic system is most commonly affected and this is most likely linked to axonal loss (demonstrated by spinal cord atrophy) rather than to demyelinating lesions.

Background : The frequency of the association between chronic demyelinating inflammatory polyneuropathy (CIDP) and central nervous system (CNS) demyelinating lesions is probably underestimated. Objective : To investigate the occurrence of combined central and peripheral demyelination in CIDP patients and to correlate visual evoked potential (VEP) abnormalities with CNS demyelinating lesions, observed on brain magnetic resonance imaging, and antibodies against glycolipids. Methods : Nerve conduction studies, brain MRI and antibodies against glycolipids were prospectively studied in 17 patients who fulfilled the diagnostic criteria proposed for CIDP (Cornblath DR, Asbury AK, Albers JW, Feasby TE, Hahn AF, McLeod JG, Mendell JR, Parry GJ, Pollard JD, Thomas PK. Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy. Neurology, 1991;41:617–618). VEPs were performed in each case before and after 6 months treatment with either intravenous immunoglobulins (IVIG) or steroids. Results : Eight patients (47%) had increased latencies in at least one eye or showed increased interocular latency difference. Four patients (23%) presented a significant high signal intensity on T2-weighted brain MRI images. Of these 4 patients, 3 had prolonged VEP latency. Two patients with delayed VEP latency had antibodies against GM1, and SGLPG and anti-sulfatides, respectively. One patient with normal VEPs also had antibodies to GM1. VEP results were not significantly modified after treatment, either with steroids or IVIG. Conclusion : This study confirmed the high frequency of abnormal VEPs in CIDP patients, and found that they are poorly correlated with CNS demyelinating lesions and antibodies against glycolipids. The VEP abnormalities of these patients may be explained by the susceptibility to immune-mediated damage of both the peripheral nervous system and the optic nerve.

Objective - Visual evoked potentials (VEPs) are a very useful tool in diagnosis of multiple sclerosis (MS). Nevertheless, in some cases of the disease, VEPs are normal. The aim of this study was to evaluate the diagnostic value of focal checkerboard reversal stimulation based on opto-acoustic modulation generated by a scanning laser ophthalmoscope (SLO) in patients whose standard neuro-ophthalmological work-up was normal. Methods - We prospectively studied 185 MS patients. In this cohort we found 30 patients with definite MS and normal neuro-ophthalmological work-up and we studied the diagnostic yield of focal visual stimulation in these patients. We performed focal SLO-elicited VEPs with two different spatial distributions: a central 8 x 8 degrees square field and a central 8 x 8 degrees exclusion square. The results were analysed in terms of age of the patient, course of the disease, and disability evaluated on the Expanded Disability Status Scale (EDSS). Results - Mean latencies of focal VEPs were increased in MS patients compared to controls. In MS, focal stimulation allowed dysfunction of the visual system to be detected in 50% of patients who have been classified as normal according to conventional VEPs. VEP abnormalities were found to be correlated with the EDSS score (P

To the Editor: Muscle glycogen storage diseases are rare inborn diseases caused by errors of metabolism associated with either dynamic, exercise-related symptoms or permanent muscle weakness. The m...

A 76-year-old male complained of numbness starting in June 2003 and was admitted to the Department of Neurology in Lille. Brain magnetic resonance imaging (MRI), electroencephalography (EEG), motor evoked potentials and electromyogram (EMG) were initially normal (Table 1). We found no biological markers of inflammatory, infectious, paraneoplastic or dysimmune disorders. The patient Helene Zephir Tanya Stojkovic Jerome de Seze Claude-Alain Maurage Katell Peoc’h Stephane Haik Patrick Vermersch

In the central nervous system (CNS), nitric oxide (NO) is thought to be involved in a variety of functions including synaptic plasticity, long term potentiation, and neurotoxicity. The aim of the present study was to investigate the expression of nitric oxide synthase (NOS) in the mouse CNS, following surgical injury to the hippocampus. NOS expression was assessed by histochemical detection of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-diaphorase) activity and immunohistochemistry of the inducible NOS (iNOS). Two days after injury to the CA1 hippocampal field, NADPH-diaphorase activity was detected in pyramidal and granular neurons and also in glial cells in the hippocampus, in contrast to the non-injured one where NADPH-diaphorase staining was observed only in a few interneurons. NADPH-diaphorase histochemistry combined with immunolabelling for GFAP and F4/80 demonstrated that these glial cells were astrocytes and microglia. This pattern of NOS expression is induced specifically after a hippocampal injury since lesion to the prefrontal or cerebellar cortex leads to NOS activity only in monocytes/macrophages like cells. Despite the large expression of NOS detected by NADPH-diaphorase histochemistry after lesioning the hippocampus, immunostaining for iNOS was confined to microglia. The fact that induction of high levels of NOS activity are detected in glial cells after a lesion to the hippocampus could be accounted for by the sensitivity of this structure to a high release of glutamate.

BackgroundCongenital disorders of glycosylation are genetic syndromes that result in impaired glycoprotein production. We evaluated patients who had a novel recessive disorder of glycosylation, with a range of clinical manifestations that included hepatopathy, bifid uvula, malignant hyperthermia, hypogonadotropic hypogonadism, growth retardation, hypoglycemia, myopathy, dilated cardiomyopathy, and cardiac arrest.MethodsHomozygosity mapping followed by whole-exome sequencing was used to identify a mutation in the gene for phosphoglucomutase 1 (PGM1) in two siblings. Sequencing identified additional mutations in 15 other families. Phosphoglucomutase 1 enzyme activity was assayed on cell extracts. Analyses of glycosylation efficiency and quantitative studies of sugar metabolites were performed. Galactose supplementation in fibroblast cultures and dietary supplementation in the patients were studied to determine the effect on glycosylation.ResultsPhosphoglucomutase 1 enzyme activity was markedly diminished in all patients. Mass spectrometry of transferrin showed a loss of complete N-glycans and the presence of truncated glycans lacking galactose. Fibroblasts supplemented with galactose showed restoration of protein glycosylation and no evidence of glycogen accumulation. Dietary supplementation with galactose in six patients resulted in changes suggestive of clinical improvement. A new screening test showed good discrimination between patients and controls.ConclusionsPhosphoglucomutase 1 deficiency, previously identified as a glycogenosis, is also a congenital disorder of glycosylation. Supplementation with galactose leads to biochemical improvement in indexes of glycosylation in cells and patients, and supplementation with complex carbohydrates stabilizes blood glucose. A new screening test has been developed but has not yet been validated. (Funded by the Netherlands Organization for Scientific Research and others.)Two brothers with an undefined congenital disorder of glycosylation were found to have phosphoglucomutase 1 deficiency, which has previously been described as a glycogen storage disorder. Supplementation with galactose improves protein glycosylation in this disease. Protein N-glycosylation is a ubiquitous process in all organ systems. During N-glycosylation, glycan precursors are assembled from monosaccharide units and then covalently attached to asparagine residues in the nascent peptide chain of a protein (Figure 1). The protein-bound glycans undergo further processing to generate mature glycoproteins. Genetic defects in protein N-glycosylation, designated as congenital disorders of glycosylation, lead to multisystem disorders. Mutations of genes involved in N-glycosylation may affect either the biosynthesis of the glycan precursor (congenital disorder of glycosylation type I [CDG-I]) or the processing of the glycan after its attachment to the protein (congenital disorder of glycosylation type ...

International audience; BACKGROUND: The BTB-KELCH protein Gigaxonin plays key roles in sustaining neuron survival and cytoskeleton architecture. Indeed, recessive mutations in the Gigaxonin-encoding gene cause Giant Axonal Neuropathy (GAN), a severe neurodegenerative disorder characterized by a wide disorganization of the Intermediate Filament network. Growing evidences suggest that GAN is a continuum with the peripheral neuropathy Charcot-Marie-Tooth diseases type 2 (CMT2). Sharing similar sensory-motor alterations and aggregation of Neurofilaments, few reports have revealed that GAN and some CMT2 forms can be misdiagnosed on clinical and histopathological examination. The goal of this study is to propose a new differential diagnostic test for GAN/CMT2. Moreover, we aim at identifying the mechanisms causing the loss-of-function of Gigaxonin, which has been proposed to bind CUL3 and substrates as part of an E3 ligase complex. RESULTS: We establish that determining Gigaxonin level constitutes a very valuable diagnostic test in discriminating new GAN cases from clinically related inherited neuropathies. Indeed, in a set of seven new families presenting a neuropathy resembling GAN/CMT2, only five exhibiting a reduced Gigaxonin abundance have been subsequently genetically linked to GAN. Generating the homology modeling of Gigaxonin, we suggest that disease mutations would lead to a range of defects in Gigaxonin stability, impairing its homodimerization, BTB or KELCH domain folding, or CUL3 and substrate binding. We further demonstrate that regardless of the mutations or the severity of the disease, Gigaxonin abundance is severely reduced in all GAN patients due to both mRNA and protein instability mechanisms. CONCLUSIONS: In this study, we developed a new penetrant and specific test to diagnose GAN among a set of individuals exhibiting CMT2 of unknown etiology to suggest that the prevalence of GAN is probably under-evaluated among peripheral neuropathies. We propose to use this new test in concert with the clinical examination and prior to the systematic screening of GAN mutations that has shown strong limitations for large deletions. Combining the generation of the structural modeling of Gigaxonin to an analysis of Gigaxonin transcripts and proteins in patients, we provide the first evidences of the instability of this E3 ligase adaptor in disease.

In the present study we report, as part of a large multiple sclerosis (MS) cohort (1800 patients), three cases of untreated patients who developed autoimmune hepatitis (AIH). The prevalence of AIH in the general population is about 0.0169% and seems to be higher in our MS cohort (0.17%). We suggest that a liver biopsy should systematically be performed in untreated MS patients with a sustained increase of liver enzyme.

About 40% of responders to treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) remain treatment dependent and have a relapse if treatment is interrupted.To look for factors associated with treatment dependence or successful withdrawal in CIDP patients.We retrospectively studied 70 responder CIDP patients comprising 34 patients who remained treatment dependent (treatment-dependent group) and 36 patients whose treatment could be discontinued (treatment withdrawal group). Clinical, biological, electrophysiological and therapeutic features were compared between these groups.A multifocal deficit was more frequent in the treatment-dependent group (35%) than in the treatment withdrawal group (8%) (p0.01). The most frequent effective treatment was intravenous immunoglobulin (IVIG) for the treatment-dependent group (79%). In this group, more patients were resistant to corticosteroids in first-line therapy (93%) than in the treatment withdrawal group (40%) (p=0.002). The delay to effective treatment was significantly shorter for the treatment withdrawal group than for the treatment-dependent group (mean 11.1 vs 31.2 months; p0.01). The rate of successful withdrawal was lower with IVIG (29%) than with corticosteroids (83%) (p0.001).When compared with the treatment withdrawal group, the treatment-dependent group was more frequently responsive to IVIG, more frequently resistant to corticosteroids in first-line treatment, had a longer delay to effective treatment and was more likely to present a multifocal deficit. The rate of successful withdrawal seems to be higher with corticosteroids, but a prospective study with a long-term follow-up is needed to confirm these features.

Background: Outcome measures for clinical trials in neuromuscular diseases are typically based on physical assessments which are dependent on patient effort, combine the effort of different muscle groups, and may not be sensitive to progression over short trial periods in slow-progressing diseases. We hypothesised that quantitative fat imaging by MRI (Dixon technique) could provide more discriminating quantitative, patient-independent measurements of the progress of muscle fat replacement within individual muscle groups. Objective: To determine whether quantitative fat imaging could measure disease progression in a cohort of limb-girdle muscular dystrophy 2I (LGMD2I) patients over a 12 month period. Methods: 32 adult patients (17 male;15 female) from 4 European tertiary referral centres with the homozygous c.826C.A mutation in the fukutin-related protein gene (FKRP) completed baseline and follow up measurements 12 months later. Quantitative fat imaging was performed and muscle fat fraction change was compared with (i) muscle strength and function assessed using standardized physical tests and (ii) standard T1-weighted MRI graded on a 6 point scale. Results: There was a significant increase in muscle fat fraction in 9 of the 14 muscles analyzed using the quantitative MRI technique from baseline to 12 months follow up. Changes were not seen in the conventional longitudinal physical assessments or in qualitative scoring of the T1w images. Conclusions: Quantitative muscle MRI, using the Dixon technique, could be used as an important longitudinal outcome measure to assess muscle pathology and monitor therapeutic efficacy in patients with LGMD2I.

Phosphoglucomutase type 1 (PGM1) deficiency is a rare metabolic myopathy in which symptoms are provoked by exercise.Because the metabolic block is proximal to the entry of glucose into the glycolytic pathway, we hypothesized that iv glucose could improve the exercise intolerance experienced by the patient.This was an experimental intervention study.The study was conducted in an exercise laboratory.Subjects were a 37-year-old man with genetically and biochemically verified PGM1 deficiency and 6 healthy subjects.Cycle ergometer, peak and submaximal exercise (70% of peak oxygen consumption), and exercise with an iv glucose infusion tests were performed.Peak work capacity and substrate metabolism during submaximal exercise with and without an iv glucose infusion were measured.Peak work capacity in the patient was normal, as were increases in plasma lactate during peak and submaximal exercise. However, the heart rate decreased 11 beats minute⁻¹, the peak work rate increased 12.5%, and exercise was rated as being easier with glucose infusion in the patient. These results were in contrast to those in the control group, in whom no improvements occurred. In addition, the patient tended to become hypoglycemic during submaximal exercise.This report characterizes PGM1 deficiency as a mild metabolic myopathy that has dynamic exercise-related symptoms in common with McArdle disease but no second wind phenomenon, thus suggesting that the condition clinically resembles other partial enzymatic defects of glycolysis. However, with glucose infusion, the heart rate decreased 11 beats min⁻¹, the peak work rate increased 12.5%, and exercise was considered easier by the patient.

Sensory chronic inflammatory demyelinating polyneuropathy (CIDP) can be difficult to diagnose.We report 22 patients with chronic sensory polyneuropathy with ≥1 clinical sign atypical for chronic idiopathic axonal polyneuropathy (CIAP) but no electrodiagnostic criteria for CIDP.Clinical signs atypical for CIAP were: sensory ataxia (59%), generalized areflexia (36%), cranial nerve involvement (32%), rapid upper limb involvement (40%), and age at onset ≤55 years (50%). Additional features were: normal sensory nerve action potentials (36%), abnormal radial/normal sural pattern (23%), abnormal somatosensory evoked potentials (SSEPs) (100%), elevated cerebrospinal fluid (CSF) protein (73%), and demyelinating features in 5/7 nerve biopsies. Over 90% of patients responded to immunotherapy. We conclude that all patients had sensory CIDP.Sensory CIDP patients can be misdiagnosed as having CIAP. If atypical clinical/electrophysiologic features are present, we recommend performing SSEPs and CSF examination. Nerve biopsy should be restricted to disabled patients if other examinations are inconclusive.

The rate of recurrent stroke after cervical artery dissection (CAD) remains unknown. The aim of this study was to evaluate the rate of recurrent stroke in the same territory in patients who were discharged alive after CAD. The secondary aims were to evaluate the rate of death, any stroke or transient ischemic attacks (TIA), recurrent CAD, reopening and residual headache or cervical pain. We contacted 110 consecutive patients with angiographically proven CAD who were discharged alive after CAD. Five of the 110 patients (4.5%) were lost to follow-up. The 105 remaining patients shared a total of 110 CAD (67 carotid, 43 vertebral). The median duration of follow-up was 36 months. Ninety-two patients had no event and 5 died 1–7 years after CAD. Two patients had a recurrent stroke and 3 had TIA in the territory of the previously dissected vessel; 3 had a recurrent dissection of the same vessel, revealed by TIA in 1 and isolated cervical pain in 2. Twenty-one patients had residual headache or cervical pain. In 90 patients who underwent a second angiography, reopening occurred in 52 (partial in 2) and an aneurysm in 5. The risk of recurrent stroke remains low in patients discharged alive after CAD. One of the most frequent sequelae is residual headache.

We report four patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who presented with phrenic nerve palsy, which was unilateral in two instances. The two patients with bilateral phrenic nerve involvement required mechanical ventilation. After treatment with intravenous immunoglobulins (i.v.Ig) or steroids, the sensorimotor deficit and respiratory parameters improved in three patients, but the fourth patient remained ventilator dependent and died from pulmonary infection. Although rare, phrenic nerve palsy may be a feature of CIDP and may be responsive to treatment with i.v.Ig or steroids.

Inherited diseases of cobalamin (cbl) intracellular metabolism are very rare disorders affecting the synthesis of adenosylcobalamin or methylcobalamin. Methylcobalamin deficiency is generally characterized by homocystinuria and hypomethioninemia in the absence of methylmalonic aciduria (figure e-1 on the Neurology ® Web site at [www.neurology.org][1]). We report one of the oldest known patients with cblG disease (deficiency of methionine synthase). [1]: http://www.neurology.org

Neuropathy in Waldenstrom's macroglobulinemia (WM) is very heterogeneous. We retrospectively studied 40 patients with WM and neuropathy to analyze the different presentations and mechanisms encountered and to propose a diagnostic strategy. Twenty-five patients (62.5%) had axonal neuropathy, related to the following mechanisms: amyloid neuropathy (n = 5), cryoglobulinemic neuropathy (n = 5), neuropathy associated with tumoral infiltration (n = 2), vasculitic neuropathy (n = 2), a clinical motor neuropathy possibly of dysimmune origin (n = 6), or an unclassified mechanism (n = 5). A demyelinating pattern was observed in 15 patients, 10 having anti-myelin-associated glycoprotein (anti-MAG) antibodies and 5 having neuropathy related to chronic inflammatory demyelinating polyradiculoneuropathy. On the basis of these results, we propose a diagnostic strategy combining: (1) an EMG to distinguish between a demyelinating and an axonal pattern; (2) measurement of anti-MAG and anti-ganglioside antibodies; (3) screening for "red flag" features to orientate further investigations. This strategy may help clinicians to identify the mechanism of neuropathy in order to adapt the therapeutic strategy.

To describe the clinical and electrophysiological features evoking CMT4C, an autosomal recessive (AR) form of Charcot-Marie-Tooth disease (CMT) due to mutations in the SH3TC2 gene, we screened the coding sequence of SH3TC2 gene in 102 unrelated patients with a demyelinating or intermediate CMT and a family history compatible with an AR transmission. We identified among this cohort 16 patients carrying two mutations in the SH3TC2 gene, but medical records finally analyzed 14 patients. We report clinical, electrophysiological, and molecular data of 14 patients (9 men, 5 women) with CMT4C. Mean age at examination was 43.6 years (median = 42.5). Among the 14 studied cases 6 had scoliosis as the presenting sign. Cranial nerve involvement affecting either the VIIIth, VIIth, XIIth or a combination of the IXth and Xth nerves was noted in 10 patients. Remarkably, 50% of the patients had proximal limb involvement at the time of examination. The hallmark of the electrophysiological study was the presence of probable conduction block and temporal dispersion. Thus the clinical and paraclinical spectrum of CMT4C can guide the clinician to perform analysis of the SH3TC2 gene.

Context Up to one-third of patients with myotonic dystrophy type 1 die suddenly. Thus far, no intervention has effectively prevented sudden death. Objective To determine whether an invasive strategy based on systematic electrophysiological studies and prophylactic permanent pacing is associated with longer survival in patients presenting with myotonic dystrophy type 1 and major infranodal conduction delays than a noninvasive strategy. Design, Setting, and Patients A retrospective study, the DM1 Heart Registry included 914 consecutive patients older than 18 years with genetically confirmed myotonic dystrophy type 1 who were admitted to the Neurological Unit of the Myology Institute of Pitie-Salpetriere Hospital, a teaching medical center in Paris, France, between January 2000 and December 2009. Interventions Among 486 patients whose electrocardiogram showed a PR interval greater than 200 milliseconds, a QRS duration greater than 100 milliseconds, or both, the outcome of 341 (70.2%) who underwent an invasive strategy was compared with 145 (29.8%) who underwent a noninvasive strategy. A propensity score risk adjustment and propensity-based matching analysis was used to account for selection biases. Main Outcome Measures Rates of overall survival (main outcome measure) and sudden death, respiratory death, and other deaths (secondary outcome measures). Results Over a median follow-up of 7.4 years (range, 0-9.9 years), 50 patients died in the invasive strategy group and 30 died in the noninvasive strategy group (hazard ratio [HR], 0.74 [95 CI, 0.47-1.16]; P = .19), corresponding to an overall 9-year survival of 74.4% (95% CI, 69.2%-79.9%). Regardless of the technique used to adjust for between-group differences in baseline characteristics, the invasive strategy was associated with a longer survival, with adjusted HRs ranging from 0.47 (95% CI, 0.26-0.84; P = .01) for a covariate-adjusted analysis of propensity-matched data to 0.61 (95% CI, 0.38-0.99; P = .047) for an analysis adjusted for propensity score quintiles. The survival difference was largely attributable to a lower incidence of sudden death, which occurred in 10 patients in the invasive strategy group and in 16 patients in the noninvasive strategy group, with HRs ranging from 0.24 (95% CI, 0.10-0.56; P = .001) for an analysis adjusted for propensity score quintiles and covariates to 0.28 (95% CI, 0.13-0.61; P = .001) for an unadjusted analysis of propensity-matched data. Conclusion Among patients with myotonic dystrophy type 1, an invasive strategy was associated with a higher rate of 9-year survival than a noninvasive strategy. Trial Registration clinicaltrials.gov Identifier: NCT01136330

We describe a long-term observational study of a large cohort of patients with sporadic inclusion body myositis and propose a sporadic inclusion body myositis weakness composite index that is easy to perform during a clinic. Data collection from two groups of patients (Paris and Oxford) was completed either during a clinic visit (52%), or by extraction from previous medical records (48%). One hundred and thirty-six patients [57% males, 61 (interquartile range 55-69) years at onset] were included. At the last visit all patients had muscle weakness (proximal British Medical Research Council scale

Collagen VI myopathies, caused by mutations in the genes encoding collagen type VI (ColVI), represent a clinical continuum with Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) at each end of the spectrum, and less well-defined intermediate phenotypes in between. ColVI myopathies also share common features with other disorders associated with prominent muscle contractures, making differential diagnosis difficult. This group of disorders, under-recognized for a long time, has aroused much interest over the past decade, with important advances made in understanding its molecular pathogenesis. Indeed, numerous mutations have now been reported in the COL6A1, COL6A2 and COL6A3 genes, a large proportion of which are de novo and exert dominant-negative effects. Genotype-phenotype correlations have also started to emerge, which reflect the various pathogenic mechanisms at play in these disorders: dominant de novo exon splicing that enables the synthesis and secretion of mutant tetramers and homozygous nonsense mutations that lead to premature termination of translation and complete loss of function are associated with early-onset, severe phenotypes. In this review, we present the current state of diagnosis and research in the field of ColVI myopathies. The past decade has provided significant advances, with the identification of altered cellular functions in animal models of ColVI myopathies and in patient samples. In particular, mitochondrial dysfunction and a defect in the autophagic clearance system of skeletal muscle have recently been reported, thereby opening potential therapeutic avenues.

Introduction Les anticorps anti-mitochondries de type M2 (AAMM2) sont observes dans 90 % des cirrhoses biliaires primitives (CBP). En 2012, 24 patients atteints de myopathie inflammatoire (MI) associee a la presence d’AAMM2 avec ou sans CBP ont ete rapportes. Leur phenotype etait particulier : forme lentement evolutive, amyotrophiante, frequemment associee a une cardiomyopathie et a une inflammation granulomateuse a l’histologie musculaire [1] . Nous presentons la seconde cohorte de patients atteints de MI associee a des AAMM2. Patients et methodes Tous les patients repertories dans la base de donnees « Myosites » (960 patients, reference CNIL 1739552) en septembre 2014 et associant les criteres de MI selon Hoogendijk [2] et la presence d’AAMM2 en immunofluorescence indirecte (IFI) ont ete inclus dans l’etude. Resultats Neuf patients (7 femmes/2 hommes) ont ete inclus. Le diagnostic de MI a ete etabli en moyenne a 48,9 ans (22,7–76,7), la duree de suivi moyenne etait de 1,3 ans. On observait 5 polymyosites (PM), 2 myopathies necrosantes auto-immunes (MNAI), 1 syndrome des anti-synthetases (SAS) et 1 myosite aspecifique. Aucun n’avait d’antecedent de dystrophie musculaire ou d’argument pour une myopathie metabolique. Un deficit musculaire proximal etait observe chez 8/9 patients au diagnostic. La patiente sans deficit moteur presentait un SAS avec une pneumonie interstitielle non specifique (PINS) et un taux de creatine kinase (CK) a 700U/L. Sept patients sur 8 avaient des difficultes a la marche. Des troubles de la deglutition etaient notes chez 3/8 dont les 2 MNAI. Parmi les PM, 3 etaient isolees, 2 rentraient dans le cadre des PM de chevauchement avec un lupus systemique et un syndrome de Sjogren pour l’une, un syndrome de Sjogren seul pour l’autre. Parmi les MNAI, un cas etait associe a une cirrhose sur hepatite C, un probable carcinome hepatocellulaire et avait ete expose aux statines, l’autre etait associe a des Ac anti-SRP. On ne retrouvait pas d’autre neoplasie dans la cohorte. Une PINS etait observee chez 2 patients (1 PM, 1 SAS). Une CBP etait observee chez 3 patients. Deux patients (PM isolee) avaient une atteinte cardiaque avec hypersignal STIR en IRM (un cas avec fraction d’ejection ventriculaire gauche [FeVG] a 37 % et bloc de branche de novo a 43 ans, le 2 e avec FeVG a 59 % a 23 ans). Cinq patients presentaient des arthralgies. Toutes les biopsies musculaires montraient des fibres atrophiques avec diametre irregulier, des fibres en necrose et une expression marquee du HLA-1 (chez 8/9). L’analyse des proteines membranaires (Western blot et immunohistochimie) etait normale. En revanche, on ne retrouvait pas de granulome. Les AAMM2 etaient isoles chez 1 patient. Des anticorps anti-Gp210 et/ou anti-Sp100 etaient retrouves chez 3 patients dont 2 atteints de CBP. Des anticorps anti-nucleaires etaient associes chez 7/9 patients dont 4 avec une fluorescence cytoplasmique granuleuse. Le dosage moyen de creatine kinase etait de 9015U/L (132–51596). Six patients sur 7 presentaient un hypersignal T2 a l’IRM musculaire, seuls 2/7 presentaient une involution graisseuse. Un traitement a ete initie chez 8/9, tous ont recu une corticotherapie par prednisone a 1 mg/kg/j, precedee pour 4 de bolus de solumedrol. Par ailleurs, 5 ont recu du methotrexate, 4 des immunoglobulines intraveineuses, 4 des echanges plasmatiques, 2 du cyclophosphamide, 1 du rituximab, 1 du mycophenolate mofetil. Le seul deces a ete observe chez le patient presentant une MNAI avec cirrhose VHC au decours d’un episode de rhabdomyolyse avec insuffisance renale aigue. Seuls 2 patients ont repondu d’emblee a une bitherapie corticoides-methotrexate. Finalement une intensification therapeutique a ete necessaire et efficace chez 6 patients. Discussion Une seule etude a etudie MI et AAMM2, au Japon, en 2012, et concernait 24 patients. Comme chez les patients japonais, nous retrouvons chez nos patients avec MI et AAMM2 une frequence elevee de CBP, atteintes cardiaques et connectivites associees. Conclusion Les AAMM2 peuvent etre les seuls auto-anticorps observes au cours d’une MI alors souvent chronique et corticoresistante. Leur identification semble associee a une cirrhose biliaire primitive et une atteinte cardiaque, necessitant une surveillance particuliere et un traitement immunosuppresseur lourd. Cette association etant nouvelle, l’exclusion d’une pathologie dystrophique en particulier pour les formes amyotrophiantes avec atrophie graisseuse musculaire est neanmoins necessaire.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease for which treatments are being developed. There is a need to define reliable and reproducible criteria to evaluate neuromuscular function in order to assess their effects. The main aim of our study consists of a follow-up of the natural history of DM1 patients over 3years. Here, baseline values for the 6-min walk distance (6MWD), the lower limb muscle strength and balance measured by the movement rate of the centre of foot pressure on a force plateform are compared between patients and age- and sex-matched healthy controls. DM1 patients and healthy controls (10 females and 7 males between 26 and 49years old in each group) of similar mean height and weight were compared. The 6MWD in percentage of predicted value was significantly reduced in DM1 patients by about 50% (Mann Whitney, p p p p p p

The authors evaluated the long-term clinical outcome of neurosarcoidosis and determined predictive factors of disease course. Twenty-seven patients with neurosarcoidosis were followed for at least 5 years from the onset of neurologic symptoms. Patients with CNS involvement during the course of the disease had a higher Modified Oxford Handicap Scale score than those with peripheral nervous system involvement (p0.02). CNS involvement may be a predictive factor for a less favorable disease course. Early and intensive treatment should be considered in such cases.

Objective Mutations in the genes encoding the extracellular matrix protein collagen VI (ColVI) cause a spectrum of disorders with variable inheritance including Ullrich congenital muscular dystrophy, Bethlem myopathy, and intermediate phenotypes. We extensively characterized, at the clinical, cellular, and molecular levels, 49 patients with onset in the first 2 years of life to investigate genotype-phenotype correlations. Methods Patients were classified into 3 groups: early-severe (18%), moderate-progressive (53%), and mild (29%). ColVI secretion was analyzed in patient-derived skin fibroblasts. Chain-specific transcript levels were quantified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and mutation identification was performed by sequencing of complementary DNA. Results ColVI secretion was altered in all fibroblast cultures studied. We identified 56 mutations, mostly novel and private. Dominant de novo mutations were detected in 61% of the cases. Importantly, mutations causing premature termination codons (PTCs) or in-frame insertions strikingly destabilized the corresponding transcripts. Homozygous PTC-causing mutations in the triple helix domains led to the most severe phenotypes (ambulation never achieved), whereas dominant de novo in-frame exon skipping and glycine missense mutations were identified in patients of the moderate-progressive group (loss of ambulation). Interpretation This work emphasizes that the diagnosis of early onset ColVI myopathies is arduous and time-consuming, and demonstrates that quantitative RT-PCR is a helpful tool for the identification of some mutation-bearing genes. Moreover, the clinical classification proposed allowed genotype-phenotype relationships to be explored, and may be useful in the design of future clinical trials. ANN NEUROL 2010;68:511–520

We retrospectively analyzed 146 patients fulfilling the European Federation of Neurological Societies and the Peripheral Nerve Society (EFNS/PNS) criteria for definite chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) to (1) evaluate the relevance of these criteria, (2) assess the frequency of CIDP variants, and (3) determine the response to treatment and the prognosis. We found that 75% of these patients fulfilled the main EFNS/PNS clinical and electrophysiological criteria (type I). The remaining patients were diagnosed using laboratory tools as supportive criteria. The common form of CIDP represented 51% of patients. We observed a high frequency of the sensory variant (35% of patients) and the rapid onset form (18%). A positive response to treatment was observed in 87% of patients, with a similar efficacy of prednisone and IVIg. However, in the long term, 40% of treated patients remained dependent on treatment. The IVIg dependency rate was higher than the prednisone or plasma exchange dependency rate (55%, 18%, and 23%, respectively; p = 0.0054). Severe handicap was observed in 24% of patients.

Ventricular repolarization dysfunction has recently been reported in multiple sclerosis (MS). We evaluated ventricular repolarization dysfunction in 52 MS patients and looked for a relationship between corrected QT (QTc) abnormalities (i.e., abnormalities of QT intervals corrected for rate) and spinal cord magnetic resonance imaging (MRI) findings. QTc intervals were increased in MS patients compared with controls (P < 0.01) and were correlated with a reduction of spinal cord area (P < 0.01). QTc abnormalities in MS were thus associated with axonal loss, reflected by spinal cord atrophy, rather than demyelination.

McArdle disease is an autosomal recessive muscle glycogenosis. In the typical clinical presentation, only exercise-related symptoms are noted. Nevertheless, permanent weakness may occur, usually late in life. In this study we report on the clinical and genetic features of fixed muscle weakness in McArdle disease. Among the 80 McArdle patients being followed at the Institute of Myology of the Salpêtrière Hospital, 9 patients have permanent weakness. The diagnosis of McArdle disease was confirmed by muscle biopsy and genetic investigations. Two patterns of muscle weakness and wasting were noted: (1) proximal and symmetric in 5 patients; and (2) asymmetric, mimicking facioscapulohumeral dystrophy (FSHD) in 4 patients. Computerized tomography scan showed fatty infiltration in the shoulder and pelvic girdle muscles. There was no clear correlation between genotype and the severity of muscle weakness. Proximal muscle weakness appeared after the age of 40 years and affected 11% of subjects in our series of 80 McArdle patients. Among patients over 40 years of age, 37.5% had muscle weakness.

To determine if magnetic resonance imaging (MR imaging) is useful in the diagnostic workup of muscular dystrophies and idiopathic inflammatory myopathies for describing the topography of muscle involvement. MR imaging was performed in 31 patients: 8 with dystrophic myotony types 1 (n = 4) or 2 (n = 4); 11 with limb-girdle muscular dystrophy, including dysferlinopathy, calpainopathy, sarcoglycanopathy, and dystrophy associated with fukutin-related protein mutation; 3 with Becker muscular dystrophy; and 9 with idiopathic inflammatory myopathies, including polymyositis, dermatomyositis, and sporadic inclusion body myositis. Analysis of T1 images enabled us to describe the most affected muscles and the muscles usually spared for each muscular disease. In particular, examination of pelvis, thigh, and leg muscles demonstrated significant differences between the muscular diseases. On STIR images, hyperintensities were present in 62% of our patients with muscular dystrophies. A specific pattern of muscular involvement was established for each muscular disease. Hyperintensities observed on STIR images precede fatty degeneration and are not specific for inflammatory myopathies.

Myofibrillar myopathies (MFMs) are rare inherited or sporadic progressive neuromuscular disorders with considerable clinical and genetic heterogeneity. In the current study, we have analyzed histopathological and immunohistochemical characteristics in genetically identified MFMs. We performed a morphological and morphometrical study in a cohort of 24 genetically identified MFM patients (12 desmin, 6 alphaB-crystallin, 4 ZASP, 2 myotilin), and an extensive immunohistochemical study in 15 of these patients, using both well-known and novel antibodies directed against distinct compartments of the muscle fibers, including Z-disc and M-band proteins. Our morphological data revealed some significant differences between the distinct MFM subgroups: the consistent presence of 'rubbed-out' fibers in desminopathies and alphaB-crystallinopathies, an elevated frequency of vacuoles in ZASPopathies and myotilinopathies, and the presence of a few necrotic fibers in the two myotilinopathy patients. Immunohistochemistry showed that in MFM only a subset of Z-disc proteins, such as filamin C and its ligands myotilin and Xin, exhibited significant alterations in their localization, whereas other Z-disc proteins like alpha-actinin, myopodin and tritopodin, did not. In contrast, M-band proteins revealed no abnormalities in MFM. We conclude that the presence of 'rubbed-out' fibers are a suggestive feature for desminopathy or alphaB-crystallinopathy, and that MFM is not a general disease of the myofibril, but primarily affects a subgroup of stress-responsive Z-disc proteins.

International audience; Mutations in dynamin 2 (DNM2) have been associated with autosomal dominant centronuclear myopathy, dominant intermediate Charcot-Marie-Tooth (CMT) type B and CMT2. Here, we report a novel DNM2 mutation in the Pleckstrin homology domain of DNM2 (p.K559del) in a patient with an axonal length-dependent sensorimotor polyneuropathy predominantly affecting the lower limbs. Neuropathy is associated with congenital cataracts, ophthalmoparesis, ptosis and neutropenia. There was no evidence of a skeletal myopathy on EMG or muscle biopsy. We suggest that this constellation of clinical features can help the diagnosis and selection of patients for direct DNM2 genetic analysis.

IntroductionLaminopathies are rare genetic diseases, with various clinical manifestations. Cardiac involvement may include conduction system disease, supraventricular and ventricular arrhythmias, and dilated cardiomyopathy. In other cardiac diseases, right ventricular dysfunction has been associated with an impaired prognosis.ObjectiveTo study the prevalence of right ventricular involvement in laminopathies and its influence on patient outcome.Methods and resultsWe retrospectively included 138 patients (age=37 [25-49], female=58%) with LMNA gene mutations. At baseline, conduction system disease was present in 36% of patients, supraventricular arrhythmias in 25%, non-sustained and sustained ventricular tachyarrhythmias (VT) in 7 and 6%, left ventricular dysfunction in 42%. The association of right ventricular systolic dysfunction and clinical signs of right heart failure was observed in 18 patients (13%) including 9 who presented with isolated right ventricular without left ventricular systolic dysfunction. Over a 13.5 median follow-up duration, 47 patients (34%) developed major cardiac adverse events, including 23 with end-stage heart failure, 28 with sustained VT, and 26 with 2nd degree Mobitz II or 3rd degree AV blocks. Right ventricular involvement was significantly associated with truncating mutations (44% vs. 22%, p=0.04), higher global mortality (44% vs. 17%, p

We report the first European tibial muscular dystrophy (TMD) family outside the Finnish population. Clinical examination showed late onset distal leg myopathy similar to the description of TMD. A molecular genetic study was made owing to the very recent TMD linkage findings on chromosome 2q31. All five clinically affected patients segregated a specific haplotype for the locus, whereas two unaffected patients had different haplotype. The results of this family without Finnish ancestors show that TMD exists outside the Finnish population.

Central nervous system manifestations in Sjögren's syndrome (SS) include focal deficits, optic neuritis, and myelopathies. Acute and chronic myelopathies are frequently severe and sometimes respond poorly to corticosteroids. The efficacy of intravenous (IV) cyclophosphamide (CYC) has been suggested in single case reports.We describe the potential usefulness of IV CYC in SS patients with severe myelopathies. Fourteen patients [with acute (n = 6) and chronic (n = 8) myelopathies] were treated with monthly CYC infusions (700 mg/m2) in addition to 500 mg of corticosteroids for one year. We evaluated the disability before and after CYC treatment using a walking distance calculation and the Expanded Disability Status Scale (EDSS).CYC treatment was well tolerated in all cases without serious adverse events. Nine patients (including the 6 with acute myelopathy) were improved after CYC treatment. Three patients were stabilized and 2 patients with chronic myelopathies had moderate progression of disability. The mean walking distance increased from 48.2 m before to 180.4 m after CYC treatment (p0.02). Mean EDSS score decreased from 6.6 to 5.7 (not significant). We found a correlation between the length of time before CYC treatment and clinical improvement for both the walking distance (p0.02) and the EDSS score (p0.05).Although a randomized multicenter controlled study is warranted to confirm our findings, IV CYC infusions seem to be useful for the treatment of myelopathies secondary to SS, particularly in acute but also in progressive cases. This treatment should be strongly considered as soon as possible when disease progression is observed.

We conducted an evaluation of changes in cognition in progressive multiple sclerosis (MS) patients receiving monthly intravenously pulse of cyclophosphamide (700 mg/m2) with methylprednisolone (1 g). Twenty-eight consecutive progressive MS patients (10 primary progressive, 18 secondary progressive MS) were evaluated before and after six and 12 months of treatment. The WAIS-R score, memory and executive functions were evaluated. Under treatment we found a significant improvement in global cognitive efficiency, encoding abilities, planning abilities and inhibition after six and 12 months. However, mechanisms of action of the positive effect of these anti-inflammatory and immunosuppressive treatments on cognition remain unclear.

Background Hereditary neuropathy with liability to pressure palsy (HNPP) first described in 1947, has been showed to be due to a 1.5Mb deletion, which includes the peripheral myelin protein 22 (PMP22) gene, on chromosome 17p11.2. HNPP is more common than previously thought. Objective We describe the clinical and molecular features in a three generation family where the index case became acutely disabled following surgery for cervical spondylosis. Method A total of 14 (including the index case) were examined. Eleven had clinical evidence of disease. The disability of this group ranged from asymptomatic (1), mild (4), moderate (4), severe (1) to death (1). The findings on examination ranged from a single nerve involvement to a confluent mononeuropathy multiplex. The patient who died had marked proximal and distal weakness. The immediate cause of death is unknown. On history two individuals (now deceased) were said to be affected. A further 2 subjects who were not available for examination but who provided blood for molecular analysis were said to be normal. A PCR based strategy for the determination of the PMP22 gene dose was undertaken in 15 subjects. Results Four of these individuals (2 on history and 2 on examination) who were clinically normal had no deletions. All the clinically affected individuals all exhibited the appropriate deletion. One was clinically normal but carried the deletion. Sample from a 16th individual, who was not examined, was insufficient. Conclusion This study is the first report of the existence of HNPP in South Africa. Cases are probably being missed. The correct diagnosis is important, as with appropriate measures and patient education, disability can be significantly reduced. Resume Introduction Decrite en 1947, la neuropathie hereditaire avec hypersensibilite a la pression (NHHP) est une neuropathie hereditaire sensitivomotrice a transmission autosomique dominante. Cette affection est liee a un defaut de synthese d\'une proteine de la myeline : la proteine PMP22 (peripheral myelin protein 22) en rapport dans pres de 90% des cas a une deletion de 1,5 megabases dans la region 17p11.2 incluant le gene PMP22. L\'HNPP parait plus frequent qu\'on ne le pensait. Objectif Nous decrivons les aspects cliniques et moleculaires d\'une famille sud africaine d\'origine indienne, sur trois generations, decouverte lors d\'une decompensation aigue suite a une intervention pour une myelopathie cervicarthrosique. Materiel et methodes 14 cas ont ete etudies. 11 patients avaient des signes cliniques evidents. Le groupe a ete classe selon les aspects suivants : asymptomatique, discret, modere, severe et deces. Les constatations etaient en rapport avec une atteinte tronculaire nerveuse, unique ou multiple. . Une enquete familiale a permis de realiser des examens cliniques et biologiques . Resultats Le PCR a ete pratique chez 15 patients. Quatre des patients asymptomatiques n\'avaient pas de deletion. Tous les patients symptomatiques avaient une deletion. Un patient asymptomatique etait porteur d\'une deletion.. Le patient decede de cause inconnue presentait une faiblesse proximale et distale tres marquee Conclusion Il s\'agit du premier cas rapporte en Republique Sud-Africaine sans que cela ne prejuge du nombre de cas qui est vraisemblablement sous-estime. Le diagnostic de HPPN ne doit pas etre omis compte tenu des eventuelles consequences fonctionnelles. (Af. J. of Neurological Sciences: 2003 22(1))

A maternally inherited and practically homoplasmic mitochondrial (mtDNA) mutation, 8527A > G, changing the initiation codon AUG into GUG, normally coding for a valine, was observed in the ATP6 gene encoding the ATPase subunit a. No alternate Met codon could replace the normal translational initiator. The patient harboring this mutation exhibited clinical symptoms suggesting a mitochondrial disease but his mother who carried the same mtDNA mutation was healthy. The mutation was absent from 100 controls and occurred once amongst 44 patients suspected of Leber Hereditary Optic Neuropathy (LHON) but devoid of typical LHON mutations. In patient fibroblasts, no effect of 8527A > G mutation could be demonstrated on the biosynthesis of mtDNA-encoded proteins, on size and the content of ATPase subunit a, on ATP hydrolysis and on mitochondrial membrane potential. In addition, ATP synthesis was barely decreased. Therefore, GUG is a functional initiation codon for the human ATP6 gene.

Devic's neuromyelitis optica (NMO) associates optic neuritis and myelopathy without other neurological signs. Many patients with NMO may be diagnosed as having multiple sclerosis (MS). However, there have been no previous studies comparing these two patho logies and it is still unclear if NMO is a separate entity or a subtype of MS. In the present study, we compared a series of NMO patients with a series of MS patients for whom optic neuritis or myelopathy was the presenting symptom, in order to determine the place of NMO in the spectrum of MS. We retrospectively studied 30 patients diagnosed with NMO and we compared these patients with 50 consecutive MS cases revealed by optic neuritis or acute myelopathy. MS patients were only included if a relapse occurred demonstrating time and space dissemination. We compared the two groups in terms of clinical presentatio n, laboratory findings (MRI and C SF) and clinical outcome. NMO patients were older and more frequently women than MS patients but the difference was not significant. C SF and MRI data were clearly different: oligoclonal bands (O C B) were found in 23% of NMO cases and 88% of MS (P B/0.001), abnormal brain MRI data were observed in 10% of NMO cases and 66% of MS (P B/0.001) and a large spinal cord lesion was observed in 67% of NMO cases and 7.4% of MS cases (P B/0.001). C linical outcome was evaluated as more severe in the NMO group (P B/0.001). O n the basis of clinical data, all NMO patients but three had dissemination in time and space. When we included MRI parameters, only two of the NMO patients met criteria for MS and one of the MS patients met criteria for NMO. O ur study demonstrates that NMO and MS should be considered as two different entities. The respective criteria for NMO and MS were able to distinguish these two patho logies but only when MRI data were applied. This finding could have implications for future therapeutic trials.