Arnaud Lacour

Clinical outcome in 19 French and Spanish patients with valosin-containing protein myopathy associated with Paget’s disease of bone and frontotemporal dementia

We report the clinical, histological and genetic findings in 10 families (19 patients) presenting mutations in the valosin-containing protein (VCP). The mean age at onset was 42 years. The clinical pattern was characterized by an early involvement of the proximal upper limbs with scapular winging. Axial and lower limb muscles were often affected, whereas facial, oculobulbar muscles were spared. Ten patients were wheelchair bound after a mean disease course of 9 years and six patients required canes for walking. Two patients required mechanically assisted ventilation and seven patients had reduced vital capacity. There was no cardiac involvement. Pagets disease of bone was observed in eight patients and cognitive impairment in nine patients. Seven patients died as a consequence of weakness and respiratory distress. Muscle biopsy showed rimmed vacuolar myopathy. Genetic analysis revealed missense heterozygous mutations mostly located in exon 5 of the VCP gene, four of which were not previously reported. We observed intrafamilial and interfamilial variability in terms of severity, distribution of weakness and presence or not of Pagets disease or cognitive impairment.

Morphologic imaging in muscular dystrophies and inflammatory myopathies

ObjectiveTo 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.Materials and methodsMR 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.ResultsAnalysis 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.ConclusionA 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.

JC-virus seroconversion in multiple sclerosis patients receiving natalizumab:

Aim: The objectives of this study were to evaluate the rate of JC virus (JCV) seroconversion/seroreversion in a French cohort of multiple sclerosis (MS) patients receiving natalizumab (NTZ), describe the characteristics of this population, identify risk factors for JCV seropositivity and analyse the additional value of quantitative JCV serology results in this context. Methods: MS patients from two French MS centres, whose JCV serological status in 2011 while receiving NTZ was known (n=357; first-generation enzyme-linked immunosorbent assay (ELISA) test (Gen1)), were proposed for inclusion in this study. We evaluated the rate of JCV seroconversion over a period of one year with a second-generation ELISA test (Gen2; n=303) and analysed the quantitative results. Multivariate analysis was performed to identify risk factors for JCV seropositivity. Results: Among the patients with Gen2 JCV serology (n=303) that had been JCV-seronegative one year before (n=165), the rate of JCV seroconversion was 26.67% (44/165). We observed a higher proportion of anti-JCV antibody seroconverters (14.5%) than expected (≤3%) but also increasing index values of anti-JCV antibody over time. Conclusion: Our data suggest that JCV reactivation occurs during NTZ therapy and leads to an increase in the anti-JCV antibodies titre, thus making them more easily detectable by the second-generation ELISA test.

Relapsing demyelinating disease affecting both the central and peripheral nervous systems

Background: Clinical and electromyographic findings of chronic inflammatory demyelinating polyradiculopathy (CIDP) are occasionally observed in patients with multiple sclerosis (MS). Objective: To define a new inflammatory demyelinating disease unlike MS or CIDP. Results: This study reports on five patients with a demyelinating disease affecting the central nervous system (CNS) and peripheral nervous system (PNS). Each case presented a relapsing–remitting course in which CNS involvement preceded PNS involvement. All patients fulfilled Barkhof’s criteria on MRI and the McDonald criteria for MS. Two patients had grey matter lesions with typical white matter changes. No systemic inflammatory disease and no metabolic or inflammatory factor for peripheral neuropathy were found. In all cases electromyography showed a demyelinating peripheral neuropathy without conduction block. Four patients fulfilled the European Federation of Neurological Societies/PNS guideline for CIDP and Nicolas et al’s criteria for CIDP, one of whom also fulfilled the Ad Hoc Subcommittee criteria for CIDP. Nerve biopsy, performed in two patients, showed histological evidence of CIDP. An improvement in clinical status and neurophysiological parameters was observed in three patients after treatment with either intravenous immunoglobulin (n = 1) or cyclophosphamide (n = 2). Conclusion: The CNS and PNS demyelination, the absence of oligoclonal bands and the peripheral demyelination without conduction block indicate pathogenic mechanisms different from MS and CIDP. The chronology of events suggests an entity unlike that involved in acute demyelinating encephalomyelitis. Immunological reactivity against antigens common to peripheral and central myelin may explain why the demyelinating disease affected both the CNS and PNS.

Regional difference and similarity of familial amyloidosis with polyneuropathy in France.

Familial amyloidosis with polyneuropathy (FAP) in France have a large genetic heterogeneity with 29 transthyretin (TTR) gene mutations; Met30-TTR is the most frequent one (62%); followed by Tyr77-TTR (11.8%) and Phe77-TTR (6.2%). Analysis of 60 FAP patients diagnosed during the period 2008–2010 showed amyloid polyneuropathy was initially suspected in only 38% patients. TTR Met30 of Portuguese ancestry is different from TTR Met30 of non Portuguese ancestry and other non Met30 variants in geographical distribution and clinical presentation. There are three additional phenotypes of the neuropathy including multifocal upper limbs neuropathy, ataxic polyneuropathy and motor neuropathy. Patients with Tyr77-TTR are characterized by a late onset (>50 years), frequent ataxic phenotype; they are localized mainly in north of France. The more frequent use of the TTR genetic tests and the French network for FAP will help in the future to improve diagnosis and care.

An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A

BackgroundCharcot-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).Methods80 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.ResultsThis 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.ConclusionsThese results confirm that PXT3003 deserves further investigation in adults and could greatly benefit CMT1A-diagnosed children, usually less affected than adults.Trial registrationEudraCT 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).

Optical Coherence Tomography in Clinically Isolated Syndrome: No Evidence of Subclinical Retinal Axonal Loss

BACKGROUND Optical coherence tomography has emerged as a new tool for quantifying axonal loss in multiple sclerosis (MS). A reduction in retinal nerve fiber layer (RNFL) thickness is correlated with Expanded Disability Status Scale score and brain atrophy. OBJECTIVE To investigate RNFL and macular volume measurements using optical coherence tomography in the clinically isolated syndrome population. DESIGN Prospective case series. Settings Neurologic clinics at the university hospitals of Lille and Strasbourg (France). PARTICIPANTS Fifty-six consecutive patients with clinically isolated syndrome (18 with optic neuritis and 38 without optic neuritis) and 32 control subjects. MAIN OUTCOME MEASURES Macular volume and RNFL thickness. RESULTS Mean (SD) overall RNFL thickness (98.98 [10.26] microm) and macular volume (6.86 [0.32] microm(3)) in the clinically isolated syndrome population were not significantly different compared with the controls (98.71 [9.08] mum and 6.92 [0.38] microm(3), respectively). No link was noted between atrophy of the RNFL or macula and conversion to MS at 6 months. CONCLUSIONS Optical coherence tomography does not reveal retinal axonal loss at the earliest clinical stage of MS and does not predict conversion to MS at 6 months.

Acute aphasia in multiple sclerosis: A multicenter study of 22 patients.

Aphasia is usually considered to be rare in multiple sclerosis (MS). To determine the clinical and radiologic characteristics of MS patients with acute aphasia, the authors investigated data from 2,700 patients from three MS centers and found 22 patients with acute aphasia (0.81%). Aphasia was the first clinical manifestation of MS in eight patients (36%). Brain MRI showed giant plaques in eight cases (40%). A full recovery was observed in 14 patients (64%). Furthermore, acute aphasia did not appear to be a criterion for poor prognosis.

The French Pompe registry. Baseline characteristics of a cohort of 126 patients with adult Pompe disease

Pompe disease is a rare autosomal recessive muscle lysosomal glycogenosis, characterised by limb-girdle muscle weakness and frequent respiratory involvement. The French Pompe registry was created in 2004 with the initial aim of studying the natural history of French patients with adult Pompe disease. Since the marketing in 2006 of enzyme replacement therapy (alglucosidase alfa, Myozyme(®)), the French Pompe registry has also been used to prospectively gather the biological and clinical follow-up data of all adult patients currently treated in France. This report describes the main clinical and molecular features, at the time of inclusion in the French registry, of 126 patients followed up in 21 hospital-based neuromuscular or metabolic centres. Sixty-five men and 61 women have been included in the registry. Median age at inclusion was 49 years, and the median age at onset of progressive limb weakness was 35 years. Fifty-five percent of the patients were walking without assistance, 24% were using a stick or a walking frame, and 21% were using a wheelchair. Forty-six percent of the patients needed ventilatory assistance, which was non-invasive in 35% of the cases. When performed, muscle biopsies showed specific features of Pompe disease in less than two-thirds of the cases, confirming the importance of acid alpha-glucosidase enzymatic assessment to establish the diagnosis. Molecular analysis detected the common c.-32-13T>G mutation, in at least one allele, in 90% of patients. The French Pompe registry is so far the largest country-based prospective study of patients with Pompe disease, and further analysis will be performed to study the impact of enzyme replacement therapy on the progression of the disease.

Kjellin Syndrome: Long-term Neuro-ophthalmologic Follow-up and Novel Mutations in the SPG11 Gene

OBJECTIVE Kjellins syndrome is a hereditary neuro-ophthalmologic syndrome. We describe the clinical phenotypes of 7 patients, identifying the responsible mutations for 4 of them. A 10-year ophthalmologic and neurologic follow-up of 5 patients allowed us to describe the diseases characteristics, early symptoms and progression, associated ocular signs, and retinal changes in carriers. DESIGN Retrospective clinical study and molecular genetics investigation. PARTICIPANTS The records of 7 patients with Kjellins syndrome were analyzed retrospectively. METHODS All patients underwent full neurologic and ophthalmologic examinations. The neurologic examinations included assessments of initial symptoms, intelligence quotient tests, psychologic tests, and either magnetic resonance imaging or computed tomography. The ophthalmologic examinations included visual acuity on an Early Treatment Diabetic Retinopathy Study chart, intraocular pressure color vision assessment, slit-lamp and fundus examination, Goldmann perimetry, fundus autofluorescence, optical coherence tomography and fluorescein angiography, electro-oculography, electroretinography, and flash visual evoked potentials. Direct sequencing of the SPG11 and SPG15 genes and gene-dosage analysis for the former were performed for 4 of these index patients. MAIN OUTCOME MEASURES Identification of new mutations in the SPG11 gene, validating its implication in Kjellins syndrome. RESULTS The first signs appear before the age of 10 years, with late verbal development and difficulty running and walking. Life expectancy is between 30 and 40 years. The secondary ophthalmologic symptoms only moderately affect visual acuity. In addition to the classic symptoms, 3 of the 7 patients displayed small whitish lens opacities, and 3 neurologically unaffected parents (father or mother), all heterozygous carriers, exhibited whitish retinal dots. All the patients who were tested carried SPG11, not SPG15, mutations. CONCLUSIONS Neurologic signs of SPG11 mutations emerge in early infancy, with walking and language difficulties. Onset of paraplegia occurs at the end of the first decade or during the second decade. Retinal changes, an integral part of SPG11 mutations in this series of patients, are only observed once the paraplegia has become apparent.