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3.
J Interferon Cytokine Res ; 28(6): 393-404, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18593334

ABSTRACT

Development of neutralizing antibodies (NAbs) to interferons (IFNs) can reduce the clinical response to IFN therapy. As current cell-based assays for quantifying NAbs have limitations, a highly sensitive and reproducible assay was developed, using division-arrested frozen human U937 cells transfected with the luciferase reportergene controlled by an IFN-responsive chimeric promoter, which allows IFN activity to be determined with precision within hours. Assay-ready PIL5 cells can be stored frozen for >3 years without loss of IFN sensitivity or the need for cell propagation. The assay is highly IFN sensitive (detecting <1.0 IU/mL), reproducible (SE +/- 15%) over concentrations from <1.0 to 100 IU/mL and able to measure different IFN subtypes and their pegylated variants. The use of this assay has shown that NAbs from patients treated with IFN-alpha2 exhibited markedly lower titers against 10 LU/mL of low specific activity IFNs, namely, IFN-alpha1, PEG-Intron(TM) (Schering-Plough, Levallois-Perret,France), or Pegasys(TM) (Hoffmann-La Roche, Neuilly-sur-Seine, France, than against 10 LU/mL IFN-alpha2. Similarly, NAbs from patients treated with IFN-beta1a exhibit lower titers against 10 LU/mL of low specific activity IFN-beta1b than against IFN-beta1a. The combination of the use of division-arrested, IFN-responsive human cells transfected with the luciferase reporter-gene makes the rapid PIL5 assay for NAbs highly advantageous.


Subject(s)
Antibodies/immunology , Immunoassay , Interferon Type I/immunology , Interferon-alpha/immunology , Antibodies/blood , Cell Division , Epitopes , Genes, Reporter , Humans , Immunotherapy, Active , Interferon alpha-2 , Interferon-alpha/therapeutic use , Luciferases , Polyethylene Glycols , Promoter Regions, Genetic , Recombinant Proteins , U937 Cells
4.
Genes Immun ; 9(3): 259-63, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18354419

ABSTRACT

Multiple sclerosis (MS) is the most common chronic inflammatory neurologic disorder diagnosed in young adults and, due to its chronic course, is responsible for a substantial economic burden. MS is considered to be a multifactorial disease in which both genetic and environmental factors intervene. The well-established human leukocyte antigen (HLA) association does not completely explain the genetic impact on disease susceptibility. However, identification and validation of non-HLA-genes conferring susceptibility to MS has proven to be difficult probably because of the small individual contribution of each of these genes. Recently, associations with two single nucleotide polymorphisms (SNPs) in the IL2RA gene (rs12722489, rs2104286) and one SNP in the IL7RA gene (rs6897932) have been reported by several groups. These three SNPs were genotyped in a French and a German population of MS patients using the hME assay by the matrix-assisted laser desorption/ionization time of flight technology (Sequenom, San Diego, CA, USA). We show that these SNPs do contribute to the risk of MS in these two unrelated European MS patient populations with odds ratios varying from 1.1 to 1.5. The discovery and validation of new genetic risk factors in independent populations may help toward the understanding of MS pathogenesis by providing valuable information on biological pathways to be investigated.


Subject(s)
Genetic Predisposition to Disease/genetics , Interleukin-2 Receptor alpha Subunit/genetics , Multiple Sclerosis/genetics , Receptors, Interleukin-7/genetics , Adult , Aged , Female , France , Gene Frequency , Genotype , Germany , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
5.
J Inherit Metab Dis ; 31(3): 295-307, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18344012

ABSTRACT

The discovery of a leukoencephalopathy is a frequent situation in neurological practice and the diagnostic approach is often difficult given the numerous possible aetiologies, which include multiple acquired causes and genetic diseases including inborn errors of metabolism (IEMs). It is now clear that IEMs can have their clinical onset from early infancy until late adulthood. These diseases are particularly important to recognize because specific treatments often exist. In this review, illustrated by personal observations, we give an overview of late-onset leukoencephalopathies caused by IEMs.


Subject(s)
Brain Diseases, Metabolic, Inborn/etiology , Hereditary Central Nervous System Demyelinating Diseases/etiology , Adrenoleukodystrophy/diagnosis , Adrenoleukodystrophy/etiology , Brain Diseases, Metabolic, Inborn/diagnosis , Electron Transport , Hereditary Central Nervous System Demyelinating Diseases/diagnosis , Homocysteine/metabolism , Humans , Leukodystrophy, Globoid Cell/diagnosis , Leukodystrophy, Globoid Cell/etiology , Leukodystrophy, Metachromatic/diagnosis , Leukodystrophy, Metachromatic/etiology , Magnetic Resonance Imaging , Phenylketonurias/diagnosis , Phenylketonurias/etiology , Xanthomatosis, Cerebrotendinous/diagnosis , Xanthomatosis, Cerebrotendinous/etiology
6.
Rev Neurol (Paris) ; 163(10): 884-96, 2007 Oct.
Article in French | MEDLINE | ID: mdl-18033024

ABSTRACT

Hereditary metabolic diseases may appear during adolescence or young adulthood, revealed by an apparently unexplained neurological or psychiatric disorder. Certain metabolic diseases respond to specific treatments and should be identified early, particularly in emergency situations where rapid introduction of a treatment can avoid fatal outcome or irreversible neurological damage. The main diseases leading to an acute neurological syndrome in the adult are urea cycle disorders, homocysteine metabolisms disorders and porphyria. More rarely, Wilson's disease, aminoacid diseases, organic aciduria, or pyruvate dehydrogenase deficiency, beta-oxidation disordes or biotin metabolism may be involved. Most emergency situations can be screen correctly with simple tests (serum ammonia, homocysteine, lactate, urinary prophyrines, acylcarnitine pattern, amino acid and organic acid chromatography). For chronic situations, the main treatable diseases are Wilson's disease, homocysteine, cerebrotendinous xanthomatosis, Refsum's disease, vitamin E deficiency, Gaucher's disease, Fabry's disease, and neurotransmitter metabolism disorders. We present treatable metabolic disorders as a function of the different clinical situations observed in adults.


Subject(s)
Metabolism, Inborn Errors/genetics , Metabolism, Inborn Errors/therapy , Nervous System Diseases/genetics , Nervous System Diseases/therapy , Adult , Brain Diseases, Metabolic, Inborn/diagnosis , Brain Diseases, Metabolic, Inborn/genetics , Brain Diseases, Metabolic, Inborn/therapy , Humans , Metabolism, Inborn Errors/diagnosis , Movement Disorders/genetics , Movement Disorders/therapy , Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/genetics , Peripheral Nervous System Diseases/therapy
7.
Rev Neurol (Paris) ; 163(10): 942-9, 2007 Oct.
Article in French | MEDLINE | ID: mdl-18033031

ABSTRACT

MRI is one of the most important tools for the investigation of white matter diseases of the central nervous system. Other techniques based on the magnetic resonance phenomena (magnetization transfer imaging, diffusion imaging, magnetic resonance spectroscopy) have joined MRI to better caracterize certain diseases, understand their pathophysiology and follow their evolution.


Subject(s)
Demyelinating Diseases/pathology , Magnetic Resonance Imaging , Myelin Sheath/pathology , Animals , Disease Progression , Humans
8.
J Inherit Metab Dis ; 30(6): 855-64, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17957490

ABSTRACT

Spastic paraparesis is a general term describing progressive stiffness and weakness in the lower limbs caused by pyramidal tract lesions. This clinical situation is frequently encountered in adult neurology. The diagnostic survey is usually limited to searching for acquired causes (spinal cord compression, inflammatory, metabolic, infectious diseases) and the so-called 'hereditary spastic paraparesis'. Although poorly recognized by neurologists, spastic paraparesis is also one of the multiple presentations of inborn errors of metabolism (IEMs) in children and adults. Pyramidal signs are usually included in a diffuse neurological or systemic clinical picture; however, in some cases spastic paraparesis remains the only symptom for years. Since these metabolic causes are often treatable, it is essential to include them in the general diagnostic approach to spastic paraparesis. Here we review IEMs causing paraparesis in adults.


Subject(s)
Metabolism, Inborn Errors/complications , Metabolism, Inborn Errors/diagnosis , Paraparesis, Spastic/complications , Paraparesis, Spastic/diagnosis , Age of Onset , Decision Trees , Female , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/genetics , Humans , Male , Methylation , Motor Neurons/metabolism , Paraparesis, Spastic/genetics , Spinal Cord/pathology , Syndrome
9.
J Inherit Metab Dis ; 30(6): 846-54, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17957491

ABSTRACT

Inborn errors of metabolism (IEMs) represent poorly known causes of epilepsy in adulthood. Although rare, these are important to recognize for several reasons: some IEMs respond to specific treatments, some antiepileptic drugs interfering with metabolic pathways may worsen the clinical condition, and specific genetic counselling can be provided. We review IEMs potentially revealed by epilepsy that can be encountered in an adult neurology department. We distinguished progressive myoclonic epilepsies (observed in some lysosomal storage diseases, respiratory chain disorders and Lafora disease), from other forms of epilepsies (observed in disorders of intermediary metabolism, including porphyrias, creatine metabolism defects, glucose transporter (GLUT-1) deficiency, Wilson disease or succinic semialdehyde dehydrogenase deficiency). We propose a diagnostic approach and point out clinical, radiological and electrophysiological features that suggest an IEM in an epileptic patient.


Subject(s)
Epilepsy/diagnosis , Epilepsy/etiology , Metabolism, Inborn Errors/complications , Metabolism, Inborn Errors/diagnosis , Adult , Decision Trees , Female , Humans , Male , Metabolic Networks and Pathways , Middle Aged , Nervous System Diseases/complications , Seizures/complications , Syndrome
10.
J Inherit Metab Dis ; 30(5): 642-53, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17879144

ABSTRACT

Although they are classically viewed as paediatric diseases, it is now recognized that inborn errors of metabolism (IEMs) can present at any age from childhood to adulthood. IEMs can involve the peripheral nervous system, mostly as part of a more diffuse neurological or systemic clinical picture. However, in some cases, the neuropathy can be the unique initial sign. Here, based on our personal experience and on a comprehensive literature analysis, we review IEMs causing neuropathies in adults. Diseases were classified according to the predominant type of neuropathies into (1) acute neuropathies, (2) mononeuropathy multiplex, (3) chronic axonal polyneuropathies, (4) chronic demyelinating polyneuropathies, (5) small-fibre neuropathies, and (6) lower motor neuron disease.


Subject(s)
Metabolism, Inborn Errors/diagnosis , Peripheral Nervous System Diseases/etiology , Acute Disease , Adolescent , Adult , Age of Onset , Chronic Disease , Decision Trees , Demyelinating Diseases/etiology , Diagnosis, Differential , Diagnostic Errors/prevention & control , Humans , Metabolism, Inborn Errors/classification , Metabolism, Inborn Errors/complications , Metabolism, Inborn Errors/epidemiology , Middle Aged , Mononeuropathies/etiology , Motor Neuron Disease/etiology , Polyneuropathies/etiology , Terminology as Topic
11.
J Inherit Metab Dis ; 30(5): 631-41, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17694356

ABSTRACT

Inborn errors of metabolism (IEMs) may present in adolescence or adulthood as a psychiatric disorder. In some instances, an IEM is suspected because of informative family history or because psychiatric symptoms form part of a more diffuse clinical picture with systemic, cognitive or motor neurological signs. However, in some cases, psychiatric signs may be apparently isolated. We propose a schematic classification of IEMs into three groups according to the type of psychiatric signs at onset. Group 1 represents emergencies, in which disorders can present with acute and recurrent attacks of confusion, sometimes misdiagnosed as acute psychosis. Diseases in this group include urea cycle defects, homocysteine remethylation defects and porphyrias. Group 2 includes diseases with chronic psychiatric symptoms arising in adolescence or adulthood. Catatonia, visual hallucinations, and aggravation with treatments are often observed. This group includes homocystinurias, Wilson disease, adrenoleukodystrophy and some lysosomal disorders. Group 3 is characterized by mild mental retardation and late-onset behavioural or personality changes. This includes homocystinurias, cerebrotendinous xanthomatosis, nonketotic hyperglycinaemia, monoamine oxidase A deficiency, succinic semialdehyde dehydrogenase deficiency, creatine transporter deficiency, and alpha and beta mannosidosis. Because specific treatments should be more effective at the 'psychiatric stage' before the occurrence of irreversible neurological lesions, clinicians should be aware of atypical psychiatric symptoms or subtle organic signs that are suggestive of an IEM. Here we present an overview of IEMs potentially revealed by psychiatric problems in adolescence or adulthood and provide a diagnostic strategy to guide metabolic investigations.


Subject(s)
Metabolism, Inborn Errors/diagnosis , Nervous System Diseases/etiology , Adolescent , Adult , Cognition , Decision Trees , Diagnosis, Differential , Female , Humans , Metabolism, Inborn Errors/classification , Metabolism, Inborn Errors/complications , Metabolism, Inborn Errors/psychology , Middle Aged , Nervous System Diseases/psychology , Neuropsychological Tests , Practice Guidelines as Topic , Terminology as Topic
12.
Rev Neurol (Paris) ; 163(3): 362-4, 2007 Mar.
Article in French | MEDLINE | ID: mdl-17404524

ABSTRACT

INTRODUCTION: Nitrous oxide is frequently used for anesthesia. It may cause spinal cord toxicity. CASE REPORTS: We report two patients who presented gait disorders after nitrous oxide anesthesia. Physical examination revealed arms and legs pyramidal syndrome and abnormal proprioception, consistent with subacute combined degeneration of the spinal cord. Serum vitamin B12 level was extremely low. The patients improved with parenteral treatment with hydroxycobalamin. CONCLUSIONS: The inactivation of methionine synthase and L methylmalonylcoA mutase by nitrous oxide has been previously demonstrated. Anesthesia-related exposure to nitrous oxide may induce neurologic disorders even in patients with no preliminary vitamin B12 deficiency.


Subject(s)
Nervous System Diseases/chemically induced , Nitric Oxide/pharmacology , Vitamin B 12 Deficiency/complications , Female , Humans , Male , Middle Aged , Nerve Degeneration/complications , Nervous System Diseases/complications
13.
Mult Scler ; 13(2): 256-9, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17439893

ABSTRACT

To determine long-term treatment (LTT) of neuromyelitis optica (NMO), we retrospectively reviewed therapies of 26 patients with NMO followed in five French neurological departments. To assess LTT efficacy, the probability of relapse free after LTT was analysed. Patients were divided into two groups according to the first treatment receiving interferon beta (IFN Group, seven patients) or immunosuppressants (IS Group, 19 patients). The probability of relapse was significantly lower in the IS Group (P =0.0007). From our results, interferon beta is not recommended, and one of the best current therapeutic options for NMO appears to be immunosuppressants.


Subject(s)
Immunologic Factors/therapeutic use , Immunosuppressive Agents/therapeutic use , Interferon-beta/therapeutic use , Neuromyelitis Optica/drug therapy , Adult , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Retrospective Studies , Secondary Prevention , Treatment Outcome
14.
Neurology ; 68(10): 779-81, 2007 Mar 06.
Article in English | MEDLINE | ID: mdl-17339588

ABSTRACT

We investigated the influence of age at disease onset on timing of the progressive phase in 957 patients with multiple sclerosis (MS). Age at onset powerfully predicts the probability of developing a primary progressive form of the disease. Moreover, age at onset strongly determines the time to conversion to secondary progression for patients presenting with a relapsing form. This suggests that age at onset strongly influences the neurodegenerative component of MS.


Subject(s)
Multiple Sclerosis/epidemiology , Multiple Sclerosis/physiopathology , Adult , Age Distribution , Age Factors , Age of Onset , Disability Evaluation , Disease Progression , Female , Humans , Longitudinal Studies , Male , Middle Aged , Proportional Hazards Models , Retrospective Studies , Risk
15.
Rev Neurol (Paris) ; 161(10): 916-31, 2005 Oct.
Article in French | MEDLINE | ID: mdl-16365621

ABSTRACT

In clinical practice, the term "genetic leukoencephalopathy" refers to a group of genetic diseases whose common point is to give an aspect of diffuse leukoencephalopathy on MRI. With progress in diagnostic techniques including radiology, biochemistry or genetics, a large number of hereditary diseases causing leukoencephalopathy have been identified. Although generally beginning in childhood, these diseases often have more insidious clinical forms which can begin in adulthood. These forms remain poorly known. Some are accessible to treatment so their diagnosis appears essential. The diagnostic steps must be guided by clinical examination (neurological, ophthalmological and systemic), electromyography and MRI. The purpose of this review is to propose a classification of the genetic leukoencephalopathies and to give a progress report applicable in neurological practice.


Subject(s)
Brain Diseases/genetics , Brain Diseases/metabolism , Demyelinating Diseases/genetics , Demyelinating Diseases/metabolism , Age of Onset , Brain Diseases/diagnosis , Demyelinating Diseases/diagnosis , Humans , Mutation
16.
Rev Neurol (Paris) ; 161(5): 596-8, 2005 May.
Article in French | MEDLINE | ID: mdl-16106815

ABSTRACT

A 60-year-old woman who had experienced isolated ptosis for two years was seen when it had been fixed for one year. She had a personal and familial history of stromal corneal dystrophy. The diagnosis of mitochondrial cytopathy was made on the basis of clinical, electrophysiological, biological and histological findings. Surgical repair of the ptosis allowed visual recovery. The relationship between ptosis, corneal dystrophy and mitochondrial cytopathy is discussed.


Subject(s)
Blepharoptosis/etiology , Blepharoptosis/pathology , Blepharoptosis/surgery , Corneal Dystrophies, Hereditary/physiopathology , Electrophysiology , Female , Humans , Middle Aged , Mitochondrial Diseases/complications , Mitochondrial Diseases/pathology , Muscle, Skeletal/pathology
17.
J Neuroradiol ; 32(1): 63-6, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15798617

ABSTRACT

We report the cases of 2 severely disabled patients with large inflammatory lesions suggestive of demyelination treated with mitoxantrone. Clinical condition was improved and brain lesions volume was reduced. On serial MR spectroscopy, there were variations in peaks between 0.9 and 1.4 ppm, suggestive of free lipids and amino acids. These variations may represent neurochemical markers of clinical recovery of large inflammatory lesions in multiple sclerosis.


Subject(s)
Brain Diseases/drug therapy , Demyelinating Diseases/drug therapy , Mitoxantrone/therapeutic use , Acute Disease , Adult , Female , Humans , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Male
18.
J Autoimmun ; 24(1): 33-7, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15725574

ABSTRACT

Demyelination events or multiple sclerosis following hepatitis B virus (HBV) vaccination have been reported. We therefore compared the T-cell response to HBsAg in patients with CNS demyelination following HBV vaccination and in HBV-vaccinated healthy individuals. Our data showed no differences in terms of T-cell proliferation or cytokine production between these groups and may help to allay concerns that HBV vaccination might trigger a deleterious immune response.


Subject(s)
Central Nervous System/immunology , Central Nervous System/pathology , Demyelinating Autoimmune Diseases, CNS/immunology , Hepatitis B Vaccines/adverse effects , Hepatitis B Vaccines/immunology , Hepatitis B/immunology , Vaccination/adverse effects , Adult , Cell Proliferation , Cytokines/biosynthesis , Cytokines/immunology , Cytokines/metabolism , Demyelinating Autoimmune Diseases, CNS/etiology , Demyelinating Autoimmune Diseases, CNS/pathology , Female , Hepatitis B virus/immunology , Humans , Male , Middle Aged , Myelin Sheath/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
20.
Am J Hum Genet ; 75(6): 1070-8, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15494893

ABSTRACT

Multiple sclerosis (MS) is a debilitating neuroimmunological and neurodegenerative disorder. Despite substantial evidence for polygenic inheritance of the disease, the major histocompatibility complex is the only region that clearly and consistently demonstrates linkage and association in MS studies. The goal of this study was to identify additional chromosomal regions that harbor susceptibility genes for MS. With a panel of 390 microsatellite markers genotyped in 245 U.S. and French multiplex families (456 affected relative pairs), this is the largest genomic screen for MS conducted to date. Four regions met both of our primary criteria for further interest (heterogeneity LOD [HLOD] and Z scores >2.0): 1q (HLOD=2.17; Z=3.38), 6p (HLOD=4.21; Z=2.26), 9q (HLOD; Z=2.71), and 16p (HLOD=2.64; Z=2.05). Two additional regions met only the Z score criterion: 3q (Z=2.39) and 5q (Z=2.17). Further examination of the data by country (United States vs. France) identified one additional region demonstrating suggestive linkage in the U.S. subset (18p [HLOD=2.39]) and two additional regions generating suggestive linkage in the French subset (1p [HLOD=2.08] and 22q [HLOD=2.06]). Examination of the data by human leukocyte antigen (HLA)-DR2 stratification identified four additional regions demonstrating suggestive linkage: 2q (HLOD=3.09 in the U.S. DR2- families), 6q (HLOD=3.10 in the French DR2- families), 13q (HLOD=2.32 in all DR2+ families and HLOD=2.17 in the U.S. DR2+ families), and 16q (HLOD=2.32 in all DR2+ families and HLOD=2.13 in the U.S. DR2+ families). These data suggest several regions that warrant further investigation in the search for MS susceptibility genes.


Subject(s)
Chromosome Mapping , Genetic Testing/methods , Genome, Human , Multiple Sclerosis/genetics , Chromosomes, Human, Pair 13/genetics , Chromosomes, Human, Pair 16/genetics , Chromosomes, Human, Pair 2/genetics , Chromosomes, Human, Pair 6/genetics , France , Gene Frequency , HLA-DR2 Antigen/genetics , Humans , Lod Score , Microsatellite Repeats/genetics , Models, Genetic , United States
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