IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations.

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.

Leukoencephalopathies associated with inborn errors of metabolism in adults.

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.

Hereditary spastic paraparesis in adults associated with inborn errors of metabolism: a diagnostic approach.

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.

Epilepsy and inborn errors of metabolism in adults: a diagnostic approach.

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.

Peripheral neuropathy and inborn errors of metabolism in adults.

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.

Psychiatric manifestations revealing inborn errors of metabolism in adolescents and adults.

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.

[Treatable hereditary neuro-metabolic diseases]. / Les maladies métaboliques héréditaires traitables en neurologie.

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.

[Myelin and nuclear magnetic resonance]. / Myéline et résonance magnétique nucléaire.

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.

[Nitric-oxide triggered neurological disorders in subjects with vitamin B12 deficiency]. / Troubles neurologiques par carence en vitamine B12 déclenchés par le protoxyde d'azote.

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.

Epidemiology and immunovirology of human T-cell leukemia/lymphoma virus type I-associated adult T-cell leukemia and chronic myelopathies as seen in France.

Seventeen patients with adult T-cell leukemia (ATL) and 21 with tropical spastic paraparesis/human T-cell leukemia/lymphoma virus type I (HTLV-I)-associated myelopathy (TSP/HAM) were observed during a 3-yr survey (1986-1988) in some hospitals in Paris, France. Most of them were black, originating from high-HTLV-I-endemic areas (West Indies or Africa), but two cases of TSP/HAM occurred in French Caucasians. In one case, the patient acquired the virus from a transfusion during a cardiac transplantation. Most of the ATL cases were diagnosed as acute leukemia or lymphoma, with a proliferation of CD2+, CD3+, CD4+, CD8-, DR+, and CD25+ lymphoid cells. Only three cases were diagnosed as a smoldering ATL. All of the TSP/HAM cases exhibited a spastic paraparesis with a chronic and slow evolution and high HTLV-I antibody titers in serum and cerebrospinal fluid, with a high HTLV-I antibody index and specific HTLV-I immunoglobulin = oligoclonal bands. In TSP/HAM, a high percentage of DR-expressing cells (15 to 40%) was found, with a slightly elevated CD4/CD8 ratio. This was associated with the presence of 1 to 10% abnormally shaped nuclei in lymphoid cells and a polyclonal integration of HTLV-I proviruses in these peripheral blood mononuclear cells. On the contrary, a clonal integration was always found in the ATL malignant cells (leukemic, lymph node, and cutaneous infiltrate). Long-term interleukin 2-dependent T-cell lines (CD2+, CD3+, CD4+, and WT31+) with activated T-cell markers (CD25+ and DR+) producing HTLV-I were established from ATL and TSP/HAM peripheral blood mononuclear cells.

High level of HTLV-I specific protein expression in a patient with adult T-cell leukemia, chronic progressive myelopathy and Kaposi's sarcoma.

Analysis was made of serum anti-HTLV-I antibodies, virus-specific proteins in peripheral blood lymphocytes (PBL) and proviruses in lymphocyte DNA of a patient with adult T-cell leukemia (ATL), Kaposi's sarcoma, and chronic myelopathy. Using Western blot and PCR (with HIV-1 specific primers), it was shown that Kaposi's sarcoma was not linked to HIV infection. Western blot analysis of serum revealed antibodies against p19, p24 and Pr 53 of HTLV-I. Examination of proteins in fresh PBL by Western blot revealed a high level of HTLV-I specific protein expression. Southern blot analysis of the patient's DNA revealed two different sites for HTLV-I provirus integration.

[Isolated ptosis in a 58-year-old woman]. / Ptosis isolé apparu chez une femme à l'âge de 58 ans.

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.

[Adult onset hereditary leukoencephalopathies]. / Leucoencéphalopathies génétiques de l'adulte.

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.

Acute demyelination: an insight into the effect of mitoxantrone on CNS lesions.

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.

Gliotoxicity, reverse transcriptase activity and retroviral RNA in monocyte/macrophage culture supernatants from patients with multiple sclerosis.

In investigating a possible link between a novel retroviral agent (provisionally called MSRV), recently characterised in multiple sclerosis (MS), and the neuropathology of MS, it was found that there was a significant correlation between gliotoxicity and reverse transcriptase activity in monocyte/macrophage culture supernatants (MMCS) unique to MS patients. MMCS from healthy controls and patients with other neurological diseases did not display either gliotoxicity or reverse transcriptase activity. The observed gliotoxic effect was an initial, intermediate filament network disorganization and subsequent cell death which was specific to astrocytes and oligodendrocytes. The reverse transcriptase activity and MSRV-specific RNA were observed during the first 2 weeks of culture in MMCS from patients with active MS. The further elucidation of the molecular form(s) of this gliotoxic factor and its original source may be crucial in elucidating important etiopathogenic mechanisms in MS.

Monocular blindness with preserved direct and consensual pupillary reflex in multiple sclerosis.

A 22-year-old woman with definite multiple sclerosis had right-eye blindness with preserved direct and consensual pupillary reflex to light. The anatomy of the fibers inside the optic nerve did not give a satisfactory explanation of this phenomenon. On the other hand, this case appeared to support the idea of biochemical differences between the myelin of visual pathways and that of reflex pathways. Studies are necessary to confirm this hypothesis.

The natural course of cerebral lesions in Sneddon syndrome.

OBJECTIVES: To characterize the clinical, biological, and neuroradiological findings in Sneddon syndrome; to correlate magnetic resonance imaging abnormalities with disability, presence of hypertension and other vascular risk factors, presence of heart valvulopathy on echography, and titer of antiphospholipid antibodies; and to compare these findings in antiphospholipid-positive and antiphospholipid-negative patients. DESIGN: Retrospective review of the records of 32 consecutive patients with livedo reticularis and neurological events, followed up in our institution between January 1991 and August 1995. PATIENTS: Twenty-six patients (20 women and 6 men) who had at least 1 cerebral ischemic arterial event associated with generalized and pathological livedo reticularis. RESULTS: The age at the first cerebral ischemic event ranged from 22 to 58 years. Motor deficit was the most frequent sign (found in 73% of cases). Disability was found in 50%, systemic hypertension in 65%, heart valvulopathy in 61%, and antiphospholipid antibodies in 42% of cases. Patients were classified in 6 groups according to magnetic resonance imaging findings. No correlation was found between the presence of hypertension or other vascular risk factors, valvulopathy, antiphospholipids, and magnetic resonance imaging abnormalities. There was no significant difference between antiphospholipid-positive and antiphospholipid-negative patients except for the presence of antinuclear antibodies. There was a significant correlation between the extent of magnetic resonance imaging abnormalities and disability. CONCLUSION: The severity of the disease seems to be correlated with magnetic resonance imaging aspects, but not to the presence of antiphospholipid antibodies. Magnetic resonance imaging may help to understand the natural course of the cerebral involvement of the disease.

Cognitive function in recent-onset demyelinating diseases.

To determine cognitive disturbances in recent demyelinating disease, we studied 21 patients with definite or probable multiple sclerosis (MS) of less than two years' duration and nine patients with recently isolated optic neuritis. None had any clinical or social evidence of cognitive impairment. Mild to moderate cognitive impairment. Mild to moderate cognitive impairment was present in 18 (60%) of 30 cases, affecting visual and/or verbal efficiency. These abnormalities were statistically significant when compared with the results of a control group of 29 patients. There was no correlation with a depressive status, between the presence of cognitive impairment and either the degree of handicap or the activity of the disease. The frequency of cognitive dysfunction (60%) appears to be comparable to that reported in other series in which MS evolution is over ten years. The natural history of cognitive functions in MS has to be identified. Neuropsychologic tests could be useful in the diagnosis of monosymptomatic or paucisymptomatic forms of MS (ie, visual or medullary).

Functional and magnetic resonance imaging correlates of callosal involvement in multiple sclerosis.

To investigate functional and anatomical features of callosal involvement in multiple sclerosis (MS), performances of 90 patients with definite MS and 25 matched normal control subjects were compared on three tasks exploring interhemispheric transfer of auditory, sensory, and motor information: a verbal dichotic listening task, a crossed tactile finger localization task, and an alternate finger tapping task. Each patient also underwent a magnetic resonance imaging (MRI) scan (1) to appreciate the extent of white-matter changes by a semiquantitative evaluation of hemispheric brain MRI hyperintensities and (2) to measure the degree of total and regional callosal atrophy using an automatized method of partition of the midsagittal callosal area. Interhemispheric transfer and/or integration was impaired in patients with MS for all modalities explored and proportional to both degree of callosal atrophy and diffusion of white-matter lesions. Moreover, in good agreement with data obtained from partial commissurotomy studies, performance on each functional task was predominantly associated with atrophy of one part of the callosum, namely left-ear dichotic suppression with the posterior callosal region, alternate finger tapping with the anterior region, and cross-localization with midanterior and posterior regions. Finally, a subgroup of patients without MRI white-matter hyperintensities also showed significant impairment of callosal function and relative atrophy of the callosum. These findings suggest the potential clinical value of callosal involvement in MS and the usefulness of MS as a model of interhemispheric disconnection.