Determination of reference values for optical properties of liquid phantoms based on Intralipid and India ink.

A multi-center study has been set up to accurately characterize the optical properties of diffusive liquid phantoms based on Intralipid and India ink at near-infrared (NIR) wavelengths. Nine research laboratories from six countries adopting different measurement techniques, instrumental set-ups, and data analysis methods determined at their best the optical properties and relative uncertainties of diffusive dilutions prepared with common samples of the two compounds. By exploiting a suitable statistical model, comprehensive reference values at three NIR wavelengths for the intrinsic absorption coefficient of India ink and the intrinsic reduced scattering coefficient of Intralipid-20% were determined with an uncertainty of about 2% or better, depending on the wavelength considered, and 1%, respectively. Even if in this study we focused on particular batches of India ink and Intralipid, the reference values determined here represent a solid and useful starting point for preparing diffusive liquid phantoms with accurately defined optical properties. Furthermore, due to the ready availability, low cost, long-term stability and batch-to-batch reproducibility of these compounds, they provide a unique fundamental tool for the calibration and performance assessment of diffuse optical spectroscopy instrumentation intended to be used in laboratory or clinical environment. Finally, the collaborative work presented here demonstrates that the accuracy level attained in this work for optical properties of diffusive phantoms is reliable.

["It was me or them!": the no exit escape of a future author of psychotic double parricide]. / « C'était eux ou moi ! ¼ : la fuite sans issue d'un futur auteur de double parricide psychotique.

CASE-REPORT: H. had perceived his father as an evil persecutor ever since his adolescence. He developed paranoid schizophrenia of persecution in which his father occupied the main role. Little by little, in his desperate resistance against his father, perceived as his enemy, he acquired such a feeling of prejudice, of violation of his personality, and of impotence that the only way out was to escape in order to survive. At the age of 18, he decides to run away from home and from France to stop suffering. He goes to Canada and later to the USA where he would stay 9 years, during which his madness does not stop. Wherever he goes, he always feels the presence of his father in his head: "He orders me, he criticizes me from a distance, he steals all my thoughts, he is in charge of my actions, he takes away the bread from my mouth to humiliate me and kill me…" Thanks to his marginal lifestyle, he maintains a relative adaptation, a fragile equilibrium in his existential bubble in which he doesn't tolerate any breaking and entering. His delusion of prejudices and persecution, of which the main character had always been his father, extends to include society in general, cornering and leading the subject to commit an offense as a reaction of irrepressible pathological self-defense. He is questioned by the police, taken to prison and later taken to an American psychiatric hospital, after shooting at those whom he thinks are "CIA agents" (who are actually people forcing him to move the boat in which he lives). After being deported back to France, he returns to his parent's home, the source of all his madness. During the following months, he lives locked up in his room afraid of being near his father and tormented by his delirious ideas. In order to stop his suffering, he decides to buy a fire-arm to kill himself. One day, his father, accompanied by his mother, break into his room. He takes the rifle hidden under the mattress, and kills his father at point blank. "I thought that I had instantly killed my father, because he fell face down on the ground. On the other hand, my mother remained standing while my sister, screaming, escaped through the window of the living room. My mother, injured on her right side, moved back to the living room. Seeing that my mother hadn't fallen to the ground and not wanting to make her suffer, I reloaded my rifle. I took out the cartridge, and reloaded the rifle with a cartridge of buckshot. It seemed to me that she was still standing in front of the couch. I fired the gun a second time without looking and at that moment she falls on the couch… dead… She is the enemy because she is my father's wife". DISCUSSION: The recounting and analysis of this double psychotic parricide case illustrate the psychopathologic constants and criminal dynamic that are most often present in this type of crime. The constants are the following: the perpetrator of the post-adolescence or adult parricide is often a psychotic young man; he/she lives a long, delusional story in which one or both parents have an important role; this insane delusion leads to suffering and/or to identifiable behavioral problems that together can constitute a criminal psychic state; The homicidal reaction takes place right after one or a group of factors (such as an argument, brawl, a fit of delusion, interruption of the therapeutic treatment…) that are set off in the criminal pathological state. These psychopathological constants, if they conjoin, are also the factors and indicators of danger. They should be considered as a warning sign to take preventive and remedial measures.

Diversity of ARSACS mutations in French-Canadians.

BACKGROUND: The growing number of spastic ataxia of Charlevoix-Saguenay (SACS) gene mutations reported worldwide has broadened the clinical phenotype of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The identification of Quebec ARSACS cases without two known SACS mutation led to the development of a multi-modal genomic strategy to uncover mutations in this large gene and explore phenotype variability. METHODS: Search for SACS mutations by combining various methods on 20 cases with a classical French-Canadian ARSACS phenotype without two mutations and a group of 104 sporadic or recessive spastic ataxia cases of unknown cause. Western blot on lymphoblast protein from cases with different genotypes was probed to establish if they still expressed sacsin. RESULTS: A total of 12 mutations, including 7 novels, were uncovered in Quebec ARSACS cases. The screening of 104 spastic ataxia cases of unknown cause for 98 SACS mutations did not uncover carriers of two mutations. Compounds heterozygotes for one missense SACS mutation were found to minimally express sacsin. CONCLUSIONS: The large number of SACS mutations present even in Quebec suggests that the size of the gene alone may explain the great genotypic diversity. This study does not support an expanding ARSACS phenotype in the French-Canadian population. Most mutations lead to loss of function, though phenotypic variability in other populations may reflect partial loss of function with preservation of some sacsin expression. Our results also highlight the challenge of SACS mutation screening and the necessity to develop new generation sequencing methods to ensure low cost complete gene sequencing.

Founder mutation for α-sarcoglycan-LGMD2D in a Magdalen Islands Acadian cluster.

BACKGROUND: We have recruited a group of four living and reviewed the records of six deceased distantly related French-Canadians of Acadian descent affected by a childhood-onset form of recessive limb-girdle muscular dystrophy (LGMD). All cases originate from the small archipelago of the Magdalen Islands (population: 13,000) isolated in the Gulf of St-Lawrence. METHODS: Based on the likely sharing of the same founder mutation we completed a 319K SNPs genome-wide scan to identify the disease locus and then screen candidate genes in this region. RESULTS: All patients had normal initial motor milestones. They presented with limb girdle weakness at the average age of seven years (5-11). Progressive weakness led to loss of ambulation at a wide range of ages (10-39). Patients also developed macroglossia, large calves and mild to moderate contractures, hyperlordosis and decreased pulmonary function. Creatine kinase levels were elevated (1,800-10,000 U/L) in the first decades, but decreased with progression of disease. Homozygosity mapping uncovered a shared chromosomal region of 6.33Mb. The alpha sarcoglycan (SGCA) gene, mutated in LGMD2D, lay in this candidate interval. Sequencing of all SGCA exons uncovered a shared homozygous missense mutation (c. 229C>T, p.R77C), the most common SGCA mutation internationally reported. Using demographic data, we estimated a high carrier rate of 1/22. CONCLUSION: The p.R77C mutation has also been observed in many populations, including in France and Spain (Basques). This corresponds to the first reported recessive founder disease for the Magdalen Islands, an archipelago settled in the XIXth century, largely by Acadian immigrants.

Mutations in FUS cause FALS and SALS in French and French Canadian populations.

BACKGROUND: The identification of mutations in the TARDBP and more recently the identification of mutations in the FUS gene as the cause of amyotrophic lateral sclerosis (ALS) is providing the field with new insight about the mechanisms involved in this severe neurodegenerative disease. METHODS: To extend these recent genetic reports, we screened the entire gene in a cohort of 200 patients with ALS. An additional 285 patients with sporadic ALS were screened for variants in exon 15 for which mutations were previously reported. RESULTS: In total, 3 different mutations were identified in 4 different patients, including 1 3-bp deletion in exon 3 of a patient with sporadic ALS and 2 missense mutations in exon 15 of 1 patient with familial ALS and 2 patients with sporadic ALS. CONCLUSIONS: Our study identified sporadic patients with mutations in the FUS gene. The accumulation and description of different genes and mutations helps to develop a more comprehensive picture of the genetic events underlying amyotrophic lateral sclerosis.

Cognitive impairment and reduced life span of oculopharyngeal muscular dystrophy homozygotes.

OBJECTIVE: To assess the evolution and life expectancy in patients with oculopharyngeal muscular dystrophy (OPMD) who are homozygotes for two (GCN)13 expansions in the PABPN1 encoding gene. BACKGROUND: OPMD is particularly frequent among French Canadians (FCs) and Uzbek Jews (UJs), who carry a same size, (GCN)13, PABPN1 mutation. The high rate of consanguinity among UJs together with late disease onset and normal fertility results in homozygous cases. METHODS: For 15 to 20 years, we followed 4 FC and 6 UJ homozygotes with OPMD and compared them with their heterozygous parents and siblings. In addition to clinical evaluation, electrodiagnostic tests, psychological tests, and brain imaging studies were performed. RESULTS: In all (GCN)13-(GCN)13 patients, OPMD started before age 35 years, with bilateral ptosis and dysphagia; external ophthalmoparesis and dysphonia followed within a few years, as well as weakness in proximal limb muscles. All patients had recurrent aspirations and lost weight; 4 patients required surgical interventions to alleviate dysphagia, and 5 required feeding gastrostomies. Most patients were followed by psychiatrists due to cognitive decline, recurrent depression, or psychotic episodes. Six patients died at ages 50, 51, 53, 56, 56, and 57 years. The eldest patient is now 51 years old; she is cachectic and requires special diet and psychiatric care for paranoid psychosis and uninhibited behavior. CONCLUSIONS: Oculopharyngeal muscular dystrophy progresses faster in homozygote compared with heterozygote patients. It is not restricted to the muscles, but also involves the CNS with cognitive decline and psychotic manifestations and leads to a reduced life expectancy.

[A proposal for reforming psychologists' training in France and in the European Union]. / Proposition de réforme de la formation des psychologues en France et dans l'Union européenne.

BACKGROUND: In France, as in the European Union, the number of psychologists continues to increase and constitutes by far the most important source of professionals in this field. The requests for services of psychologists in many various domains have also increased in an unprecedented way over a number of years. In spite of this development, which should continue to increase considerably, the initial training of psychologists remains uneven and disparate and often remote from, even unsuitable to, the legitimate expectations of users. It is therefore important to reform this training by extending, updating, homogenising and adapting it to current knowledge and needs, and by marking it by a single and specific degree: that of a doctorate. This new eight-year doctoral curriculum would be at the same time more complete and simpler than the European Diploma in Psychology model (EuroPsy), for instance. This latter is a very complicated and insufficient subject and would not completely resolve the great problems of psychologists' training and the competences they need to gain in order to access professional practise, research and teaching. This extension of the psychologists' training would make it possible to integrate new data concerning traditional fields of psychology and data concerning new fields of application of psychology and should obviously include the essential training for psychotherapies referred to the great theoretical and practical models, since their interest is clinically acknowledged (psychoanalysis and psychoanalytical therapies, cognitive and behavioural therapies, systemic therapies, therapies for individuals, couples, families, groups...). This polyreferred training would make it possible to go from a culture still too often axed on orientation and deficiencies of the therapist, to a culture of indication, opening and competence, focused on the patient's interest. Teaching of psychophysiology and neurosciences should be updated and harmonised by taking into account the great current and future stakes of public health. It should be supplemented by psychopharmacology lectures. This reform of psychologists' training would ensure a common pedestal of increased knowledge coupled with theoretical/practical competence. The positive consequences of such a reform would relate to many fields. Here are six examples. TRACKS OF WORK: Education: prevention, tracking, treatment of personal problems or of instruction from nursery school to university; orientation; council, assistance with managing difficulties of teaching staff, etc. Health: tracking, prevention, diagnosis, treatment of psychic and behavioural disorders, of addictive attitudes, of psychological problems related to somatic pathologies (cancer, HIV, etc.), of problems related to ageing of population; training and supervision of medical staff, etc. Justice: caring of victims, of offenders in prison or out of prison, fight against repetition, expertise, staff training (magistrates, lawyers, penitentiary staff, social workers...). Work context: (companies, public and private organisations): recruitment, management of staff problems, human resources management, coaching, competence assessment, orientation, etc. Sport: assessment, management and improvement of performances, management of stress, success, failures, and career; fight against doping; help for retraining after suspension of activity, etc. RESEARCH: development of many useful research axes in relation to ground needs in all application fields of psychology. Such a reform, which would make it possible to shift towards a training more adapted to reality, more homogeneous and aiming at excellence, would ensure better guarantees of service to psychologist users and to their possible employers. Beyond a deep improvement of their initial training and their offer of competence, it would also enable psychologists to witness a very clear improvement of their professional status as well as their level of remuneration. The number of trained psychologists could be adapted to the needs of our society by organizing a numerus clausus for access in a Master 1. This regulation would leave at least three years to students to show their motivations and competence. It would also give a valuable licence level (clearly recognized on the European scene) to students who do not continue the university course in psychology and want to reorientate themselves (entrance exams, studies or professions requiring good prerequisite in social studies and nature studies, etc.). SOME SUGGESTIONS: Those already authorised to hold the title of psychologist when this doctorate is created would not be obliged to validate it, but would profit from the progress generated by this important improvement in the initial training (status, remuneration, etc). If some of these people wished to validate it, they could do so within a defined time and according to defined methods (additional training, validation of experience assets, thesis, etc.). To help students to materially take up the extension of the curriculum, systems of financial assistance for the last three years of studies should be set up either in the form of study allowances, or in the form of internship with remunerated professional implication in the great sectors of exercise of psychology (education, legal and paralegal sectors, industry and work sectors, health, etc.) in parallel and in addition to university training. Internship should be privileged because it would permit the achievement of four objectives: immersion of very advanced students in professional exercise while maintaining training them under supervision, to offer them various and crucial grounds of exercise and research that are adapted to reality, to remunerate them and hence also, offer an important professional service to users (individuals or institutions). The most important and essential improvement added to the initial training of psychologists by the creation of this new doctoral course would not exclude continuous training when necessary in career course. This reform aiming at excellence, which is socially and humanly highly necessary, must obviously also be accompanied by an indispensable and important revision of the criteria in the selection and competence of those who will dispense this renewed training (the current criteria used to recruit psychology teachers have been widely contested and deemed to be, justly so, the main cause of shortcomings of the initial training of psychologists and of their professional segmentation). An aggregative or postdoctoral route should thus be created to recruit future psychology teachers in the higher education (public and private). This recruitment should take into account candidates' theoretical knowledge, but also their knowledge of the profession and their qualities in its exercise. Thus the following criteria are essential when recruiting psychology teachers: validation of the reformed doctorate in psychology (and possibly validation of trainings complementing this doctorate); practice in the field of the psychologist's job (during at least 10 years full-time, followed by the possibility of becoming practitioner-teacher-researcher in psychology, in the sector of experiments and acquired competences, if the candidate is selected at aggregation); ability to teach and capacity to train the future psychologists for the professional acts they will be susceptible to conduct; capacity to conceive, initiate, carry out, direct and communicate useful research. Recruiting all psychology teachers in the stock of professional psychologists who are experienced, talented, skilled and who perform in all the application fields of the discipline as practitioner-teacher-researcher, is vital to implement these essential improvements in psychologists' training, exercise and research. It is therefore a priority for the future of French and European psychologists to set up as fast as possible a reformed doctorate and an aggregation (or, with regard to the aggregation, an equivalent formalised cursus); it is the common interest of psychology professionals, of their trainers and even more so of their users (people or institutions). This reform, based on the excellence of training and services offered, would also make it possible to preserve the essential unity of discipline and profession beyond the multiplicity of their sectors of application and intervention. It would also facilitate possibilities for insertion, for change of sector in career course and for professional geographical mobility. It would finally clarify the "psy" nebula for users, which is very important and necessary. CONCLUSION: It is more than ever essential to develop and update in excellence the high level "psy" generalist profession, the profession of psychologist, which users need in many fields of their private, professional or social life. We should guarantee that European Union countries, eager for development and modernity, will rapidly be able to initiate this type of good sense reform, which, by improving care for people and collective balance, would be a new and important step in their humanistic traditions (according to the World Health Organization, one person out of four is in psychological distress). Since psychism and human behaviour are complex and central in all fields of life, the existence of highly qualified psychologists to help them is imperative. Reaching this high level of updated qualification is technically possible and humanly impossible to avoid. Fast reforms must make this requirement achievable. It is in the interest of all the European Union, and all its member states must become a reference and an example in the world for teaching and professional practise of what has become a key discipline: psychology.

Association of paraoxonase gene cluster polymorphisms with ALS in France, Quebec, and Sweden.

BACKGROUND: The paraoxonase gene cluster on chromosome 7 comprising the PON1-3 genes is an attractive candidate for association in amyotrophic lateral sclerosis (ALS) given the role of paraoxonase genes during the response to oxidative stress and their contribution to the enzymatic break down of nerve toxins. Oxidative stress is considered one of the mechanisms involved in ALS pathogenesis. Evidence for this includes the fact that mutations of SOD1, which normally reduce the production of toxic superoxide anion, account for 12% to 23% of familial cases in ALS. In addition, PON variants were shown to be associated with susceptibility to ALS in several North American and European populations. METHODS: We extended this analysis to examine 20 single nucleotide polymorphisms (SNPs) across the PON gene cluster in a set of patients from France (480 cases, 475 controls), Quebec (159 cases, 95 controls), and Sweden (558 cases, 506 controls). RESULTS: Although individual SNPs were not considered associated on their own, a haplotype of SNPs at the C-terminal portion of PON2 that includes the PON2 C311S amino acid change was significant in the French (p value 0.0075) and Quebec (p value 0.026) populations as well as all three populations combined (p value 1.69 x 10(-6)). Stratification of the samples showed that this variation was pertinent to ALS susceptibility as a whole, and not to a particular subset of patients. CONCLUSIONS: These findings contribute to the increasing weight of evidence that genetic variants in the paraoxonase gene cluster are associated with amyotrophic lateral sclerosis.

[Hereditary ataxias, spastic parapareses and neuropathies in Eastern Canada]. / Ataxies, paraparésies spastiques et neuropathies héréditaires fréquentes dans l'Est du Canada.

It has been demonstrated, for many inherited diseases, that historical events have shaped the various regional gene pools of Eastern Canada. In so doing, it has given rise to the increased prevalence of some rare diseases due, to founder effects. The following neurogenetic disorders were first identified in patients from Eastern Canada: AOA-2, Arsacs, HSN-2, Arca-1, HMSN/ACC and Arsal. The population of Eastern Canada, we are convinced, will still allow the identification of new rare forms of hereditary ataxias, spastic parapareses and neuropathies as well as contribute to the uncovering of their mutated genes. We have summarized our current knowledge of the various hereditary ataxias, spastic parapareses and neuropathies in Eastern Canada. The study of the more common and homogenous features of these diseases has been largely completed.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay: a report of MR imaging in 5 patients.

We present findings on MR imaging in 5 patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). In the literature, early atrophy of the superior vermis as well as progressive atrophy of the cerebellar hemispheres and cervical cord was described. We found linear hypointensity on T2 and T2 fluid-attenuated inversion recovery-weighted images in the pons in all of our 5 patients.

A novel autosomal recessive limb-girdle muscular dystrophy with quadriceps atrophy maps to 11p13-p12.

Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of pathologies. We have identified a cohort of 14 French-Canadian patients from eight different families displaying a novel form of LGMD with an autosomal recessive inheritance. These patients share some features with previously described cases of 'quadriceps myopathy' that evolved into an LGMD. All demonstrate quadriceps femoris asymmetrical atrophy. Creatine kinase values were variable from normal to 6000 U/l. Clinical evaluations and MRI studies demonstrate a variable intrafamilial and interfamilial phenotype. Asymmetrical muscle involvement was clinically observed and confirmed by imaging. MRI studies suggest that the hamstrings and the adductor magnus are the first limb muscles to demonstrate fatty infiltration. Muscle pathology shows no sign of active inflammation but increased endomysial connective tissue associated with basal lamina duplication and collagen disorganization. A genome-wide scan using the two largest families uncovered linkage to marker D11S1360 on chromosome 11p12 [multipoint logarithm of the odds (LOD) score of 2.78]. Further genotyping for the eight families confirmed linkage to this new LGMD locus (multipoint LOD score of 4.56). Fine mapping subsequently defined a less than 3.3 cM candidate interval on 11p13-p12. Haplotype analysis of carrier chromosomes suggests that the most frequent mutation may account for up to 81.3% of French-Canadian mutations. In this study, we describe the chromosomal locus of a new form of recessive LGMD with prominent quadriceps femoris atrophy.

A new autosomal recessive spastic ataxia associated with frequent white matter changes maps to 2q33-34.

Recessive ataxias are a heterogeneous group of diseases. We identified a group of 23 French-Canadian cases belonging to 17 families affected by an autosomal recessive spastic ataxia associated with frequent white matter changes. The fact that 59% of these families have a genealogical relationship to the Portneuf County of Quebec suggests that this is a new form of ataxia with a regional founder effect. All cases present with cerebellar ataxia and spasticity. There is great intrafamilial and interfamilial variability, as illustrated by the spectrum of age of diagnosis (range: 2-59 years, mean: 15.0) and the presence of white matter changes on MRI in 52.4% of cases. The more severe cases have spasticity from birth, scoliosis, dystonia and cognitive impairment and were considered cases of cerebral palsy. Brain MRI constantly shows cerebellar atrophy, which in some cases may be associated with cortical atrophy, leucoencephalopathy and corpus callosum thinning. A genome wide scan uncovered linkage of three families to marker D2S2321 localized on chromosome 2q33-34. Linkage analysis confirmed that all families are linked to the same region [multipoint log of the odds (LOD) score of 5.95]. Haplotype analysis and allele sharing suggest that one common mutation may account for 97% of carrier chromosomes in Quebec. The uncovering of the mutated gene may point to a common pathway for pyramidal and cerebellar degeneration as both are often observed in recessive ataxias and complicated paraplegias.

K-Cl cotransport in red blood cells from patients with KCC3 isoform mutants.

Red blood cells (RBCs) possess the K-Cl cotransport (KCC) isoforms 1, 3, and 4. Mutations within a given isoform may affect overall KCC activity. In a double-blind study, we analyzed, with Rb as a K congener, K fluxes (total flux, ouabain-sensitive Na+/K+ pump, and bumetanide-sensitive Na-K-2Cl cotransport, Cl-dependent, and ouabain- and bumetanide-insensitive KCC with or without stimulation by N-ethylmaleimide (NEM) and staurosporine or Mg removal, and basal channel-mediated fluxes, osmotic fragility, and ions and water in the RBCs of 8 controls, and of 8 patients with hereditary motor and sensory neuropathy with agenesis of corpus callosum (HMSN-ACC) with defined KCC3 mutations (813FsX813 and Phe529FsX532) involving the truncations of 338 and 619 C-terminal amino acids, respectively. Water and ion content and, with one exception, mean osmotic fragility, as well as K fluxes without stimulating agents, were similar in controls and HMSN-ACC RBCs. However, the NEM-stimulated KCC was reduced 5-fold (p < 0.0005) in HMSN-ACC vs control RBCs, as a result of a lower Vmax (p < 0.05) rather than a lower Km (p = 0.109), accompanied by corresponding differences in Cl activation. Low intracellular Mg activated KCC in 6 out of 7 controls vs 1 out of 6 HMSN-ACC RBCs, suggesting that regulation is compromised. The lack of differences in staurosporine-activated KCC indicates different action mechanisms. Thus, in HMSN-ACC patients with KCC3 mutants, RBC KCC activity, although indistinguishable from that of the control group, responded differently to biochemical stressors, such as thiol alkylation or Mg removal, thereby indirectly indicating an important contribution of KCC3 to overall KCC function and regulation.

Randomized study of once-weekly interferon beta-1la therapy in relapsing multiple sclerosis: three-year data from the OWIMS study.

BACKGROUND: Once weekly interferon beta-1a for multiple sclerosis (OWIMS) demonstrated modest, but significant, magnetic resonance imaging (MRI) benefit of once-weekly (qw) interferon (IFN) beta-1a at 48 weeks, but no significant effect on relapses. OBJECTIVE: An OWIMS extension permitted assessment of longer-term efficacy/safety of qw IFN beta-1a in relapsing-remitting multiple sclerosis (RRMS). METHODS: Placebo patients were rerandomized to IFN beta-1a, 22 or 44 mcg qw, for two additional 48-week intervals. Primary outcome was MRI lesion activity. Relapse rate and other MRI measures were secondary outcomes. RESULTS: After three years, median (mean) T2 lesion count/patient/scan was 1.3 (2.6) for 44 mcg, 1.7 (3.3) for 22 mcg, 1.7 (3.4) for placebo/22 mcg, 2.0 (3.6) for placebo/44 mcg (all differences not significant). Annualized relapse rates were lowest for 44 mcg (0.77) versus other groups (0.83-0.86, not significant). Persistent neutralizing antibodies did not affect relapse rates, but MRI active lesions were increased in antibody-positive patients receiving 44 mcg compared to antibody negative patients. CONCLUSIONS: In RRMS, once weekly IFN beta-1a, particularly 44 mcg, can induce a significant MRI, but not relapse, effect, compared with placebo. No significant dose effect was seen. In contrast to the significant effect observed with three-times-weekly dosing of subcutaneous IFN beta-1a compared with placebo, this study confirms the lack of meaningful clinical benefit with once-weekly dosing.

Genetic susceptibility to MS: a second stage analysis in Canadian MS families.

Four published genome screens have identified a number of markers with increased sharing in multiple sclerosis (MS) families, although none has reached statistical significance. One hundred and five markers previously identified as showing increased sharing in Canadian, British, Finnish, and American genome screens were genotyped in 219 sibling pairs ascertained from the database of the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). No markers examined met criteria for significant linkage. Markers located at 5p14 and 17q22 were analyzed in a total of 333 sibling pairs and attained mlod scores of 2.27 and 1.14, respectively. The known HLA Class II DRB1 association with MS was confirmed (P<0.0001). Significant transmission disequilibrium was also observed for D17S789 at 17q22 (P=0.0015). This study highlights the difficulty of searching for genes with only mild-to-moderate effects on susceptibility, although large effects of specific loci may still be present in individual families. Future progress in the genetics of this complex trait may be helped by (1) focussing on more ethnically homogeneous samples, (2) using an increased number of MS families, and (3) using transmission disequilibrium analysis in candidate regions rather than the affected relative pair linkage analysis.

A founder mutation in French-Canadian families with X-linked hereditary neuropathy.

BACKGROUND: The aim of the present study was to identify the mutations in the connexin 32 gene in French-Canadian families with X-linked Charcot-Marie-Tooth disease (CMTX). METHODS: Molecular analysis was performed by nonisotopic single strand conformation polymorphism (SSCP) analysis and sequencing. Clinical evaluation was carried out according to the scale defined by the European Hereditary Motor and Sensory Neuropathy Consortium. RESULTS: In one family, the mutation Arg142Trp was located in the transmembrane domain III whereas, in four other families we identified a novel mutation (Ser26Trp) located in the transmembrane domain I of the connexin 32 gene. Haplotype analysis revealed that these four families are related and suggests a founder mutation. Sixteen patients from these four families were studied. As expected, all the affected males were more clinically affected than the females and all affected patients exhibited some electrophysiological characteristics of demyelination. CONCLUSION: Our study suggests that the Ser26Trp mutation may cause a primary demyelinating neuropathy that is not associated with a specific clinical phenotype. We also find evidence that the majority of kindreds share a common ancestor.

Rapid detection of the sacsin mutations causing autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS; MIM SACS 270550) is frequent in northeastern Québec. Two causal mutations have been identified in the 11.7-kb single exon sacsin gene by sequence-based analyses. Mutation g.6594delT (DeltaT) was reported in 96% of the patients whereas a g.5254C --> T nonsense mutation has been observed only in 2 families. Here we report a reliable and inexpensive method to detect more than 95% of the ARSACS disease alleles from northeastern Québec using allele-specific oligonucleotide (ASO) hybridization. This procedure is being incorporated into the diagnosis of ARSACS, as well as being used for carrier detection in at-risk families from northeastern Québec.

Oculopharyngeal MD among Bukhara Jews is due to a founder (GCG)9 mutation in the PABP2 gene.

OBJECTIVE: To determine whether all cases of oculopharyngeal muscular dystrophy (OPMD) among Bukhara Jews share the same founder mutation. BACKGROUND: Autosomal dominant OPMD is caused by a (GCG)8-13 repeat expansion in the polyadenylation binding protein 2 (PABP2) gene. The disease has a worldwide distribution but is particularly prevalent in Bukhara Jews and in French Canadians, in whom it was introduced by three sisters in 1648. METHODS: We established the size of the PABP2 mutation in 23 Bukhara Jewish patients belonging to eight unrelated families. In all families, we constructed haplotypes for the carrying chromosomes composed of the alleles for eight chromosome 14q polymorphic markers. RESULTS: All patients share a (GCG)9 PABP2 mutation and a four-marker haplotype. Furthermore, a shared intron single nucleotide polymorphism (SNP) in the PABP2 gene 2.6Kb from the mutation was not observed in 22 families with (GCG)9 mutations from nine different countries. The smaller size of the chromosomal region in linkage disequilibrium around the mutation in Bukhara Jews, as compared with French Canadians, suggests a founder effect that occurred more than 350 years ago. Based on the Luria-Delbrück corrected "genetic clock," we estimate that the mutation appeared or was introduced once in the Bukhara Jewish population between AD 872 and 1512 (mean, AD 1243). CONCLUSION: OPMD among Bukhara Jews is the result of a shared, historically distinct, PABP2 (GCG)9 mutation that likely arose or was introduced in this population at the time they first settled in Bukhara and Samarkand during the 13th or 14th centuries.

ARSACS, a spastic ataxia common in northeastern Québec, is caused by mutations in a new gene encoding an 11.5-kb ORF.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS or SACS) is an early onset neurodegenerative disease with high prevalence (carrier frequency 1/22) in the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region of Quebec. We previously mapped the gene responsible for ARSACS to chromosome 13q11 and identified two ancestral haplotypes. Here we report the cloning of this gene, SACS, which encodes the protein sacsin. The ORF of SACS is 11,487 bp and is encoded by a single gigantic exon spanning 12,794 bp. This exon is the largest to be identified in any vertebrate organism. The ORF is conserved in human and mouse. The putative protein contains three large segments with sequence similarity to each other and to the predicted protein of an Arabidopsis thaliana ORF. The presence of heat-shock domains suggests a function for sacsin in chaperone-mediated protein folding. SACS is expressed in a variety of tissues, including the central nervous system. We identified two SACSmutations in ARSACS families that lead to protein truncation, consistent with haplotype analysis.