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.

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.

Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy.

Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease with a world-wide distribution. It usually presents in the sixth decade with progressive swallowing difficulties (dysphagia), eyelid drooping (ptosis) and proximal limb weakness. Unique nuclear filament inclusions in skeletal muscle fibres are its pathological hallmark. We isolated the poly(A) binding protein 2 gene (PABP2) from a 217-kb candidate interval on chromosome 14q11 (B.B. et al., manuscript submitted). A (GCG)6 repeat encoding a polyalanine tract located at the N terminus of the protein was expanded to (GCG)8-13 in the 144 OPMD families screened. More severe phenotypes were observed in compound heterozygotes for the (GCG)9 mutation and a (GCG)7 allele that is found in 2% of the population, whereas homozygosity for the (GCG)7 allele leads to autosomal recessive OPMD. Thus the (GCG)7 allele is an example of a polymorphism which can act either as a modifier of a dominant phenotype or as a recessive mutation. Pathological expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei.

A full genome search in multiple sclerosis.

The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.

["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.

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.

[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.

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.

[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 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.

Transplantation of human myoblasts in SCID mice as a potential muscular model for myotonic dystrophy.

Myotonic dystrophy (DM), the most frequent hereditary myopathy in adults, is characterized clinically by muscle weakness, myotonia, and systemic symptoms. Although the specific genetic basis for DM has been established, less is known about the cellular defects responsible for its pleiotropic manifestations. DM pathogenesis studies are presently limited due to the absence of animal models. In the present study, we transplanted myoblasts of DM patients into the Tibialis anterior of Severe Combined Immunodeficient (SCID) mice to determine whether this approach could reproduce the muscular characteristics of DM. One to 4 months after transplantation, a variable number of innervated human muscle fibers, recognized by an antibody specific for the human dystrophin, were found in the transplanted muscles. The CTG expansion was retained in human muscle fibers as determined by Southern blot analysis. Although the histological characteristics of DM were absent in these fibers, electromyographic recording showed typical myotonic discharges in muscles transplanted with DM myoblasts. The specificity of the myotonic runs was demonstrated by its inhibition by apamin, a drug that specifically blocks DM myotonia. We conclude that transplantation of myoblasts from DM patients into SCID mice represents a potential in vivo model for basic studies of this disease.

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.

Clinical trials of riluzole in patients with ALS. ALS/Riluzole Study Group-II.

Two double-blinded, placebo-controlled clinical trials of riluzole have now been carried out in more than 1,100 patients with ALS. The results of both studies show a modest benefit in prolonging survival that is statistically significant. These results led to the availability of this drug by the Food and Drug Administration for use in the United States beginning in early 1996. This is the first drug that has been available for ALS. It begins a new era in both basic and clinical research in an attempt to find a cure for this disease.

Role of the striatum, cerebellum and frontal lobes in the automatization of a repeated visuomotor sequence of movements.

Recently, Doyon et al. [20] demonstrated that lesions to both the striatum and to the cerebellum in humans produce a similar deficit in the learning of a repeated visuomotor sequence, which occurs late in the acquisition process. We now report the results of two experiments that were designed to examine whether this impairment was due to a lack of automatization of the repeating sequence of finger movements by using a dual-task paradigm and by testing for long-term retention of this skill. In Experiment 1, the performance of groups of patients with Parkinson's disease, or with damage to the cerebellum or to the frontal lobes, was compared to that of matched control subjects on the Repeated Sequence Test (primary task) and the Brooks' Matrices Test (secondary task). These two tests were administered concomitantly in both early and late learning phases of the visuomotor sequence. Overall, the groups did not differ in their ability to execute the primary task. By contrast, in accordance with the predictions, patients in Stages 2-3 of Parkinson's disease or with a cerebellar lesion failed to reveal the expected increase in performance on the secondary task seen with learning, suggesting that the latter groups of patients did not have access to the same level of residual cognitive resources to complete the matrices compared to controls. In Experiment 2, the same groups of patients and control subjects were retested again 10-18 months later. They were given four blocks of 100 trials each of the repeating sequence task, followed by a questionnaire and a self-generation task that measured their declarative knowledge of that sequence. The results revealed a long-term retention impairment only in patients who changed from Stage I to Stage II of the disease (suggesting further striatal degeneration) during the one-year interval, or who had a cerebellar lesion. By contrast, performance of the three clinical groups did not differ from controls on declarative memory tests. These findings suggest that both the striatum and the cerebellum participate to the automatization process during the late (slow) learning stage of a sequence of finger movements and that these structures also play a role in the neuronal mechanism subserving long-term retention of such a motor sequence behavior.

André Barbeau and the oculopharyngeal muscular dystrophy in French Canada and North America.

André Barbeau (1931-1986) is best known world-wide in the neurologic community for his contributions to the study of Parkinson's disease, Huntington's chorea and Friedreich's ataxia. But in Québec, Canada, his name is associated with oculopharyngeal muscular dystrophy (OPMD), often called here 'maladie de Barbeau', on which he conducted a series of genealogic, genetic and clinical studies early in his career, most intensively from 1964 to 1966. He then demonstrated that most of the reported cases in North America could be traced back to French-Canadian ancestors. Furthermore, he identified this ancestor couple and linked them with a probable case in Niort, in France. Because he was the first to see over a hundred patients, his clinical studies were definitive. He did little work on OPMD after 1967 when he rushed back to the study of L-DOPA in the treatment of Parkinson's disease, a work that he had previously so brilliantly pioneered.

Recent studies on oculopharyngeal muscular dystrophy in Québec.

In 1990, we launched a major study to ascertain the clinical picture of OPMD in Québec and to identify large families for linkage analysis. In 14 patients, the chromosomes were karyotyped to eliminate any deletion or translocation. Relevant family information and clinical data were computerized and correlations were sought for the age of onset, the identification of the first symptom and the distribution of weakness. A simple test to detect dysphagia was validated. Twenty-one families have taken part in the study, which led to our localization of the gene in 1995 [Brais B, Xie Y-G, Sanson M, et al. Hum Mol Genet 1995; 4:429-434]. At least one case in each family underwent muscle biopsy to confirm the presence of the typical nuclear filaments found in OPMD. Electrodiagnostic and pathologic studies were also conducted to better understand the disease process. An illustrative case is presented.

Oculopharyngeal muscular dystrophy in Italy.

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant myopathy particularly frequent in Québec. The few Italian cases thus far described with bilateral ptosis, dysphagia and variable muscle weakness, show non-specific dystrophic findings on muscle biopsies by light microscopy. We describe a 70-year-old Italian woman with an adult-onset ptosis, mild dysphagia and proximal muscle weakness belonging to a family segregating OPMD according to an autosomal dominant mode of inheritance. Clinical features of four of her relatives are reviewed. Muscle biopsy studied by electron microscopy showed the typical 8.5 nm in diameter intranuclear filamentous inclusions (INI). To our knowledge, this is the first Italian report of OPMD with INI. The identification of nuclear inclusions is mandatory in order to confirm the diagnosis prior to linkage analysis.

Upper esophageal sphincter myotomy in oculopharyngeal muscular dystrophy: long-term clinical results.

From 1980 to 1995, 53 patients with oculopharyngeal muscular dystrophy (OPMD) underwent an upper esophageal sphincter (UES) myotomy for the control of marked dysphagia. From this number, a group of 21 patients had been evaluated for preoperative and postoperative symptoms in 1987. The same clinical assessment was performed in 1995 by an independent evaluator for a total of 37 patients including 12 patients from the first group. As a whole, after a mean follow-up of 6.2 years, surgery succeeded in 18 patients (49%), gave a partial improvement in 12 (32%) and failed in seven (19%). The 12 patients evaluated twice (in 1987 and 1995) have had very good early results, 8-69 months after UES myotomy: dysphagia was totally relieved in eight patients, occurred rarely in three and was moderate in one. Nevertheless, the very long-term follow-up (8 years later) has shown a recurrence of the swallowing and tracheobronchial symptoms in many cases.

A pilot study on upper esophageal sphincter dilatation for the treatment of dysphagia in patients with oculopharyngeal muscular dystrophy.

Upper esophageal sphincter (UES) dilatation was done for the treatment of moderate to severe dysphagia with a Maloney bougie in 14 patients with oculopharyngeal muscular dystrophy (OPMD) or with an achalasia dilator in three patients. The severity of dysphagia prior to UES dilatation was evaluated by a 15-point dysphagia score, a pharyngeal and esophageal manometry and a radionuclide pharyngoesophageal transit study. Using actuarial life table, the improvement rate after dilatation with Maloney bougie was 64.3% (95% CI 39.2-89.4) at 3- and 6-month follow-ups, and was 55.7% (95% CI 28.9-82.5) at 12- and 18-month follow-ups. At 3-month post-dilatation, we observed a significant reduction of the mean dysphagia score from 9.6 to 7.2 (P = 0.05). No significant manometric or radionuclide factors were found to predict effective dilatation. The results of this pilot study showed that UES dilatation with Maloney bougie or achalasia dilator may be an effective treatment of moderate dysphagia in patients with OPMD. However, further studies with larger sample sizes are needed to corroborate these results and to assess long-term outcome.