Postural stability limits in manifest and premanifest Huntington's disease under different sensory conditions.

Increasing evidence indicates that Huntington's disease (HD) produces postural control impairments even before the clinical diagnosis. It has been suggested that postural disorders of HD patients are explained by deficits in the processing and integration of sensory information, but this hypothesis has been under-explored. In the present study, we evaluated the amplitude of the center of pressure (COP) displacement during maximum leaning in four directions (forward, backward, rightward and leftward) and under three sensory conditions (eyes open, eyes closed and eyes closed standing on foam). We assessed the stability limits in 20 individuals with a positive HD genetic test (12 premanifests; eight manifests HD) and 15 healthy controls. The COP displacements were analyzed during the first and second phases of maintenance of the maximum leaning position. Manifest HD patients showed significantly greater COP ranges than healthy controls in both learning phases and all sensory conditions, but the greatest deterioration of their performance was found in the foam condition. In contrast, premanifest HD patients displayed larger COP ranges than controls only during the second phase of maximum learning, especially in the foam condition. Furthermore, both HD groups had significantly smaller limits of stability than healthy subjects during the second phase of maximum learning. However, their ability to maintain the maximum leaning position was degraded during both learning phases. Together, these findings demonstrate that HD reduces the limits of stability even before the clinical disease onset. Furthermore, our results indicate that dynamic postural tasks with high demand for sensorimotor integration and especially the use of proprioception are highly sensitive to early HD disease processes. This dynamic postural task may become a useful biomarker of HD progression.

Genome-wide association study of Tourette's syndrome.

Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder.

Sensorimotor adaptation in Parkinson's disease: evidence for a dopamine dependent remapping disturbance.

Sensorimotor adaptation is thought to involve a remapping of the kinematic and kinetic parameters associated with movements performed within a changing environment. Patients with Parkinson's disease (PD) are known to be affected on this type of learning process, although the specific role of dopamine depletion in these deficits has not yet been elucidated. The present study was an attempt to clarify whether dopamine depletion in PD may directly affect the capacity to internally reorganize the visuomotor remapping of a distorted environment. Fourteen PD patients were tested twice, while they were treated and while they were withdrawn from their regular levodopa treatment. Fourteen control subjects were also enrolled and tested twice. Two parallel forms of the Computed Mirror Pointing Task (CMPT), requiring making a reaching movement in a visually transformed environment (mirror inversion), were administered to each participant. Each of them had to perform 40 trials at each of the 2 testing sessions. At each trial, sensorimotor adaptation was evaluated by the initial direction angle (IDA), which reflects the direction of movement before any visually guided readjustment. Results revealed no IDA difference at baseline, between control subject and PD patients, whether they were treated or not. In all group, IDA values at that time were large, reflecting a tendency to make movements according to the real life visuomotor mapping (based on the natural direct vision). However, striking differences appeared during sensorimotor learning, in that IDA reduction along trials was poorer in patient not treated with levodopa than both control subjects and the same PD patient treated with levodopa. No difference was observed between the treated PD patients and control subjects. Given that IDA is thought to reflect the internal representation of the visuomotor mapping, it is concluded that dopamine depletion in PD would affects sensorimotor adaptation, in that it facilitates old and poorly adapted movements (real life mapping), instead of new and more adapted ones (mirror transformed mapping).

Postural control anomalies in children with Tourette syndrome.

The goal of the present study was to determine whether postural control is affected in Gilles-de-la-Tourette syndrome (TS). Center of pressure (COP) displacements were recorded in children with TS and unaffected siblings in three conditions using a force platform: (1) Eyes-Open, (2) Eyes-Closed, (3) One-Leg standing with eyes open. The COP range and velocity were higher in children with TS than in unaffected siblings in all conditions. These differences could not be attributed to age, present tic severity, comorbidities (hyperactivity and compulsions) or medication. The data suggest that sub-clinical postural control anomalies are present in TS.

Sensorimotor mapping affects movement correction deficits in early Huntington's disease.

Huntington's disease (HD) is associated with early voluntary movement problems linked to striatal dysfunction. In pointing movements, HD increases the irregularity of the terminal part of movements, suggesting a dysfunction in error feedback control. We tested this hypothesis in movements requiring continuous feedback control. Patients in the early stages of HD and controls traced as fast and accurately as possible circles within a 5-mm annulus on a digitizing tablet when visual feedback of the hand and the circle was direct or indirect (through a monitor). Patients deviated more often from the annulus and showed larger corrections toward the circle than controls when using indirect visual feedback but not with direct visual feedback. When velocity requirements were removed, patients showed little change in these control problems. These results suggest that HD does not affect error feedback control in all movements and that the striatal contribution to voluntary movement is sensitive to sensorimotor mapping.

Phenylalanine loading as a diagnostic test for DRD: interpreting the utility of the test.

Phenylalanine loading has been proposed as a diagnostic test for autosomal dominant DRD (dopa-responsive dystonia), and recently, a phenylalanine/tyrosine (phe/tyr) ratio of 7.5 after 4 h was reported as diagnostic of DRD. To test the utility of this test in another sample with DRD, we administered an oral challenge of phenylalanine (100 mg/kg) to 11 individuals with DRD and one non-manifesting gene carrier. Only 6/12 had a 4 h phe/tyr ratio of greater than 7.5, suggesting that additional parameters must be set to avoid missing the diagnosis of DRD, including the need for the plasma phenylalanine to reach a minimum level 600 in order for the test to be valid. We propose that in cases where this minimum plasma phenylalanine level is not reached, plasma tetrahydrobiopterin should be measured or alternatively other symptomatic family members should be screened.

Restless legs in Tourette syndrome.

Restless legs syndrome (RLS) and Tourette's syndrome (TS) share some common features, including the phenomenology of sensations relieved by movements, but few studies have examined the links between RLS and TS. We examined RLS and other TS comorbidities in 144 probands with TS or chronic tics and their parents. RLS was present in 10% of probands and 23% of parents with no gender differences. RLS in probands was linked significantly to maternal RLS but not paternal RLS, suggesting that a maternal RLS factor may contribute to the variable expression of TS.

Tourette syndrome and dopaminergic genes: a family-based association study in the French Canadian founder population.

Tourette syndrome (TS) is a genetically complex disorder for which no causative genes have been unequivocally identified. Nevertheless, a number of molecular genetic studies have investigated several candidate genes, particularly those implicated in dopamine modulation. The results of these studies were inconclusive, which may be due, at least in part, to the variable ethnicity of the patients included in different studies and the chosen research design. In this study, we used a family-based association approach to investigate the implication of dopamine-related candidate genes, which had been previously reported as possibly associated with TS [genes that encode for the dopamine receptors DRD2, DRD3 and DRD4, the dopamine transporter 1 (SLC6A3) and the monoamine oxidase-A (MAO-A). The studied group was composed of 110 TS patients. These patients were selected from the French Canadian population, which displays a founder effect. Excess transmission of the 7-repeat allele of the DRD4 exon-3 VNTR polymorphism (chi(2) TDT =4.93, 1 df, P=0.026) and the putative 'high-activity' alleles of the MAO-A promoter VNTR polymorphism (chi(2) TDT =7.124, 1 df P=0.0076) were observed. These results were confirmed in a subgroup of patients with no attention deficit/hyperactivity or obsessive compulsive comorbid disorders. Haplotype analysis using one or two supplemental polymorphism in each of these genes confirmed these associations and allowed one to identify risk haplotypes. No associations were found for DRD2, DRD3 or SLC6A3. These data support the notion that DRD4 and MOA-A genes may confer an increased risk for developing TS in the French Canadian population.

Do high functioning persons with autism present superior spatial abilities?

This series of experiments was aimed at assessing spatial abilities in high functioning individuals with autism (HFA), using a human-size labyrinth. In the context of recent findings that the performance of individuals with HFA was superior to typically developing individuals in several non-social cognitive operations, it was expected that the HFA group would outperform a typically developing comparison group matched on full-scale IQ. Results showed that individuals with autism performed all spatial tasks at a level at least equivalent to the typically developing comparison group. No differences between groups were found in route and survey tasks. Superior performance for individuals with HFA was found in tasks involving maps, in the form of superior accuracy in graphic cued recall of a path, and shorter learning times in a map learning task. We propose that a superior ability to detect [Human Perception and Performance 27 (3) (2001) 719], match [Journal of Child Psychology and Psychiatry 34 (1993) 1351] and reproduce [Journal of Child Psychology and Psychiatry 40 (5) (1999) 743] simple visual elements yields superior performance in tasks relying on the detection and graphic reproduction of the visual elements composing a map. Enhanced discrimination, detection, and memory for visually simple patterns in autism may account for the superior performance of persons with autism on visuo-spatial tasks that heavily involve pattern recognition, either in the form of recognizing and memorizing landmarks or in detecting the similarity between map and landscape features. At a neuro-anatomical level, these findings suggest an intact dorso-lateral pathway, and enhanced performance in non social tasks relying on the infero-temporal pathway.

Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in CHAC were screened for mutations by denaturing high-performance liquid chromatography in 43 probands with ChAc. We identified 57 different mutations, 54 of which have not previously been reported, in 39 probands. The novel mutations comprise 15 nonsense, 22 insertion/deletion, 15 splice-site and two missense mutations and are distributed throughout the CHAC gene. Three mutations were found in multiple families within this or our previous study. The preponderance of mutations that are predicted to cause absence of gene product is consistent with the recessive inheritance of this disease. The high proportion of splice-site mutations found is probably a reflection of the large number of exons that comprise the CHAC gene. The CHAC protein product, chorein, appears to have a certain tolerance to amino-acid substitutions since only two out of nine substitutions described here appear to be pathogenic.

Adult onset tic disorders.

BACKGROUND: Tic disorders presenting during adulthood have infrequently been described in the medical literature. Most reports depict adult onset secondary tic disorders caused by trauma, encephalitis, and other acquired conditions. Only rare reports describe idiopathic adult onset tic disorders, and most of these cases represent recurrent childhood tic disorders. OBJECTIVE: To describe a large series of patients with tic disorders presenting during adulthood, to compare clinical characteristics between groups of patients, and to call attention to this potentially disabling and underrecognised neurological disorder. METHODS: Using a computerised database, all patients with tic disorders who presented between 1988 and 1998 to the movement disorders clinic at Columbia-Presbyterian Medical Center after the age of 21 were identified. Patients' charts were retrospectively reviewed for demographic information, age of onset of tics, tic phenomenology, distribution, the presence of premonitory sensory symptoms and tic suppressibility, family history, and associated psychiatric features. These patients' videotapes were reviewed for diagnostic confirmation and information was obtained about disability, course, and response to treatment in a structured follow up interview. RESULTS: Of 411 patients with tic disorders in the database, 22 patients presented for the first time with tic disorders after the age of 21. In nine patients, detailed questioning disclosed a history of previous childhood transient tic disorder, but in 13 patients, the adult onset tic disorder was new. Among the new onset cases, six patients developed tics in relation to an external trigger, and could be considered to have secondary tic disorders. The remaining patients had idiopathic tic disorders. Comparing adult patients with recurrent childhood tics and those with new onset adult tics, the appearance of the tic disorder, the course and prognosis, the family history of tic disorder, and the prevalence of obsessive-compulsive disorder were found to be similar. Adults with new onset tics were more likely to have a symptomatic or secondary tic disorder, which in this series was caused by infection, trauma, cocaine use, and neuroleptic exposure. CONCLUSIONS: Adult onset tic disorders represent an underrecognised condition that is more common than generally appreciated or reported. The clinical characteristics of adults newly presenting to a movement disorder clinic with tic disorders are reviewed, analysed, and discussed in detail. Clinical evidence supports the concept that tic disorders in adults are part of a range that includes childhood onset tic disorders and Tourette's syndrome.

Evidence for voltage-gated potassium channel beta-subunits with oxidoreductase motifs in human and rodent pancreatic beta cells.

Voltage-gated K(+) channel alpha subunits (K(V) alpha) have been previously identified in pancreatic islet beta-cells where it has been suggested they have a role in membrane repolarization and insulin secretion. Here we report the cloning of the three mammalian K(V) beta subunits, including splice variants of these subunits, from both human and rat pancreatic islets and from the rat insulinoma cell line INS-1. Two of the splice variants, K(V) beta1a and K(V) beta3, previously reported to be neuronal tissue specific, are expressed in islets and INS-1 cells. In addition, a splice variant of K(V) beta2 that lacks two potential protein kinase C phosphorylation sites at the amino terminus is present. Immunoblot analysis suggests a high level of K(V) beta2 subunit protein in rat pancreatic islets and immunoprecipitation with anti-K(V) beta2 antibody pulls down a protein from INS-1 cells that reacts with anti-aldose reductase antibody. The K(V) beta subunits, which are attached to the cytoplasmic face of the alpha subunits and are members of the aldose reductase superfamily of NADPH oxidoreductases, may have an as yet undetermined role in the regulation of insulin secretion by the intracellular redox potential. Finally, we suggest that a systematic nomenclature for K(V) beta subunits first proposed by McCormack et al. be adopted for this family of potassium channel subunits as it corresponds with the nomenclature used for their cognate K(V) alpha subunits.

Experience with tranylcypromine in early Parkinson's disease.

A leading hypothesis of the pathogenesis of neuronal degeneration of the substantia nigra dopamine-containing cells in Parkinson's disease (PD) is excessive oxidative stress. In part, this oxidative stress is the result of the oxidation of dopamine by the action of monoamine oxidases (MAO) A and B to generate hydrogen peroxide and subsequent oxygen free radicals. Because of this hypothesis we have treated patients with early PD, not yet requiring any symptomatic treatment, with tranylcypromine, a drug that inhibits both MAO's. These patients were required to observe a tyramine-restricted diet. Thirty-seven patients on tranylcypromine have been followed by us for up to 33 months. Four patients discontinued the drug because of pending surgery. Of the remaining 33, six had adverse effects that lead to discontinuation of the drug, mainly impotency in men. Another common adverse effect encountered was insomnia, but this problem was not a cause of stopping the drug. Depression lifted in all five patients who had this problem at the time tranylcypromine was initiated. Only two patients have so far required treatment with levodopa or a dopamine agonist, and this need occurred within the first 6 months of treatment. The evaluation of all 37 patients revealed that parkinsonian symptoms improved slightly on introduction of tranylcypromine as measured by the United Parkinson's Disease Rating Scale, the Hoehn & Yahr Staging Scale, and the Schwab & England Activities of Daily Living Scale. Follow-up evaluations for a minimum of 6 months between the first post-tranylcypromine visit and the most recent visit revealed only slight worsening of parkinsonian signs and symptoms, with a mean interval of almost 1.5 years. A longer period of follow-up is needed to determine how long the severity of PD will remain mild in this group of patients.

Interaction of the K channel beta subunit, Hyperkinetic, with eag family members.

Assembly of K channel alpha subunits of the Shaker (Sh) family occurs in a subfamily specific manner. It has been suggested that subfamily specificity also applies in the association of beta subunits with Sh channels (Rhodes, K. J., Keilbaugh, S. A., Barrezueta, N. X., Lopez, K. L., and Trimmer, J. S. (1995) J. Neurosci. 15, 5360-5371; Sewing, S., Roeper, J. and Pongs, O. (1996) Neuron 16, 455-463; Yu, W., Xu, J., and Li, M. (1996) Neuron 16, 441-453). Here we show that the Drosophila beta subunit homologue Hyperkinetic (Hk) associates with members of the ether go-go (eag), as well as Sh, families. Anti-EAG antibody coprecipitates EAG and HK indicating a physical association between proteins. Heterologously expressed Hk dramatically increases the amplitudes of eag currents and also affects gating and modulation by progesterone. Through their ability to interact with a range of alpha subunits, the beta subunits of voltage-gated K channels are likely to have a much broader impact on the signaling properties of neurons and muscle fibers than previously suggested.

Agreement among movement disorder specialists on the clinical diagnosis of essential tremor.

Even though essential tremor (ET) is the most prevalent movement disorder, there has been little agreement in the neurologic literature regarding diagnostic criteria for ET. The authors attempted to determine the extent and source of agreement and disagreement among neurologists regarding diagnostic criteria for clinically definite ET. The authors designed and mailed a semistructured questionnaire to 160 neurologists who specialize in movement disorders in 24 countries. The questionnaire included three sections: a list of inclusion criteria, a list of exclusion criteria, and a list of potential clinical scenarios (for example, isolated site-specific tremor and primary orthostatic tremor). The questionnaire was completed by 98 (61%) of 160 targeted neurologists. There was greater consensus regarding features considered unnecessary inclusion criteria for clinically definite ET (extent of disability, disease duration, and positive family history) than for those considered necessary inclusion criteria (postural versus action tremor). With regard to exclusion criteria, there was some consensus in terms of the presence of Parkinson's disease, dystonia, history of hyperthyroidism or concurrent use of tremor-inducing medications, and cerebellar signs. The majority of neurologists would diagnose ET in the setting of isolated head or voice tremor. There are areas of both consensus and divergence among neurologists with regard to diagnostic criteria for ET. The choice of diagnostic criteria may vary depending on the intended use of the criteria (that is, clinical versus genetic studies). Hopefully, this study will foster further discussion to achieve a more general consensus.

Idiopathic torsion dystonia linked to chromosome 8 in two Mennonite families.

The DYT1 locus on chromosome 9q34 is responsible for most childhood limb-onset idiopathic torsion dystonia (ITD). Linkage to DYT1 has been excluded in families with adult-onset, and predominantly cranial-cervical, ITD. We mapped a locus (DYT6) associated with prominent cranial-cervical ITD in two large Mennonite families to chromosome 8. An identical haplotype spanning 40-cM segregates with ITD in these families, suggesting a shared mutation from the recent past.

A potassium channel beta subunit related to the aldo-keto reductase superfamily is encoded by the Drosophila hyperkinetic locus.

Genetic and physiological studies of the Drosophila Hyperkinetic (Hk) mutant revealed defects in the function or regulation of K+ channels encoded by the Shaker (Sh) locus. The Hk polypeptide, determined from analysis of cDNA clones, is a homologue of mammalian K+ channel beta subunits (Kv beta). Coexpression of Hk with Sh in Xenopus oocytes increases current amplitudes and changes the voltage dependence and kinetics of activation and inactivation, consistent with predicted functions of Hk in vivo. Sequence alignments show that Hk, together with mammalian Kv beta, represents an additional branch of the aldo-keto reductase superfamily. These results are relevant to understanding the function and evolutionary origin of Kv beta.

Reversibility of renal tubular dysfunction in streptozotocin-induced diabetes in the rat.

Enzymuria and specific proteinuria were examined over a period of 19 days in 4 groups of 5 rats: a control group, a nondiabetic polyuric group, a group of streptozotocin-induced diabetic rats treated with insulin as of the 10th day after the injection of the drug, and a similar group of untreated diabetic rats. Increased urinary excretion of beta-N-acetyl-D-glucosaminidase, lactate dehydrogenase, and alanine aminopeptidase was observed shortly after the induction of diabetes. It was partly or totally reversible following insulin treatment. Nondiabetic polyuria had a slight effect on the excretion of alanine aminopeptidase only. The urinary excretion of beta 2-microglobulin also rapidly increased after the onset of diabetes to a level approximately 50 times the control values. This effect was largely reversible with insulin treatment and was absent in the nondiabetic polyuric group. A small but significant 3-fold increase in albumin excretion was also noted but was not affected by insulin treatment. We conclude that streptozotocin-induced diabetes causes an early tubular dysfunction that is unrelated to polyuria and is reversible upon insulin treatment. This tubular dysfunction is best revealed by the urinary excretion of the low molecular weight protein beta 2-microglobulin. Our results suggest that it would be of interest to further examine the usefulness of sensitive markers of tubular dysfunction, especially low molecular weight proteinuria, in the detection of early stages of diabetic nephropathy.

Enzymuria and tubular proteinuria in diabetic rats: a 12-week follow-up study.

Various biochemical parameters of renal tubular function were examined for a period of up to 12 weeks in rats rendered diabetic by an i.v. injection of streptozotocin. Except for a statistically significant decrease in the urinary excretion of gamma-glutamyl-transpeptidase to 64% of control values, the urinary excretion of beta-N-acetyl-D-glucosaminidase, beta-galactosidase, alanine aminopeptidase, and lactate dehydrogenase significantly increases in diabetic rats to between 154% and 712% of control values. This increased enzymuria is not correlated to the marked polyuria induced by diabetes (r between 0.14 and 0.35, not significant). Enzymuria is also accompanied by a 10-fold increase in the urinary excretion of the low molecular weight protein beta 2-microglobulin while the excretion of albumin is not significantly modified, indicating impairment of tubular reabsorption in diabetic animals. Clearance studies reveal that the clearance of both beta 2-microglobulin and infused egg-white lysozyme are also increased. Finally the histopathologic examination of paraffin sections of the kidney show hydropic degenerescence and pycnosis of the tubular cells. It is concluded that early-stage diabetes results in tubular impairment and that the streptozotocin-rat model appears well suited to the study of these early signs of renal dysfunction.