Paul Jarman

Angiotensin-converting-enzyme gene insertion/deletion polymorphism and response to physical training.

BACKGROUND The function of local renin-angiotensin systems in skeletal muscle and adipose tissue remains largely unknown. A polymorphism of the human angiotensin converting enzyme (ACE) gene has been identified in which the insertion (I) rather than deletion (D) allele is associated with lower ACE activity in body tissues and increased response to some aspects of physical training. We studied the association between the ACE gene insertion or deletion polymorphism and changes in body composition related to an intensive exercise programme, to investigate the metabolic effects of local human renin-angiotensin systems. METHODS We used three independent methods (bioimpedance, multiple skinfold-thickness assessment of whole-body composition, magnetic resonance imaging of the mid-thigh) to study changes in body composition in young male army recruits over 10 weeks of intensive physical training. FINDINGS Participants with the II genotype had a greater anabolic response than those with one or more D alleles for fat mass (0.55 vs -0.20 kg, p=0.04 by bioimpedance) and non-fat mass (1.31 vs -0.15 kg, p=0.01 by bioimpedance). Changes in body morphology with training measured by the other methods were also dependent on genotype. INTERPRETATION II genotype, as a marker of low ACE activity in body tissues, may conserve a positive energy balance during rigorous training, which suggests enhanced metabolic efficiency. This finding may explain some of the survival and functional benefits of therapy with ACE inhibitors.

Reward Pays the Cost of Noise Reduction in Motor and Cognitive Control.

Summary Speed-accuracy trade-off is an intensively studied law governing almost all behavioral tasks across species. Here we show that motivation by reward breaks this law, by simultaneously invigorating movement and improving response precision. We devised a model to explain this paradoxical effect of reward by considering a new factor: the cost of control. Exerting control to improve response precision might itself come at a cost—a cost to attenuate a proportion of intrinsic neural noise. Applying a noise-reduction cost to optimal motor control predicted that reward can increase both velocity and accuracy. Similarly, application to decision-making predicted that reward reduces reaction times and errors in cognitive control. We used a novel saccadic distraction task to quantify the speed and accuracy of both movements and decisions under varying reward. Both faster speeds and smaller errors were observed with higher incentives, with the results best fitted by a model including a precision cost. Recent theories consider dopamine to be a key neuromodulator in mediating motivational effects of reward. We therefore examined how Parkinson’s disease (PD), a condition associated with dopamine depletion, alters the effects of reward. Individuals with PD showed reduced reward sensitivity in their speed and accuracy, consistent in our model with higher noise-control costs. Including a cost of control over noise explains how reward may allow apparent performance limits to be surpassed. On this view, the pattern of reduced reward sensitivity in PD patients can specifically be accounted for by a higher cost for controlling noise.

Genetic and clinical heterogeneity in paroxysmal kinesigenic dyskinesia: Evidence for a third EKD gene

Paroxysmal kinesigenic dyskinesia (PKD) is characterised by paroxysms of choreic, dystonic, ballistic, or athetoid movements. The attacks typically last seconds to minutes in duration and are induced by sudden voluntary movement. PKD loci have been identified on chromosome 16. We present the clinical and genetic details of two British and an Indian family with PKD. Linkage to the PKD loci on chromosome 16 has been excluded in one of these families, providing evidence for a third loci for PKD. Detailed clinical descriptions highlight the presence of both adolescent and infantile seizures in some of the PKD families. This study attempts to clarify the relationship of adolescent and infantile seizures to PKD and provides evidence that PKD is both genetically and clinically heterogeneous.

GTP cyclohydrolase I mutations in patients with dystonia responsive to anticholinergic drugs

OBJECTIVES to investigate the hypothesis that GTP cyclohydrolase I (GCH1) mutations are responsible for the phenotype of highly anticholinergic responsive dystonia in patients with apparent primary torsion dystonia. METHODS from 107 British patients with clinically diagnosed primary torsion dystonia, seven patients were identified with an excellent response to anticholinergic drugs. All six exons of the GCH1 gene were sequenced in these patients to identify mutations. RESULTS three novel GCH1 mutations were identified in two patients. One patient was a compound heterozygote with asymptomatic carrier parents. The clinical phenotype of patients with and without GCH1 mutations was similar. CONCLUSIONS these findings show that a proportion of patients with apparent primary torsion dystonia and a good response to anticholinergic drugs have GCH1 mutations and therefore have a variant of dopa responsive dystonia. The difficulty in distinguishing clinically between patients with and without mutations underscores the importance of considering the diagnosis of a levodopa responsive dystonia in all such patients.

Visual short-term memory deficits associated with GBA mutation and Parkinson’s disease

Individuals with mutation in the lysosomal enzyme glucocerebrosidase (GBA) gene are at significantly high risk of developing Parkinson’s disease with cognitive deficit. We examined whether visual short-term memory impairments, long associated with patients with Parkinson’s disease, are also present in GBA-positive individuals—both with and without Parkinson’s disease. Precision of visual working memory was measured using a serial order task in which participants observed four bars, each of a different colour and orientation, presented sequentially at screen centre. Afterwards, they were asked to adjust a coloured probe bar’s orientation to match the orientation of the bar of the same colour in the sequence. An additional attentional ‘filtering’ condition tested patients’ ability to selectively encode one of the four bars while ignoring the others. A sensorimotor task using the same stimuli controlled for perceptual and motor factors. There was a significant deficit in memory precision in GBA-positive individuals—with or without Parkinson’s disease—as well as GBA-negative patients with Parkinson’s disease, compared to healthy controls. Worst recall was observed in GBA-positive cases with Parkinson’s disease. Although all groups were impaired in visual short-term memory, there was a double dissociation between sources of error associated with GBA mutation and Parkinson’s disease. The deficit observed in GBA-positive individuals, regardless of whether they had Parkinson’s disease, was explained by a systematic increase in interference from features of other items in memory: misbinding errors. In contrast, impairments in patients with Parkinson’s disease, regardless of GBA status, was explained by increased random responses. Individuals who were GBA-positive and also had Parkinson’s disease suffered from both types of error, demonstrating the worst performance. These findings provide evidence for dissociable signature deficits within the domain of visual short-term memory associated with GBA mutation and with Parkinson’s disease. Identification of the specific pattern of cognitive impairment in GBA mutation versus Parkinson’s disease is potentially important as it might help to identify individuals at risk of developing Parkinson’s disease.

Hereditary Geniospasm: Linkage to Chromosome 9q13-q21 and Evidence for Genetic Heterogeneity

Hereditary geniospasm is an unusual movement disorder causing episodes of involuntary tremor of the chin and the lower lip. Episodes typically start in early childhood and may be precipitated by stress, concentration, and emotion. Hereditary geniospasm is inherited as an autosomal dominant trait, and its cause is not known. We report the results of a genomewide genetic linkage study in a four-generation British family with hereditary geniospasm. Positive two-point LOD scores were obtained for 15 microsatellite markers on the peri-centromeric region of chromosome 9. A maximum two-point LOD score of 5.24 at theta = .00 was obtained for the marker D9S1837. Construction of haplotypes defined an interval of 2.1 cM between the flanking markers D9S1806 and D9S175, thus assigning one locus for hereditary geniospasm to the proximal long arm of chromosome 9q13-q21. Hereditary geniospasm in a second British family is not linked to this region, indicating genetic heterogeneity. These findings may have implications for other inherited focal movement disorders that as yet remain unmapped.

Hyperkalaemia in diabetes: prevalence and associations.

Hyperkalaemia is associated with diabetes, but there are no recent reports of its prevalence and associations. Serum potassium concentrations were measured in all 1764 patients attending a diabetic clinic over a 12-month period and found to be > 5.0 mmol/l in 270 (15%), and > 5.4 mmol/l in 67 (4%). There was no other evident cause of hyperkalaemia in 41 of these 67 patients. These data serve to highlight the risk of dangerous hyperkalaemia in diabetic patients, particularly with concurrent administration of angiotensin-converting-enzyme inhibitors and potassium-sparing diuretics.

Sarcoidosis presenting with chylothorax.

A patient in whom chylothorax was the presenting feature of sarcoidosis is reported. Mediastinal lymphadenopathy was shown by computed tomographic scanning. Obstruction of the thoracic duct by enlarged lymph nodes or fibrosis is the probable cause of chylothorax in this case. The association of chylothorax and sarcoidosis is extremely rare.

Short and long term outcome of bilateral pallidal stimulation in chorea-acanthocytosis

Background Chorea-acanthocytosis (ChAc) is a neuroacanthocytosis syndrome presenting with severe movement disorders poorly responsive to drug therapy. Case reports suggest that bilateral deep brain stimulation (DBS) of the ventro-postero-lateral internal globus pallidus (GPi) may benefit these patients. To explore this issue, the present multicentre (n=12) retrospective study collected the short and long term outcome of 15 patients who underwent DBS. Methods Data were collected in a standardized way 2-6 months preoperatively, 1-5 months (early) and 6 months or more (late) after surgery at the last follow-up visit (mean follow-up: 29.5 months). Results Motor severity, assessed by the Unified Huntington’s Disease Rating Scale-Motor Score, UHDRS-MS), was significantly reduced at both early and late post-surgery time points (mean improvement 54.3% and 44.1%, respectively). Functional capacity (UHDRS-Functional Capacity Score) was also significantly improved at both post-surgery time points (mean 75.5% and 73.3%, respectively), whereas incapacity (UHDRS-Independence Score) improvement reached significance at early post-surgery only (mean 37.3%). Long term significant improvement of motor symptom severity (≥20 % from baseline) was observed in 61.5 % of the patients. Chorea and dystonia improved, whereas effects on dysarthria and swallowing were variable. Parkinsonism did not improve. Linear regression analysis showed that preoperative motor severity predicted motor improvement at both post-surgery time points. The most serious adverse event was device infection and cerebral abscess, and one patient died suddenly of unclear cause, 4 years after surgery. Conclusion This study shows that bilateral DBS of the GPi effectively reduces the severity of drug-resistant hyperkinetic movement disorders such as present in ChAc.

Paroxysmal dystonic choreoathetosis: Clinical features and investigation of pathophysiology in a large family

Paroxysmal dystonic choreoathetosis (PDC) is an unusual hyperkinetic movement disorder characterized by attacks of chorea, dystonia, and ballism with onset in childhood. We report a large British family with dominantly inherited PDC linked to chromosome 2q and describe the clinical features in 20 affected family members. Attacks were precipitated by a variety of factors, including caffeine, alcohol, or emotion, and could be relieved by short periods of sleep in most subjects. The clinical features in the family are compared with those of 11 other PDC families in the literature and a core phenotype for PDC suggested. CSF monoamine metabolites measured at baseline and during an attack in one subject were found to increase during the attack. Magnetic resonance spectroscopy of brain and basal ganglia performed both during and between attacks was normal. Positron emission tomography using the D2 receptor ligand, 11C‐raclopride, showed no abnormalities.