Modelling the spatial tuning of the Hermann grid illusion.

PURPOSE: Does a physiologically plausible model of the retinal ganglion cell (RGC) receptive field (RF) predict the spatial tuning properties of the Hermann Grid Illusion (HGI)? METHODS: The spatial tuning of a single intersection HGI was measured psychophysically in normal observers using a nulling technique at different vertical grid line luminances. We used a model based upon a standard RGC RF, balanced to produce zero response under uniform illumination, to predict the response of the model cell to the equivalent range of stimulus conditions when placed in either the 'street' or the 'intersection' of a single element of a Hermann grid. We determined the equivalent of the nulling luminance required to balance these responses and minimise the HGI. RESULTS: The model and the psychophysical data demonstrated broad spatial tuning with similarly shaped tuning profiles and similar strengths of illusion. The line width at the peak of the model tuning function was around twice the model RGC RF centre size. Modelling the psychophysical functions gave RF centre sizes smaller than expected from human anatomical evidence but similar to that suggested by primate physiological evidence. In the model and psychophysically the strength of the illusion varied with the luminance of the vertical grid line when HGI strength was expressed as a Michelson nulling contrast, but this effect was smaller when HGI strength was expressed as a nulling luminance. CONCLUSIONS: The shape, width, height and position of the spatial tuning function of the HGI can be well modelled by a RGC RF based model. The broad tuning of these functions does not appear to require a broad range of different cell sizes either in the retina or later in the visual pathway.

Quality of life and well-being of patients with myasthenia gravis.

The cardinal symptom of myasthenia gravis (MG) is weakness of voluntary muscles, a feature that may restrict full participation in life activities. In turn, such limitations may negatively affect quality of life (QOL) and well-being among individuals with the disease. In the present study, we administered a measure of QOL to 27 patients with generalized MG. Results revealed that functional status was negatively impacted in the domains of physical functioning, energy, and general health. However, a clinically meaningful difference was evident only on perceived ability to accomplish physical tasks. The results suggest that although MG requires accommodations in physical activities, general QOL and well-being does not differ markedly from the general population.

What have we learned about cognition in myasthenia gravis?: a review of methods and results.

Most individuals with myasthenia gravis (MG) complain of cognitive impairment, but empirical studies of cognition in MG have produced mixed results. In the present review, we critically examined the methodology and results of previous studies that investigated cognition in MG. Results from our review revealed that none of the studies met at least 50% of criteria under review. The most common shortcomings of previous studies included small sample size, no exclusion for visual difficulties in patients, inadequate assessment of mood, and poor control for prednisone use. Despite these methodological difficulties, mild impairments on measures of learning have been identified. These findings need to be replicated with adequate control of potential confounds before any conclusions can be made regarding cognition in this disease. Suggestions for design of future studies are provided.

Severity of mood, self-evaluative, and vegetative symptoms of depression in myasthenia gravis.

The mood, self-evaluative, and vegetative symptoms of depression in myasthenia gravis were assessed. The frequency of depression was significantly elevated only when assessed by measuring vegetative symptoms. These findings suggest that mood in neuroimmune disorders should be assessed with scales that separate the different dimensions of depression.

Cognitive dysfunction in individuals with myasthenia gravis.

In the present study we administered a battery of cognitive measures that examined attention, response fluency, information processing, and verbal and visual learning and retention to 28 individuals with generalized myasthenia gravis (MG) and 18 demographically similar control subjects. Results revealed that MG patients performed significantly more poorly than control subjects on the measures of response fluency, information processing and most measures of verbal and visual learning. Significant group differences were not evident on the measure of attention span or on the indices of retention of information. Cognitive performances of the MG group were not related to mood disturbance, disease duration, or daily dose of prednisone. While these results suggest central involvement in MG, previous studies have not provided evidence that MG antibodies bind to central nicotinic receptors. Possible alternative mechanisms underlying cognitive dysfunction in MG are discussed.

Myotilin is mutated in limb girdle muscular dystrophy 1A.

We have identified a mutation in the myotilin gene in a large North American family of German descent expressing an autosomal dominant form of limb girdle muscular dystrophy (LGMD1A). We have previously mapped this gene to 5q31. Symptoms of this adult onset disease are progressive weakness of the hip and shoulder girdles, as well as a distinctive dysarthric pattern of speech. Muscle of affected individuals shows degeneration of myofibers, variations in fiber size, fiber splitting, centrally located myonuclei and a large number of autophagic vesicles. Affected muscle also exhibits disorganization and streaming of the Z-line similar to that seen in nemaline myopathy. We have identified a C450T missense mutation in the myotilin gene that is predicted to result in the conversion of residue 57 from threonine to isoleucine. This mutation has not been found in 396 control chromosomes. The mutant allele is transcribed and normal levels of correctly localized myotilin protein are seen in LGMD1A muscle. Myotilin is a sarcomeric protein that binds to alpha-actinin and is localized in the Z-line. The observed missense mutation does not disrupt binding to alpha-actinin.

Fatigue and its impact on patients with myasthenia gravis.

We have examined fatigue in myasthenia gravis (MG) by administering a measure of cognitive and physical fatigue to patients and control subjects before and after administration of a lengthy cognitive battery. Subjects also completed a scale that assessed the impact of fatigue on physical, social, and cognitive function. Results of the study revealed that MG patients experience significantly more cognitive and physical fatigue than do control subjects, and the patients' perceptions of both cognitive and physical fatigue increased significantly following completion of demanding cognitive work. Control subjects reported no significant change in fatigue. Furthermore, MG patients reported that fatigue produced mild to moderate effects on cognitive and social function and moderate effects on physical function. Results from this study indicate that cognitive fatigue is an important symptom of MG and that fatigue produces pervasive impairments in important aspects of patients' lives. Additional studies are needed to understand the neurobehavioral determinants of cognitive fatigue in this population.

Use of a CEPH meiotic breakpoint panel to refine the locus of limb-girdle muscular dystrophy type 1A (LGMD1A) to a 2-Mb interval on 5q31.

Limb-girdle muscular dystrophy type 1A (LGMD1A) is an autosomal dominant disease characterized by progressive weakness of the hip and shoulder girdle. The gene for LGMD1A had been localized to a 7-cM interval at 5q31 in a single large family (Family 39). To refine the localization of LGMD1A further and to aid in its identification, a high-resolution physical map of the locus was used to identify and provisionally localize 25 polymorphic markers. A subset of these markers was then ordered genetically, using a CEPH meiotic breakpoint panel, resulting in an integrated physical-genetic map of the locus. Relevant markers were genotyped on the members of Family 39 who contained informative recombination events, resulting in a further narrowing of LGMD1A to an interval bounded by D5S479 and D5S594, estimated to be 2 Mb in size. Integration of the genetic and physical map permits the identification of several transcription units from within the narrowed LGMD1A interval, including one that is muscle specific, representing candidate genes for this familial dystrophy.

Exclusion of identified LGMD1 loci from four dominant limb-girdle muscular dystrophy families.

The limb-girdle muscular dystrophies are a clinically and genetically heterogeneous group of disorders. Recent linkage analyses and positional cloning studies have identified numerous loci responsible for the recessive and dominant forms, underscoring the inherent heterogeneity. In this report, we investigate four large autosomal dominant limb-girdle pedigrees and exclude these pedigrees from linkage to these loci. In addition, there is no evidence for linkage to any of the seven recessive LGMD loci.

Using neural networks as an aid in the determination of disease status: comparison of clinical diagnosis to neural-network predictions in a pedigree with autosomal dominant limb-girdle muscular dystrophy.

Studies of the genetics of certain inherited diseases require expertise in the determination of disease status even for single-locus traits. For example, in the diagnosis of autosomal dominant limb-girdle muscular dystrophy (LGMD1A), it is not always possible to make a clear-cut determination of disease, because of variability in the diagnostic criteria, age at onset, and differential presentation of disease. Mapping such diseases is greatly simplified if the data present a homogeneous genetic trait and if disease status can be reliably determined. Here, we present an approach to determination of disease status, using methods of artificial neural-network analysis. The method entails "training" an artificial neural network, with input facts (based on diagnostic criteria) and related results (based on disease diagnosis). The network contains weight factors connecting input "neurons" to output "neurons," and these connections are adjusted until the network can reliably produce the appropriate outputs for the given input facts. The trained network can be "tested" with a second set of facts, in which the outcomes are known but not provided to the network, to see how well the training has worked. The method was applied to members of a pedigree with LGMD1A, now mapped to chromosome 5q. We used diagnostic criteria and disease status to train a neural network to classify individuals as "affected" or "not affected." The trained network reproduced the disease diagnosis of all individuals of known phenotype, with 98% reliability. This approach defined an appropriate choice of clinical factors for determination of disease status. Additionally, it provided insight into disease classification of those considered to have an "unknown" phenotype on the basis of standard clinical diagnostic methods.

Evidence for anticipation in autosomal dominant limb-girdle muscular dystrophy.

Anticipation, an increase in severity or decrease in age of onset (AO) inherent in the transmission of the disease gene from affected parent to affected child, has been increasingly described in human disease. To assess anticipation in a large kindred in which autosomal dominant limb-girdle muscular dystrophy (LGMD1A) is segregating, age of disease onset was collected from patient interviews of affected family members. A total of 25 parent-offspring pairs, in which the parents are three (3R), four (4R), or five (5R) generations removed from a common founding ancestor, were available for analysis. Life table analyses showed significant decreases in age at first reported symptoms in the offspring of the 3R (chi2=5.55, p=0.02) and 4R (chi2=7.81, p=0.005) parents. Pairwise analyses confirmed this decrease with a median decrease of 13 years in transmission to offspring from 3R parents and 18 years in transmission to offspring from 4R parents. The finding of anticipation in this pedigree suggests that the mutation in LGMD1A may be the result of the expansion of an unstable trinucleotide repeat.

Confirmation of linkage of oculopharyngeal muscular dystrophy to chromosome 14q11.2-q13 in American families suggests the existence of a second causal mutation.

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, autosomal dominant disorder characterized by progressive ptosis, dysphagia, and extremity weakness. Linkage of OPMD to 14q11.2-q13 has been reported in a series of French-Canadian families. Tightly linked markers have been defined and haplotype analysis in these data show a single segregating disease chromosome throughout the OPMD French-Canadian families. We have ascertained and sampled five multigenerational outbred American OPMD families. Four of the five families have known French-Canadian ancestry while the fifth is of English/Scottish origin. Linkage analysis was performed using standard likelihood methods. A peak multipoint lod score of 6.30 was obtained for the marker MYH7.1 in the OPMD families. The English/ Scottish family exhibited a different chromosomal haplotype for the OPMD alleles than the families of French-Canadian origin. These data suggest this family may represent a second, possibly independent mutation in this disorder. Linkage was confirmed to chromosome 14q11.2-q13 with no evidence of genetic heterogeneity.

Confirmation of linkage of oculopharyngeal muscular dystrophy to chromosome 14q11.2-q13.

Oculopharyngeal muscular dystrophy is a late-onset, autosomally dominant disorder characterized by progressive ptosis, dysphagia, and extremity weakness. Linkage of oculopharyngeal muscular dystrophy to 14q11.2-q13 has been reported in a series of French Canadian families. Haplotype analysis in these data shows a single segregating disease chromosome, suggesting a founder effect in this population. We ascertained and sampled for linkage studies 5 multigenerational American families with oculopharyngeal muscular dystrophy. Four of the 5 families have known French Canadian ancestry while the fifth is of English/Scottish origin. A peak multipoint lod score of 6.30 was obtained for the marker MYH7.1 in the families, confirming linkage to 14q11.2-q13. The English/Scottish family exhibited a different chromosomal haplotype for the oculopharyngeal muscular dystrophy alleles than did the families of French Canadian origin. These data suggest that this family may represent a second, possibly independent mutation in this disorder.

Adult-onset MELAS. Evidence for involvement of neurons as well as cerebral vasculature in strokelike episodes.

BACKGROUND: We report a 46-year-old woman with implications regarding pathogenesis of strokelike episodes in MELAS (mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes). She had a 10-month history of episodic seizures, strokes, cognitive decline, vomiting, and ileus. She also had sensorineural hearing loss, insulin-dependent diabetes mellitus of several years' duration, and persistent lactic acidosis. Family history was pertinent for a similar syndrome in her deceased mother (onset in her sixties), for hearing loss and diabetes mellitus in two brothers, and for hearing loss in her only child, a son. CASE DESCRIPTION: Serial MRIs of the brain revealed severe but evanescent cerebral cortical abnormalities. A left temporal brain biopsy was performed to exclude encephalitis. Light microscopy revealed a diffuse fibrillary gliosis with abundant reactive gemistocytes, focal evidence of ischemic neuronal injury, and edema. Electron microscopy revealed bizarre enlarged mitochondria and changes consistent with cellular edema. Succinate dehydrogenase staining was strongly reactive within cerebral blood vessels and within neurons. A point mutation was subsequently found at nt 3243 of the mitochondrial tRNA(Leu(UUR) gene in peripheral leukocytes and in brain, confirming the clinical diagnosis of MELAS. Quantitation revealed that 82% of brain mitochondria carried the disease mutation, indicating that most, if not all, tissues were affected. CONCLUSIONS: Our findings suggest that strokelike episodes in MELAS result from defects in neuronal metabolism, as well as in cerebral vasculature.

Multifocal motor neuropathy with conduction block and Campylobacter jejuni.

We describe a patient with acute multifocal motor neuropathy with conduction block (MMNCB) and high titers of immunoglobulin G anti-GM1 antibodies after Campylobacter jejuni enteritis. Treatment with intravenous immune globulin led to rapid improvement with return of normal function by 6 weeks. This is the first report of C. jejuni enteritis preceding MMNCB.

Evidence for locus heterogeneity in autosomal dominant limb-girdle muscular dystrophy.

Limb-girdle muscular dystrophy (LGMD) is a diagnostic classification encompassing a broad group of proximal myopathies. A gene for the dominant form of LGMD (LGMD1A) has recently been localized to a 7-cM region of chromosome 5q between D5S178 and IL9. We studied three additional dominant LGMD families for linkage to these two markers and excluded all from localization to this region, providing evidence for locus heterogeneity within the dominant form of LGMD. Although patterns of muscle weakness were similar in all families studied, the majority of affected family members in the chromosome 5-linked pedigree have a dysarthric speech pattern, which is not present in any of the five unlinked families. The demonstration of heterogeneity within autosomal dominant LGMD is the first step in attempting to subclassify these families with similar clinical phenotypes on a molecular level.

Dynamical analysis of neuromuscular transmission jitter.

Utilizing prolonged axonal stimulation single fiber EMG, neuromuscular transmission becomes a time-series of interpotential intervals (IPIs). In this form, the underlying processes of neuromuscular transmission can be studied using standard numerical techniques to determine whether these processes can be described by a simple mathematical model. In particular, neuromuscular transmission jitter can be examined in this way. In this article, we attempt to determine whether healthy jitter is noise or deterministic chaos. The presence of deterministic chaos was assessed by analysis of the IPI time-series using visual inspection of both phase-space plots and their principal component dimensions, and using the Grassberger-Procaccia algorithm to determine the correlation dimension of the time-series dynamics. These graphical and mathematical techniques provided little evidence for the existence of deterministic chaos. Linear autoregression time-series prediction also failed to account for the variability of the data and IPI histograms exhibited simple gaussian distributions. These results suggest normal neuromuscular transmission jitter is the result of intrinsic noise.