Fiona Molloy

Temporal Discrimination Threshold: VBM evidence for an endophenotype in adult onset primary torsion dystonia

Familial adult-onset primary torsion dystonia is an autosomal dominant disorder with markedly reduced penetrance. Most adult-onset primary torsion dystonia patients are sporadic cases. Disordered sensory processing is found in adult-onset primary torsion dystonia patients; if also present in their unaffected relatives this abnormality may indicate non-manifesting gene carriage. Temporal discrimination thresholds (TDTs) are abnormal in adult-onset primary torsion dystonia, but their utility as a possible endophenotype has not been examined. We examined 35 adult-onset primary torsion dystonia patients (17 familial, 18 sporadic), 42 unaffected first-degree relatives of both familial and sporadic adult-onset primary torsion dystonia patients, 32 unaffected second-degree relatives of familial adult-onset primary torsion dystonia (AOPTD) patients and 43 control subjects. TDT was measured using visual and tactile stimuli. In 33 unaffected relatives, voxel-based morphometry was used to compare putaminal volumes between relatives with abnormal and normal TDTs. The mean TDT in 26 control subjects under 50 years of age was 22.85 ms (SD 8.00; 95% CI: 19.62-26.09 ms). The mean TDT in 17 control subjects over 50 years was 30.87 ms (SD 5.48; 95% CI: 28.05-33.69 ms). The upper limit of normal, defined as control mean + 2.5 SD, was 42.86 ms in the under 50 years group and 44.58 ms in the over 50 years group. Thirty out of thirty-five (86%) AOPTD patients had abnormal TDTs with similar frequencies of abnormalities in sporadic and familial patients. Twenty-two out of forty-two (52%) unaffected first-degree relatives had abnormal TDTs with similar frequencies in relatives of sporadic and familial AOPTD patients. Abnormal TDTs were found in 16/32 (50%) of second-degree relatives. Voxel-based morphometry analysis comparing 13 unaffected relatives with abnormal TDTs and 20 with normal TDTs demonstrated a bilateral increase in putaminal grey matter in unaffected relatives with abnormal TDTs. The prevalence of abnormal TDTs in sporadic and familial AOPTD patients and their first-degree relatives follows the rules for a useful endophenotype. A structural correlate of abnormal TDTs in unaffected first-degree relatives was demonstrated using voxel-based morphometry. Voxel-based morphometry findings indicate that putaminal enlargement in AOPTD is a primary phenomenon. TDTs may be an effective tool in AOPTD research with particular relevance to genetic studies of the disorder.

Sensory abnormalities in unaffected relatives in familial adult-onset dystonia

Somatosensory abnormalities are found in adult-onset primary torsion dystonia (PTD). Therefore we assessed spatial discrimination thresholds (SDT), a measure of spatial acuity, in four multiplex families with adult-onset PTD. In family members aged 20 to 45 years vs controls (mean + 2.5 SD), abnormal SDTs were found in four of five affected with adult-onset PTD and in 12 of 49 unaffected relatives. Sensory abnormalities may be an endophenotype, possibly expressed later as adult-onset PTD.

Temporal discrimination, a cervical dystonia endophenotype: penetrance and functional correlates.

The pathogenesis of adult‐onset primary dystonia remains poorly understood. There is variable age‐related and gender‐related expression of the phenotype, the commonest of which is cervical dystonia. Endophenotypes may provide insight into underlying genetic and pathophysiological mechanisms of dystonia. The temporal discrimination threshold (TDT)—the shortest time interval at which two separate stimuli can be detected as being asynchronous—is abnormal both in patients with cervical dystonia and in their unaffected first‐degree relatives. Functional magnetic resonance imaging (fMRI) studies have shown that putaminal activation positively correlates with the ease of temporal discrimination between two stimuli in healthy individuals. We hypothesized that abnormal temporal discrimination would exhibit similar age‐related and gender‐related penetrance as cervical dystonia and that unaffected relatives with an abnormal TDT would have reduced putaminal activation during a temporal discrimination task. TDTs were examined in a group of 192 healthy controls and in 158 unaffected first‐degree relatives of 84 patients with cervical dystonia. In 24 unaffected first‐degree relatives, fMRI scanning was performed during a temporal discrimination task. The prevalence of abnormal TDTs in unaffected female relatives reached 50% after age 48 years; whereas, in male relatives, penetrance of the endophenotype was reduced. By fMRI, relatives who had abnormal TDTs, compared with relatives who had normal TDTs, had significantly less activation in the putamina and in the middle frontal and precentral gyri. Only the degree of reduction of putaminal activity correlated significantly with worsening of temporal discrimination. These findings further support abnormal temporal discrimination as an endophenotype of cervical dystonia involving disordered basal ganglia circuits.

Comparing endophenotypes in adult-onset primary torsion dystonia.

Adult‐onset primary torsion dystonia (AOPTD) has an autosomal dominant pattern of inheritance with markedly reduced penetrance; the genetic causes of most forms of AOPTD remain unknown. Endophenotypes, markers of sub‐clinical gene carriage, may be of use detecting non‐manifesting gene carriers in relatives of AOPTD patients. The aim of this study was to compare the utility of the spatial discrimination threshold (SDT) and temporal discrimination threshold (TDT) as potential endophenotypes in AOPTD. Data on other published candidate endophenotypes are also considered. Both SDT and TDT testing were performed in 24 AOPTD patients and 34 of their unaffected first degree relatives; results were compared with normal values from a control population. Of the 24 AOPTD patients 5 (21%) had abnormal SDTs and 20 (83%) had abnormal TDTs. Of the 34 first degree relatives 17 (50%) had abnormal SDTs and 14 (41%) had abnormal TDTs. Discordant results on SDT and TDT testing were found in 16 (67%) AOPTD patients and 21 (62%) first degree relatives. TDT testing has superior sensitivity compared to SDT testing in AOPTD patients; although false positive TDTs are recognised, the specificity of TDT testing in unaffected relatives is not determinable. The high level of discordance between the two tests probably relates methodological difficulties with SDT testing. The SDT is an unreliable AOPTD endophenotype; TDT testing fulfils criteria for a reliable endophenotype with a high sensitivity.

The endophenotype and the phenotype: Temporal discrimination and adult‐onset dystonia

The pathogenesis and the genetic basis of adult‐onset primary torsion dystonia remain poorly understood. Because of markedly reduced penetrance in this disorder, a number of endophenotypes have been proposed; many of these may be epiphenomena secondary to disease manifestation. Mediational endophenotypes represent gene expression; the study of trait (endophenotypic) rather than state (phenotypic) characteristics avoids the misattribution of secondary adaptive cerebral changes to pathogenesis. We argue that abnormal temporal discrimination is a mediational endophenotype; its use facilitates examination of the effects of age, gender, and environment on disease penetrance in adult‐onset dystonia. Using abnormal temporal discrimination in unaffected first‐degree relatives as a marker for gene mutation carriage may inform exome sequencing techniques in families with few affected individuals. We further hypothesize that abnormal temporal discrimination reflects dysfunction in an evolutionarily conserved subcortical‐basal ganglia circuit for the detection of salient novel environmental change. The mechanisms of dysfunction in this pathway should be a focus for future research in the pathogenesis of adult‐onset primary torsion dystonia.

Cervical dystonia: a disorder of the midbrain network for covert attentional orienting

While the pathogenesis of cervical dystonia remains unknown, recent animal and clinical experimental studies have indicated its probable mechanisms. Abnormal temporal discrimination is a mediational endophenotype of cervical dystonia and informs new concepts of disease pathogenesis. Our hypothesis is that both abnormal temporal discrimination and cervical dystonia are due to a disorder of the midbrain network for covert attentional orienting caused by reduced gamma-aminobutyric acid (GABA) inhibition, resulting, in turn, from as yet undetermined, genetic mutations. Such disinhibition is (a) subclinically manifested by abnormal temporal discrimination due to prolonged duration firing of the visual sensory neurons in the superficial laminae of the superior colliculus and (b) clinically manifested by cervical dystonia due to disinhibited burst activity of the cephalomotor neurons of the intermediate and deep laminae of the superior colliculus. Abnormal temporal discrimination in unaffected first-degree relatives of patients with cervical dystonia represents a subclinical manifestation of defective GABA activity both within the superior colliculus and from the substantia nigra pars reticulata. A number of experiments are required to prove or disprove this hypothesis.

Inflammatory myopathy in thyrotoxicosis

Article abstract-A 45-year-old man with a 3-month history of episodic muscle weakness, MRC grade 4/5 symmetric hip flexor weakness, elevated CK, and an inflammatory myopathy was found to have elevated free thyroxine and T3. Treatment with carbimazole resulted in complete resolution of symptoms and return of muscle power to normal. A repeat biopsy revealed resolution of the inflammatory endomysial infiltrate and an absence of necrosis. Complete clinical and pathologic resolution of a thyrotoxicosis-associated inflammatory myopathy without steroid therapy has not been previously described. The favorable outcome experienced by this patient indicates that steroids may not be necessary in thyrotoxicosis-associated inflammatory myopathy. NEUROLOGY 1997;48: 339-341

Epidemiological, clinical and genetic aspects of adult onset isolated focal dystonia in Ireland.

Adult onset idiopathic isolated focal dystonia presents with a number of phenotypes. Reported prevalence rates vary considerably; well‐characterized cohorts are important to our understanding of this disorder.

Huntington's disease presenting as amyotrophic lateral sclerosis

We present the clinical, electrophysiological and molecular genetic findings of a 58-year-old male with genetically confirmed Huntingtons disease (HD) and concurrent clinically definite ALS by El Escorial criteria. The patient presented with asymmetric upper limb amyotrophy and weakness, and subsequently developed chorea and cognitive change. Genetic testing confirmed the presence of expanded trinucleotide repeats in huntingtin, consistent with a diagnosis of Huntingtons disease. This case confirms the rare coexistence of Huntingtons disease and motor neuron degeneration.

Formative evaluation of a telemedicine model for delivering clinical neurophysiology services part I: Utility, technical performance and service provider perspective

BackgroundFormative evaluation is conducted in the early stages of system implementation to assess how it works in practice and to identify opportunities for improving technical and process performance. A formative evaluation of a teleneurophysiology service was conducted to examine its technical and sociological dimensions.MethodsA teleneurophysiology service providing routine EEG investigation was established. Service use, technical performance and satisfaction of clinical neurophysiology personnel were assessed qualitatively and quantitatively. These were contrasted with a previously reported analysis of the need for teleneurophysiology, and examination of expectation and satisfaction with clinical neurophysiology services in Ireland. A preliminary cost-benefit analysis was also conducted.ResultsOver the course of 40 clinical sessions during 20 weeks, 142 EEG investigations were recorded and stored on a file server at a satellite centre which was 130 miles away from the host clinical neurophysiology department. Using a virtual private network, the EEGs were accessed by a consultant neurophysiologist at the host centre for interpretation. The model resulted in a 5-fold increase in access to EEG services as well as reducing average waiting times for investigation by a half. Technically the model worked well, although a temporary loss of virtual private network connectivity highlighted the need for clarity in terms of responsibility for troubleshooting and repair of equipment problems. Referral quality, communication between host and satellite centres, quality of EEG recordings, and ease of EEG review and reporting indicated that appropriate organisational processes were adopted by the service. Compared to traditional CN service delivery, the teleneurophysiology model resulted in a comparable unit cost per EEG.ConclusionObservations suggest that when traditional organisational boundaries are crossed challenges associated with the social dimension of service delivery may be amplified. Teleneurophysiology requires a governance and management that recognises its socio-technical nature.