Sean O'Riordan

PROGRESSIVE ENCEPHALOMYELITIS, RIGIDITY, AND MYOCLONUS: A NOVEL GLYCINE RECEPTOR ANTIBODY

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare disorder of subacute onset presenting as limb and truncal rigidity, muscle spasms, brainstem signs, and hyperekplexia.1 Life-threatening, it is part of the spectrum of stiff-person syndrome (SPS) with anti-glutamic acid decarboxylase (GAD) antibodies in up to 80% of patients.1 It may also be paraneoplastic with anti-amphiphysin antibodies.2 Mutations in the α1 subunit of the glycine receptor gene GLRA1 have been identified in hereditary hyperekplexia.3 Glycine receptors are concentrated in the caudal pontine brainstem and spinal cord; in PERM, hyperekplexia (brainstem myoclonus or excessive startle)4 implies disruption of the normal inhibitory glycinergic mechanism in the caudal pons where the nucleus reticularis pontis caudalis mediates the startle reflex. We report a patient with typical severe PERM associated with a novel anti-glycine receptor antibody. ### Clinical summary. A 54-year-old man presented in January 2001 with 3 weeks of left flank tingling and 2 weeks of worsening brief frequent violent jerks, spontaneous and triggered by sensory and auditory stimuli; his upper limbs would abduct and flex and his trunk and legs extend. Neurologic examination was otherwise normal; he was intubated and ventilated. The CSF contained 60 lymphocytes × 109/L, the CSF IgG index was 0.72 (n < 0.7), oligoclonal bands negative. Cranial and spinal MRI scans with gadolinium were normal. After …

Age at onset as a factor in determining the phenotype of primary torsion dystonia

Background: The genetic basis of most forms of primary torsion dystonia (PTD) is unknown; multiplex families are uncommon due to low penetrance. Intrafamilial, age-related, phenotypic heterogeneity was noted in 14 PTD families. The authors hypothesized that the clinical presentation of PTD was modulated by the age at onset of the dystonia, irrespective of the genotype. Methods: This hypothesis was addressed in a study of 14 PTD families and a meta-analysis of 83 published series of PTD. Results: In 12 families with adult-onset PTD, the index cases presented with cervical dystonia (CD); of the 22 affected relatives, 17 had CD, 2 had writer’s cramp, 1 had blepharospasm, and 2 had spasmodic dysphonia. In the two other PTD families, the probands and all 10 symptomatic relatives had limb-onset dystonia at <20 years of age. There were differences between the median ages at onset of the different phenotypes (p = 0.0037). Analysis of 83 published series including 5,057 patients indicated significant differences in the mean age at onset of five phenotypes of PTD (mean age at onset; 95% CI): DYT1 dystonia (11.3 years; 10.3 to 12.2), writer’s cramp (38.4; 36.9 to 39.9), CD (40.8; 40.3 to 41.3), spasmodic dysphonia (43.0; 42.2 to 43.9), and blepharospasm–oromandibular dystonia (55.7; 55.1 to 56.4). Conclusion: Phenotypic variation in PTD presentation is due to the effect of age at onset modulating the expression of a genetic disorder with a caudal-to-rostral change in the site of onset.

SGCE mutations cause psychiatric disorders: clinical and genetic characterization

Myoclonus dystonia syndrome is a childhood onset hyperkinetic movement disorder characterized by predominant alcohol responsive upper body myoclonus and dystonia. A proportion of cases are due to mutations in the maternally imprinted SGCE gene. Previous studies have suggested that patients with SGCE mutations may have an increased rate of psychiatric disorders. We established a cohort of patients with myoclonus dystonia syndrome and SGCE mutations to determine the extent to which psychiatric disorders form part of the disease phenotype. In all, 89 patients with clinically suspected myoclonus dystonia syndrome were recruited from the UK and Ireland. SGCE was analysed using direct sequencing and for copy number variants. In those patients where no mutation was found TOR1A (GAG deletion), GCH1, THAP1 and NKX2-1 were also sequenced. SGCE mutation positive cases were systematically assessed using standardized psychiatric interviews and questionnaires and compared with a disability-matched control group of patients with alcohol responsive tremor. Nineteen (21%) probands had a SGCE mutation, five of which were novel. Recruitment of family members increased the affected SGCE mutation positive group to 27 of whom 21 (77%) had psychiatric symptoms. Obsessive-compulsive disorder was eight times more likely (P < 0.001) in mutation positive cases, compulsivity being the predominant feature (P < 0.001). Generalized anxiety disorder (P = 0.003) and alcohol dependence (P = 0.02) were five times more likely in mutation positive cases than tremor controls. SGCE mutations are associated with a specific psychiatric phenotype consisting of compulsivity, anxiety and alcoholism in addition to the characteristic motor phenotype. SGCE mutations are likely to have a pleiotropic effect in causing both motor and specific psychiatric symptoms.

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.

Sporadic adult onset dystonia: sensory abnormalities as an endophenotype in unaffected relatives

Background: Most patients with adult onset primary torsion dystonia (AOPTD) have the sporadic form of the disease. They may however be the only manifesting family members of a poorly penetrant genetic disorder. Sensory changes, including structural abnormalities of the primary sensory cortex, are found in AOPTD. Spatial discrimination threshold (SDT), a measure of sensory cortical organisation, is abnormal in AOPTD and in unaffected relatives of patients with familial AOPTD. Our hypothesis was that abnormal SDTs might be found in unaffected relatives of patients with sporadic AOPTD. Methods: SDTs were assessed at the index finger bilaterally by a grating orientation task. Normal age related SDTs were derived from 141 control subjects aged 20–64 years. SDTs were considered abnormal when greater than 2.5 SD above the control mean. In total, 105 of 171 (61%) eligible unaffected siblings and offspring of patients with cervical dystonia had SDT examined. Results: Fourteen of 48 siblings (29%) and 10 of 57 (18%) offspring were found to have an abnormal SDT. Only five of the 20 patients examined had abnormal SDTs. In 11 of the 25 families, no abnormality was found in an unaffected relative. In the 14 families where at least one unaffected relative had an abnormal SDT, 14 of 37 siblings (38%) and 10 of 33 offspring (30%) had abnormal SDTs. Conclusion: Sensory abnormalities found in unaffected relatives of patients with apparently sporadic AOPTD may be a surrogate marker for the carriage of an abnormal gene.

Sporadic adult onset primary torsion dystonia is a genetic disorder by the temporal discrimination test

Adult-onset primary torsion dystonia is an autosomal dominant disorder with markedly reduced penetrance; patients with sporadic adult-onset primary torsion dystonia are much more prevalent than familial. The temporal discrimination threshold is the shortest time interval at which two stimuli are detected to be asynchronous and has been shown to be abnormal in adult-onset primary torsion dystonia. The aim was to determine the frequency of abnormal temporal discrimination thresholds in patients with sporadic adult-onset primary torsion dystonia and their first-degree relatives. We hypothesized that abnormal temporal discrimination thresholds in first relatives would be compatible with an autosomal dominant endophenotype. Temporal discrimination thresholds were examined in 61 control subjects (39 subjects <50 years of age; 22 subjects >50 years of age), 32 patients with sporadic adult-onset primary torsion dystonia (cervical dystonia n = 30, spasmodic dysphonia n = 1 and Meiges syndrome n = 1) and 73 unaffected first-degree relatives (36 siblings, 36 offspring and one parent) using visual and tactile stimuli. Z-scores were calculated for all subjects; a Z > 2.5 was considered abnormal. Abnormal temporal discrimination thresholds were found in 1/61 (2%) control subjects, 27/32 (84%) patients with adult-onset primary torsion dystonia and 32/73 (44%) unaffected relatives [siblings (20/36; 56%), offspring (11/36; 31%) and one parent]. When two or more relatives were tested in any one family, 22 of 24 families had at least one first-degree relative with an abnormal temporal discrimination threshold. The frequency of abnormal temporal discrimination thresholds in first-degree relatives of patients with sporadic adult-onset primary torsion dystonia is compatible with an autosomal dominant disorder and supports the hypothesis that apparently sporadic adult-onset primary torsion dystonia is genetic in origin.

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.

Inherited myoclonus-dystonia and epilepsy: Further evidence of an association?

Epilepsy and electroencephalogram (EEG) abnormalities have been considered exclusion criteria for the clinical diagnosis of myoclonus‐dystonia (M‐D). We report on the second M‐D family in which several clinically affected ϵ‐sarcoglycan gene (SGCE) mutation carriers have seizures in addition to myoclonus and dystonia, adding to the evidence that epilepsy and EEG abnormalities may form part of the phenotypic spectrum of the condition. A nonsense mutation in exon 3 (289C→T) of SGCE resulting in the insertion of a premature stop codon (R97X) was detected in affected members of this family.

Pallidal stimulation for cervical dystonia does not correct abnormal temporal discrimination

We investigated whether clinical improvement observed after deep brain stimulation (DBS) of the globus pallidus internus (GPi) in cervical dystonia (CD) is paralleled by the normalisation of temporal discrimination thresholds (TDTs), a marker of abnormal sensory processing in CD.