The clinical and genetic heterogeneity of paroxysmal dyskinesias.

Paroxysmal dyskinesia can be subdivided into three clinical syndromes: paroxysmal kinesigenic dyskinesia or choreoathetosis, paroxysmal exercise-induced dyskinesia, and paroxysmal non-kinesigenic dyskinesia. Each subtype is associated with the known causative genes PRRT2, SLC2A1 and PNKD, respectively. Although separate screening studies have been carried out on each of the paroxysmal dyskinesia genes, to date there has been no large study across all genes in these disorders and little is known about the pathogenic mechanisms. We analysed all three genes (the whole coding regions of SLC2A1 and PRRT2 and exons one and two of PNKD) in a series of 145 families with paroxysmal dyskinesias as well as in a series of 53 patients with familial episodic ataxia and hemiplegic migraine to investigate the mutation frequency and type and the genetic and phenotypic spectrum. We examined the mRNA expression in brain regions to investigate how selective vulnerability could help explain the phenotypes and analysed the effect of mutations on patient-derived mRNA. Mutations in the PRRT2, SLC2A1 and PNKD genes were identified in 72 families in the entire study. In patients with paroxysmal movement disorders 68 families had mutations (47%) out of 145 patients. PRRT2 mutations were identified in 35% of patients, SLC2A1 mutations in 10%, PNKD in 2%. Two PRRT2 mutations were in familial hemiplegic migraine or episodic ataxia, one SLC2A1 family had episodic ataxia and one PNKD family had familial hemiplegic migraine alone. Several previously unreported mutations were identified. The phenotypes associated with PRRT2 mutations included a high frequency of migraine and hemiplegic migraine. SLC2A1 mutations were associated with variable phenotypes including paroxysmal kinesigenic dyskinesia, paroxysmal non-kinesigenic dyskinesia, episodic ataxia and myotonia and we identified a novel PNKD gene deletion in familial hemiplegic migraine. We found that some PRRT2 loss-of-function mutations cause nonsense mediated decay, except when in the last exon, whereas missense mutations do not affect mRNA. In the PNKD family with a novel deletion, mRNA was truncated losing the C-terminus of PNKD-L and still likely loss-of-function, leading to a reduction of the inhibition of exocytosis, and similar to PRRT2, an increase in vesicle release. This study highlights the frequency, novel mutations and clinical and molecular spectrum of PRRT2, SLC2A1 and PNKD mutations as well as the phenotype-genotype overlap among these paroxysmal movement disorders. The investigation of paroxysmal movement disorders should always include the analysis of all three genes, but around half of our paroxysmal series remain genetically undefined implying that additional genes are yet to be identified.

Congenital Myasthenic Syndromes with Predominant Limb Girdle Weakness.

Congenital myasthenic syndromes are a heterogeneous group of genetically determined disorders characterized by impaired neuromuscular transmission. They usually present from birth to childhood and are characterised by exercise induced weakness and fatigability. Genotype-phenotype correlations are difficult. However, in some patients particular phenotypic aspects may point towards a specific genetic defect. The absence of ptosis and ophthalmoparesis in patients with limb-girdle weakness makes the diagnosis of a neuromuscular transmission defect particularly challenging (LG-CMS). This is illustrated by a well-documented case published by Walton in 1956. The diagnosis of LG-CMS is secured by demonstrating a neuromuscular transmission defect with single fibre EMG or repetitive nerve stimulation, in the absence of auto-antibodies. Ultimately, a genetic test is required to identify the underlying cause and assure counselling and optimization of treatment. LG-CMS are inherited in autosomal recessive traits, and are often associated with mutations in DOK7 and GFPT1, and less frequently with mutations in COLQ, ALG2, ALG14 and DPAGT. Genetic characterization of CMS is of the upmost importance when choosing the adequate treatment. Some of the currently used drugs can either ameliorate or aggravate the symptoms depending on the underlying genetic defect. The drug most frequently used for the treatment of CMS is pyridostigmine an acetylcholinesterase inhibitor. However, pyridostigmine is not effective or is even detrimental in DOK7- and COLQ-related LG-CMS, while beta-adrenergic agonists (ephedrine, salbutamol) show some sustained benefit. Standard clinical trials may be difficult, but standardized follow-up of patients and international collaboration may help to improve the standards of care of these conditions.

A multicentre postal survey investigating the contribution of illness perceptions, coping and optimism to quality of life and mood in adults with muscle disease.

OBJECTIVE: To replicate the finding that illness perceptions influence quality of life in adults with muscle disease and to explore the additional influence of coping and optimism on quality of life and mood. DESIGN: A postal survey including questionnaires recording quality of life, mood, illness perceptions, optimism, coping and functional impairment. SETTING: National Health Service muscle clinics in the United Kingdom. PARTICIPANTS: A convenience sample of adults with muscle disease. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Individualised Neuromuscular Quality of Life Questionnaire, Hospital Anxiety and Depression Scale. RESULTS: A total of 226 completed questionnaires were returned. Although functional impairment explained most of the variance in three out of eight quality of life domains, psychological factors explained greater amounts of variance (between 19% and 52% of variance) in all other quality of life domains and in both mood domains (between 45% and 48% of variance). Overall, illness perceptions explained much of the variance in quality of life and mood score (between 5% and 37% of variance), while coping (up to 8% of variance) and optimism (up to 15% of variance) explained smaller amounts of variance. CONCLUSION: The results confirm that illness perceptions are associated with quality of life in muscle disease and suggest that they also influence mood. The addition of optimism and coping variables into the analysis yielded small increases in the proportions of variance in quality of life and mood which were explained. These results have implications for the composition of future psychological interventions.

In vivo assessment of HCN channel current (I(h)) in human motor axons.

The "Trond" protocol of nerve excitability tests has been used widely to assess axonal function in peripheral nerve. In this study, the routine Trond protocol was expanded to refine assessment of cAMP-dependent, hyperpolarization-activated current (I(h)) activity. I(h) activity is generated by hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels in response to hyperpolarization. It limits activity-dependent hyperpolarization, contributes to neuronal automaticity, and is implicated in chronic pain states. Published data regarding I(h) activity in motor nerve are scant. We used additional strong, prolonged hyperpolarizing conditioning stimuli in the threshold electrotonus component of the Trond protocol to demonstrate the time-course of activation of I(h) in motor axons. Fifteen healthy volunteers were tested on four occasions during 1 week. I(h) action was revealed in the threshold electrotonus by the limiting and often reversal, after about 100 ms, of the threshold increase caused by strong hyperpolarizing currents. Statistical analysis by repeated-measures analysis of variance enabled confidence limits to be established for variation between subjects and within subjects. The results demonstrate that, of all the excitability parameters, those dependent on I(h) were the most characteristic of an individual, because variance between subjects was more than four times the variance within subjects. This study demonstrates a reliable method for in vivo assessment of I(h,) and also serves to document the normal variability in nerve excitability properties within subjects.

The phenomenon of disproportionate antecollis in Parkinson's disease and multiple system atrophy.

We sought to explore the phenomenon of disproportionate antecollis in multiple system atrophy (MSA) and Parkinson's disease (PD). The etiology is much debated and the main issue is whether it represents a primary myopathy or is secondary to the underlying motor disorder. The clinical, electrophysiological, and biopsy data of MSA or PD patients with antecollis were reviewed. We reviewed 16 patients (7 MSA and 9 PD) who developed antecollis during the course of their disease. The interval between onset of motor symptoms and of antecollis was shorter in the MSA group (4.6 +/- 1.7 years vs. 10.5 +/- 7.0 years). In 6 patients, the antecollis developed subacutely, and in 2 the abnormal neck flexion was initially an off-period phenomenon. Two additional patients also showed some dopa-responsiveness. Clinically, the antecollis was characterized by a forward flexion and anterior shift of the neck, with prominent cervical paraspinal and levator scapulae muscles, usually without weakness of residual neck extension. Electromyography of cervical paraspinal muscles showed mixed myopathic, normal, and neurogenic units, without early recruitment. Cervical paraspinal muscle biopsy in 2 patients disclosed fibrosis and nonspecific myopathic changes. We suggest that, in the context of MSA or PD, the initiating event in antecollis could be a disproportionately increased tone in anterior neck muscles that leads to secondary fibrotic and myopathic changes. However, a primary but yet unexplained neck extensor myopathy still remains the alternative possibility and longitudinal studies are necessary to settle this issue.