In vivo impact of presynaptic calcium channel dysfunction on motor axons in episodic ataxia type 2.

Ion channel dysfunction causes a range of neurological disorders by altering transmembrane ion fluxes, neuronal or muscle excitability, and neurotransmitter release. Genetic neuronal channelopathies affecting peripheral axons provide a unique opportunity to examine the impact of dysfunction of a single channel subtype in detail in vivo. Episodic ataxia type 2 is caused by mutations in CACNA1A, which encodes the pore-forming subunit of the neuronal voltage-gated calcium channel Cav2.1. In peripheral motor axons, this channel is highly expressed at the presynaptic neuromuscular junction where it contributes to action potential-evoked neurotransmitter release, but it is not expressed mid-axon or thought to contribute to action potential generation. Eight patients from five families with genetically confirmed episodic ataxia type 2 underwent neurophysiological assessment to determine whether axonal excitability was normal and, if not, whether changes could be explained by Cav2.1 dysfunction. New mutations in the CACNA1A gene were identified in two families. Nerve conduction studies were normal, but increased jitter in single-fibre EMG studies indicated unstable neuromuscular transmission in two patients. Excitability properties of median motor axons were compared with those in 30 age-matched healthy control subjects. All patients had similar excitability abnormalities, including a high electrical threshold and increased responses to hyperpolarizing (P < 0.00007) and depolarizing currents (P < 0.001) in threshold electrotonus. In the recovery cycle, refractoriness (P < 0.0002) and superexcitability (P < 0.006) were increased. Cav2.1 dysfunction in episodic ataxia type 2 thus has unexpected effects on axon excitability, which may reflect an indirect effect of abnormal calcium current fluxes during development.

Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology.

Dravet syndrome is an epilepsy syndrome of infantile onset, frequently caused by SCN1A mutations or deletions. Its prevalence, long-term evolution in adults and neuropathology are not well known. We identified a series of 22 adult patients, including three adult post-mortem cases with Dravet syndrome. For all patients, we reviewed the clinical history, seizure types and frequency, antiepileptic drugs, cognitive, social and functional outcome and results of investigations. A systematic neuropathology study was performed, with post-mortem material from three adult cases with Dravet syndrome, in comparison with controls and a range of relevant paediatric tissue. Twenty-two adults with Dravet syndrome, 10 female, were included, median age 39 years (range 20-66). SCN1A structural variation was found in 60% of the adult Dravet patients tested, including one post-mortem case with DNA extracted from brain tissue. Novel mutations were described for 11 adult patients; one patient had three SCN1A mutations. Features of Dravet syndrome in adulthood include multiple seizure types despite polytherapy, and age-dependent evolution in seizure semiology and electroencephalographic pattern. Fever sensitivity persisted through adulthood in 11 cases. Neurological decline occurred in adulthood with cognitive and motor deterioration. Dysphagia may develop in or after the fourth decade of life, leading to significant morbidity, or death. The correct diagnosis at an older age made an impact at several levels. Treatment changes improved seizure control even after years of drug resistance in all three cases with sufficient follow-up after drug changes were instituted; better control led to significant improvement in cognitive performance and quality of life in adulthood in two cases. There was no histopathological hallmark feature of Dravet syndrome in this series. Strikingly, there was remarkable preservation of neurons and interneurons in the neocortex and hippocampi of Dravet adult post-mortem cases. Our study provides evidence that Dravet syndrome is at least in part an epileptic encephalopathy.

Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data.

We have established that the frequency of LRRK2 mutations in a series of 118 cases of familial Parkinson's disease is 5.1%. In the largest family with autosomal dominant, late-onset Parkinson's disease where affected subjects share a Y1699C missense mutation we provide a detailed clinical, pathological and imaging report. The phenotype in this large British kindred included asymmetrical, levodopa-responsive parkinsonism where unilateral leg tremor at onset and foot dystonia were prominent features. There was no significant abnormality of cognition but there was prominent behavioural disorder. We observed a lower age of onset in successive generations. Histopathology in one patient showed substantia nigra cell loss and Lewy body formation, with small numbers of cortical Lewy bodies. 18F-dopa positron emission tomography (PET) in another patient showed a pattern of nigrostriatal dysfunction typical of idiopathic Parkinson's disease. 18F-dopa-PET scans in unaffected family members prior to identifying the disease locus did not detect subclinical nigrostriatal dysfunction. Olfaction was assessed in affected subjects and Lewy bodies were identified in the olfactory bulb as well as cortex and brainstem of one deceased patient. In order to assess the role of mutations in this gene in other familial cases we undertook a mutation screen of all 51 exons of LRRK2 in 117 other smaller British kindreds with familial Parkinson's disease. The commonest mutation was G2019S and we also identified two novel mutations, R1941H and T2356I, in the coding sequence. These data suggest that parkinsonism caused by mutations in LRRK2 is likely to represent the commonest locus for autosomal dominant Parkinson's disease with a phenotype, pathology and in vivo imaging similar to idiopathic, late-onset Parkinson's disease.

Genetic linkage analysis of a large family with photoparoxysmal response.

In this study, we report the results of a genetic linkage analysis of a large family with photoparoxysmal response, defined by the presence of a photoparoxysmal response (PPR) on EEG. The participants were genotyped using an 8 cM whole genome wide scan, and both parametric and non-parametric linkage analysis were carried out. The parametric analysis by MLINK did not identify any definite conclusion but a region of interest on chromosome 1 near marker D1S2865; and non-parametric linkage analysis found a locus of interest on chromosome 16, near marker D16S2621. The possible confounding factors for, and pathogenic implication of, and the results are discussed.