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Dravet syndrome is a severe infantile onset epileptic encephalopathy associated with mutations in the sodium channel alpha 1 subunit gene SCN1A. To date no large studies have systematically examined the prognostic, clinical and demographic features of the disease. We prospectively collected data on a UK cohort of individuals with Dravet syndrome during a 5-year study period and analysed demographic information based on UK population and birth figures. From structured referral data we examined a range of clinical characteristics including epilepsy phenotype, seizure precipitants, electroencephalography data, imaging studies, mutation class and response to medication. Predictors of developmental outcome were determined by logistic regression. We identified 241 cases with SCN1A mutation-positive Dravet syndrome, 207 of which were UK-based. The incidence of mutation-positive Dravet syndrome is at least 1:40 900 UK births. Clinical features predicting a worse developmental outcome included status epilepticus (odds ratio = 3.1; confidence interval = 1.5-6.3; P = 0.003), interictal electroencephalography abnormalities in the first year of life (odds ratio = 5.7; confidence interval = 1.9-16.8; P = 0.002) and motor disorder (odds ratio = 3.3; confidence interval = 1.7-6.4; P < 0.001). No significant effect was seen for seizure precipitants, magnetic resonance imaging abnormalities or mutation class (truncating versus missense). Abnormal magnetic resonance imaging was documented in 11% of cases, principally with findings of non-specific brain atrophy or hippocampal changes. Sodium valproate, benzodiazepines and topiramate were reported as being the most helpful medications at the time of referral. Aggravation of seizures was reported for carbamazepine and lamotrigine. The identification of factors influencing prognosis both aids counselling and encourages early, syndrome-specific therapy. Prevention of status epilepticus with regular medication and emergency protocols is important and may influence developmental outcome.

Objective: Most mutations in SCN1A-related epilepsies are novel and when an infant presents with febrile seizures (FS) it is uncertain if they will have simple FS, FS+, or develop a severe epilepsy such as Dravet syndrome. Our objective was to examine whether the nature of a SCN1A mutation affects the epilepsy phenotype., Methods: We retrospectively evaluated clinical and genetic data from 273 individuals with SCN1A mutations identified in our laboratory and reviewed data from 546 published cases. We examined whether the mutation class or distribution or nature of amino acid substitution correlated with the epilepsy phenotype, using the Grantham Score (GS) as a measure of physicochemical difference between amino acids., Results: Compared to missense mutations, truncating mutations were associated with earlier mean onset of prolonged seizures (7.4 vs 8.8 months; p = 0.040), myoclonic seizures (16.4 vs 19.4 months; p = 0.041), and atypical absence seizures (19.1 vs 30.6 months; p = 0.001). The median GS was higher in patients with Dravet syndrome compared to polymorphisms (94 vs 58; p = 0.029) and orthologs (94 vs 45; p < 0.001). A high GS was correlated with early onset of seizures (r(s) = -0.235; p = 0.008). Missense mutations occurred most frequently in the voltage and ion-pore regions where changes in amino acid polarity were greater in the Dravet group compared to the genetic epilepsy with febrile seizures plus group (3.6 vs 2.7; p = 0.031)., Conclusions: These findings help define the clinical significance of specific SCN1A mutations based on mutation class and amino acid property and location.

In 1988 we reported two sisters with bilateral Coats' disease, sparse hair, dystrophic nails, and primeval splashes of intracranial calcification. We now provide an update on this family documenting the occurrence of skeletal defects comprising abnormal bone marrow, osteopenia, and sclerosis with a tendency to fractures, a mixed cerebellar and extrapyramidal movement disorder, infrequent epileptic seizures, leukodystrophic changes, and postnatal growth failure. Additionally, we present two previously unreported individuals from Ireland and Switzerland with the identical disorder which we designate Coats' plus. Since our original publication a number of other authors have described, frequently as a "new" syndrome, cases with a variable combination of the same features observed in our patients. We review this literature and suggest that the phenotypic overlap with dyskeratosis congenita may provide a clue to the molecular aetiology of this multisystem disorder.

Background: The genetic basis of most common forms of human paroxysmal disorders of the central nervous system, such as epilepsy, remains unidentified. Several animal models of absence epilepsy, commonly accompanied by ataxia, are caused by mutations in the brain P/Q-type voltage-gated calcium (Ca(2+)) channel. We aimed to determine whether the P/Q-type Ca(2+) channel is associated with both epilepsy and episodic ataxia type 2 in human beings., Methods: We identified an 11-year-old boy with a complex phenotype comprising primary generalised epilepsy, episodic and progressive ataxia, and mild learning difficulties. We sequenced the entire coding region of the gene encoding the voltage-gated P/Q-type Ca(2+) channel (CACNA1A) on chromosome 19. We then introduced the newly identified heterozygous mutation into the full-length rabbit cDNA and did detailed electrophysiological expression studies of mutant and wild type Ca(2+) channels., Findings: We identified a previously undescribed heterozygous point mutation (C5733T) in CACNA1A. This mutation introduces a premature stop codon (R1820stop) resulting in complete loss of the C terminal region of the pore-forming subunit of this Ca(2+) channel. Expression studies provided direct evidence that this mutation impairs Ca(2+) channel function. Mutant/wild-type co-expression studies indicated a dominant negative effect., Interpretation: Human absence epilepsy can be associated with dysfunction of the brain P/Q-type voltage-gated Ca(2+) channel. The phenotype in this patient has striking parallels with the mouse absence epilepsy models.

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an uncommon, idiopathic partial epilepsy characterized by clusters of motor seizures occurring in sleep. We describe a mutation of the beta2 subunit of the nicotinic acetylcholine receptor, effecting a V287M substitution within the M2 domain. The mutation, in an evolutionary conserved region of CHRNB2, is associated with ADNFLE in a Scottish family. Functional receptors with the V287M mutation are highly expressed in Xenopus oocytes and characterized by an approximately 10-fold increase in acetylcholine sensitivity. CHRNB2 is a new gene for idiopathic epilepsy, the second acetylcholine receptor subunit implicated in ADNFLE.

Hashimoto's encephalopathy is a very rare complication of Hashimoto's thyroiditis. It is a progressive or relapsing encephalopathy associated with elevation of thyroid specific autoantibodies. Patients usually present when euthyroid and this diagnosis should be considered in any unexplained encephalopathy or progressive cognitive decline in the euthyroid patient.

One hundred paediatric, muscle ultrasound examinations performed in the evaluation of suspected neuromuscular disease were reviewed. The results were related to the presence or absence of neuromuscular disease in each child assessed. The group comprised 66 males and 34 females, age range 2 months to 16 years (mean 5.3 years). Scans were graded I-IV, according to muscle echogenicity, using Heckmatt's criteria. Thirty-two children had a final diagnosis of neuromuscular disease. The sensitivity of ultrasound in detecting neuromuscular disease was 78% with 91% specificity. The test was more reliable in the sub-group of > 3 years with a sensitivity of 81% and specificity of 96%. There was a significant difference in disease status, (with and without neuromuscular disease), between children with a normal, grade I, scan and those with an abnormal, grade II, III, IV, image (chi-square, P < 0.001, 95% confidence limits 0.54-0.86). Muscle ultrasound is a specific and sensitive investigation for suspected neuromuscular disease in children.

Episodic ataxia type 1 (EA1) is a rare autosomal dominant disorder characterized by brief episodes of ataxia associated with continuous interattack myokymia. Point mutations in the human voltage-gated potassium channel (Kv1.1) gene on chromosome 12p13 have recently been shown to associate with EA1. A Scottish family with EA1 harbouring a novel mutation in this gene is reported. Of the five affected individuals over three generations, two had partial epilepsy in addition to EA1. The detailed clinical, electrophysiological and molecular genetic findings are presented. The heterozygous point mutation is located at nucleotide position 677 and results in a radical amino acid substitution at a highly conserved position in the second transmembrane domain of the potassium channel. Functional studies indicated that mutant subunits exhibited a dominant negative effect on potassium channel function and would be predicted to impair neuronal repolarization. Potassium channels determine the excitability of neurons and blocking drugs are proconvulsant. A critical review of previously reported EA1 families shows an over-representation of epilepsy in family members with EA1 compared with unaffected members. These observations indicate that this mutation is pathogenic and suggest that the epilepsy in EA1 may be caused by the dysfunctional potassium channel. It is possible that such dysfunction may be relevant to other epilepsies in man.