Concise guidance: diagnosis and management of the epilepsies in adults.

This concise guidance comprises a distillation of recommendations for the diagnosis and management of epilepsies for non-specialists and is based on updated clinical guideline 137 published by the National Institute of Health and Care Excellence (NICE). It is intended to provide the generalist at the front line (particularly but not exclusively in the acute hospital setting) with an accessible and up-to-date outline of key guidance on assessment, clinical management, communication and referral. Recommendations abstracted verbatim from the guideline are highlighted. Brief explanatory or supporting comment is given where appropriate.

Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation.

Neuroferritinopathy is a progressive potentially treatable adult-onset movement disorder caused by mutations in the ferritin light chain gene (FTL1). Features overlap with common extrapyramidal disorders: idiopathic torsion dystonia, idiopathic Parkinson's disease and Huntington's disease, but the phenotype and natural history have not been defined. We studied a genetically homogeneous group of 41 subjects with the 460InsA mutation in FTL1, documenting the presentation, clinical course, biochemistry and neuroimaging. The mean age of onset was 39.4 years (SD = 13.3, range 13-63), beginning with chorea in 50%, focal lower limb dystonia in 42.5% and parkinsonism in 7.5%. The majority reported a family history of a movement disorder often misdiagnosed as Huntington's disease. The disease progressed relentlessly, becoming generalized over a 5-10 year period, eventually leading to aphonia, dysphagia and severe motor disability with subcortical/frontal cognitive dysfunction as a late feature. A characteristic action-specific facial dystonia was common (65%), and in 63% there was asymmetry throughout the disease course. Serum ferritin levels were low in the majority of males and post-menopausal females, but within normal limits for pre-menopausal females. MR brain imaging was abnormal on all affected individuals and one presymptomatic carrier. In conclusion, isolated parkinsonism is unusual in neuroferritinopathy, and unlike Huntington's disease, cognitive changes are absent or subtle in the early stages. Depressed serum ferritin is common and provides a useful screening test in routine practice, and gradient echo brain MRI will identify all symptomatic cases.

A mitochondrial cytochrome b mutation causing severe respiratory chain enzyme deficiency in humans and yeast.

Whereas the majority of disease-related mitochondrial DNA mutations exhibit significant biochemical and clinical heterogeneity, mutations within the mitochondrially encoded human cytochrome b gene (MTCYB) are almost exclusively associated with isolated complex III deficiency in muscle and a clinical presentation involving exercise intolerance. Recent studies have shown that a small number of MTCYB mutations are associated with a combined enzyme complex defect involving both complexes I and III, on account of the fact that an absence of assembled complex III results in a dramatic loss of complex I, confirming a structural dependence between these two complexes. We present the biochemical and molecular genetic studies of a patient with both muscle and brain involvement and a severe reduction in the activities of both complexes I and III in skeletal muscle due to a novel mutation in the MTCYB gene that predicts the substitution (Arg318Pro) of a highly conserved amino acid. Consistent with the dramatic biochemical defect, Western blotting and BN-PAGE experiments demonstrated loss of assembled complex I and III subunits. Biochemical studies of the equivalent amino-acid substitution (Lys319Pro) in the yeast enzyme showed a loss of enzyme activity and decrease in the steady-state level of bc1 complex in the mutant confirming pathogenicity.

Spectrum of movement disorders in neuroferritinopathy.

Neuroferritinopathy is a recently recognized, dominantly inherited movement disorder caused by a mutation of the ferritin light chain gene. We present video case reports of 4 individuals with neuroferritinopathy chosen to illustrate how this disorder can present and subsequently progress clinically. The clinical phenotype of this disorder is highly variable with symptoms beginning in the third to sixth decades. Chorea, dystonia, or an akinetic-rigid syndrome can predominate in different individuals. Neuroferritinopathy is not restricted to the UK and it has been described in apparently sporadic cases. The diagnosis should therefore be considered in patients with a wide variety of different movement disorders. Characteristic neuroimaging assists in identifying affected individuals.

Sporadic mitochondrial myopathy due to a new mutation in the mitochondrial tRNASer(UCN) gene.

We describe a young woman with a progressive mitochondrial myopathy that started with muscle weakness and went on to include deafness, dementia and ataxia. Skeletal muscle showed the histological and biochemical features of mitochondrial respiratory chain dysfunction. Genetic analysis identified a novel, heteroplasmic, A to G transition in tRNA(Ser(UCN)) at position 7480 affecting a highly conserved base in the anticodon loop. Single-fibre PCR showed highest levels of mutation in cytochrome c-oxidase-deficient fibres and quantification in two biopsies taken 5 years apart showed no change in percentage heteroplasmy. The mutation was present at lower levels in the patient's blood, but was not found in either her mother's or sister's blood and skeletal muscle, suggesting a sporadic occurrence. This is the eighth disease-causing mutation in this tRNA gene and confirms serine (UCN) as one of the most common sites for mtDNA mutation.

Neuroferritinopathy: a window on the role of iron in neurodegeneration.

Neuroferritinopathy is a recently recognised genetic disease resulting in a dominantly inherited movement disorder. The condition was mapped by linkage analysis to chromosome 19q13.3 and found to be due to a single adenine insertion in the ferritin light chain (FTL) gene at position 460-461 which is predicted to alter the C terminus of the FTL polypeptide. Clinical features of neuroferritinopathy are highly variable, with chorea, dystonia, and Parkinsonian features predominating in different affected individuals. The most consistent feature is a dystonic dysarthria. Symptoms and abnormal physical signs appear to be restricted to the nervous system and onset is typically in the fourth to sixth decades. Low serum ferritin also characterises this condition. Brain MR imaging of affected patients demonstrates iron deposition in the basal ganglia, progressing over years to cystic degeneration, and brain histochemistry shows abnormal aggregates of ferritin and iron. Now that the molecular basis of the condition is known, therapeutic interventions to reduce or reverse brain iron deposition are being evaluated. This rare disease provides evidence of a central role for iron metabolism in neurodegenerative disorders.