Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal ‘dominant optic atrophy plus’ variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44–6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08–4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.

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In view of the steadily rising demand for treatment of dystonia with botulinum toxin (BT), a relatively expensive neurologic paralytic agent, an exploratory study was undertaken to assess the extent to which dystonia and BT treatment affect the quality of people's lives. One hundred thirty adults with a current diagnosis of dystonia completed two generic measures of health-related quality of life (HRQoL) at regular intervals over a minimum of 6 months. One hundred two participants were receiving regular injections of BT; 28 were not taking BT. The HRQoL instruments used were the EuroQol and the Short Form 36 health survey questionnaire (SF-36). Compared with general population samples, study participants reported greater impairment on all EuroQol and SF-36 dimensions and gave a lower rating to their own health status. Participants with nonfocal dystonia had significantly more problems with usual activities than participants with focal dystonia, and a higher number had problems with mobility and self-care. The groups reported similar levels of pain and emotional well-being. Small improvements in HRQoL were seen after the administration of BT, although few of these were statistically significant. The study results offer further psychometric evidence for the discriminant and construct validity of both the EuroQol and the SF-36.

The clinical features of Hashimoto's encephalopathy have been attributed to a cerebral vasculitis, but pathologic material is rarely available. The authors describe an individual with Hashimoto's encephalopathy complicated by fatal status epilepticus. Postmortem examination demonstrated mild perivascular lymphocytic infiltration throughout the brain and leptomeninges plus diffuse gliosis of gray matter in the cortex, basal ganglia, thalami, hippocampi, and, to a lesser extent, the parenchymal white matter.

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