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.

Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding (TARDBP) and unrelated genes (eg,C9orf72). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.

Non‐technical summary Neural activity in parts of the cerebral cortex related to movement oscillates at frequencies around 20 Hz. These oscillations are correlated with similar rhythms in contracting muscles on the opposite side of the body. In this work, we used an analysis method called directed coherence to investigate the direction of oscillatory coupling. We find that oscillations travel not only from cortex to muscle (as expected for a motor command), but also back from muscle to cortex (reflecting sensory input). This oscillatory loop may allow the cortex to measure features of the limb state, integrating sensory inflow with the motor command.

Gait disturbance is an early feature in Parkinson’s disease. Its pathophysiology is poorly understood; however, cholinergic dysfunction may be a non-dopaminergic contributor to gait. Short-latency afferent inhibition is a surrogate measure of cholinergic activity, allowing the contribution of cholinergic dysfunction to gait to be evaluated. We hypothesized that short-latency afferent inhibition would be an independent predictor of gait dysfunction in early Parkinson’s disease. Twenty-two participants with Parkinson’s disease and 22 age-matched control subjects took part in the study. Gait was measured objectively using an instrumented walkway (GAITRite), and subjects were asked to walk at their preferred speed for 2 min around a 25-m circuit. Spatiotemporal characteristics (speed, stride length, stride time and step width) and gait dynamics (variability described as the within subject standard deviation of: speed, stride time, stride length and step width) were determined. Short-latency afferent inhibition was measured by conditioning motor evoked potentials, elicited by transcranial magnetic stimulation of the motor cortex, with electrical stimuli delivered to the contralateral median nerve at intervals ranging from N20 (predetermined) to N20 + 4 ms. Short-latency afferent inhibition was determined as the percentage difference between test and conditioned response for all intervals and was described as the group mean. Participants were optimally medicated at the time of testing. Participants with Parkinson’s disease had significantly reduced gait speed (P = 0.002), stride length (P = 0.008) and stride time standard deviation (P = 0.001). Short-latency afferent inhibition was also significantly reduced in participants with Parkinson’s disease (P = 0.004). In participants with Parkinson’s disease, but not control subjects, significant associations were found between gait speed, short-latency afferent inhibition, age and postural instability and gait disorder score (Movement Disorders Society Unified Parkinson’s Disease Rating Scale) and attention, whereas global cognition and depression were marginally significant. No other gait variables were associated with short-latency afferent inhibition. A multiple hierarchical regression model explored the contribution of short-latency afferent inhibition to gait speed, controlling for age, posture and gait symptoms (Postural Instability and Gait Disorder score—Movement Disorders Society Unified Parkinson’s Disease Rating Scale), attention and depression. Regression analysis in participants with Parkinson’s disease showed that reduced short-latency afferent inhibition was an independent predictor of slower gait speed, explaining 37% of variability. The final model explained 72% of variability in gait speed with only short-latency afferent inhibition and attention emerging as independent determinants. The results suggest that cholinergic dysfunction may be an important and early contributor to gait dysfunction in Parkinson’s disease. The findings also point to the contribution of non-motor mechanisms to gait dysfunction. Our study provides new insights into underlying mechanisms of non-dopaminergic gait dysfunction, and may help to direct future therapeutic approaches.