The effect of triethyltin on oxidative phosphorylation and mitochondrial adenosine triphosphatase activation

Triethyltin inhibits the respiration of rat brain slices following in vitro and in vivo administration. When added in vitro this alkyltin compound uncouples oxidative phosphorylation of rat brain and liver homogenates and mitochondria. Triethyltin also inhibits both the magnesium and the 2:4-dinitrophenol activated adenosine triphosphatases of isolated rat liver mitchondria.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32365/1/0000440.pd

Multi-system neurological disease is common in patients with OPA1 mutations

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

Characterizing a neurodegenerative syndrome: primary progressive apraxia of speech

Apraxia of speech is a disorder of speech motor planning and/or programming that is distinguishable from aphasia and dysarthria. It most commonly results from vascular insults but can occur in degenerative diseases where it has typically been subsumed under aphasia, or it occurs in the context of more widespread neurodegeneration. The aim of this study was to determine whether apraxia of speech can present as an isolated sign of neurodegenerative disease. Between July 2010 and July 2011, 37 subjects with a neurodegenerative speech and language disorder were prospectively recruited and underwent detailed speech and language, neurological, neuropsychological and neuroimaging testing. The neuroimaging battery included 3.0 tesla volumetric head magnetic resonance imaging, [18F]-fluorodeoxyglucose and [11C] Pittsburg compound B positron emission tomography scanning. Twelve subjects were identified as having apraxia of speech without any signs of aphasia based on a comprehensive battery of language tests; hence, none met criteria for primary progressive aphasia. These subjects with primary progressive apraxia of speech included eight females and four males, with a mean age of onset of 73 years (range: 49–82). There were no specific additional shared patterns of neurological or neuropsychological impairment in the subjects with primary progressive apraxia of speech, but there was individual variability. Some subjects, for example, had mild features of behavioural change, executive dysfunction, limb apraxia or Parkinsonism. Voxel-based morphometry of grey matter revealed focal atrophy of superior lateral premotor cortex and supplementary motor area. Voxel-based morphometry of white matter showed volume loss in these same regions but with extension of loss involving the inferior premotor cortex and body of the corpus callosum. These same areas of white matter loss were observed with diffusion tensor imaging analysis, which also demonstrated reduced fractional anisotropy and increased mean diffusivity of the superior longitudinal fasciculus, particularly the premotor components. Statistical parametric mapping of the [18F]-fluorodeoxyglucose positron emission tomography scans revealed focal hypometabolism of superior lateral premotor cortex and supplementary motor area, although there was some variability across subjects noted with CortexID analysis. [11C]-Pittsburg compound B positron emission tomography binding was increased in only one of the 12 subjects, although it was unclear whether the increase was actually related to the primary progressive apraxia of speech. A syndrome characterized by progressive pure apraxia of speech clearly exists, with a neuroanatomic correlate of superior lateral premotor and supplementary motor atrophy, making this syndrome distinct from primary progressive aphasia

The alterations of tonus and movements through the interplay between the cerebral hemispheres and the cerebellum

This paper deals with the experimental production of involuntary movenients and abnormal tonus in macaques ( Macacu mulatta ) and their alterations in these animals and in children with cerebral palsy and other cerebral lesions. The first major subdivision of the paper has three parts. The first part describes the effects of lesions in the macaque cerebral hemispheres, ranging from a small destructive lesion in area 4 to an essentially complete bicortectomy. The case histories of a few patients document some of the results. The second part reports the effects of lesions in the macaque cerebellum ranging from small vermal injuries to complete cerebellectomies. The third part is concerned with successive lesions in the cerebellum and cerebral hemispheres of macaques and with planned cerebellar lesions in a few children with grave hypertonicity and marked involuntary movements. This subdivision is illustrated with photographs of the monkeys and the children at various stages of the procedures, photographs of many monkey brains at postmortem, and some photomicrographs showing lesions. The second major subdivision has a discussion of the anatomic and the physiologic bases for the experimental results obtained and for the operations on the children. It correlates the material presented with data from the literature and is illustrated with photomicrographs of degenerated tracts and with diagrams. The paper stresses the balancing of cerebral hemisphere and cerebellar discharges in the regulation of tonus and in the stabilizing of movements. It discusses the possibility of producing more effective tonus by making carefully planned lesions in cerebellar areas of animals or of children with highly handicapping hypertonicity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49991/1/901270502_ftp.pd