Patterns of symptom development in patients with motor neuron disease

<p><i>Objective</i>: To investigate whether symptom development in motor neuron disease (MND) is a random or organized process. <i>Methods</i>: Six hundred patients with amyotrophic lateral sclerosis (ALS), upper motor neuron (UMN) or lower motor neuron (LMN) phenotypes were invited for a questionnaire concerning symptom development. A binomial test was used to examine distribution of symptoms from site of onset. Development of symptoms over time was evaluated by Kaplan-Meier analysis. <i>Results</i>: There were 470 respondents (ALS = 254; LMN = 100; UMN = 116). Subsequent symptoms were more often in the contralateral limb following unilateral limb onset (ALS: arms <i>p</i> = 1.05 × 10⁻⁸, legs <i>p</i> < 2.86 × 10⁻¹⁵; LMN phenotype: arms <i>p</i> = 6.74 × 10⁻⁹, legs <i>p</i> = 6.26 × 10⁻⁶; UMN phenotype: legs <i>p</i> = 4.07 × 10⁻¹⁴). In patients with limb onset, symptoms occurred significantly faster in the contralateral limb, followed by the other limbs and lastly by the bulbar region. Patterns of non-contiguous symptom development were also reported: leg symptoms followed bulbar onset in 30%, and bulbar symptoms followed leg onset in 11% of ALS patients. <i>Conclusions</i>: Preferred spread of symptoms from one limb to the contralateral limb, and to adjacent sites appears to be a characteristic of MND phenotypes, suggesting that symptom spread is organized, possibly involving axonal connectivity. Non-contiguous symptom development, however, is not uncommon, and may involve other factors.</p

“ALS reversals”: demographics, disease characteristics, treatments, and co-morbidities

<p><i>Objective</i>: To identify differences in demographics, disease characteristics, treatments, and co-morbidities between patients with “amyotrophic lateral sclerosis (ALS) reversals” and those with typically progressive ALS. <i>Methods:</i> Cases of possible ALS reversals were found in prior publications, in the Duke ALS clinic, through self-referral or referral from other Neurologists, and on the internet. Of 89 possible reversals identified, 36 cases were included because chart or literature review confirmed their diagnosis and a robust, sustained improvement in at least one objective measure. Controls were participants in the Pooled Resource Open-Access ALS Clinical Trials database and the National ALS Registry. Cases and controls were compared using descriptive statistics. <i>Results</i>: ALS reversals were more likely to be male, have limb onset disease, and initially progress faster. The prevalences of myasthenia gravis (MG) and purely lower motor neuron disease in cases were higher than estimates of these prevalences in the general population. The odds of taking curcumin, luteolin, cannabidiol, azathioprine, copper, glutathione, vitamin D, and fish oil were greater for cases than controls. <i>Conclusions:</i> When compared to patients with typically progressive ALS, patients with reversals differed in their demographics, disease characteristics, and treatments. While some of these patients may have had a rare antibody-mediated ALS mimicker, such as atypical myasthenia gravis, details of their exams, EMGs and family histories argue that this was unlikely. Instead, our data suggest that ALS reversals warrant evaluation for mechanisms of disease resistance and that treatments associated with multiple ALS reversals deserve further study.</p

Functional pathway analysis of differentially expressed genes.

<p>FDR = False Discovery Rate.</p

The FUS R521G mutant induces increased skipping of exons relative to the R522G mutant.

<p>The FUS R521G mutant induces increased skipping of exons relative to the R522G mutant.</p

The FUS R521G mutant causes increased up-regulation of genes as compared to the R522G mutant.

<p>The FUS R521G mutant causes increased up-regulation of genes as compared to the R522G mutant.</p

Venn diagram of genes displaying intron retention.

<p>A Venn diagram that compares our conditions to the vector shows that 1,099 retained intron events are shared (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060788#pone-0060788-t007" target="_blank">Table 7</a> and Table S5 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060788#pone.0060788.s001" target="_blank">File S1</a>).</p

Venn diagram of differentially expressed genes.

<p>A comparison between each condition (wild-type FUS, siRNA against <i>FUS</i> and mutants) and the vector reveals that 13 differentially expressed genes are shared amongst them (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0060788#pone-0060788-t004" target="_blank">Table 4</a>).</p

The FUS R522G mutant induces increased retention of introns relative to the R521G mutant.

<p>The FUS R522G mutant induces increased retention of introns relative to the R521G mutant.</p

Functional pathway analysis of shared genes for retained introns analysis as shown by Venn diagram.

<p>Functional pathway analysis of shared genes for retained introns analysis as shown by Venn diagram.</p

Number of differentially expressed genes by mutant FUS, <i>FUS</i> overexpression, and <i>FUS</i> knock-down.

<p>Number of differentially expressed genes by mutant FUS, <i>FUS</i> overexpression, and <i>FUS</i> knock-down.</p