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Clinical and Radiographic Findings in Patients with the C9orf72 Repeat Expansion and ALS

4/5/2017
 
Two studies in JAMA Neurology and Journal of Neurology, Neurosurgery, and Psychiatry not only describe a new phenotypic model for ALS, but they also provide new imaging modalities for ALS subtyping, linking brain MRI findings with genetic or clinical manifestations.

Van Mossevelde S, van der Zee J, Gijselinck I, Sleegers K, De Bleecker J, Sieben A et al for the Belgian Neurology (BELNEU) Consortium. Clinical Evidence of Disease Anticipation in Families Segregating a C9orf72 Repeat Expansion JAMA Neurology, February 13, 2017

Westeneng HJ, Walhout R, Straathof M, Schmidt R, Hendrikse J, Veldink JH, et al. Widespread Structural Brain Involvement in ALS is Not Limited to the C9orf72 Repeat Expansion. Journal of Neurology, Neurosurgery, and Psychiatry. 2016;87(12):1354-60.

Submitted by Rocio (Carolina) Garcia Santibanez, MD, and Francisco Gomez, MD, News Science Editorial Board

Recent studies have explored the relationship between the C9orf72 repeat expansion and ALS.  The following two studies portray new information regarding clinical and radiographic findings in patients with the C9orf72 expansion.
 
In the first study the researchers sought to determine if in families that carried a C9orf72 repeat expansion there was any evidence of disease anticipation as well as differences in disease duration and age at death. From 2000 to 2016 they identified 36 families with a total of 126 patients. The patients were subdivided on their disease phenotype: pure dementia, ALS and FTD-ALS. They found that age at onset was reduced in successive generations. Generation 4 had an onset at 62.5 years, generation 3 onset at 57.1, generation 2 onset at 54.6 and generation 1 onset at 49.3. Men had an earlier onset and there was no difference in the age onset depending to the sex of the affected parent. There was no difference in disease duration or age at death between generations. Patients with pure dementia had longer disease duration and ALS patients had earlier age at death.

In the second study the authors explore the value of neuroimaging as a diagnostic tool in the setting of ALS. In this original research paper, the investigators describe a new MRI brain phenotype, with correlates to a specific mutation, C9orf72 (c9+) repeat expansion. They recruited 14 C9+ patients and 156 C9- patients. They then proceeded to describe the MRI pattern of brain involvement in C9+ ALS, analyzing 92 brain structures and defining involvement of 11 regions in particular. They tested for cortical thickness, subcortical and ventricular volumes and white matter integrity. The C9+ patients presented with widespread cortical thinning and diminished volume in several regions.
 
In their testing, said variables permitted accurate classification of a sample into the C9+ or C9- categories 40/42(95.2%) of times. The developed model was later applied to a larger C9- cohort of 128 patients, identifying 27 C9- patients with C9+ imaging phenotype. In addition to imaging, cognitive assessments were performed via Verbal Fluency Index and Frontal Assessment Battery, in which patients with C9+ or C9- patients with C9+ MRI phenotype scored worse than those with C9- ALS, correlating with higher incidence of behavioral impairment.
 
Comment: These two studies not only describe a new phenotypic model for ALS, but they also provide new imaging modalities for ALS subtyping, linking brain MRI findings with genetic or clinical manifestations. This information could be useful to further characterize the phenotype of ALS disease and to provide genetic counseling to patients and pre-symptomatic individuals.
 
About the AANEM News Science Editorial Board
The board helps to highlight significant, timely science news items for AANEM members. It reviews articles in journals and websites, identifies newsworthy items in the field, and writes article summaries.


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