Characterization of novel CACNA1A splice variants by RNA-sequencing in patients with episodic or congenital ataxia.

Loss of function variants in CACNA1A cause a broad spectrum of neurological disorders, including episodic ataxia, congenital or progressive ataxias, epileptic manifestations or developmental delay. Variants located on the AG/GT consensus splice sites are usually considered as responsible of splicing defects, but exonic or intronic variants located outside of the consensus splice site can also lead to abnormal splicing. We investigated the putative consequences on splicing of 11 CACNA1A variants of unknown significance (VUS) identified in patients with episodic ataxia or congenital ataxia. In silico splice predictions were performed and RNA obtained from fibroblasts was analyzed by Sanger sequencing. The presence of abnormal transcripts was confirmed in 10/11 patients, nine of them were considered as deleterious and one remained of unknown significance. Targeted next-generation RNA sequencing was done in a second step to compare the two methods. This method was successful to obtain the full cDNA sequence of CACNA1A. Despite the presence of several isoforms in the fibroblastic cells, it detected most of the abnormally spliced transcripts. In conclusion, RNA sequencing was efficient to confirm the pathogenicity of nine novel CACNA1A variants. Sanger or Next generation methods can be used depending on the facilities and organization of the laboratories.

Predictors of clinical or cerebral lesion progression in adult moyamoya angiopathy.

OBJECTIVE: To identify independent predictors of clinical or cerebral lesion progression in a large sample of adult patients with moyamoya angiopathy (MMA) prior to decisions regarding revascularization surgery. METHODS: Ninety participants (median age, 37.5 years) were assessed at baseline and followed for a median time of 42.8 months. Incident ischemic and hemorrhagic strokes, death, as well as any incident ischemic and hemorrhagic lesions on MRI were recorded. Multiple demographic, clinical, and cerebral imaging measures at baseline were considered as potential predictors of clinical or cerebral tissue change at follow-up. Data were analyzed based on the Andersen-Gill counting process model, followed by internal validation of the prediction model. RESULTS: Among multiple potential predictive measures considered in the analysis, Asian origin, a history of TIAs, and a reduction in hemodynamic reserve, as detected by imaging, were found to be significantly associated with an increased risk of combined clinical and imaging events. While the model estimated the risk of clinical or cerebral lesion progression to be approximately 0.5% per year when none of these factors was present, this risk exceeded 20% per year when all factors were present. CONCLUSION: A simple combination of demographic, clinical, and cerebral perfusion imaging measures may aid in predicting the risk of incident stroke and cerebral lesion progression in adult patients with MMA. These results may help to improve therapeutic decisions and aid in the design of future trials in adults with this rare condition.

Optical Coherence Tomography Angiography of Familial Retinal Arteriolar Tortuosity.

BACKGROUND AND OBJECTIVE: To analyze the location of familial retinal arterial tortuosity (fRAT) in the three-dimensional structure of retinal capillaries. PATIENTS AND METHODS: Retrospective observational study. Twelve eyes of six patients (two of whom were brothers) were imaged by optical coherence tomography angiography (OCTA). The data from their ocular and systemic examinations were recorded. RESULTS: OCTA imaging clearly showed increased tortuosity of second- and third-order retinal arteries in all cases, visible in the superficial vascular plexus (SVP) up to the arteriole termination in the capillaries. No change was visible in the deep capillary plexus (DCP). CONCLUSIONS: OCTA shows that fRAT affects all the course of the arterioles up to the capillaries in the SVP. The DCP does not show arteriolar tortuosity because it does not contain arterioles. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:397-401.].

French women from multiplex abdominal aortic aneurysm families should be screened.

BACKGROUND: Multiplex abdominal aortic aneurysm families (MAAAFs) (> or =1 subject plus the proband) represent 1% to 34% of abdominal aortic aneurysm (AAA), but the percentage in France is unknown. METHOD: The MAAAF rate was retrospectively defined by analysis of 3 groups: 72 of 104 consecutive individuals undergoing AAA surgery during 1994, 24 of 53 women and 35 of 76 men with giant (> or =9 cm) AAA operated on during 1986 to 1994. MAAAF characteristics were determined based on 10 families issued from these 3 groups and 34 others identified nationwide. Data were obtained from a standardized questionnaire for probands and relatives, detailed pedigrees of each family, and computed tomography (CT) scans without contrast medium of the aorta and lower limb arteries for first-degree relatives > or =40-year-of age. RESULTS: The MAAAF rate was 4.2% for the consecutive-surgery patients (proband M/F ratio, 17:1; mean age at surgery, 68.5 +/- 8.5 years). CT detected no additional AAA among them (screened individuals M/F ratio, 0.63; mean age, 54.0 +/- 11.2 years). MAAAF rates were 8.3% and 14.3% for the women's and giant-AAA groups with CT screening, respectively. Characteristics were investigated in 104 affected subjects from 44 MAAAFs: female relatives were more often affected than probands (P < 0.025). Compared with men, affected female relatives were significantly older at diagnosis and surgery (P < 0.05 and P < 0.02, respectively), as were affected women (P < 0.02 and P < 0.01, respectively). CT scan screening identified significantly more AAA and abdominal aortic dilatations among the 44 MAAAFs than the consecutive-surgery group (5 and 4, respectively; P < 0.001). CONCLUSION: Although the MAAAF rate seems low in France, women from MAAAF were affected more often and later, suggesting that they should be screened.