Optimized testing strategy for the diagnosis of GAA-FGF14 ataxia/spinocerebellar ataxia 27B.

Dominantly inherited GAA repeat expansions in FGF14 are a common cause of spinocerebellar ataxia (GAA-FGF14 ataxia; spinocerebellar ataxia 27B). Molecular confirmation of FGF14 GAA repeat expansions has thus far mostly relied on long-read sequencing, a technology that is not yet widely available in clinical laboratories. We developed and validated a strategy to detect FGF14 GAA repeat expansions using long-range PCR, bidirectional repeat-primed PCRs, and Sanger sequencing. We compared this strategy to targeted nanopore sequencing in a cohort of 22 French Canadian patients and next validated it in a cohort of 53 French index patients with unsolved ataxia. Method comparison showed that capillary electrophoresis of long-range PCR amplification products significantly underestimated expansion sizes compared to nanopore sequencing (slope, 0.87 [95% CI, 0.81 to 0.93]; intercept, 14.58 [95% CI, - 2.48 to 31.12]) and gel electrophoresis (slope, 0.84 [95% CI, 0.78 to 0.97]; intercept, 21.34 [95% CI, - 27.66 to 40.22]). The latter techniques yielded similar size estimates. Following calibration with internal controls, expansion size estimates were similar between capillary electrophoresis and nanopore sequencing (slope: 0.98 [95% CI, 0.92 to 1.04]; intercept: 10.62 [95% CI, - 7.49 to 27.71]), and gel electrophoresis (slope: 0.94 [95% CI, 0.88 to 1.09]; intercept: 18.81 [95% CI, - 41.93 to 39.15]). Diagnosis was accurately confirmed for all 22 French Canadian patients using this strategy. We also identified 9 French patients (9/53; 17%) and 2 of their relatives who carried an FGF14 (GAA)≥250 expansion. This novel strategy reliably detected and sized FGF14 GAA expansions, and compared favorably to long-read sequencing.

Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.

BACKGROUND: The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis. METHODS: We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines. RESULTS: In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of FGF14, which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA]≥250). There was significant association between FGF14 (GAA)≥250 expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95% confidence interval [CI], 31.09 to 334.20; P<0.001) and in the German series (odds ratio, 8.76; 95% CI, 3.45 to 20.84; P<0.001). The repeat expansion was present in 61%, 18%, 15%, and 10% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an FGF14 (GAA)≥250 expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein. CONCLUSIONS: A dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.).

Appropriateness of MRI Requests for Low Back Pain and Neck Pain.

BACKGROUND: There is a high prevalence of low back pain and neck pain in Canada, and a large proportion can be treated without spine magnetic resonance imaging (MRI). We hypothesized that there is overuse of lumbar and cervical spine MRI. The primary objective was to describe the proportion of appropriate, possibly appropriate, and inappropriate MRI requests for low back pain and neck pain. METHODS: We conducted a retrospective observational study in the electromyography (EMG) clinic in Centre Hospitalier Universitaire de Sherbrooke. All ambulatory cases of low back pain or neck pain who had an EMG evaluation and a request of lumbar and/or cervical spine MRI between March 1, 2018, and May 31, 2018, were analyzed. One hundred and twenty MRI orders were classified as appropriate, possibly appropriate, and inappropriate according to the interactive decision support guide of Institut National d'Excellence en Santé et Services Sociaux for optimal use of MRI. RESULTS: Sixty-three requests (53%) were classified as inappropriate, with a higher proportion in the cervical group (34 (64%)) than the lumbar group (28 (43%)). Appropriate and possibly appropriate requests were 19 (16%) and 38 (31%), respectively. The subgroup with an MRI ordered within 90 days of symptom onset had a similar proportion of inappropriate use. INTERPRETATION: Our study demonstrates that despite recommendations against ordering spine MRI in low back pain or neck pain without red flags, there is an overuse of this imaging modality in our region, contributing to the delay in MRI access for appropriate indications.

Use of brain imaging (computed tomography and magnetic resonance imaging) in first-episode psychosis: review and retrospective study.

OBJECTIVE: To identify and review available evidence on the diagnostic yield of brain computed tomographies (CTs) and magnetic resonance images (MRIs) in first-episode psychosis, and examine yield in our own institution (Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec). METHOD: Using MEDLINE (1966 to October 2007) and EMBASE (1980 to October 2007), we identified and analyzed studies that examined imaging yields in first-episode psychosis; yield being defined as the percentage of scans showing abnormalities that may result in psychosis. We also retrospectively analyzed diagnostic yields in 46 patients hospitalized in our institution between 2001 and 2006 for first-episode psychosis. RESULTS: Five studies were deemed relevant. Including our own series, the sample comprised 384 CT and 184 MRI scans. Point estimate for diagnostic yield was 1.3% for CT and 1.1% for MRI scans. These yields likely overestimate clinical usefulness of findings. MRI scans also resulted in a sizeable number of fortuitous, clinically irrelevant findings. CONCLUSIONS: In first-episode psychosis, routine CT or MRI scans are of little benefit and should be reserved for situations where history or examination suggests neurological causation, or possibly for people aged 50 years and older.

Susac syndrome: report of four cases and review of the literature.

Susac syndrome is a rare disease of unknown pathogenesis. It is caused by a microangiopathy affecting the arterioles of the brain, retina, and cochlea, giving the classic clinical triad of subacute encephalopathy, visual loss secondary to retinal branch occlusions, and sensorineural hearing loss. The features of four cases of this syndrome are presented. MR imaging, retinal fluorescein angiography, and audiography findings enable diagnosis. Early therapy may reduce sequelae and improve recovery.