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.

Background Dominantly inherited GAA repeat expansions inFGF14are a common cause of spinocerebellar ataxia (GAA-FGF14ataxia; SCA27B, late-onset). Molecular confirmation ofFGF14GAA repeat expansions has thus far mostly relied on long-read sequencing, a technology that is not yet widely available in clinical laboratories. Methods We developed and validated a strategy to detectFGF14GAA 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. Results Diagnosis was accurately confirmed for all 22 French Canadian patients using this strategy. Method comparison showed that capillary electrophoresis of long-range PCR 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]). We identified 9 French patients (9/53; 17%) and 2 of their relatives who carried anFGF14(GAA)≥250 expansion. Conclusion This novel strategy reliably detected and sizedFGF14GAA expansions. It compared favorably to long-read sequencing and can readily be implemented in clinical laboratories.

Background Epilepsy seems to be an important comorbidity in patients with Alzheimer’s disease (AD), especially in young onset AD (<65 years old). At this time epileptic seizures are still underestimated in this population. However, seizures may interact with AD evolution with possible acceleration of cognitive decline and early institutionalization. Seizures may also be a marker of a more aggressive subtype of AD. This study aims to determine the prevalence of the epileptic comorbidity in patients with early onset AD. Secondly, it will investigate the temporal relationship between AD and epilepsy and extract specific characteristics of AD patients at higher risk of epilepsy. Method All patients diagnosed as early‐onset Alzheimer disease between 2013 and 2019, with abnormal CSF biomarkers for Alzheimer disease, and followed at the University Hospital of Nancy (AD regional center) were selected. Patients with cortical focal lesion or old history of epilepsy were excluded. The usual clinical follow‐up was extended with a prolonged EEG and a specific consultation with an epilepsy expert. Based on this dedicated interrogation and EEG results, patients were then classified as epileptic or non‐epileptic. We collected demographic data and information on epilepsy and AD disorders. Result Among the 22 included patients, 10 were classified as epileptic with a prevalence of 45%. Considering seizure types, patients presented generalized seizures (n=4), typical temporal seizures (n=4), myoclonus (n=1) and extratemporal seizures (n=1). EEG recordings were not useful in our population. Epileptic patients presented a more severe cognitive decline than patients without seizures (MMSE 8.4+/‐6.9 versus MMSE non epileptic 20.9 +/‐ 5.45). 100% of patients with a MMSE <10 had epileptic comorbidity. In our population, epilepsy never occurred before AD diagnosis. Conclusion Epilepsy appears to be a frequent comorbidity in early onset AD patients, with a prevalence of 45% in our study. This comorbidity seems to be a marker for severe AD. The role of the epileptic disorder in the acceleration of cognitive decline as the positive impact of antiepileptic drugs still need to be determined.

Background: Epilepsy seems to be an important comorbidity in patients with early onset Alzheimer’s disease (EOAD). Currently, seizures are still underestimated in this population. However, seizures may interact with AD evolution with possible acceleration of cognitive decline and early institutionalization. Objective: To better define the epileptic disorders observed in patients with EOAD. Methods: All patients diagnosed as EOAD in our hospital between 2013 and 2019 and with positive CSF biomarkers for AD were selected. The usual follow-up was extended with a 3 h EEG and a consultation with an epilepsy expert. Information on epilepsy and AD were collected and analyzed. Results: Among the 25 included patients, 10 (40%) were classified as epileptic. Considering the seizure types, patients presented tonic-clonic seizures (n = 3), typical temporal seizures (n = 3), myoclonus (n = 3), focal extra-temporal seizures (n = 1), and other seizure types (n = 2). AD-E patients had a significant lower MMSE (15.3±8.4 AD-E versus 22.1±5.1 AD-NE, p = 0.036) and a lower autonomy (IADL 4.1±2.7 AD-E versus 6.4±1.9 AD-NE, p = 0.046) at AD diagnosis with comparable ages between AD-E and AD-NE. Epileptic patients seemed to present a faster cognitive decline compared to AD patients without seizures ([ΔMMSE per year 1.7±1.3 AD-E versus 0.9±1.4 AD-NE; p = 0.09). All patients with severe cognitive impairment (MMSE ≤ 10) had an epileptic comorbidity. Conclusion: Epilepsy is a frequent comorbidity in EOAD patients, with a percentage of 40% in our study. This comorbidity may be associated with a severe form of EOAD. The role of epilepsy in the acceleration of cognitive decline and the positive impact of antiepileptic drugs on cognition need further research.

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