Xavier Ayrignac

Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification

Objectives: To identify a new idiopathic basal ganglia calcification (IBGC)-causing gene. Methods: In a 3-generation family with no SLC20A2 mutation, we performed whole exome sequencing in 2 affected first cousins, once removed. Nonsynonymous coding variants, splice acceptor and donor site variants, and frameshift coding indels (NS/SS/I) were filtered against dbSNP131, the HapMap Project, 1000 Genomes Project, and our in-house database including 72 exomes. Results: Seventeen genes were affected by identical unknown NS/SS/I variations in the 2 patients. After screening the relatives, the p.Leu658Pro substitution within the PDGFRB gene remained the sole unknown mutation segregating with the disease in the family. This variation, which is predicted to be highly damaging, was present in 13 of 13 affected subjects and absent in 8 relatives without calcifications. Sequencing PDGFRB of 19 other unrelated IBGC cases allowed us to detect another potentially pathogenic substitution within PDGFRB, p.Arg987Trp, also predicted to be highly damaging. PDGFRB encodes a protein involved in angiogenesis and in the regulation of inorganic phosphate (Pi) transport in vascular smooth muscle cells via Pit-1, a Pi transporter encoded by SLC20A1. Conclusion: Mutations of PDGFRB further support the involvement of this biological pathway in IBGC pathophysiology.

Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases

Mutations in one of the five eukaryotic initiation factor 2B genes (EIF2B1-5) were first described in childhood ataxia with cerebral hypomyelination--vanishing white matter syndrome. The syndrome is characterized by (i) cerebellar and pyramidal signs in children aged 2-5 years; (ii) extensive cavitating leucoencephalopathy; and (iii) episodes of rapid deterioration following stress. Since then a broad clinical spectrum from congenital to adult-onset forms has been reported, leading to the concept of eIF2B-related disorders. Our aim was to describe clinical and brain magnetic resonance imaging characteristics, genetic findings and natural history of patients with adult-onset eIF2B-related disorders (after age 16). The inclusion criteria were based on the presence of eIF2B mutations and a disease onset after the age of 16 years. One patient with an asymptomatic diagnosis (age 16 years) was also included. Clinical and magnetic resonance findings were retrospectively recorded in all patients. All patients were examined to assess clinical evolution, using functional, pyramidal, cerebellar and cognitive scales. This multi-centric study included 16 patients from 14 families. A sex ratio imbalance was noted (male/female = 3/13). The mean age of onset was 31.1 years (range 16-62). Initial symptoms were neurologic (n = 11), psychiatric (n = 2) and ovarian failure (n = 2). Onset of the symptoms was linked to a precipitating factor in 13% of cases that included minor head trauma and delivery. During follow-up (mean: 11.2 years, range 2-22 years) 12.5% of the patients died. Of the 14 survivors, 62% showed a decline in their cognitive functions, and 79% were severely handicapped or bedridden. One case remained asymptomatic. Stress worsened clinical symptoms in 38% of the patients. Magnetic resonance imaging findings consist of constant cerebral atrophy, extensive cystic leucoencephalopathy (81%), corpus callosum (69%) and cerebellar (38%) T2-weighted hyperintensities. All families except one showed mutations in the EIF2B5 gene. The recurrent p.Arg113His-eIF2Bepsilon mutation was found in 79% of the 14 eIF2B-mutated families, mainly at a homozygous state. The family with a mutation in EIF2B2 had the relatively prevalent p.Glu213Gly mutation. eIF2B-related disorder is probably underestimated as an adult-onset inherited leucoencephalopathy. In this late-onset form, presentation ranges from neurologic symptoms to psychiatric manifestations or primary ovarian failure. Cerebral atrophy is constant, whereas the typical vanishing of the white matter can be absent. Functional and/or cognitive prognosis remains severe. Molecular diagnosis is facilitated for these forms by the screening of the two recurrent p.Arg113His-eIF2Bepsilon and p.Glu213Gly-eIF2Bbeta mutations, positive in 86% of cases.

Lack of confirmation of anti-inward rectifying potassium channel 4.1 antibodies as reliable markers of multiple sclerosis.

Background: auto-antibodies against the potassium channel inward rectifying potassium channel 4.1 (Kir4.1) have previously been identified in 46% of patients with multiple sclerosis (MS). Objectives: to confirm these findings. Methods: we evaluated the presence of anti-Kir4.1 antibodies by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence in 268 MS patients, 46 patients with other neurological diseases (OND) and 45 healthy controls. Results: anti-Kir4.1 antibodies were found in 7.5% of MS patients, 4.3% of OND patients and 4.4% of healthy controls. Immunofluorescence analysis did not identify any specific staining. Conclusions: we confirmed the presence of anti-Kir4.1 antibodies in MS patients, but at a much lower prevalence than previously reported.

Sensory chronic inflammatory demyelinating polyneuropathy: An under‐recognized entity?

Sensory chronic inflammatory demyelinating polyneuropathy (CIDP) can be difficult to diagnose.

Patient Selection for Stroke Endovascular Therapy— DWI-ASPECTS Thresholds Should Vary among Age Groups: Insights from the RECOST Study

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the benefits of endovascular intervention in large-vessel occlusion strokes, depending on age class. MATERIALS AND METHODS: A clinical management protocol including intravenous treatment and mechanical thrombectomy was instigated in our center in 2009 (Prognostic Factors Related to Clinical Outcome Following Thrombectomy in Ischemic Stroke [RECOST] study). All patients with acute ischemic stroke with an anterior circulation major-vessel occlusion who presented within 6 hours were evaluated with an initial MR imaging examination and were analyzed according to age subgroups (younger than 50 years, 50–59 years, 60–69 years, 70–79 years; 80 years or older). The mRS score at 3 months was the study end point. RESULTS: One hundred sixty-five patients were included in the analysis. The mean age was 67.4 years (range, 29–90 years). The mean baseline NIHSS score was 17.24 (range, 3–27). The mean DWI-derived ASPECTS was 6.4. Recanalization of TICI 2b/3 was achieved in 80%. At 3 months, 41.72% of patients had a good outcome, with a gradation of prognosis depending on the age subgroup and a clear cutoff at 70 years. Only 19% of patients older than 80 years had a good outcome at 3 months (mean ASPECTS = 7.4) with 28% for 70–79 years (mean ASPECTS = 6.8), but 58% for 60–69 years (mean ASPECTS = 6), 52% for 50–59 years (mean ASPECTS = 5.91), and 72% for younger than 50 years (mean ASPECTS = 6.31). In contrast, the mortality rate was 35% for 80 years and older, and 26% for 70–79 versus 5%–9% for younger than 70 years. CONCLUSIONS: The elderly may benefit from thrombectomy when their ischemic core volume is low in comparison with younger patients who still benefit from acute recanalization despite larger infarcts. Stroke volume thresholds should, therefore, be related and adjusted to the patients age group.

Endovascular Management of Tandem Occlusion Stroke Related to Internal Carotid Artery Dissection Using a Distal to Proximal Approach: Insight from the RECOST Study.

The authors analyzed all carotid artery dissection tandem occlusion strokes and isolated anterior circulation occlusions from their ongoing prospective stroke data base. For carotid artery dissection, the revascularization procedure consisted of initial distal recanalization by a stent retriever in the intracranial vessel. Following assessment of the circle of Willis, ICA stent placement was only performed in case of insufficiency. Two hundred fifty-eight patients with an anterior circulation stroke were analyzed, including 20 with carotid artery dissection–related occlusion. Only 5 carotid artery dissections (25%) necessitated cervical stent placement. No early ipsilateral stroke recurrence was recorded, despite the absence of stent placement in 15 patients (75%) with carotid artery dissection. Mechanical endovascular treatment of carotid artery dissection tandem occlusions is safe and effective compared with isolated anterior circulation occlusion stroke therapy. The authors favor a complete evaluation of the circle of Willis in these patients, which requires a contralateral femoral puncture, allowing selective contralateral common carotid and vertebrobasilar catheterizations. BACKGROUND AND PURPOSE: Internal carotid artery dissection is a common cause of stroke in young adults. It may be responsible for tandem occlusion defined by a cervical steno-occlusive carotid wall hematoma associated with an intracranial large-vessel stroke. Intravenous thrombolysis is associated with a poor clinical outcome in these cases, and endovascular treatment has not been specifically evaluated to date. Our aim was to evaluate endovascular treatment technical and clinical efficiency in this specific occlusion topography, in comparison with treatment of isolated anterior circulation stroke. MATERIALS AND METHODS: As part of our ongoing prospective stroke data base started in August 2009 (Prognostic Factors Related to Clinical Outcome Following Thrombectomy in Ischemic Stroke [RECOST] Study), we analyzed all carotid artery dissection tandem occlusion strokes and isolated anterior circulation occlusions. All patients were selected for endovascular treatment according to clinical-radiologic mismatch, NIHSS ≥ 7 and DWI-ASPECTS ≥5, within 6 hours after onset. For carotid artery dissection, the revascularization procedure consisted first of distal recanalization by a stent retriever in the intracranial vessel. Following assessment of the circle of Willis, internal carotid artery stent placement was only performed in case of insufficiency. Carotid artery dissection treatment efficacy, safety, and clinical outcome were compared with the results of the isolated anterior circulation occlusion cohort. RESULTS: Two hundred fifty-eight patients with an anterior circulation stroke were analyzed, including 57 with tandem occlusions (22%); among them, 20 were carotid artery dissection–related occlusions (7.6%). The median age of patients with tandem occlusions with internal carotid dissection was 52.45 versus 66.85 years for isolated anterior circulation occlusion (P < .05); the mean initial NIHSS score was 17.53 ± 4.11 versus 17.55 ± 4.8 (P = .983). The median DWI-ASPECTS was 6.05 versus 6.64 (P = .098), and the average time from onset to puncture was 4.38 for tandem occlusions versus 4.53 hours in isolated anterior circulation occlusion (P = .704). Complication rates and symptomatic intracranial hemorrhage were comparable in both groups (5% versus 3%, P = .49). The duration of the procedure was significantly prolonged in case of tandem occlusion (80.69 versus 65.45 minutes, P = .030). Fourteen patients with carotid artery dissection (70%) had a 3-month mRS of ≤ 2, without a significant difference from patients with an isolated anterior circulation occlusion (44%, P = .2). Only 5 carotid artery dissections (25%) necessitated cervical stent placement. No early ipsilateral stroke recurrence was recorded, despite the absence of stent placement in 15 patients (75%) with carotid artery dissection. CONCLUSIONS: Mechanical endovascular treatment of carotid artery dissection tandem occlusions is safe and effective compared with isolated anterior circulation occlusion stroke therapy. Hence, a more conservative approach with stent placement only in cases of circle of Willis insufficiency may be a reliable and safe strategy.

Adult-onset genetic leukoencephalopathies: A MRI pattern-based approach in a comprehensive study of 154 patients

Inherited white matter diseases are rare and heterogeneous disorders usually encountered in infancy. Adult-onset forms are increasingly recognized. Our objectives were to determine relative frequencies of genetic leukoencephalopathies in a cohort of adult-onset patients and to evaluate the effectiveness of a systematic diagnostic approach. Inclusion criteria of this retrospective study were: (i) symmetrical involvement of white matter on the first available brain MRI; (ii) age of onset above 16 years. Patients with acquired diseases were excluded. Magnetic resonance imaging analysis identified three groups (vascular, cavitary and non-vascular/non-cavitary) in which distinct genetic and/or biochemical testing were realized. One hundred and fifty-four patients (male/female = 60/94) with adult-onset leukoencephalopathies were identified. Mean age of onset was 38.6 years. In the vascular group, 41/55 patients (75%) finally had a diagnosis [including CADASIL (cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, n = 32) and COL4A1 mutation, n = 7]. In the cavitary group, 13/17 (76%) patients had a diagnosis of EIF2B-related disorder. In the third group (n = 82), a systematic biological screening allowed a diagnosis in 23 patients (28%) and oriented direct genetic screening identified 21 additional diseases (25.6%). Adult-onset genetic leukoencephalopathies are a rare but probably underestimated entity. Our study confirms the use of a magnetic resonance imaging-based classification with a final diagnosis rate of 64% (98/154) cases.

COL4A1 mutation revealed by an isolated brain hemorrhage.

Discussion The spectrum of COL4A1-related disorders includes perinatal cerebral hemorrhage and porencephaly [2] , cerebral small vessel disease with retinal arteriolar tortuosity and leukoencephalopathy [3] , HANAC syndrome (Hereditary Angiopathy, Nephropathy, Aneurysms, and Muscle Cramps) and other eye abnormalities, including the Axenfeld-Rieger anomaly and cataract. A frequent white matter involvement is reported [3, 4] . Interestingly, some HANAC patients may have a normal brain MRI. However, except for one patient who suffered from migraine, these patients were free from neurologic symptoms [5, 6] . Recently, Weng et al. [7] reported COL4A1 variants in 2/96 patients with sporadic ICH. Their phenotype was not described in Introduction Ten to fifteen percent of strokes are related to an intracerebral hemorrhage (ICH). Etiologies are mainly arterial hypertension, amyloid deposition, and vascular malformations. In cases of a young age without vascular risk factors and vascular malformations, a genetic cause has to be suspected, especially a mutation in the gene coding for type IV collagen alpha 1 (COL4A1) [1] . We report a COL4A1 gene mutation in a 45-year-old woman with an isolated ICH in the absence of any other MRI abnormality, which further extends the clinical spectrum of COL4A1 mutations.

Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias.

Next‐generation sequencing (NGS) has an established diagnostic value for inherited ataxia. However, the need of a rigorous process of analysis and validation remains challenging. Moreover, copy number variations (CNV) or dynamic expansions of repeated sequence are classically considered not adequately detected by exome sequencing technique. We applied a strategy of mini‐exome coupled to read‐depth based CNV analysis to a series of 33 patients with probable inherited ataxia and onset <50 years. The mini‐exome consisted of the capture of 4,813 genes having associated clinical phenotypes. Pathogenic variants were found in 42% and variants of uncertain significance in 24% of the patients. These results are comparable to those from whole exome sequencing and better than previous targeted NGS studies. CNV and dynamic expansions of repeated CAG sequence were identified in three patients. We identified both atypical presentation of known ataxia genes (ATM, NPC1) and mutations in genes very rarely associated with ataxia (ERCC4, HSD17B4). We show that mini‐exome bioinformatics data analysis allows the identification of CNV and dynamic expansions of repeated sequence. Our study confirms the diagnostic value of the proposed genetic analysis strategy. We also provide an algorithm for the multidisciplinary process of analysis, interpretation, and validation of NGS data.

High CD3+ Cells in Intracranial Thrombi Represent a Biomarker of Atherothrombotic Stroke

Background and Purpose Approximately 30% of strokes are cryptogenic despite an exhaustive in-hospital work-up. Analysis of clot composition following endovascular treatment could provide insight into stroke etiology. T-cells already have been shown to be a major component of vulnerable atherosclerotic carotid lesions. We therefore hypothesize that T-cell content in intracranial thrombi may also be a biomarker of atherothrombotic origin. Materials and Methods We histopathologically investigated 54 consecutive thrombi retrieved after mechanical thrombectomy in acute stroke patients. First, thrombi were classified as fibrin-dominant, erythrocyte-dominant or mixed pattern. We then performed quantitative analysis of CD3+ cells on immunohistochemically-stained thrombi and compared T-cell content between “atherothrombotic”, “cardioembolism” and “other causes” stroke subtypes. Results Fourteen (26%) thrombi were defined as fibrin-dominant, 15 (28%) as erythrocyte-dominant, 25 (46%) as mixed. The stroke cause was defined as “atherothrombotic” in 10 (18.5%), “cardioembolism” in 25 (46.3%), and “other causes” in 19 (35.2%). Number of T-cells was significantly higher in thrombi from the “atherothrombotic” group (53.60 ± 28.78) than in the other causes (21.77 ± 18.31; p<0.0005) or the “cardioembolism” group (20.08 ± 15.66; p<0.0003). Conclusions The CD3+ T-cell count in intracranial thrombi was significantly higher in “atherothrombotic” origin strokes compared to all other causes. Thrombi with high content of CD3+ cells are more likely to originate from an atherosclerotic plaque.