Dimitri Hemelsoet

Belgian Fabry Study Prevalence of Fabry Disease in a Cohort of 1000 Young Patients With Cerebrovascular Disease

Background and Purpose— Data on the prevalence of Fabry disease in patients with central nervous system pathology are limited and controversial. In this study, we assessed the prevalence of Fabry disease in young patients presenting with cerebrovascular disease in Belgium. Methods— In this national, prospective, multicenter study, we screened for Fabry disease in 1000 patients presenting with ischemic stroke, transient ischemic attack, or intracranial hemorrhage; unexplained white matter lesions; or vertebrobasilar dolichoectasia. In male patients, we measured &agr;-galactosidase A (&agr;-GAL A) activity in dried blood spots. Female patients were screened for mutations by exonic DNA sequencing of the &agr;-GAL A gene. Results— &agr;-GAL A activity was deficient in 19 men (3.5%), although all had normal &agr;-GAL A gene sequences. Enzymatic deficiency was confirmed on repeat assessment in 2 male patients (0.4%). We identified missense mutations in 8 unrelated female patients (1.8%): Asp313Tyr (n=5), Ala143Thr (n=2), and Ser126Gly (n=1). The pathogenicity of the 2 former missense mutations is controversial. Ser126Gly is a novel mutation that can be linked to late-onset Fabry disease. Conclusion— &agr;-GAL A deficiency may play a role in up to 1% of young patients presenting with cerebrovascular disease. These findings suggest that atypical variants of Fabry disease with late-onset cerebrovascular disease exist, although the clinical relevance is unclear in all cases.

Seizures and epilepsy in patients with a spontaneous intracerebral haematoma

BACKGROUND Seizures occur more frequently in patients with an intracerebral haematoma (ICH) than in those with a cerebral infarct. However, the risk factors for seizures in association with an ICH are less well known. PURPOSE The characteristics of medically treated patients with spontaneous ICHs, who developed seizures, were retrospectively compared to those who did not. PATIENTS Fourteen patients were admitted to the Stroke Unit during 2004-2006 for seizures related to an ICH. Their characteristics were compared to those of 51 patients admitted during 2002-2004 for an ICH without subsequent seizures. RESULTS Early-onset seizures, occurring within 48 h of stroke onset, were observed in six patients with ICH related epileptic spells (42.9%). Late-onset ones occurred in eight patients, on average 8 months after the ICH. A focal onset of the seizures was documented in 75.7% of cases. Status epilepticus was observed in 21.4% of the patients. The seizures recurred in only 28.6% of the patients. Lobar haematomas were present in 78.6% of the seizure group, compared to 21.4% in the control group (P=0.008). In the former group a frontal lobe involvement was present in 57.1% compared to 9.8% in the latter group (P<0.001). On the post-ictal EEG, intermittent rhythmic delta activities were observed in 28.6% and periodic lateralized epileptic discharges in 21.4% of the seizure patients. CONCLUSIONS Seizures are more prone to occur in patients with frontal lobar haematomas. EEG can be helpful for the diagnosis of seizures in approximately 50% of the cases.

Questioning the Pathogenic Role of the GLA p.Ala143Thr “Mutation” in Fabry Disease: Implications for Screening Studies and ERT

Fabry disease is an X-linked inborn error of glycosphingolipid metabolism caused by quantitative or qualitative defects in the lysosomal enzyme alfa-Galactosidase A (aGAL A), ultimately resulting in vital organ dysfunction. Mainly the kidneys, the heart, and the central nervous system are involved. While the classical phenotype of Fabry disease is readily recognizable, screening studies have identified clinical variants. Here, we report the phenotype associated with the GLA p.Ala143Thr (c.427G>A) mutation in 12 patients aged 42-83 years. None of the patients had classical Fabry signs or symptoms as angiokeratoma, hypohidrosis, acroparesthesia, or cornea verticillata. Possible Fabry manifestations were renal failure (5/12), stroke (7/12), and left ventricular hypertrophy (5/12), but these were not necessarily attributable to the p.Ala143Thr mutation, as a cardiac biopsy in one female and left ventricular hypertrophy and kidney biopsies in two males with renal failure and microalbuminuria lacked Gb-3 deposits. The literature data on this mutation as well as data collected in the Fabry Outcome Survey (FOS) database confirm these findings. The association of renal failure, stroke, and left ventricular hypertrophy with this mutation could be the result of selection bias, as most patients were detected in screening studies.We conclude that care should be taken with attribution of vital organ dysfunction to GLA sequence alterations. In case of the p.Ala143Thr mutation, and possibly also other mutations associated with an attenuated phenotype, diagnostic tools such as biopsy and imaging should critically evaluate the relation of end-organ failure with Fabry disease, as this has important consequences for enzyme replacement therapy.

Cognate Effects and Executive Control in a Patient with Differential Bilingual Aphasia

We describe a case study of a French–Dutch bilingual patient with differential aphasia, showing clearly larger impairments in Dutch than in French. We investigated whether this differential impairment in both languages was due to selective damage to language-specific brain areas resulting in the “loss” of the language representation itself, or rather if it reflects an executive control deficit. We assessed cross-linguistic interactions (involving lexical activation in the most affected language) with cognates in a lexical decision (LD) task, and executive control using a flanker task. We used a generalized LD task (any word requires a “yes” response) and a selective LD task in the patients two languages (only words in a given target language require a “yes” response). The cognate data unveil a differential pattern in the three tasks, with a clear cognate facilitation effect in the generalized LD tasks and almost no cognate effect in the selective LD tasks. This implies that a more impaired language can still affect the processing of words in the best-preserved language, but only with low cross-language competition demands (generalized LD). Additionally, the flanker task showed a larger congruency effect for the patient compared with controls, indicating cognitive control difficulties. Together, these results support accounts of differential bilingual aphasia in terms of language-control difficulties.

Prevalence of Fabry disease in a predominantly hypertensive population with left ventricular hypertrophy

BACKGROUND Patients with Fabry disease (FD) develop progressive left ventricular hypertrophy (LVH). In screening studies in patients with LVH, the prevalence of FD ranges from 0 to 12%. This variability is attributable to different factors like diverging inclusion and exclusion criteria, the evaluation of selected populations and suboptimal screening methods. In this study, we aimed to determine the prevalence of FD in an unselected population of everyday clinical practice presenting LVH, defined as a maximal end-diastolic septal or posterior wall thickness ≥ 13 mm, without exclusion of patients with arterial hypertension or valvular pathology, and using optimal screening methods. METHODS In adult males, a two-tier approach was used; α-Galactosidase A (aGAL A) activity was measured using a dried bloodspot test (DBS) and diagnosis was confirmed by mutation analysis of the GLA gene. In females, mutation analysis was the primary screening tool. RESULTS 362 men and 178 women were screened. Six patients were diagnosed with a genetic sequence alteration of the GLA gene. One man had a novel mutation, GLA p.Ala5Glu (c.44C>A), presenting as classical FD. Another man and three women had the previously described GLA p.Ala143Thr (c.427G>A) mutation, which generally presents as an attenuated phenotype. One woman had a novel sequence alteration c.639+6A>C, which appeared to be a polymorphism. All true Fabry patients had arterial hypertension (AHT), and one had hypertrophic obstructive cardiomyopathy (HOCM). CONCLUSIONS In a group of unselected patients with LVH, we found a prevalence of Fabry disease of 0.9%. AHT or type of hypertrophy should not be an exclusion criterion for screening for FD.

Transcript profiles of dendritic cells of PLOSL patients link demyelinating CNS disorders with abnormalities in pathways of actin bundling and immune response

Rare monogenic dementias have repeatedly exposed novel pathways guiding to details of the molecular pathogenesis behind this complex clinical phenotype. In this paper, we have studied polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), an early onset dementia with bone fractures caused by mutations in TYROBP (DAP12) and TREM2 genes, which encode important signaling molecules in human dendritic cells (DCs). To identify the pathways and biological processes associated with DAP12/TREM2-mediated signaling, we performed genome wide transcript analysis of in vitro differentiated DCs of PLOSL patients representing functional knockouts of either DAP12 or TREM2. Both DAP12- and TREM2-deficient cells differentiated into DCs and responded to pathogenic stimuli. However, the DCs showed morphological differences compared to control cells due to defects in the actin filaments. Not unexpectedly, transcript profiles of the patient DCs showed differential expression of genes involved in immune response. Importantly, significantly diverging transcript levels were also evident for genes earlier associated with other disorders of the central nervous system (CNS) and genes involved in the remodeling of bone, linking these two immunological genes with critical tissue phenotypes of patients. The data underline the functional diversity of the molecules of the innate immune system and implies their significant contribution also in demyelinating CNS disorders, including those resulting in dementia.

Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young

OBJECTIVE In the Belgian Fabry Study (BeFaS), the prevalence of Fabry disease was assessed in 1000 young patients presenting with stroke, unexplained white matter lesions or vertebrobasilar dolichoectasia. The results of the BeFaS suggested that Fabry disease may play a role in up to 1% of young patients presenting with cerebrovascular disease. However, the clinical relevance was unclear in all cases. We report on detailed phenotyping in subjects identified with α-galactosidase A (α-Gal A) enzyme deficiency or GLA mutations identified in the BeFaS (n=10), and on the results of family screening in this population. METHODS Family screening was performed to identify additional mutation carriers. Biochemical and/or clinical evaluation of all subjects (BeFaS index patients and relatives carrying a GLA mutation) was performed. RESULTS Genetic family screening revealed 18 additional GLA mutation carriers. Bloodspot α-Gal A enzyme activity was normal in all GLA mutation carriers, even in 2 males with the p.A143T mutation. Plasma Gb3 and lyso-Gb3 levels were normal in all subjects. Elevated Gb3 in urine was detected in 2 subjects. Some classic clinical signs of Fabry disease, like angiokeratoma or cornea verticillata, could not be detected in our population. Cardiac symptoms of Fabry disease were found in 6 out of 10 p.A143T carriers. No signs of cerebrovascular disease were found in the relatives with a GLA mutation. CONCLUSIONS We could not identify mutations causing the classical clinical phenotype of Fabry disease in our cerebrovascular disease population. Enzyme activity analysis in bloodspots and plasma may fail to identify late-onset variants of Fabry disease. We recommend genetic testing when an atypical, late-onset variant of Fabry disease is suspected in a male cerebrovascular disease patient. However, this may lead to the identification of non-disease causing or controversial genetic variants.

Hereditary Connective Tissue Diseases in Young Adult Stroke: A Comprehensive Synthesis

Though the genetic background of ischaemic and haemorrhagic stroke is often polygenetic or multifactorial, it can in some cases result from a monogenic disease, particularly in young adults. Besides arteriopathies and metabolic disorders, several connective tissue diseases can present with stroke. While some of these diseases have been recognized for decades as causes of stroke, such as the vascular Ehlers-Danlos syndrome, others only recently came to attention as being involved in stroke pathogenesis, such as those related to Type IV collagen. This paper discusses each of these connective tissue disorders and their relation with stroke briefly, emphasizing the main clinical features which can lead to their diagnosis.

Repeated assessment of larynx compound muscle action potentials using a self-sizing cuff electrode around the vagus nerve in experimental rats.

RATIONALE Vagus nerve stimulation (VNS) is an adjunctive treatment for patients with refractory epilepsy. In more than 30% of the patients VNS has no therapeutic effect. The goal of this study was to find an objective parameter that can be used as an indicator of effective stimulation of the vagus nerve. METHODS The electrophysiological response to VNS was recorded from the vagus nerve, recurrent laryngeal nerve and larynx muscles. Nerve lesions and muscle relaxing agent were used to find the source of the electrophysiological response. A cuff-electrode for chronic stimulation and recording was implanted for chronic recording of the VNS-induced electrophysiological response after implantation. Dose-response curves were determined daily during a follow-up period of 2 months. RESULTS VNS induced an electrophysiological response around 3 ms after start of the stimulation. This response was identified as a larynx compound action potential (LCMAP) LCMAP could be recorded immediately after surgery in 11/21 rats, while in the other 10/21 rats, a recovery period with an average of 25 days was required. Once the LCAMP could be recorded, the latency and overall characteristics of the doses response curves of the LCMAP remained stable during the entire follow-up period. CONCLUSIONS In this study, we provide an objective electrophysiological parameter for vagus nerve activation. LCAMP may indicate recovery of the vagus nerve after implantation, which may help to determine when uptitration of VNS therapy can be initiated. LCAMP could be of value in future experiments for objectification of VNS in animal models for epilepsy.

Transcervical carotid stenting with dynamic flow reversal demonstrates embolization rates comparable to carotid endarterectomy

Purpose: To evaluate a series of patients treated electively with carotid endarterectomy (CEA), transfemoral carotid artery stenting with distal filter protection (CASdp), and transcervical carotid stenting with dynamic flow reversal (CASfr) monitored continuously with transcranial Doppler (TCD) during the procedure to detect intraoperative embolization rates. Methods: Thirty-four patients (mean age 67.6 years; 24 men) with significant carotid stenosis underwent successful TCD monitoring during the revascularization procedure (10 CEA, 8 CASdp, and 16 CASfr). Ipsilateral microembolic signals were segregated into 3 phases: preprotection (until internal carotid artery cross-shunted or clamped if no shunt was used, filter deployed, or flow reversal established), protection (until clamp/shunt was removed, filter retrieved, or antegrade flow reestablished), and postprotection (after clamp/shunt or filter removal or restoration of normal flow). Results: CASdp showed higher embolization rates than CEA or CASfr in the preprotection phase (p<0.001). In the protection phase, CASdp was again associated with more embolization compared with CEA and CASfr (p<0.001). In the postprotection phase, no differences between the revascularization therapies were observed. CASfr and CEA did not show significant differences in intraoperative embolization during any of the phases. Conclusion: TCD recordings demonstrated a significant reduction in embolization to the brain during transcervical carotid artery stent placement with the use of dynamic flow reversal compared to transfemoral CAS using distal filters. No significant differences in microembolization could be detected between CEA and CASfr. The observed lower embolization rates and lack of adverse events suggest that transcervical CAS with dynamic flow reversal is a promising technique and may be the preferred method when performing CAS.