Episodic ataxia type 6 (EA6) is caused by mutations in SLC1A3 that encodes excitatory amino acid transporter 1 (EAAT1), a glial glutamate transporter. EAAT1 regulates the extent and durations of ...glutamate-mediated signal by the clearance of glutamate after synaptic release. In addition, EAAT1 also has an anion channel activity that prevents additional glutamate release. We identified a missense mutation in SLC1A3 in a family with EA. The proband exhibited typical EA2-like symptoms such as recurrent ataxia, slurred speech with a duration of several hours, interictal nystagmus and response to acetazolamide, but had late-onset age of sixth decade. Whole-exome sequencing detected a heterozygous c.1177G>A mutation in SLC1A3. This mutation predicted a substitution of isoleucine for a highly conserved valine residue in the seventh transmembrane domain of EAAT1. The mutation was not present in 100 controls, a large panel of in-house genome data and various mutation databases. Most functional prediction scores revealed to be deleterious. Same heterozygous mutation was identified in one clinically affected family member and two asymptomatic members. Our data expand the mutation spectrum of SLC1A3 and the clinical phenotype of EA6.
Background
Mutations in the three‐prime repair exonuclease 1 (TREX1) gene have been associated with neurological diseases, including Retinal Vasculopathy with Cerebral Leukoencephalopathy (RVCL). ...However, the endogenous expression of TREX1 in human brain has not been studied.
Methods
We produced a rabbit polyclonal antibody (pAb) to TREX1 to characterize TREX1 by Western blotting (WB) of cell lysates from normal controls and subjects carrying an RVCL frame‐shift mutation. Dual staining was performed to determine cell types expressing TREX1 in human brain tissue. TREX1 distribution in human brain was further evaluated by immunohistochemical analyses of formalin‐fixed, paraffin‐embedded samples from normal controls and patients with RVCL and ischemic stroke.
Results
After validating the specificity of our anti‐TREX1 rabbit pAb, WB analysis was utilized to detect the endogenous wild‐type and frame‐shift mutant of TREX1 in cell lysates. Dual staining in human brain tissues from patients with RVCL and normal controls localized TREX1 to a subset of microglia and macrophages. Quantification of immunohistochemical staining of the cerebral cortex revealed that TREX1+ microglia were primarily in the gray matter of normal controls (22.7 ± 5.1% and 5.5 ± 1.9% of Iba1+ microglia in gray and white matter, respectively) and commonly in association with the microvasculature. In contrast, in subjects with RVCL, the TREX1+ microglia were predominantly located in the white matter of normal appearing cerebral cortex (11.8 ± 3.1% and 38.9 ± 5.8% of Iba1+ microglia in gray and white matter, respectively). The number of TREX1+ microglia was increased in ischemic brain lesions in central nervous system of RVCL and stroke patients.
Conclusions
TREX1 is expressed by a subset of microglia in normal human brain, often in close proximity to the microvasculature, and increases in the setting of ischemic lesions. These findings suggest a role for TREX1+ microglia in vessel homeostasis and response to ischemic injury.
Pontocerebellar hypoplasia with spinal muscular atrophy, also known as PCH1, is a group of autosomal recessive disorders characterized by generalized muscle weakness and global developmental delay ...commonly resulting in early death. Gene defects had been discovered only in single patients until the recent identification of EXOSC3 mutations in several families with relatively mild course of PCH1. We aim to genetically stratify subjects in a large and well-defined cohort to define the clinical spectrum and genotype-phenotype correlation.
We documented clinical, neuroimaging, and morphologic data of 37 subjects from 27 families with PCH1. EXOSC3 gene sequencing was performed in 27 unrelated index patients of mixed ethnicity.
Biallelic mutations in EXOSC3 were detected in 10 of 27 families (37%). The most common mutation among all ethnic groups was c.395A>C, p.D132A, responsible for 11 (55%) of the 20 mutated alleles and ancestral in origin. The mutation-positive subjects typically presented with normal pregnancy, normal birth measurements, and relative preservation of brainstem and cortical structures. Psychomotor retardation was profound in all patients but lifespan was variable, with 3 subjects surviving beyond the late teens. Abnormal oculomotor function was commonly observed in patients surviving beyond the first year. Major clinical features previously reported in PCH1, including intrauterine abnormalities, postnatal hypoventilation and feeding difficulties, joint contractures, and neonatal death, were rarely observed in mutation-positive infants but were typical among the mutation-negative subjects.
EXOSC3 mutations account for 30%-40% of patients with PCH1 with variability in survival and clinical severity that is correlated with the genotype.
Bilateral vestibulopathy is a rare, but important cause of imbalance that is underrecognized and not well understood. Clinically heterogeneous, it is variably associated with recurrent vertigo, ...hearing loss, migraine, peripheral neuropathy, or cerebellar degeneration. In about half of all patients with bilateral vestibulopathy, no cause can be identified. There have been several reports of familial bilateral vestibulopathy, suggesting genetic predisposition. The identification of genetic defects underlying hereditary deafness syndromes has greatly advanced the understanding of the functional components and the development of cochlea. In contrast, the progress in bilateral vestibulopathy has been slow, likely hampered by the difficulty in diagnosis outside of academic centers and a lack of animal models that recapitulate the progressive clinical features that are not apparent from birth. It is reasonable to anticipate that there will be an equally large number of genetic disorders underlying bilateral vestibulopathy as in deafness. Understanding the pathophysiology of bilateral vestibulopathy may suggest possible causes for the gradual decline in vestibular function that occurs with normal aging. Furthermore, the study of bilateral vestibulopathy may shed light on the pathophysiology of more common vestibular syndromes such as benign recurrent vertigo and vestibular migraine.
Cerebroretinal vasculopathy (CRV) and the related diseases hereditary endotheliopathy with retinopathy, neuropathy, and stroke (HERNS), hereditary vascular retinopathy (HVR) and hereditary systemic ...angiopathy (HSA) subsequently combined as retinovasculopathy and cerebral leukodystrophy (RVCL) are devastating autosomal‐dominant disorders of early to middle‐age onset presenting with a core constellation of neurologic and ophthalmologic findings. This family of diseases is linked by specific mutations targeting a core region of a gene. Frameshift mutations in the carboxyl‐terminus of three prime exonuclease‐1 (TREX1), the major mammalian 3′ to 5′ DNA exonuclease on chromosome 3p21.1‐p21.3, result in a systemic vasculopathy that follows an approximately 5‐year course leading to death secondary to progressive neurologic decline, with sometimes a more protracted course in HERNS. Neuropathological features include a fibrinoid vascular necrosis or thickened hyalinized vessels associated with white matter ischemia, necrosis and often striking dystrophic calcifications. Ultrastructural studies of the vessel walls often demonstrate unusual multilaminated basement membranes.
Each of the thousands of rare neurological diseases requires a widely distributed network of centres, investigators and patients, so as to foster multidisciplinary investigations and involve ...sufficient numbers of patients in the discovery of disease pathogenesis and novel treatment. In this Review, we highlight the value of this collaborative approach in patient-oriented research into rare neurological channelopathies. Two networks, the Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) and the Clinical Research Consortium for Studies of Cerebellar Ataxias (CRC-SCA), provide a link between patients with rare channelopathies and investigators who are studying disease pathogenesis and developing novel treatments. Interactions between patients, researchers and advocacy groups promote shared agendas that benefit patient education and recruitment, research collaboration and funding, and training and mentoring of junior investigators who are attracted to the study of the diseases that provide the focus for the two networks. Here, we discuss how linkage of national and international centres has enabled recruitment of study participants, provided opportunities for novel studies of pathogenesis, and facilitated successful clinical trials.
Outbreaks of respiratory virus infection at mass gatherings pose significant health risks to attendees, host communities, and ultimately the global population if they help facilitate viral emergence. ...However, little is known about the genetic diversity, evolution, and patterns of viral transmission during mass gatherings, particularly how much diversity is generated by
transmission compared to that imported from other locations. Here, we describe the genome-scale evolution of influenza A viruses sampled from the Hajj pilgrimages at Makkah during 2013 to 2015. Phylogenetic analysis revealed that the diversity of influenza viruses at the Hajj pilgrimages was shaped by multiple introduction events, comprising multiple cocirculating lineages in each year, including those that have circulated in the Middle East and those whose origins likely lie on different continents. At the scale of individual hosts, the majority of minor variants resulted from
mutation, with only limited evidence of minor variant transmission or minor variants circulating at subconsensus level despite the likely identification of multiple transmission clusters. Together, these data highlight the complexity of influenza virus infection at the Hajj pilgrimages, reflecting a mix of global genetic diversity drawn from multiple sources combined with local transmission, and reemphasize the need for vigilant surveillance at mass gatherings.
Large population sizes and densities at mass gatherings such as the Hajj (Makkah, Saudi Arabia) can contribute to outbreaks of respiratory virus infection by providing local hot spots for transmission followed by spread to other localities. Using a genome-scale analysis, we show that the genetic diversity of influenza A viruses at the Hajj gatherings during 2013 to 2015 was largely shaped by the introduction of multiple viruses from diverse geographic regions, including the Middle East, with only little evidence of interhost virus transmission at the Hajj and seemingly limited spread of subconsensus mutational variants. The diversity of viruses at the Hajj pilgrimages highlights the potential for lineage cocirculation during mass gatherings, in turn fuelling segment reassortment and the emergence of novel variants, such that the continued surveillance of respiratory pathogens at mass gatherings should be a public health priority.
Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift ...mutations in TREX1, which encodes a 3′-5′ exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias.
Abstract Background Opsoclonus is felt to be a saccadic oscillation disorder but the neuroanatomical substrate for generating the abnormal eye movements is poorly understood. Methods We recorded eye ...movements and studied serum samples from 7 patients who presented with opsoclonus and with either myoclonus or generalized tremor. Anti neuronal antibodies were detected by immunohistochemestry using rat and human cerebellar sections. Results In all patients but one the opsoclonus resolved within 2 weeks (after immunosuppression in 4, resection of the underlying neoplasm in 1 and spontaneously in 1). Opsoclonus was arrhythmic and multidirectional with a wide frequency range (4–10 Hz). No known paraneoplastic antibodies were found in the initial commercial screen. Three patients had antiPurkinje cell antibodies with a characteristic punctate staining in the molecular layer. Conclusions The clinical and immunological findings are consistent with the hypothesis, that in some patients, opsoclonus results from antibodies directed at the parallel fiber-Purkinje cell synapse. The antibodies block parallel fiber input to Purkinje cells allowing spontaneous oscillating activity generated in the inferior olives to be passed on to the oculomotor nuclei via the flocculus.
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