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Episodic ataxia type 6 (EA6) is caused by mutations in SLC1A3that 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 SLC1A3in 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 SLC1A3and the clinical phenotype of EA6.

The RNA exosome is a conserved multiprotein complex that achieves a large number of processive and degradative functions in eukaryotic cells. Recently, mutations have been mapped to the gene encoding one of the subunits of the exosome, EXOSC3 (yeast Rrp40p), which results in pontocerebellar hypoplasia with motor neuron degeneration in human patients. However, the molecular impact of these mutations in the pathology of these diseases is not well understood. To investigate the molecular consequences of mutations in EXOSC3that lead to neurological diseases, we analyzed the effect of three of the mutations that affect conserved residues of EXOSC3/Rrp40p (G31A, G191C, and W238R; G8A, G148C, and W195R, respectively, in human and yeast) in S. cerevisiae. We show that the severity of the phenotypes of these mutations in yeast correlate with that of the disease in human patients, with the W195R mutant showing the strongest growth and RNA processing phenotypes. Furthermore, we show that these mutations affect more severely pre-ribosomal RNA processing functions of the exosome rather than other nuclear processing or surveillance functions. These results suggest that delayed or defective pre-rRNA processing might be the primary defect responsible for the pathologies detected in patients with mutations affecting EXOSC3 function in residues conserved throughout eukaryotes.

SCL25A46 is a mitochondrial carrier protein that localizes to the outer membrane. Mutation L341P causes rapid degradation of SLC25A46 by the ubiquitin-proteasome system, independent of activated stress pathways, including mitophagy and apoptosis. SLC25A46 regulates oligomerization of MFN1/2 and mitochondrial dynamics.

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.

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 EXOSC3mutations 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.

BACKGROUND Episodic ataxia (EA) is variably associated with additional neurologic symptoms. At least 4 genes have been implicated. Recently, a mutation in the SLC1A3 gene encoding the glutamate transporter EAAT1 was identified in a patient with severe episodic and progressive ataxia, seizures, alternating hemiplegia, and migraine headache. The mutant EAAT1 showed severely reduced uptake of glutamate. The syndrome was designated EA6 and shares overlapping clinical features with EA2, which is caused by mutations in CACNA1A. OBJECTIVE To test the role of the SLC1A3 gene in EA. DESIGN Genetic and functional studies. We analyzed the coding region of the SLC1A3 gene by direct sequencing. SETTING Academic research. PATIENTS DNA samples from 20 patients with EA (with or without interictal nystagmus) negative for CACNA1A mutations were analyzed. MAIN OUTCOME MEASURES We identified 1 novel EAAT1 mutation in a family with EA and studied the functional consequences of this mutation using glutamate uptake assay. RESULTS We identified a missense C186S mutation that segregated with EA in 3 family members. The mutant EAAT1 showed a modest but significant reduction of glutamate uptake. CONCLUSIONS We broadened the clinical spectrum associated with SLC1A3 mutations to include milder manifestations of EA without seizures or alternating hemiplegia. The severity of EA6 symptoms appears to be correlated with the extent of glutamate transporter dysfunction.Arch Neurol. 2009;66(1):97-101--

To focus on recent advances in the genetics of recurrent vertigo, with an overview on episodic ataxia, benign recurrent vertigo (mainly migraine-associated vertigo), bilateral vestibulopathy, and Ménière's disease.

BACKGROUND Multiple episodic ataxia phenotypes and genotypes have been described. OBJECTIVE To describe a new episodic ataxia syndrome. DESIGN Genomewide linkage analysis with dense single nucleotide polymorphism arrays. SETTING University clinic. PATIENTS Family with lifelong episodes of ataxia and normal interictal examination results. RESULTS Suggestive linkage (logarithm of odds score, 3.27) to a 10-centimorgan region on chromosome 19q13. CONCLUSION A new dominantly inherited episodic ataxia syndrome is linked to chromosome 19q.Arch Neurol. 2007;64:749-752 --

We discovered intronic mutations in two episodic ataxia type 2 (EA2) families: a four‐nucleotide GAGT deletion at IVS41+(3–6) and a single nucleotide insertion (insT) at IVS24+3. We expressed minigenes harboring the mutations in cell lines to demonstrate exon skipping from the deletion mutation and the activation of a cryptic splice donor site from the insertion mutation. The identification of these disease‐causing mutations expands the spectrum of EA2 mutations and emphasizes the importance of intronic sequences in regulating gene expression. Ann Neurol 2005;57:131–135

The familial episodic ataxias are prototypical inherited channelopathies that result in episodes of vertigo and ataxia triggered by stress and exercise. Episodic ataxia type 1 (EA-1) is caused by missense mutations in the potassium channel gene KCNA1, whereas episodic ataxia type 2 (EA-2) is caused by missense and nonsense mutations in the calcium channel gene CACNA1A. These ion channels are crucial for both central and peripheral neurotransmission. Within the last few years, the genetic mechanisms underlying these relatively rare familial episodic ataxia syndromes have been worked out. They provide a model for understanding the mechanisms of more common recurrent vertigo and ataxia syndromes, particularly those associated with migraine. Migraine affects as many as 15-20 of the general population, and it has been estimated that about 25 of patients with migraine experience spontaneous attacks of vertigo and ataxia. We identified 24 families with migraine and benign recurrent vertigo inherited in an autosomal dominant fashion. These families have numerous features in common with EA-1 and EA-2 (particularly EA-2), suggesting that benign recurrent vertigo may be an inherited channelopathy. An ion channel mutation shared by brain and inner ear could explain the combined central and peripheral features of the syndrome.

We describe quantitative oculomotor findings in a patient with subclinical spinocerebellar ataxia type 7 (SCA7) and a borderline mutation of 38 CAG repeats and her daughter with SCA7 and 46 repeats. Both subjects demonstrated significant slowing of voluntary and involuntary saccades, but retinal examination was normal. Smooth pursuit and fixation suppression of VOR were mildly impaired. Slow saccades may be the earliest neurologic finding even in asymptomatic SCA7 patients with normal ocular fundi. The SCA7 mutation probably has an early impact on brainstem fast eye movement centers.

Benign recurrent vertigo (BRV) has been previously linked to migraine but there have been no prior studies of families with BRV. We studied the families of 24 patients who presented to our clinic with BRV and who reported a family history of similar attacks of vertigo. All probands underwent diagnostic evaluation to exclude identifiable causes of recurrent vertigo and they completed a standardized medical questionnaire pertaining to episodic vertigo and the features of migraine. This questionnaire was also sent to all relatives of the probands who agreed to participate. Of 220 relatives who returned questionnaires, 37% reported BRV and 50% met the diagnostic criteria for migraine. By contrast, only one of 43 (2%) unrelated spouses reported BRV and 10 of 43 (23%) met the diagnostic criteria for migraine. More than two-thirds of relatives with BRV met the diagnostic criteria for migraine and the majority reported that they had a typical migraine headache with at least some of their episodes of vertigo. Both BRV and migraine showed a female preponderance (more than 2 to 1). Familial BRV seems to be a migraine syndrome, probably inherited in an autosomal dominant fashion with decreased penetrance in men. In the search for the causative gene, vertigo may be a more useful marker than migraine because recurrent vertigo is relatively rare in the general population whereas migraine is very common. © 2001 Wiley-Liss, Inc.

We searched for mutations in the voltage-gated calcium channel gene, CACNA1A, in nine propositi of families with migraine headaches and episodic vertigo inherited in an autosomal dominant pattern. All 47 exons and flanking introns in CACNA1A were subjected to single-strand conformation polymorphism analysis of polymerase chain reaction-amplified genomic DNA. Exons with aberrantly migrating fragments were sequenced using standard techniques. We also determined the CAG repeat length at the 3' end of CACNA1A. Several polymorphisms were found but no mutations identified in any of the 47 exons of the 9 patients. No index-case had a CAG repeat length greater than 13 (normal <17). Mutations in CACNA1A are not common in families with migraine headaches and episodic vertigo. Other ion channel genes expressed in the brain and inner ear remain candidate genes. Am. J. Med. Genet. 79:148–151, 1998. © 1998 Wiley-Liss, Inc.

With the recent report of mutations in the calcium channel gene CACNA1A in two families with episodic ataxia type 2, we investigated a patient with nonfamilial episodic vertigo and ataxia responsive to acetazolamide for similar mutations. Single-strand conformation polymorphism (SSCP) analysis of exon 23 identified an extra band in the patient that was not present in other relatives or in normal controls. Exon 23 of the patient showed a spontaneous C to T substitution at position 4410 resulting in an early stop codon. Patients with nonfamilial episodic ataxia may respond to acetazolamide and may have mutations in CACNA1A. Am. J. Med. Genet. 77:298–301, 1998. © 1998 Wiley-Liss, Inc.

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare fatal autosomal dominant vasculopathy associated with mutations in the TREX1gene. Only one de novo case has been reported in the literature. We report the long-term clinical, radiological, and pathological presentation of a patient with a de novoand novel mutation in this gene. Description of the clinical, genetic, imaging and pathologic characteristics is important to better characterize RVCL-S and prevent unnecessary interventions. RVCL-S should be considered in patients with tumefactive brain lesions unresponsive to immunotherapy.

A 44-year-old woman with a history of retinal vasculopathy presented with headaches and hemiparesis. MRI brain showed a right frontal peripherally enhancing mass with surrounding edema (figure 1) thought to represent a malignant glioma; however, pathology showed necrosis with reactive gliosis but no evidence of neoplasm (figure 2). Family history was significant for multiple relatives with similar lesions on head MRIs suspicious for neoplasm but excluded by biopsy. An underlying familial leukoencephalopathy was suspected, and a novel heterozygous nonsense mutation c.1359G>T; p.Glu285* was identified in TREX1, in which C-terminal frameshift mutations cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.1