Although spontaneous remyelination does occur in multiple sclerosis lesions, its extent within the global population with this disease is presently unknown. We have systematically analysed the incidence and distribution of completely remyelinated lesions (so-called shadow plaques) or partially remyelinated lesions (shadow plaque areas) in 51 autopsies of patients with different clinical courses and disease durations. The extent of remyelination was variable between cases. In 20% of the patients, the extent of remyelination was extensive with 60-96% of the global lesion area remyelinated. Extensive remyelination was found not only in patients with relapsing multiple sclerosis, but also in a subset of patients with progressive disease. Older age at death and longer disease duration were associated with significantly more remyelinated lesions or lesion areas. No correlation was found between the extent of remyelination and either gender or age at disease onset. These results suggest that the variable and patient-dependent extent of remyelination must be considered in the design of future clinical trials aimed at promoting CNS repair.

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG) exp ] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG) 11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.

The association of bilateral vestibulopathy with cerebellar ataxia was first reported in 1991 and delineated as a distinct syndrome with a characteristic and measurable clinical sign--an absent visually enhanced vestibulo-ocular reflex--in 2004. We reviewed 27 patients with this syndrome and show that a non-length-dependent sensory deficit with absent sensory nerve action potentials is an integral component of this syndrome, which we now call "cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome" (CANVAS). All patients had brain MRI and 22/27 had evidence of cerebellar atrophy involving anterior and dorsal vermis, as well as the hemispheric crus I. Brain and temporal bone pathology in one patient showed marked loss of Purkinje cells and of vestibular, trigeminal, and facial ganglion cells, but not of spiral ganglion cells. There are two sets of sibling pairs, suggesting CANVAS is a late-onset recessive disorder. The characteristic clinical sign-the visual vestibulo-ocular reflex deficit-can be demonstrated and measured clinically using video-oculography.

We report a case of fatal neurogenic pulmonary edema in progressive multiple sclerosis (MS). The patient had one isolated relapse-like episode. Six years later progressive disease began, lasting 5 years until unexpected death during sleep. Medico-legal autopsy revealed pulmonary edema and neuropathological examination showed infiltrations with lymphocytes and microglia in the respiratory centers of the medulla. More classical demyelinated lesions were found in the white matter of spinal cord and in the gray matter of the brain along with disseminated perivascular lymphocytic infiltrates. Medullary inflammation in progressive MS may result in sudden fatal respiratory failure.

80Genomic technologies such as Next Generation Sequencing (NGS) are revolutionizing 81 molecular diagnostics and clinical medicine. However, these approaches have proven 82 inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of 83 bioinformatics tools that can be utilized to identify either known or novel expanded repeat 84 sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 85 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular 86 areflexia syndrome (CANVAS). Analysis of whole genome sequence (WGS) data with five 87 independent algorithms identified a recessively inherited intronic repeat expansion 88 [(AAGGG) exp ] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported 89 in the reference sequence, localized to an Alu element and replaced the reference (AAAAG) 11 90 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 91 CANVAS families and identified a core ancestral haplotype, estimated to have arisen in 92 Europe over twenty-five thousand years ago. WGS of the four RFC1 negative CANVAS 93 families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic 94 ataxia of the Charlevoix-Saguenay type and SCA45. This study identified the genetic basis of 95 CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic 96 utility of WGS to determine the genetic basis of a heterogeneous group of clinically 97 overlapping neurogenetic disorders. 98 99 126 specific neurophysiological protocol. 18 A characteristic radiological pattern of cerebellar 127 atrophy has also been described and verified on post-mortem pathology. 11 The characteristic 128 oculomotor abnormality seen in combined cerebellar and vestibular impairment is the 129 visually-enhanced vestibulo-ocular reflex (VVOR), and this can now be evaluated using a 130 commercially available instrumented assessment tool. 19-21 Altogether, these advances have 131 allowed the formulation of diagnostic criteria to aid identification of CANVAS, contributing 132 both research and clinical benefits including improved prognostication and targeted 133 157 A number of bioinformatics tools now exist that allow screening of short-read 158 sequencing data for expanded STRs. 25 Initially, STR detection tools, such as lobSTR and 159 hipSTR, were limited to short STRs that were encompassed by a single sequencing read. 160 However, in the last two years, multiple methods have been released that can screen WES 161 and WGS datasets for REs without being limited by read length. These include 162 ExpansionHunter (EH) 28 , exSTRa 8 , TREDPARSE 29 , STRetch 30 and GangSTR. 31 These are 163 all reference based methods -i.e. they rely on a catalogue of STR loci and motifs and are 164 therefore limited to detecting expansion of previously defined STRs, such as those catalogued 165 in the UCSC track. Moreover, the normal variability in STR length and repeat composition ...