These definitions are proposed for clinical and research purposes. Their utility will depend on the outcomes of their application in prospective research.

In the absence of a biological marker, the distinction between ADEM and MS cannot be made with certainty at the time of first presentation, but the authors suggest that a viral prodrome, early-onset ataxia, high lesion load on MRI, involvement of the deep gray matter, and absence of oligoclonal bands are more indicative of ADEM.

Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.

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RNA exosomes are multi-subunit complexes conserved throughout evolution1 and emerging as the major cellular machinery for processing, surveillance, and turnover of a diverse spectrum of coding and non-coding RNA substrates essential for viability2. By exome sequencing, we discovered recessive mutations in exosome component 3 (EXOSC3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly, and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 [PCH1; OMIM 607596]3–6. We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment with small brain and poor motility, reminiscent of human clinical features and largely rescued by coinjected wildtype but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome gene responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.