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Background Perrault syndrome is a rare autosomal recessive disorder that is characterized by the association of sensorineural hearing impairment and ovarian dysgenesis in females, whereas males have only hearing impairment. In some cases, patients present with a diversity of neurological signs. To date, mutations in six genes are known to cause Perrault syndrome, but they do not explain all clinically-diagnosed cases. In addition, the number of reported cases and the spectra of mutations are still small to establish conclusive genotype–phenotype correlations. Methods Affected siblings from family SH19, who presented with features that were suggestive of Perrault syndrome, were subjected to audiological, neurological and gynecological examination. The genetic study included genotyping and haplotype analysis for microsatellite markers close to the genes involved in Perrault syndrome, whole-exome sequencing, and Sanger sequencing of the coding region of the TWNK gene. Results Three siblings from family SH19 shared similar clinical features: childhood-onset bilateral sensorineural hearing impairment, which progressed to profound deafness in the second decade of life; neurological signs (spinocerebellar ataxia, polyneuropathy), with onset in the fourth decade of life in the two females and at age 20 years in the male; gonadal dysfunction with early cessation of menses in the two females. The genetic study revealed two compound heterozygous pathogenic mutations in the TWNK gene in the three affected subjects: c.85C>T (p.Arg29*), previously reported in a case of hepatocerebral syndrome; and a novel missense mutation, c.1886C>T (p.Ser629Phe). Mutations segregated in the family according to an autosomal recessive inheritance pattern. Conclusions Our results further illustrate the utility of genetic testing as a tool to confirm a tentative clinical diagnosis of Perrault syndrome. Studies on genotype–phenotype correlation from the hitherto reported cases indicate that patients with Perrault syndrome caused by TWNK mutations will manifest neurological signs in adulthood. Molecular and clinical characterization of novel cases of recessive disorders caused by TWNK mutations is strongly needed to get further insight into the genotype–phenotype correlations of a phenotypic continuum encompassing Perrault syndrome, infantile-onset spinocerebellar ataxia, and hepatocerebral syndrome.

The availability of two or more connectivity providers (configuration known as multihoming) allows improvements in failure tolerance and enables traffic engineering capabilities. Current IPv4 multihoming solutions suffer from scalability limitations. In this article we present a solution that allow IPv6 networks to benefit from multihoming, taking advantage from the fact that each provider delegates its own set of addresses. The proposed solution consists in multiple mechanisms that provide different benefits to the multihomed site. More precisely, the solution includes a mechanism for the provision of ingress filtering compatibility, a mechanism for establishing new communications after an outage, a set of tools for traffic engineering and a protocol for preserving established communications through outages. In addition we propose a roadmap for the incremental deployment of the set of mechanisms included in the solution based on the trade-off between deployment effort required by each mechanism and the benefits obtained by the involved party. q

Although there are many reasons towards the adoption of a multi-path routing paradigm in the Internet, nowadays the required multi-path support is far from universal. It is mostly limited to some domains that rely on IGP features to improve load distribution in their internal infrastructure or some multi-homed parties that base their load balance on traffic engineering. This chapter explains the motivations for a multi-path routing Internet scheme, commenting the existing alternatives and detailing two new proposals. Part of this work has been done within the framework of the Trilogy 1 research and development project, whose main objectives are also commented in the chapter.

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