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Autosomal dominantly inherited mutations of BICD2 are associated with congenital-onset spinal muscular atrophy characterised by lower limb predominance. A few cases have also showed upper motor neuron pathology, including presenting with features resembling hereditary spastic paraplegia. The age-of-onset for the published families is usually at birth but also included cases with childhood- and adult-onset disease. In this report we described two isolated probands that presented in utero with features associated with reduced fetal movements. Both cases were diagnosed at birth with arthrogryposis multiplex congenita (AMC) and hypotonia. Other variable features included congenital fractures, hip dislocation, micrognathia, respiratory insufficiency, microcephaly and bilateral perisylvian polymicrogyria. Patient 1 is 4 years of age and stable, but shows significant motor developmental delay and delayed speech. Patient 2 passed away at 7 weeks of age. Through next generation sequencing we identified the same missense substitution in BICD2 (p.Arg694Cys) in both probands. Sanger sequencing showed that in both cases the mutation arose de novo . The in utero onset in both cases suggests that the p.Arg694Cys substitution may have a more deleterious effect on BICD2 function than previously described mutations. Our results broaden the phenotypes associated with BICD2 mutations to include AMC and cortical malformations and therefore to a similar phenotypic spectrum to that associated with its binding partner DYNC1H1. [ABSTRACT FROM AUTHOR]

Acute necrotizing encephalopathy (ANE) is a rare disease presenting with rapidly progressing encephalopathy. It usually occurs in otherwise healthy children after common viral infections. The hallmarks of ANE are the neuroradiological findings of multiple symmetric lesions in the thalami, midbrain, pons and brainstem. Most cases are sporadic and non recurrent. However, recurrent or familial forms of ANE due to mutations in RANBP2 gene have been reported. It has been suggested to give these cases the term ANE1. We report the clinical course in two male infants (P1, P2) with ANE1 and a variable clinical course and outcome. One patient is heterozygous for the most common RANBP2 missense mutation p.Thr585Met. In the other patient we observed a novel de novo missense mutation p.Trp681Cys in the RANBP2 gene causing recurrent ANE. Clinical and radiological features are presented and differential diagnoses are discussed. This report adds to the current knowledge of the phenotype in ANE, caused by mutations in RANBP2 gene. [ABSTRACT FROM AUTHOR]

Primarymicrocephaly and severe developmental delay are complex but unspecific signs pointing to various genetic or acquired diseases. A concomitant finding of hematological failure may lead to the differential diagnosis of rare genetic diseases such as chromosome breakage disorders or diseases associated with telomere dysfunction. X-linked Hoyeraal-Hreidarsson syndrome (HHS) is a rare heterogenic disorder characterized by severe neurological impairment and progressive bone marrow failure. The latter represents the main cause of mortality, usually in early childhood. We report on the clinical course of an infant with HHS due to a novel mutation in the DKC1 gene and the particular finding of pontocerebellar hypoplasia. [ABSTRACT FROM AUTHOR]

The major transactivator protein IE2p86 of human cytomegalovirus (HCMV) has previously been shown to undergo posttranslational modification by the covalent attachment of SUMO proteins, termed SUMOylation, which occurs at two lysine residues located at amino acid positions 175 and 180. Mutation of the acceptor lysines resulted in the abrogation of IE2p86 SUMOylation in mammalian cells and a strong reduction of IE2p86-mediated transactivation. In this paper, we identify an additional SUMO interaction motif (SIM) within IE2p86, which mediates noncovalent binding to SUMO, as shown by yeast two-hybrid analyses. Transient-expression experiments revealed that an IE2p86 SIM mutant exhibited significantly reduced SUMOylation, strongly suggesting that noncovalent SUMO interactions affect the efficacy of covalent SUMO coupling. In order to define the relevance of IE2p86 SUMO interactions for viral replication, recombinant viruses originating from two different HCMV strains (AD169 and VR1814) were generated. Analysis of viruses expressing SUMOylation-negative IE2p86 revealed strongly impaired replication due to reduced viral DNA and protein accumulation, as well as diminished initiation of immediate-early gene expression. The additional introduction of the SIM mutation into the viral genome did not further compromise viral replication but resulted in altered expression of viral proteins at late times postinfection. In summary, this paper clearly shows that IE2p86 SUMOylation is necessary for efficient replication of the HCMV laboratory strain AD169 and the clinical isolate VR1814 and thus for the in vivo function of this viral transcription factor. [ABSTRACT FROM AUTHOR]