Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation - a novel phenotype of the mitochondrial disease.

In 1999, based on a single family, spondyloepimetaphyseal dysplasia (SEMD) with mental retardation (MR) was described as a novel syndrome with probably X-linked recessive inheritance and unknown molecular defect (MIM 300232). Our purpose was to search for the causative defect in the originally described family and in an independently ascertained second family. All patients had slowly progressive neurodegeneration with central and peripheral involvement and identical skeletal dysplasia. Whole exome sequencing performed in two subjects showed a single plausible candidate - the p.Asp237Gly variant in AIFM1 (chr. Xq26.1). The p.Asp237Gly segregated with disease as indicated by linkage analysis [maximum logarithm of odds score (LOD) score at theta 0 for the two families was 3.359]. This variant had not been previously reported and it was predicted to be pathogenic by Polyphen2, SIFT, MutationTaster and Mutation Assessor. AIFM1 encodes mitochondria associated apoptosis-inducing factor. The AIFM1 gene has been linked with COXPD6 encephalomyopathy (MIM 300816), Cowchock syndrome (MIM 310490) and X-linked deafness with neuropathy (DFNX5, MIM 300614), none of which are similar to SEMD-MR. Our results place SEMD as the third instance of a skeletal phenotype associated with a mitochondrial disease (the others being EVEN-PLUS syndrome caused by mutations of HSPA9 and CODAS syndrome due to LONP1 mutations).

Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations.

BACKGROUND: Thoracic aortic aneurysms and dissections (TAAD) are silent but possibly lethal condition with up to 40 % of cases being hereditary. Genetic background is heterogeneous. Recently next-generation sequencing enabled efficient and cost-effective examination of gene panels. Aim of the study was to define the diagnostic yield of NGS in the 51 TAAD patients and to look for genotype-phenotype correlations within families of the patients with TAAD. METHODS: 51 unrelated TAAD patients were examined by either whole exome sequencing or TruSight One sequencing panel. We analyzed rare variants in 10 established thoracic aortic aneurysms-associated genes. Whenever possible, we looked for co-segregation in the families. Kaplan-Meier survival curve was constructed to compare the event-free survival depending on genotype. Aortic events were defined as acute aortic dissection or first planned aortic surgery. RESULTS AND DISCUSSION: In 21 TAAD patients we found 22 rare variants, 6 (27.3 %) of these were previously reported, and 16 (73.7 %) were novel. Based on segregation data, functional analysis and software estimations we assumed that three of novel variants were causative, nine likely causative. Remaining four were classified as of unknown significance (2) and likely benign (2). In all, 9 (17.6 %) of 51 probands had a positive result when considering variants classified as causative only and 18 (35.3 %) if likely causative were also included. Genotype-positive probands (n = 18) showed shorter mean event free survival (41 years, CI 35-46) than reference group, i.e. those (n = 29) without any plausible variant identified (51 years, CI 45-57, p = 0.0083). This effect was also found when the 'genotype-positive' group was restricted to probands with 'likely causative' variants (p = 0.0092) which further supports pathogenicity of these variants. The mean event free survival was particularly low (37 years, CI 27-47) among the probands with defects in the TGF beta signaling (p = 0.0033 vs. the reference group). CONCLUSIONS: This study broadens the spectrum of genetic background of thoracic aneurysms and dissections and supports its potential role as a prognostic factor in the patients with the disease.

Influence of experience on orientation maps in cat visual cortex.

Experience is known to affect the development of ocular dominance maps in visual cortex, but it has remained controversial whether orientation preference maps are similarly affected by limiting visual experience to a single orientation early in life. Here we used optical imaging based on intrinsic signals to show that the visual cortex of kittens reared in a striped environment responded to all orientations, but devoted up to twice as much surface area to the experienced orientation as the orthogonal one. This effect is due to an instructive role of visual experience whereby some neurons shift their orientation preferences toward the experienced orientation. Thus, although cortical orientation maps are remarkably rigid in the sense that orientations that have never been seen by the animal occupy a large portion of the cortical territory, visual experience can nevertheless alter neuronal responses to oriented contours.

Intrinsic and environmental factors in the development of functional maps in cat visual cortex.

In the mammalian visual cortex, key neuronal response properties such as orientation preference and ocular dominance (OD) are mapped in an orderly fashion across the cortical surface. It has been known for some time that manipulating early postnatal visual experience can change the appearance of the OD map. Similar evidence for developmental plasticity of the orientation map has been scarce. We employed optical imaging of intrinsic signals to examine the contribution of intrinsic and environmental factors to the development of cortical maps, using the paradigms of strabismus, reverse occlusion and rearing in a single-orientation environment ('stripe-rearing'). For several weeks after induction of strabismus, the pattern of OD domains remained stable in young kittens. The isotropic magnification of the OD map matched the postnatal growth of the visual cortical surface during the same period. In reverse-occluded and in stripe-reared kittens, orientation preference maps obtained through the left and the right eye were very similar, although the two eyes had never shared any visual experience. We suggest that the geometry of functional maps in the visual cortex is intrinsically determined, while the relative strength of representation of different response properties can be modified through visual experience.