Classification of osteogenesis imperfecta: Importance for prophylaxis and genetic counseling

Osteogenesis imperfecta (OI) is a genetically heterogeneous monogenic disease characterized by decreased bone mass, bone fragility, and recurrent fractures. The phenotypic spectrum varies considerably ranging from prenatal fractures with lethal outcomes to mild forms with few fractures and normal stature. The basic mechanism is a collagen-related defect, not only in synthesis but also in folding, processing, bone mineralization, or osteoblast function. In recent years, great progress has been made in identifying new genes and molecular mechanisms underlying OI. In this context, the classification of OI has been revised several times and different types are used. The Sillence classification, based on clinical and radiological characteristics, is currently used as a grading of clinical severity. Based on the metabolic pathway, the functional classification allows identifying regulatory elements and targeting specific therapeutic approaches. Genetic classification has the advantage of identifying the inheritance pattern, an essential element for genetic counseling and prophylaxis. Although genotype-phenotype correlations may sometimes be challenging, genetic diagnosis allows a personalized management strategy, accurate family planning, and pregnancy management decisions including options for mode of delivery, or early antenatal OI treatment. Future research on molecular pathways and pathogenic variants involved could lead to the development of genotype-based therapeutic approaches. This narrative review summarizes our current understanding of genes, molecular mechanisms involved in OI, classifications, and their utility in prophylaxis.     

Exome sequencing in a Romanian Bardet-Biedl syndrome cohort revealed an overabundance of causal BBS12 variants

Bardet-Biedl syndrome (BBS), is an emblematic ciliopathy hallmarked by pleiotropy, phenotype variability, and extensive genetic heterogeneity. BBS is a rare (~1/140,000 to ~1/160,000 in Europe) autosomal recessive pediatric disorder characterized by retinal degeneration, truncal obesity, polydactyly, cognitive impairment, renal dysfunction, and hypogonadism. Twenty-eight genes involved in ciliary structure or function have been implicated in BBS, and explain the molecular basis for ~75%–80% of individuals. To investigate the mutational spectrum of BBS in Romania, we ascertained a cohort of 24 individuals in 23 families. Following informed consent, we performed proband exome sequencing (ES). We detected 17 different putative disease-causing single nucleotide variants or small insertion–deletions and two pathogenic exon disruptive copy number variants in known BBS genes in 17 pedigrees. The most frequently impacted genes were BBS12 (35%), followed by BBS4, BBS7, and BBS10 (9% each) and BBS1, BBS2, and BBS5 (4% each). Homozygous BBS12 p.Arg355* variants were present in seven pedigrees of both Eastern European and Romani origin. Our data show that although the diagnostic rate of BBS in Romania is likely consistent with other worldwide cohorts (74%), we observed a unique distribution of causal BBS genes, including overrepresentation of BBS12 due to a recurrent nonsense variant, that has implications for regional diagnostics.     

Complexity analysis from EEG data in congestive heart failure: A study via approximate entropy

Aim

Congestive heart failure (CHF) is a very complex clinical syndrome that may lead to ischemic cerebral hypoxia condition. The aim of the present study is to analyze the effects of CHF on brain activity through electroencephalographic (EEG) complexity measures, like approximate entropy (ApEn).

Methods

Twenty patients with CHF and 18 healthy elderly people were recruited. ApEn values were evaluated in the total spectrum (0.2–47 Hz) and main EEG frequency bands: delta (2–4 Hz), theta (4–8 Hz), alpha 1 (8–11 Hz), alpha 2 (11–13 Hz), beta 1 (13–20 Hz), beta 2 (20–30 Hz), and gamma (30–45 Hz) to identify differences between CHF group and control. Moreover, a correlation analysis was performed between ApEn parameters and clinical data (i.e., B-type natriuretic peptides (BNP), New York Heart Association (NYHA), and systolic blood pressure (SBP)) within the CHF group.

Results

Statistical topographic maps showed statistically significant differences between the two groups in the total spectrum and theta frequency band. Within the CHF group, significant negative correlations were found between total ApEn and BNP in O2 channel and between theta ApEn and NYHA scores in Fp1, Fp2, and Fz channels; instead, a significant positive correlation was found between theta ApEn and SBP in C3 channel and a nearly significant positive correlation was obtained between theta ApEn and SBP in F4 channel.

Conclusion

EEG abnormalities in CHF are very similar to those observed in cognitive-impaired patients, suggesting analogies between the effects of neurodegeneration and brain chronic hypovolaemia due to heart disorder and underlying high brain sensitivity to CHF.