Osteogenesis imperfecta: Pathophysiology and current treatment strategies

Osteogenesis imperfecta (OI) is a hereditary disease of the bones and fascia. It is associated with an increased tendency to fracture, deformities of the extremities, and extra-skeletal signs. A short description of the clinical course, diagnostic recommendations and the current treatment are followed by an extensive overview of the genetic and pathophysiological background of the disease and future therapeutic options. Approximately 80% of patients present with mutations in genes coding for collagen (COL1A1/A2). In these patients, no clear correlation between phenotype and genotype is described for the collective. Stop mutations usually cause a quantitative collagen defect, which results in less normal collagen and a mild phenotype. Missense mutations lead to structurally changed collagen (qualitative defect) and to a more severe phenotype. Nonetheless, there is high variability and it is difficult to predict the course of an individual patient. In addition to changes in the collagen coding genes, there are mutations that affect the modification and secretion of collagen. A specific group consists of genes involved in the differentiation of osteoblasts. As with the other genes (which are not referred to in more detail), these are often superior genes, whose function in osteogenesis is not fully understood. Based on the pathophysiological principles, existing treatments may well be more precisely deployed in the future. An example is the receptor activator of nuclear factor kappa-B ligand (RANKL) antibody denosumab, which is more specific than bisphosphonates, and is already used in OI type VI (SERPINF1). Further treatments such as antisclerostin or stem cell therapies are currently being investigated with a focus on pathophysiology

Hypomagnesemia is underestimated in children with HNF1B mutations

Background Hypomagnesemia in patients with congenital anomalies of the kidneys and urinary tract or autosomal dominant tubulointerstitial kidney disease is highly suggestive of HNF1B-associated disease. Intriguingly, the frequency of low serum Mg2+ (sMg) level varies and is lower in children than in adults with HNF1B mutations that could be partially due to application of inaccurate normal limit of sMg, irrespective of age and gender. We aimed to re-assess cross-sectionally and longitudinally the frequency of hypomagnesemia in HNF1B disease by using locally derived reference values of sMg. Methods Fourteen children with HNF1B-associated kidney disease were included. Control group comprising 110 subjects served to generate 2.5th percentiles of sMg as the lower limits of normal. Results In both controls and patients, sMg correlated with age, gender, and fractional excretion of Mg2+. In girls, sMg concentration was higher than in boys when analyzed in the entire age spectrum (p < 0.05). In HNF1B patients, mean sMg was lower than in controls as compared with respective gender- and age-specific interval (p < 0.001). Low sMg levels (< 0.7 mmol/l) were found in 21.4% of patients at diagnosis and 36.4% at last visit, which rose to 85.7% and 72.7% respectively when using the age- and gender-adjusted reference data. Similarly, in the longitudinal observation, 23% of sMg measurements were < 0.7 mmol/l versus 79.7% when applying respective references. Conclusions Hypomagnesemia is underdiagnosed in children with HNF1B disease. sMg levels are age- and gender-dependent; thus, the use of appropriate reference data is crucial to hypomagnesemia in children

Novel methanol dehydrogenase enzymes from bacillus

The present invention relates to a nucleic acid molecule, which encodes a polypeptide having alcohol dehydrogenase activity, in particular methanol dehydrogenase activity, comprising having a nucleotide sequence selected from the group consisting of: (i) a nucleotide sequence as set forth in any one of SEQ ID NOs: 1 (mdh2-MGA3), 3 (mdh3-MGA3), or 5 (mdh2-PB1); (ii) a nucleotide sequence having at least 90% sequence identity, more particularly at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity, with a nucleotide sequence as set forth in any one of SEQ ID NOs: 1, 3 or 5; (iii) a nucleotide sequence which is degenerate with any one of the nucleotide sequences of SEQ ID NOs: 1, 3 or 5; (iv) a nucleotide sequence which is a part of the nucleotide sequence of any one of SEQ ID NOs: 1, 3 or 5, or of a nucleotide sequence which is degenerate with a sequence of SEQ ID NOs:1, 3 or 5; (v) a nucleotide sequence encoding all or part of a polypeptide whose amino acid sequence is set forth in any one of SEQ ID NOs : 2 (Mdh2-MGA3), 4 (Mdh3-MGA3) or 6 (Mdh2-PB1); and (vi) a nucleotide sequence encoding all or part of a polypeptide which has an amino acid sequence having at least 90% sequence identity, preferably at least 91, 92, 93, 94, 95, 96, 97, 98 or 99% sequence identity, with an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 4 or 6; or a nucleic acid molecule comprising a nucleotide sequence which is complementary to the nucleotide sequence of any one of (i) to (vi). Also provided are recombinant constructs, vectors and host cells comprising such a nucleic acid molecule and polypeptides encoded thereby. Such molecules may advantageously be used in the genetic modification of host cells, for example to introduce or modify methanol dehydrogenase activity

O’Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum

BackgroundO'Donnell-Luria-Rodan syndrome (ODLURO) is an autosomal-dominant neurodevelopmental disorder caused by pathogenic, mostly truncating variants in KMT2E. It was first described by O'Donnell-Luria et al in 2019 in a cohort of 38 patients. Clinical features encompass macrocephaly, mild intellectual disability (ID), autism spectrum disorder (ASD) susceptibility and seizure susceptibility.MethodsAffected individuals were ascertained at paediatric and genetic centres in various countries by diagnostic chromosome microarray or exome/genome sequencing. Patients were collected into a case cohort and were systematically phenotyped where possible.ResultsWe report 18 additional patients from 17 families with genetically confirmed ODLURO. We identified 15 different heterozygous likely pathogenic or pathogenic sequence variants (14 novel) and two partial microdeletions of KMT2E. We confirm and refine the phenotypic spectrum of the KMT2E-related neurodevelopmental disorder, especially concerning cognitive development, with rather mild ID and macrocephaly with subtle facial features in most patients. We observe a high prevalence of ASD in our cohort (41%), while seizures are present in only two patients. We extend the phenotypic spectrum by sleep disturbances.ConclusionOur study, bringing the total of known patients with ODLURO to more than 60 within 2 years of the first publication, suggests an unexpectedly high relative frequency of this syndrome worldwide. It seems likely that ODLURO, although just recently described, is among the more common single-gene aetiologies of neurodevelopmental delay and ASD. We present the second systematic case series of patients with ODLURO, further refining the mutational and phenotypic spectrum of this not-so-rare syndrome

O'Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum

Background O'Donnell-Luria-Rodan syndrome (ODLURO) is an autosomal-dominant neurodevelopmental disorder caused by pathogenic, mostly truncating variants in KMT2E. It was first described by O'Donnell-Luria et al in 2019 in a cohort of 38 patients. Clinical features encompass macrocephaly, mild intellectual disability (ID), autism spectrum disorder (ASD) susceptibility and seizure susceptibility. Methods Affected individuals were ascertained at paediatric and genetic centres in various countries by diagnostic chromosome microarray or exome/genome sequencing. Patients were collected into a case cohort and were systematically phenotyped where possible. Results We report 18 additional patients from 17 families with genetically confirmed ODLURO. We identified 15 different heterozygous likely pathogenic or pathogenic sequence variants (14 novel) and two partial microdeletions of KMT2E. We confirm and refine the phenotypic spectrum of the KMT2E-related neurodevelopmental disorder, especially concerning cognitive development, with rather mild ID and macrocephaly with subtle facial features in most patients. We observe a high prevalence of ASD in our cohort (41%), while seizures are present in only two patients. We extend the phenotypic spectrum by sleep disturbances. Conclusion Our study, bringing the total of known patients with ODLURO to more than 60 within 2 years of the first publication, suggests an unexpectedly high relative frequency of this syndrome worldwide. It seems likely that ODLURO, although just recently described, is among the more common single-gene aetiologies of neurodevelopmental delay and ASD. We present the second systematic case series of patients with ODLURO, further refining the mutational and phenotypic spectrum of this not-so-rare syndrome