The International Standard Set of Outcome Measures for the Assessment of Hearing in People with Osteogenesis Imperfecta.

OBJECTIVE: The aim is to recommend a minimum standard set of clinician-reported outcome measures (CROMs) and patient-reported outcome measures (PROMs) on hearing for people with osteogenesis imperfecta (OI). This project is part of the larger "Key4OI" project initiated by the "Care4BrittleBones foundation" of which the goal is to improve quality of life of people with OI. Key4OI provides a standard set of outcome measures and covers a large set of domains affecting the well-being of people with OI. METHODS: An international team of experts in OI, comprising specialists in audiological science, medical specialists, and an expert patient representative, used a modified Delphi consensus process to select CROMs and PROMs to evaluate hearing problems in people with OI. In addition, focus groups of people with OI identified key consequences of their hearing loss. These criteria were matched to categories of preselected questionnaires to select a PROM that matched their specific hearing-related concerns best. RESULTS: Consensus on PROMs for adults and CROMs for adults and children was reached. The focus of the CROMs was on specific audiological outcome measures and standardized follow-up. CONCLUSIONS: This project resulted in a clear consensus statement for standardization of hearing-related PROMs and CROMs and follow-up management of patients with OI. This standardization of outcome measurements will facilitate comparability of research and easier international cooperation in OI and hearing loss. Furthermore, it can improve standard of care in people with OI and hearing loss by incorporating the recommendations into care pathways.

Mitochondrial m.1584A 12S m62A rRNA methylation in families with m.1555A>G associated hearing loss.

The mitochondrial DNA mutation m.1555A>G predisposes to hearing loss following aminoglycoside antibiotic exposure in an idiosyncratic dose-independent manner. However, it may also cause maternally inherited hearing loss in the absence of aminoglycoside exposure or any other clinical features (non-syndromic hearing loss). Although m.1555A>G was identified as a cause of deafness more than twenty years ago, the pathogenic mechanism of this mutation of ribosomal RNA remains controversial. Different mechanistic concepts have been proposed. Most recently, evidence from cell lines and animal models suggested that patients with m.1555A>G may have more 12S rRNA N6, N6-dimethyladenosine (m(6) 2A) methylation than controls, so-called 'hypermethylation'. This has been implicated as a pathogenic mechanism of mitochondrial dysfunction but has yet to be validated in patients. 12S m(6) 2A rRNA methylation, by the mitochondrial transcription factor 1 (TFB1M) enzyme, occurs at two successive nucleotides (m.1584A and m.1583A) in close proximity to m.1555A>G. We examined m(6) 2A methylation in 14 patients with m.1555A>G, and controls, and found all detectable 12S rRNA transcripts to be methylated in both groups. Moreover, different RNA samples derived from the same patient (lymphocyte, fibroblast and lymphoblast) revealed that only transformed cells contained some unmethylated 12S rRNA transcripts, with all detectable 12S rRNA transcripts derived from primary samples m(6) 2A-methylated. Our data indicate that TFB1M 12S m(6) 2A rRNA hypermethylation is unlikely to be a pathogenic mechanism and may be an artefact of previous experimental models studied. We propose that RNA methylation studies in experimental models should be validated in primary clinical samples to ensure that they are applicable to the human situation.