LYRM7-associated mitochondrial complex III deficiency with non-cavitating leukoencephalopathy and stroke-like episodes.

Defects of respiratory chain complex III (CIII) result in characteristic but rare mitochondrial disorders associated with distinct neuroradiological findings. The underlying molecular defects affecting mitochondrial CIII assembly factors are few and yet to be identified. LYRM7 assembly factor is required for proper CIII assembly where it acts as a chaperone for the Rieske iron-sulfur (UQCRFS1) protein in the mitochondrial matrix and stabilizing it. We present here the seventeenth individual with LYRM7-associated mitochondrial leukoencephalopathy harboring a previously reported rare pathogenic homozygous LYRM 7 variant, c.2T>C, (p.Met1?). Like previously reported individuals, our 5-year-old male proband presented with recurrent metabolic and lactic acidosis, encephalopathy, and fatigue. Further, he has additional, previously unreported features, including an acute stroke like episode with bilateral central blindness and optic neuropathy, recurrent hyperglycemia and hypertension associated with metabolic crisis. However, he has no signs of psychomotor regression. He has been stable clinically with residual left-sided reduced visual acuity and amblyopia, and no more metabolic crises for 2-year-period while on the mitochondrial cocktail. Although the reported brain MRI findings in other affected individuals are homogenous, it is slightly different in our index, revealing evidence of bilateral almost symmetric multifocal periventricular T2 hyperintensities with hyperintensities of the optic nerves, optic chiasm, and corona radiata but with no cavitation or cystic changes. This report describes new clinical and radiological findings of LYRM7-associated disease. The report also summarizes the clinical and molecular data of previously reported individuals describing the full phenotypic spectrum.

Knowledge and Awareness of Dental Practitioners About the Utilization of Endocrown in Post-endodontic Management.

BACKGROUND: The objective of this study was to evaluate the knowledge, and awareness of dentists in Ha'il, Kingdom of Saudi Arabia, regarding the use of endocrown as post-endodontic restorations, utilizing an online questionnaire. METHODS: A cross-sectional study was carried out among dental practitioners working in Ha'il, Kingdom of Saudi Arabia. Dentists who practice in the Ha'il were included in the current study. The survey study involved a sample size of 245 participants. The researchers employed the snowball sampling technique in this investigation. The validated, closed-ended questionnaires were disseminated to the entire sample of selected dental practitioners using electronic mail. The initial section of the survey encompassed inquiries pertaining to the demographic characteristics of the participants, encompassing variables such as gender, years of professional experience, and workplace. The subsequent section of the survey focused on assessing the participants' knowledge and opinions regarding the endocrown technique. The Chi-square test was employed to assess the associations between categorical variables. RESULTS: The most of participants 228 (93.1%) had knowledge about endocrown and 94 (38.4%) of them received information from their educational institutions. Among the responses of the participants, 232 (94.7%) expressed their preference for utilizing endocrown restorations specifically for molar teeth. Moreover, 183 (74.7%) of respondents indicated that the endocrown is preferred when there is a restricted amount of inter-arch space available. A majority of respondents 152 (62.0%) indicated that the ferrule does not exert any influence on the endocrown. A majority of participants 135 (55.1%) expressed a preference for utilizing lithium disilicate ceramic in the fabrication of endocrown. The most of participants 209 (85.3%) opted to use resin cement for the purpose of cementation. The characteristics of gender, experience, and working place were found to have a significant relationship with the knowledge of the participants about endocrown (p <0.05). CONCLUSIONS: The study participants need to enhance their knowledge and awareness pertaining to the utilization of endocrowns as a post-endodontic treatment.

A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes.

BACKGROUND: Huntington disease (HD) is caused by an unstable CAG/CAA repeat expansion encoding a toxic polyglutamine tract. Here, we tested the hypotheses that HD outcomes are impacted by somatic expansion of, and polymorphisms within, the HTT CAG/CAA glutamine-encoding repeat, and DNA repair genes. METHODS: The sequence of the glutamine-encoding repeat and the proportion of somatic CAG expansions in blood DNA from participants inheriting 40 to 50 CAG repeats within the TRACK-HD and Enroll-HD cohorts were determined using high-throughput ultra-deep-sequencing. Candidate gene polymorphisms were genotyped using kompetitive allele-specific PCR (KASP). Genotypic associations were assessed using time-to-event and regression analyses. FINDINGS: Using data from 203 TRACK-HD and 531 Enroll-HD participants, we show that individuals with higher blood DNA somatic CAG repeat expansion scores have worse HD outcomes: a one-unit increase in somatic expansion score was associated with a Cox hazard ratio for motor onset of 3·05 (95% CI = 1·94 to 4·80, p = 1·3 × 10-6). We also show that individual-specific somatic expansion scores are associated with variants in FAN1 (pFDR = 4·8 × 10-6), MLH3 (pFDR = 8·0 × 10-4), MLH1 (pFDR = 0·004) and MSH3 (pFDR = 0·009). We also show that HD outcomes are best predicted by the number of pure CAGs rather than total encoded-glutamines. INTERPRETATION: These data establish pure CAG length, rather than encoded-glutamine, as the key inherited determinant of downstream pathophysiology. These findings have implications for HD diagnostics, and support somatic expansion as a mechanistic link for genetic modifiers of clinical outcomes, a driver of disease, and potential therapeutic target in HD and related repeat expansion disorders. FUNDING: CHDI Foundation.