Biomed Res Int. 2023 Feb 22;2023:8340209. doi: 10.1155/2023/8340209. eCollection 2023.

ABSTRACT

PURPOSE: Malignant hyperthermia (MH) is a rare genetic disorder but one of the most severe complications of general anesthesia. The mortality rate of MH has dropped from 70% in the 1960s to 15% because of dantrolene, the only currently accepted specific treatment for MH. In this study, we retrospectively identified the optimal dantrolene administration conditions to reduce MH mortality further.

METHODS: Our database performed a retrospective analysis of patients with MH clinical grading scale (CGS) grade 5 (very likely) or 6 (almost certain) between 1995 and 2020. We examined whether dantrolene administration affected mortality and compared the clinical variables associated with improved prognosis. Furthermore, a multivariable logistic regression analysis was used to identify specific variables associated with improved prognosis.

RESULTS: 128 patients met the inclusion criteria. 115 patients were administered dantrolene; 104 survived, and 11 died. The mortality rate of patients who were not administered dantrolene was 30.8%, which was significantly higher than those of patients who were administered dantrolene (P = 0.047). Among patients administered dantrolene, the interval from the first sign of MH to the start of dantrolene administration was significantly longer in the deceased than in the survivors (100 min vs. 45.0 min, P < 0.001), and the temperature at the start of dantrolene administration was also significantly higher in the deceased (41.6°C vs. 39.1°C, P < 0.001). There was no significant difference in the rate of increase in temperature between the two, but there was a substantial difference in the maximum temperature (P < 0.001). The multivariable analysis also showed that the patient's temperature at dantrolene administration and interval from the first MH sign to dantrolene administration was significantly associated with improved prognosis.

CONCLUSIONS: Dantrolene should be given as rapidly as possible once MH has been diagnosed. Beginning treatment at a more normal body temperature can prevent critical elevations associated with a worse prognosis.

PMID:36874927 | PMC:PMC9977521 | DOI:10.1155/2023/8340209

Indian J Ophthalmol. 2023 Mar;71(3):1030-1032. doi: 10.4103/ijo.IJO_949_22.

ABSTRACT

Bilateral acute depigmentation of the iris (BADI) is a rare disease characterized by iris atrophy. Although it can be self-limiting, it is sometimes progressive and can lead to glaucoma and severe vision loss. Two female patients were admitted to our clinic because of a change in iris color following coronavirus disease 2019 (COVID-19) infection. After the exclusion of other etiologies in the eye examination, BADI was diagnosed in both cases. Thus, it was shown that COVID-19 may also be involved in the etiology of BADI.

PMID:36872735 | DOI:10.4103/ijo.IJO_949_22

Indian J Ophthalmol. 2023 Mar;71(3):729-735. doi: 10.4103/ijo.IJO_1920_22.

ABSTRACT

The extended use of ethambutol beyond 2 months for treating tuberculosis has increased risk of optic neuropathy. We performed a systematic review of studies evaluating optic neuropathy in extended ethambutol use since 2010 and compared the outcome with a similar systematic review (1965-2010) by Ezer et al. Literature search was conducted in PubMed, Medline, EMBASE, and Cochrane databases. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Main outcome measures were visual acuity, color vision, visual field defects, optical coherence tomography (OCT), and visual evoked potential (VEP). The JBI Critical Appraisal Checklists were used for quality assessment. Twelve studies were selected (out of 639 studies) for analysis of ethambutol optic neuropathy. Visual acuity improvement after stopping ethambutol was statistically significant. Similar improvement was not noted for other outcome measures. On comparing the results of this review with those by Ezer et al., significant improvement was noted in visual acuity, color vision, and visual field defects. Moreover, more patients reported increased optic nerve toxicity, color vision defects, and visual field defects in the present review. Hence, we conclude that the extended use of ethambutol beyond 2 months results in significant optic nerve toxicity. Further randomized controlled trials with different populations are needed to understand the magnitude of this issue.

PMID:36872667 | DOI:10.4103/ijo.IJO_1920_22

NPJ Genom Med. 2023 Mar 6;8(1):7. doi: 10.1038/s41525-023-00350-3.

ABSTRACT

A male infant presented at term with neonatal respiratory failure and pulmonary hypertension. His respiratory symptoms improved initially, but he exhibited a biphasic clinical course, re-presenting at 15 months of age with tachypnea, interstitial lung disease, and progressive pulmonary hypertension. We identified an intronic TBX4 gene variant in close proximity to the canonical donor splice site of exon 3 (hg 19; chr17:59543302; c.401 + 3 A > T), also carried by his father who had a typical TBX4-associated skeletal phenotype and mild pulmonary hypertension, and by his deceased sister who died shortly after birth of acinar dysplasia. Analysis of patient-derived cells demonstrated a significant reduction in TBX4 expression resulting from this intronic variant. Our study illustrates the variable expressivity in cardiopulmonary phenotype conferred by TBX4 mutation and the utility of genetic diagnostics in enabling accurate identification and classification of more subtly affected family members.

PMID:36878902 | DOI:10.1038/s41525-023-00350-3

Am J Case Rep. 2023 Mar 4;24:e939175. doi: 10.12659/AJCR.939175.

ABSTRACT

BACKGROUND Dental anomalies are common congenital disturbances that can occur as single findings or as components of specific syndromes. Primary bi-rooted canine teeth are rare dental anomalies that are more common in the maxilla. It is unusual for a child to have a bi-rooted maxillary canine, as this tooth is known for having a single long root, more than twice the length of the crown. The present report describes the extraction of a bi-rooted primary maxillary canine tooth in a 9-year-old Saudi boy. The report aims to contribute to a better understanding of the possible etiological factors of these rare conditions as well as to review the data available so far in the literature. CASE REPORT A 9-year-old Saudi boy presented to the clinic for an initial visit. The patient was medically fit. The chief complaint was "I have pain in my upper front left region". A thorough oral examination revealed that the upper left primary canine was carious. The panoramic radiograph showed that the former tooth was bi-rooted. The tooth was claimed to be non-restorable. Thus, we planned for extraction. The tooth was extracted in the subsequent visit. CONCLUSIONS The presence of bi-rooted primary canines is rare. Dentists should always assess the presence of any dental abnormality. Panoramic radiographs may give an initial sign of the existence of abnormal bi-rooted teeth, and the abnormality can be confirmed by taking intraoral radiographs. Although the data availability in the literature is limited, ethnicity and gender seem to have an impact on its prevalence.

PMID:36869581 | DOI:10.12659/AJCR.939175

J Neurodev Disord. 2023 Mar 4;15(1):10. doi: 10.1186/s11689-023-09479-9.

ABSTRACT

BACKGROUND: Developing biomarkers is a priority for drug development for all conditions, but vital in the rare neurodevelopmental disorders where sensitive outcome measures are lacking. We have previously demonstrated the feasibility and tracking of evoked potentials to disease severity in Rett syndrome and CDKL5 deficiency disorder. The aim of the current study is to characterize evoked potentials in two related developmental encephalopathies, MECP2 duplication syndrome and FOXG1 syndrome, and compare across all four groups to better understand the potential of these measures to serve as biomarkers of clinical severity for the developmental encephalopathies.

METHODS: Visual and auditory evoked potentials were acquired from participants with MECP2 duplication syndrome and FOXG1 syndrome across five sites of the Rett Syndrome and Rett-Related Disorders Natural History Study. A group of age-matched individuals (mean = 7.8 years; range = 1-17) with Rett syndrome, CDKL5 deficiency disorder, and typically-developing participants served as a comparison group. The analysis focused on group-level differences as well as associations between the evoked potentials and measures of clinical severity from the Natural History Study.

RESULTS: As reported previously, group-level comparisons revealed attenuated visual evoked potentials (VEPs) in participants with Rett syndrome (n = 43) and CDKL5 deficiency disorder (n = 16) compared to typically-developing participants. VEP amplitude was also attenuated in participants with MECP2 duplication syndrome (n = 15) compared to the typically-developing group. VEP amplitude correlated with clinical severity for Rett syndrome and FOXG1 syndrome (n = 5). Auditory evoked potential (AEP) amplitude did not differ between groups, but AEP latency was prolonged in individuals with MECP2 duplication syndrome (n = 14) and FOXG1 syndrome (n = 6) compared to individuals with Rett syndrome (n = 51) and CDKL5 deficiency disorder (n = 14). AEP amplitude correlated with severity in Rett syndrome and CDKL5 deficiency disorder. AEP latency correlated with severity in CDKL5 deficiency disorder, MECP2 duplication syndrome, and FOXG1 syndrome.

CONCLUSIONS: There are consistent abnormalities in the evoked potentials in four developmental encephalopathies some of which correlate with clinical severity. While there are consistent changes amongst these four disorders, there are also condition specific findings that need to be further refined and validated. Overall, these results provide a foundation for further refinement of these measures for use in future clinical trials for these conditions.

PMID:36870948 | DOI:10.1186/s11689-023-09479-9

Eur J Med Chem. 2023 Mar 15;250:115238. doi: 10.1016/j.ejmech.2023.115238. Epub 2023 Feb 27.

ABSTRACT

Conjunctival melanoma (CM), a rare and fatal malignant ocular tumor, lacks proper diagnostic biomarkers and therapy. Herein, we revealed the novel application of propafenone, an FDA-approved antiarrhythmic medication, which was identified effective in inhibiting CM cells viability and homologous recombination pathway. Detailed structure-activity relationships generated D34 as one of the most promising derivatives, which strongly suppressed the proliferation, viability, and migration of CM cells at submicromolar concentrations. Mechanically, D34 had the potential to increase γ-H2AX nuclear foci and aggravated DNA damage by suppressing homologous recombination pathway and its factors, particularly the complex of MRE11-RAD50-NBS1. D34 bound to human recombinant MRE11 protein and inhibited its endonuclease activity. Moreover, D34 dihydrochloride significantly suppressed tumor growth in the CRMM1 NCG xenograft model without obvious toxicity. Our finding shows that propafenone derivatives modulating the MRE11-RAD50-NBS1 complex will most likely provide an approach for CM targeted therapy, especially for improving chemo- and radio-sensitivity for CM patients.

PMID:36868105 | DOI:10.1016/j.ejmech.2023.115238

Am J Hum Genet. 2023 Mar 2;110(3):419-426. doi: 10.1016/j.ajhg.2023.01.018.

ABSTRACT

Australian Genomics is a national collaborative partnership of more than 100 organizations piloting a whole-of-system approach to integrating genomics into healthcare, based on federation principles. In the first five years of operation, Australian Genomics has evaluated the outcomes of genomic testing in more than 5,200 individuals across 19 rare disease and cancer flagship studies. Comprehensive analyses of the health economic, policy, ethical, legal, implementation and workforce implications of incorporating genomics in the Australian context have informed evidence-based change in policy and practice, resulting in national government funding and equity of access for a range of genomic tests. Simultaneously, Australian Genomics has built national skills, infrastructure, policy, and data resources to enable effective data sharing to drive discovery research and support improvements in clinical genomic delivery.

PMID:36868206 | DOI:10.1016/j.ajhg.2023.01.018

Turk J Pediatr. 2023;65(1):124-128. doi: 10.24953/turkjped.2022.254.

ABSTRACT

BACKGROUND: Klippel-Trenaunay syndrome (KTS) is an overgrowth syndrome associated with capillary/venous/ lymphatic malformations with limb hypertrophy and cancer risk. Various cancers, mostly Wilms tumor, have been reported in patients with KTS, but not leukemia. Chronic myeloid leukemia (CML) is also a rare disease in children, where there is no known disease or syndrome to predispose to CML.

CASE: We report a case of CML incidentally diagnosed in a child with KTS when he was bleeding from surgery of the left groin for vascular malformation.

CONCLUSIONS: This case reflects the variety of cancer types that may accompany KTS and provides information about CML prognosis in such patients.

PMID:36866992 | DOI:10.24953/turkjped.2022.254

Blood. 2023 Mar 2;141(9):963-964. doi: 10.1182/blood.2022019105.

NO ABSTRACT

PMID:36862438 | DOI:10.1182/blood.2022019105

Am J Med Genet C Semin Med Genet. 2023 Mar;193(1):64-76. doi: 10.1002/ajmg.c.32037. Epub 2023 Feb 28.

ABSTRACT

The National Center for Advancing Translational Sciences' virtual 2021 conference on gene-targeted therapies (GTTs) encouraged multidisciplinary dialogue on a wide range of GTT topic areas. Each of three parallel working groups included social scientists and clinical scientists, and the three major sessions included a presentation on economic issues related to their focus area. These experts also coordinated their efforts across the three groups. The economics-related presentations covered three areas with some overlap: (1) value assessment, uncertainty, and dynamic efficiency; (2) affordability, pricing, and financing; and (3) evidence generation, coverage, and access. This article provides a synopsis of three presentations, some of their key recommendations, and an update on related developments in the past year. The key high-level findings are that GTTs present unique data and policy challenges, and that existing regulatory, health technology assessment, as well as payment and financing systems will need to adapt. But these adjustments can build on our existing foundation of regulatory and incentive systems for innovation, and much can be done to accelerate progress in GTTs. Given the substantial unmet medical need that exists for these oft-neglected patients suffering from rare diseases, it would be a tragedy to not leverage these exciting scientific advances in GTTs.

PMID:36854952 | DOI:10.1002/ajmg.c.32037

Eur J Dermatol. 2022 Nov 1;32(6):812-814. doi: 10.1684/ejd.2022.4384.

NO ABSTRACT

PMID:36856400 | DOI:10.1684/ejd.2022.4384

Minerva Gastroenterol (Torino). 2023 Mar;69(1):50-60. doi: 10.23736/S2724-5895.20.02792-0.

ABSTRACT

Assessment of Health-Related Quality of Life (HRQoL) has emerged as an important tool in the evaluation of both the well-being of patients and the results of their clinical management. Over the years, a large number of questionnaires focusing on various aspects of quality of life have been developed. They are frequently divided into generic questionnaires, which can be used under various conditions, disease-specific and symptom-specific questionnaires. Autoimmune liver diseases, such as autoimmune hepatitis, primary sclerosing cholangitis, or primary biliary cirrhosis, comprise a group of rare liver conditions (i.e. affecting fewer than 5 in 10,000 people in the general population). Unfortunately, HRQoL has not been well-studied in this group of patients. In this review, we comprehensively summarize the data available in the literature on HRQoL in these conditions, emphasizing the important role that quality of life plays in the successful management of such patients.

PMID:36856273 | DOI:10.23736/S2724-5895.20.02792-0

BMC Neurol. 2023 Feb 28;23(1):88. doi: 10.1186/s12883-023-03133-6.

ABSTRACT

BACKGROUND: Spinal muscular atrophy (SMA) is a rare neuromuscular disorder leading to early death in the majority of affected individuals without treatment. Recently, targeted treatment approaches including Onasemnogene Abeparvovec (OA) were introduced. This study describes the first real-world experience with OA in Switzerland.

METHODS: Prospective observational case series study using data collected within the Swiss Registry for Neuromuscular Disorders from SMA patients treated with OA. Development of motor, bulbar and respiratory function, appearance of scoliosis, and safety data (platelet count, liver function, and cardiotoxicity) were analyzed.

RESULTS: Nine individuals were treated with OA and followed for 383 ± 126 days: six SMA type 1 (of which two with nusinersen pretreatment), one SMA type 2, and two pre-symptomatic individuals. In SMA type 1, CHOP Intend score increased by 28.1 from a mean score of 20.5 ± 7.6 at baseline. At end of follow-up, 50% of SMA type 1 patients required nutritional support and 17% night-time ventilation; 67% developed scoliosis. The SMA type 2 patient and two pre-symptomatically treated individuals reached maximum CHOP Intend scores. No patient required adaptation of the concomitant prednisolone treatment, although transient decrease of platelet count and increase of transaminases were observed in all patients. Troponin-T was elevated prior to OA treatment in 100% and showed fluctuations in 57% thereafter.

CONCLUSIONS: OA is a potent treatment for SMA leading to significant motor function improvements. However, the need for respiratory and especially nutritional support as well as the development of scoliosis must be thoroughly evaluated in SMA type 1 patients even in the short term after OA treatment.

PMID:36855136 | DOI:10.1186/s12883-023-03133-6

J Transl Med. 2023 Feb 28;21(1):157. doi: 10.1186/s12967-023-04011-y.

ABSTRACT

BACKGROUND: The United Nations recently made a call to address the challenges of an estimated 300 million persons worldwide living with a rare disease through the collection, analysis, and dissemination of disaggregated data. Epidemiologic Information (EI) regarding prevalence and incidence data of rare diseases is sparse and current paradigms of identifying, extracting, and curating EI rely upon time-intensive, error-prone manual processes. With these limitations, a clear understanding of the variation in epidemiology and outcomes for rare disease patients is hampered. This challenges the public health of rare diseases patients through a lack of information necessary to prioritize research, policy decisions, therapeutic development, and health system allocations.

METHODS: In this study, we developed a newly curated epidemiology corpus for Named Entity Recognition (NER), a deep learning framework, and a novel rare disease epidemiologic information pipeline named EpiPipeline4RD consisting of a web interface and Restful API. For the corpus creation, we programmatically gathered a representative sample of rare disease epidemiologic abstracts, utilized weakly-supervised machine learning techniques to label the dataset, and manually validated the labeled dataset. For the deep learning framework development, we fine-tuned our dataset and adapted the BioBERT model for NER. We measured the performance of our BioBERT model for epidemiology entity recognition quantitatively with precision, recall, and F1 and qualitatively through a comparison with Orphanet. We demonstrated the ability for our pipeline to gather, identify, and extract epidemiology information from rare disease abstracts through three case studies.

RESULTS: We developed a deep learning model to extract EI with overall F1 scores of 0.817 and 0.878, evaluated at the entity-level and token-level respectively, and which achieved comparable qualitative results to Orphanet's collection paradigm. Additionally, case studies of the rare diseases Classic homocystinuria, GRACILE syndrome, Phenylketonuria demonstrated the adequate recall of abstracts with epidemiology information, high precision of epidemiology information extraction through our deep learning model, and the increased efficiency of EpiPipeline4RD compared to a manual curation paradigm.

CONCLUSIONS: EpiPipeline4RD demonstrated high performance of EI extraction from rare disease literature to augment manual curation processes. This automated information curation paradigm will not only effectively empower development of the NIH Genetic and Rare Diseases Information Center (GARD), but also support the public health of the rare disease community.

PMID:36855134 | DOI:10.1186/s12967-023-04011-y

Hum Genomics. 2023 Mar 2;17(1):16. doi: 10.1186/s40246-023-00464-w.

ABSTRACT

BACKGROUND: Congenital hydrocephalus is characterized by ventriculomegaly, defined as a dilatation of cerebral ventricles, and thought to be due to impaired cerebrospinal fluid (CSF) homeostasis. Primary congenital hydrocephalus is a subset of cases with prenatal onset and absence of another primary cause, e.g., brain hemorrhage. Published series report a Mendelian cause in only a minority of cases. In this study, we analyzed exome data of PCH patients in search of novel causal genes and addressed the possibility of an underlying oligogenic mode of inheritance for PCH.

MATERIALS AND METHODS: We sequenced the exome in 28 unrelated probands with PCH, 12 of whom from families with at least two affected siblings and 9 of whom consanguineous, thereby increasing the contribution of genetic causes. Patient exome data were first analyzed for rare (MAF < 0.005) transmitted or de novo variants. Population stratification of unrelated PCH patients and controls was determined by principle component analysis, and outliers identified using Mahalanobis distance 5% as cutoff. Patient and control exome data for genes biologically related to cilia (SYScilia database) were analyzed by mutation burden test.

RESULTS: In 18% of probands, we identify a causal (pathogenic or likely pathogenic) variant of a known hydrocephalus gene, including genes for postnatal, syndromic hydrocephalus, not previously reported in isolated PCH. In a further 11%, we identify mutations in novel candidate genes. Through mutation burden tests, we demonstrate a significant burden of genetic variants in genes coding for proteins of the primary cilium in PCH patients compared to controls.

CONCLUSION: Our study confirms the low contribution of Mendelian mutations in PCH and reports PCH as a phenotypic presentation of some known genes known for syndromic, postnatal hydrocephalus. Furthermore, this study identifies novel Mendelian candidate genes, and provides evidence for oligogenic inheritance implicating primary cilia in PCH.

PMID:36859317 | DOI:10.1186/s40246-023-00464-w

BMJ. 2023 Feb 28;380:p483. doi: 10.1136/bmj.p483.

NO ABSTRACT

PMID:36854467 | DOI:10.1136/bmj.p483

MMW Fortschr Med. 2023 Feb;165(Suppl 1):6-10. doi: 10.1007/s15006-023-2322-4.

NO ABSTRACT

PMID:36849763 | DOI:10.1007/s15006-023-2322-4

MMW Fortschr Med. 2023 Feb;165(Suppl 1):3. doi: 10.1007/s15006-023-2338-9.

NO ABSTRACT

PMID:36849762 | DOI:10.1007/s15006-023-2338-9

PLoS Genet. 2023 Feb 27;19(2):e1010587. doi: 10.1371/journal.pgen.1010587. eCollection 2023 Feb.

ABSTRACT

Photoreceptor cells (PRCs) are the light-detecting cells of the retina. Such cells can be non-invasively imaged using optical coherence tomography (OCT) which is used in clinical settings to diagnose and monitor ocular diseases. Here we present the largest genome-wide association study of PRC morphology to date utilising quantitative phenotypes extracted from OCT images within the UK Biobank. We discovered 111 loci associated with the thickness of one or more of the PRC layers, many of which had prior associations to ocular phenotypes and pathologies, and 27 with no prior associations. We further identified 10 genes associated with PRC thickness through gene burden testing using exome data. In both cases there was a significant enrichment for genes involved in rare eye pathologies, in particular retinitis pigmentosa. There was evidence for an interaction effect between common genetic variants, VSX2 involved in eye development and PRPH2 known to be involved in retinal dystrophies. We further identified a number of genetic variants with a differential effect across the macular spatial field. Our results suggest a continuum between common and rare variation which impacts retinal structure, sometimes leading to disease.

PMID:36848389 | PMC:PMC9997913 | DOI:10.1371/journal.pgen.1010587