Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion

Cataloged from PDF version of article.Cerebellar ataxia, mental retardation and dysequilibrium syndrome is a rare and heterogeneous condition. We investigated a consanguineous family from Turkey with four affected individuals exhibiting the condition. Homozygosity mapping revealed that several shared homozygous regions, including chromosome 13q12. Targeted next-generation sequencing of an affected individual followed by segregation analysis, population screening and prediction approaches revealed a novel missense variant, p.I376M, in ATP8A2. The mutation lies in a highly conserved C-terminal transmembrane region of E1 E2 ATPase domain. The ATP8A2 gene is mainly expressed in brain and development, in particular cerebellum. Interestingly, an unrelated individual has been identified, in whom mental retardation and severe hypotonia is associated with a de novo t(10;13) balanced translocation resulting with the disruption of ATP8A2. These findings suggest that ATP8A2 is involved in the development of the cerebro-cerebellar structures required for posture and gait in humans. © 2013 Macmillan Publishers Limited All rights reserved

MAB21L1 loss of function causes a syndromic neurodevelopmental disorder with distinctive cerebellar, ocular, craniofacial and genital features (COFG syndrome).

BACKGROUND: Putative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs. OBJECTIVE: A homozygous truncating variant in MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. We employed a combination of exome sequencing and homozygosity mapping to identify the underlying genetic cause in subjects with similar phenotypic features descending from five unrelated consanguineous families. RESULTS: We identified four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cardinal features of this syndrome include a characteristic facial gestalt, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds and scrotum/scrotal agenesis as well as cerebellar hypoplasia with ataxia and variable microcephaly. CONCLUSION: This report defines an ultrarare but clinically recognisable Cerebello-Oculo-Facio-Genital syndrome associated with recessive MAB21L1 variants. Additionally, our findings further support the critical role of MAB21L1 in cerebellum, lens, genitalia and as craniofacial morphogenesis

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Comparison of rigid and flexible transbronchial needle aspiration in the staging of bronchogenic carcinoma

Annual Meeting of the European-Respiratory-Society -- SEP 16-20, 1995 -- BARCELONA, SPAINWOS: 000077319000004PubMed ID: 9817958In staging bronchogenic carcinoma by transbronchial needle aspiration (TBNA), rigid histology needles are generally preferred to flexible cytology needles owing to the widespread opinion that rigid needles have higher diagnostic yield and less false-positive results. The objective of this study was to compare the efficacy and safety of the rigid and flexible TBNAs in staging bronchogenic carcinoma to establish whether a flexible cytology needle method can replace the rigid needle. A prospective study was conducted in 138 consecutive patients with extra- or endobronchial masses suggestive of bronchogenic carcinoma and amenable to surgical procedures. All 8 mm and larger paratracheal, carinal, hilar and/or main bronchial lymph nodes determined before bronchoscopy by computed tomography (CT) were sampled by successive 18-gauge rigid and 21-gauge flexible TBNAs in the same session. The anatomic landmarks were followed precisely during TBNAs, and a proper technique applied in sampling and specimen processing. Malignant lymph node involvement was specified in 97 (72%) cases of bronchogenic carcinoma by rigid, and in 89 (66%) by flexible TBNA. There were 4 (100%) benign cases (3 with tuberculosis and 1 with sarcoidosis) of 101 (73%) with positive rigid TBNAs (82 with histological and 19 with cytological specimens). TBNAs determined malignant lymph node involvement :in a total of 104 (78%) patients. Of 30 TBNA-negative patients, 14 were proven to have false-negative TBNAs by mediastinoscopy/mediastinotomy/minithoracotomy, and 16 to have true-negative TBNAs by thoracotomy. Thoracotomy confirmed true positivity in 52 rigid and 49 flexible TBNAs, and false negativity in 4 rigid and 7 flexible TBNAs. Further staging was confirmed in these 7 cases. Four had proven false negative results by both methods. The presence of small cell carcinoma (21) or N-3 disease (27) presented a contraindication to thoracotomy in 48 TBNA-positive patients. Adequate-quality and malignant lymph node specimens were more frequently obtained by both techniques at advanced tumor and node stages. However, malignant lymph node invasion was significantly more frequent in rigid and flexible TBNA specimens only in the presence of advanced tumor status and abnormal endoscopic appearance. The sensitivities of rigid and flexible TBNAs were 74 and 70%, respectively (p > 0.05), but both had a specificity of 100%. Neither false-positive results nor serious complications other than hemorrhage of 30-100 mi (rigid: 5%, flexible: 2%)were encountered with either technique. These results indicate that in bronchogenic carcinoma, hilar and mediastinal lymph nodes can be staged by 21-gauge flexible TBNA (76%) as accurately as by 18-gauge rigid TBNA (79%) if a proper technique is applied and anatomic landmarks are followed precisely (p > 0.05).European Resp So

Hereditary haemochromatosis gene (HFE) H63D mutation shows an association with abnormal sperm motility

The aim of this study was to screen infertile men for HFE H63D mutation in correlation with clinical characteristics of infertile men (sperm concentration, sperm motility, morphology, testicular volume, Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH) and total Testosterone levels) and find out if the HFE H63D mutation has an effect on male infertility. After excluding hormonal treatment, any scrotal pathology, having any systemic diseases such as diabetes mellitus, sickle cell anemia and microdeletions of the Y chromosome, a total of 148 infertile men with age range between 17 and 52-years-old (average age 29.6 ± 7.2) were enrolled into the study. Our analysis indicates that the mean FSH levels are significantly higher (6.3 ± 4.6 mIU/ml, P = 0.03), whereas sperm motility is significantly lower (36.6 ± 28.1%, P = 0.01) in the infertile men with the HFE H63D mutation compared with subjects lacking this mutation. Comparison of allele frequencies of the infertile men with Ts 50% revealed a significant difference as expected (P = 0.001, OR = 0.14, %95 CI = 0.04-0.44). Comparison of allele frequencies of infertile men with abnormal sperm motility versus infertile men with normal sperm motility revealed a highly significant difference (P = 0.005, OR = 3.11, %95 CI = 1.41-6.86). Thus, the HFE H63D mutation seems to be an important risk factor for impaired sperm motility and is clinically associated with male infertility. © 2008 Springer Science+Business Media B.V.KÜ AF 03/08.01.03Acknowledgments This work was supported by Kirikkale University Research Found (KÜ AF 03/08.01.03). We thank the infertility patients who made this analysis possible

hip dysplasia

The aim of this prospective study was to evaluate the outcome of open reduction and Tonnis acetabuloplasty as the first method of treating developmental dysplasia of the hip (DDH) in children in early childhood at walking age.Between 2005 and 2009, 34 hips of 34 children were operated on with the aforementioned method. Mean age was 25.6 (range 12-44) months, and mean follow-up was 3.6 years. During the follow-up period ,the hips were evaluated using the acetabular index and for development of avascular necrosis and redislocation. Functional evaluation was also conducted.Clinically, 97.3 % of patients had excellent and good results. The acetabular angle decreased from 45A degrees preoperatively to 21A degrees early postoperatively and at the last follow-up had improved to 18A degrees. In two hips, type 2 avascular necrosis developed. Hip instability was not observed, and no additional surgery was performed.Tonnis acetabuloplasty is a powerful tool to increase primary stability of the hip when acetabular coverage is inadequate in DDH. Besides its acute correction ability, when performed properly, it has no unwanted effects on acetabular growth. As an isolated procedure or as a part of combined open reduction and/or femoral osteotomy, Tonnis type acetabuloplasty is a safe and effective method