Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype.

OBJECTIVE: Mitochondrial complex-I deficiency, nuclear type 16, is a rare autosomal recessive disorder caused by biallelic pathogenic variants in NDUFAF5 (C20orf7) (OMIM 618238). The aim of this study was to describe a severe early prenatal manifestation of this disorder, which was previously considered to occur only postnatally. METHODS: This was a multicenter retrospective case series including five fetuses from three non-related families, which shared common sonographic abnormalities, including brain cysts, corpus callosal malformations, non-immune hydrops fetalis and growth restriction. Genetic evaluation included chromosomal microarray analysis and exome sequencing. Two fetuses from the same family were also available for pathology examination, including electron microscopy. RESULTS: Chromosomal microarray analysis revealed no chromosomal abnormality in any of the tested cases. Trio exome sequencing demonstrated that three affected fetuses from three unrelated families were compound heterozygous or homozygous for likely pathogenic variants in NDUFAF5. No other causative variants were detected. The association between NDUFAF5 variants and fetal malformations was further confirmed by segregation analysis. Histological evaluation of fetal tissues and electron microscopy of the skeletal muscle, liver, proximal tubules and heart demonstrated changes that resembled postmortem findings in patients with mitochondrial depletion disorders as well as previously undescribed findings. CONCLUSIONS: Mitochondrial complex-I deficiency and specifically biallelic mutations in NDUFAF5 have a role in abnormal fetal development, presenting with severe congenital malformations. Mitochondrial complex-I disorders should be considered in the differential diagnosis of corpus callosal malformations and brain cysts, especially when associated with extracranial abnormalities, such as fetal growth restriction and non-immune hydrops fetalis. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Clinical utility of expanded non-invasive prenatal screening compared with chromosomal microarray analysis in over 8000 pregnancies without major structural anomaly.

OBJECTIVES: To evaluate the theoretical added value of two types of non-invasive prenatal screening (NIPS) expansions in pregnancies without major structural anomalies over the commonly used NIPS for chromosomes 13, 18, 21, X and Y (5-NIPS) and to compare them with the added value of chromosomal microarray analysis (CMA). METHODS: This was a retrospective cohort study based on CMA results of all pregnancies with normal ultrasound (including pregnancies with soft markers and with abnormal maternal serum screening) that had undergone amniocentesis between January 2013 to February 2022 and were registered in the database of the Rabin Medical Center genetic laboratory. We calculated the theoretical yield of 5-NIPS and compared the added value of expanded 5-NIPS for common microdeletions (1p36.3-1p36.2, 4p16.3-4p16.2, 5p15.3-5p15.1, 15q11.2-15q13.1 and 22q11.2) and genome-wide NIPS (including variants > 5 Mb) with the added value of CMA in the overall cohort and in subgroups according to indication for invasive testing. RESULTS: Among the 8605 examined pregnancies, 122 (1.4%) clinically significant CMA results were demonstrated. Of these, 44 (36.1%) were theoretically detectable on 5-NIPS, with the rates of 1.56% in 642 pregnancies with abnormal maternal serum screening, 0.63% in 318 pregnancies with soft markers, 0.62% in 4378 women with advanced maternal age (≥ 35 years) and 0.15% in 3267 women younger than 35 years. In addition to aneuploidies detectable on 5-NIPS, three (0.03%) cases detectable on 5-NIPS expanded for common microdeletions and nine (0.10%) cases detectable on genome-wide NIPS (excluding common microdeletions) were identified in the overall cohort. The added value of expanded NIPS tools over 5-NIPS was significantly lower compared with that of CMA, for the overall cohort and subgroups. CONCLUSIONS: 5-NIPS and even genome-wide NIPS would miss 63.9% and 54.1% of clinically significant CMA findings, respectively. The added value of 5-NIPS expanded to detect common microdeletions over 5-NIPS is about 0.035%, and the overall added value of genome-wide NIPS aimed at large CNVs is about 0.14%, both much lower compared with the added value of CMA (0.91%). These findings should assist healthcare practitioners in guiding couples towards informed decision-making regarding the choice between prenatal invasive testing and NIPS. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

A novel founder MSH2 deletion in Ethiopian Jews is mainly associated with early-onset colorectal cancer.

Lynch syndrome is an inherited cancer predisposition syndrome caused by germline defects in any of the mismatch repair (MMR) genes. Diagnosis of carriers makes precision prevention, early detection, and tailored treatment possible. Herein we report a novel founder deletion of 18,758 bp, mediated by Alu repeats on both sides, detected in Ethiopian Jews. The deletion, which encompasses exon 9-10 of the MSH2 coding sequence, is associated mainly with early-onset MSH2/MSH6-deficient colorectal cancer (CRC) and liposarcoma. Testing of 35 members of 5 seemingly unrelated families of Ethiopian origin yielded 10/21 (48%) carriers, of whom 9 had CRC. Age at first tumor diagnosis ranged from 16 to 89 years. Carriers from the oldest generations were diagnosed after age 45 years (mean 57), and carriers from the younger generation were diagnosed before age 45 years (mean 30). Awareness of this founder deletion is important to improve patient diagnosis, institute surveillance from an early age, and refer patients for genetic counseling addressing the risk of bi-allelic constitutional MMR deficiency syndrome.

Women's responses and understanding of polygenic breast cancer risk information.

It is estimated that polygenic factors can explain up to 18% of familial breast cancer. Clinical implementation of polygenic testing has begun, with several commercial laboratories now testing. Despite commercial implementation, there is little research investigating how women respond and understand polygenic risk information. This study aimed to explore women's experience receiving their personalised polygenic risk score (PRS) and compare responses of women at different levels of polygenic risk. Eligible participants were affected and unaffected women from families clinically assessed to be at high risk for breast cancer who had received their personalised PRS as part of the Variants in Practice Psychosocial Study (ViPPs). In-depth semi-structured interviews were conducted with 21 women (mean age 53.4 years) up to four weeks after receiving their PRS. Interviews were transcribed verbatim and analysed using thematic analysis. Eleven women received a PRS that was in the top quartile of PRS distribution and 10 in the lowest quartile. Women's lived experience with breast cancer informed how they responded to their PRS, constructed and made sense of breast cancer risk following receipt of their PRS, and integrated this new information into their breast cancer risk management. Regardless of polygenic risk level, all participants demonstrated broad knowledge of concepts related to polygenic information and were able to accurately describe the implications of their PRS. Receiving PRS did not appear to negatively impact women's reported distress levels. Our findings suggest polygenic breast cancer information is well received and understood by women at high-risk for breast cancer.

Novel WWOX deleterious variants cause early infantile epileptic encephalopathy, severe developmental delay and dysmorphism among Yemenite Jews.

The human WW Domain Containing Oxidoreductase (WWOX) gene was originally described as a tumor suppressor gene. However, recent reports have demonstrated its cardinal role in the pathogenesis of central nervous systems disorders such as epileptic encephalopathy, intellectual disability, and spinocerebellar ataxia. We report on six patients from three unrelated families of full or partial Yemenite Jewish ancestry exhibiting early infantile epileptic encephalopathy and profound developmental delay. Importantly, four patients demonstrated facial dysmorphism. Exome sequencing revealed that four of the patients were homozygous for a novel WWOX c.517-2A > G splice-site variant and two were compound heterozygous for this variant and a novel c.689A > C, p.Gln230Pro missense variant. Complementary DNA sequencing demonstrated that the WWOX c.517-2A > G splice-site variant causes skipping of exon six. A carrier rate of 1:177 was found among Yemenite Jews. We provide the first detailed description of patients harboring a splice-site variant in the WWOX gene and propose that the clinical synopsis of WWOX related epileptic encephalopathy should be broadened to include facial dysmorphism. The increased frequency of the c.517-2A > G splice-site variant among Yemenite Jews coupled with the severity of the phenotype makes it a candidate for inclusion in expanded preconception screening programs.

Analysis of autofluorescence pattern in birdshot chorioretinopathy.

PURPOSE: To characterize and correlate the different patterns of fundus autofluorescence (FAF) in patients with birdshot chorioretinopathy (BSCR), with functional and anatomical parameters. METHODS: Twenty-one BSCR patients were prospectively studied in 2013 and 2014. Each patient underwent visual acuity (VA) and visual field (SITA standard 30.2) testing as well as fluorescein and indocyanine green angiography, spectral-domain optical coherence tomography (SD-OCT) B scan, enhanced depth imaging (EDI), and fundus autofluorescence (FAF) imaging. The disease was classified as active, chronic, or quiescent. RESULTS: The patients' mean age was 60.3 ± 9.2 years and 60% were female. Disease duration was 5.7 ± 3.7 years. Autofluorescence imaging showed punctiform hyper-FAF spots in 23 out of the 29 eyes (79%), which was significantly associated with a greater visual field mean deviation (-7 ± 7 versus -3 ± 2 dB, p = 0.04). Hypo-FAF was defined as peripapillary (n = 25; 86.2%), macular (n = 10; 34.5%), lichenoid (n = 17; 58.6%), and/or diffuse (n = 13; 44.8%). Lichenoid hypo-FAF was significantly associated with worse VA (0.18 ± 0.24 vs. 0.05 ± 0.07 LogMAR, p = 0.04). Macular hypo-FAF was associated with a history of macular edema (62.5%; p = 0.06). Diffuse hypo-FAF was observed more frequently (p = 0.01) in chronic disease (66.7%) than in active (0%) or quiescent disease (27.3%). CONCLUSIONS: Autofluorescence analysis in BRSC patients contributes to evaluating disease activity and could be useful to guide follow-up and treatment.

The long-term clinical and radiological outcomes in patients who suffer recurrent injuries to the anterior cruciate ligament after reconstruction.

AIMS: The aim of this study was to investigate the long-term clinical and radiological outcome of patients who suffer recurrent injuries to the anterior cruciate ligament (ACL) after reconstruction and require revision surgery. PATIENTS AND METHODS: From a consecutive series of 200 patients who underwent primary reconstruction following rupture of the ACL, we identified 36 who sustained a further rupture, 29 of whom underwent revision surgery. Patients were reviewed prospectively at one, two, seven, 15 and about 20 years after their original surgery. Primary outcome measures were the number of further ruptures, the posterior tibial slope (PTS), and functional and radiological outcomes. These were compared with a gender and age matched cohort of patients who underwent primary ACL reconstruction only. RESULTS: At a mean follow-up of 18.3 years (14.3 to 20.2), 29 patients had undergone revision surgery and within this revision group 11 had sustained more than three ruptures of the ACL (3 to 6). The mean age at the time of revision reconstruction was 26.4 years (14 to 54). The mean PTS was significantly higher in those patients who suffered a further injury to the ACL (11°) compared with the control group (9°) (p < 0.001). The mean PTS in those patients who sustained more than three ruptures was 12°. CONCLUSION: Patients who suffer recurrent injuries to the ACL after reconstruction have poorer functional and radiological outcomes than those who suffer a single injury. The causes of further injury are likely to be multifactorial but an increased PTS appears to have a significant association with recurrent ACL injuries. Cite this article: Bone Joint J 2017;99-B:337-43.

Elastic coupling between spin-crossover particles and cellulose fibers.

Composite materials made of cellulose fibers and spin crossover micro-particles were investigated by magnetic measurements and dynamic mechanical analysis (DMA). The storage modulus of the cellulose handsheet (0.6 GPa at room T) is significantly enhanced in the composite (1.7 GPa). The latter also displays a reversible increase of ca. 10% when switching the magnetic spin state of the particles from the low spin (LS) to the high spin (HS) form. Around the spin transition temperature a loss modulus peak is also observed, highlighting the strong viscoelastic coupling between the particles and the cellulose matrix. These results pave the way for the development of a novel family of actuator materials based on spin crossover-polymer composites.

Follow-up after surgery for hemorrhagic AMD.

INTRODUCTION: The long-term functional results of macular hematoma (MH) surgery in exudative AMD are often limited. The goal of this study was to compare visual outcomes of monthly versus bimestrial follow-up in these patients. METHODS: Retrospective, interventional case series. Population : 21 eyes of 21 patients with SMH associated with exudative AMD. INCLUSION CRITERIA: first SMH associated with exudative AMD, with 1-year postoperative follow-up. EXCLUSION CRITERIA: blood located exclusively underneath the retinal pigment epithelium on OCT imaging, SMH due to different etiology, lost to follow-up, ≤5 postoperative visits and a different surgical protocol as described. Patients were divided into two groups according to the number of postoperative visits (number of intravitreal injections [IVT] combined with the number of consultations, only one visit was recorded when IVT and consultation occurred on the same day) during the 1-year postoperative follow-up: group 1 had ≥11 visits (n=8); group 2 had 6 to 10 visits (n=13). All eyes underwent vitrectomy with subretinal injection of recombinant tissue plasminogen activator, fluid-gas exchange and anti-VEGF intravitreal injection. The main outcome was change in best-corrected visual acuity (BCVA). RESULTS: Considering visual acuity (VA) change between 1-month and 1-year postoperative follow-up examinations, group 1 had statistically significant greater VA changes (logMAR -0.29±0.44 vs logMAR 0.42±0.73; P=0.016; P=0.016). In patients that had exudative recurrences (ER), group 1 received more anti-VEGF IVT than group 2 (P=0.045). CONCLUSION: Our results showed that monthly follow-up, between the IVT series, is highly recommended to preserve postoperative VA in patients undergoing surgery for SMH associated with AMD.

Total knee arthroplasty with an oxidised zirconium femoral component: ten-year survivorship analysis.

AIMS: Oxidised zirconium was introduced as a material for femoral components in total knee arthroplasty (TKA) as an attempt to reduce polyethylene wear. However, the long-term survival of this component is not known. METHODS: We performed a retrospective review of a prospectively collected database to assess the ten year survival and clinical and radiological outcomes of an oxidised zirconium total knee arthroplasty with the Genesis II prosthesis. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS) and a patient satisfaction scale were used to assess outcome. RESULTS: A total of 303 consecutive TKAs were performed in 278 patients with a mean age of 68 years (45 to 89). The rate of survival ten years post-operatively as assessed using Kaplan-Meier analysis was 97% (95% confidence interval 94 to 99) with revision for any reason as the endpoint. There were no revisions for loosening, osteolysis or failure of the implant. There was a significant improvement in all components of the WOMAC score at final follow-up (p < 0.001). The mean individual components of the KOOS score for symptoms (82.4 points; 36 to 100), pain (87.5 points; 6 to 100), activities of daily life (84.9 points; 15 to 100) and quality of life (71.4 points; 6 to 100) were all at higher end of the scale. DISCUSSION: This study provides further supportive evidence that the oxidised zirconium TKA gives comparable rates of survival with other implants and excellent functional outcomes ten years post-operatively. TAKE HOME MESSAGE: Total knee arthroplasty with an oxidised zirconium femoral component gives comparable long-term rates of survival and functional outcomes with conventional implants.

Enhanced luminescence stability with a Tb-spin crossover nanocomposite for spin state monitoring.

[Fe(Htrz)2(trz)]BF4@SiO2 nanorods were synthesized using a reverse emulsion technique and a Tb(3+) complex was chemically bound to the silica surface. This Tb-spin crossover nanocomposite demonstrates high luminescence stability under continuous thermal cycling. A reabsorption mechanism is determined to be responsible for the luminescence intensity variation during the spin state switching of the iron complex.

The outcome at ten years of lateral closing-wedge high tibial osteotomy: determinants of survival and functional outcome.

The aim of this study was to examine the functional outcome at ten years following lateral closing wedge high tibial osteotomy for medial compartment osteoarthritis of the knee and to define pre-operative predictors of survival and determinants of functional outcome. 164 consecutive patients underwent high tibial osteotomy between 2000 and 2002. A total of 100 patients (100 knees) met the inclusion criteria and 95 were available for review at ten years. Data were collected prospectively and included patient demographics, surgical details, long leg alignment radiographs, Western Ontario and McMaster Universities osteoarthritis index (WOMAC) and Knee Society scores (KSS) pre-operatively and at five and ten years follow-up. At ten years, 21 patients had been revised at a mean of five years. Overall Kaplan-Meier survival was 87% (95% confidence interval (CI) 81 to 94) and 79% (95% CI 71 to 87) at five and ten years, respectively. When compared with unrevised patients, those who had been revised had significantly lower mean pre-operative WOMAC Scores (47 (21 to 85) vs 65 (32 to 99), p < 0.001), higher mean age (54 yrs (42 to 61) vs 49 yrs (26 to 66), p = 0.006) and a higher mean BMI (30.2; 25 to 39 vs 27.9; 21 to 36, p = 0.005). Each were found to be risk factors for revision, with hazard ratios of 10.7 (95% CI 4 to 28.6; pre-operative WOMAC < 45), 6.5 (95% CI 2.4 to 17.7; age > 55) and 3.0 (95%CI 1.2 to 7.6; BMI > 30). Survival of patients with pre-operative WOMAC > 45, age < 55 and BMI < 30 was 97% at five and ten years. WOMAC and KSS in surviving patients improved significantly between pre-operative (mean 61; 32 to 99) and five (mean 88; 35 to 100, p = 0.001) and ten years (mean 84; 38 to 100, p = 0.001). Older patients had better functional outcomes overall, despite their higher revision rate. This study has shown that improved survival is associated with age < 55 years, pre-operative WOMAC scores > 45 and, a BMI < 30. In patients over 55 years of age with adequate pre-operative functional scores, survival can be good and functional outcomes can be significantly better than their younger counterparts. We recommend the routine use of pre-operative functional outcome scores to guide decision-making when considering suitability for high tibial osteotomy.

[Multimodal imaging in the diagnosis of acute macular neuroretinopathy]. / Intérêt de l'imagerie multimodale dans le diagnostic de neurorétinopathie maculaire aiguë

INTRODUCTION: Acute macular neuroretinopathy is a retinal disease, usually presenting with a "normal fundus". Thus, this condition can be mistaken for optic neuropathy. Herein we present five clinical cases of patients affected with acute macular neuroretinopathy; one of them is a retrospective diagnosis while the others were diagnosed on initial examination. In the five cases, multimodal imaging with infrared photography and OCT helped to establish the diagnosis. MATERIAL AND METHODS: Retrospective study of five clinical cases. Initial and final best visual acuities as well as infrared and OCT imaging were collected for all patients. RESULTS: All patients initially reported a visual disturbance associated with a more or less severe decrease in visual acuity. Infrared imaging showed a dark, perifoveolar appearance of the lesions. In all cases, OCT images showed thickening and hyperreflectivity of the outer plexiform layer, extending towards the outer retinal layers. CONCLUSION: Acute macular neuroretinopathy is a clinical entity that has been long-described, which now benefits widely from new imaging technologies, allowing an earlier and more accurate diagnosis, but calling into question the actual name of this condition. The exact pathophysiology of the condition remains nonetheless incompletely elucidated.

Incidence of graft rupture 15 years after bilateral anterior cruciate ligament reconstructions: a case-control study.

Between 1993 and 1994, 891 patients underwent primary anterior cruciate ligament (ACL) reconstruction. A total of 48 patients had undergone bilateral ACL reconstruction and 42 were available for review. These patients were matched to a unilateral ACL reconstruction control group for gender, age, sport of primary injury, meniscal status and graft type. At 15-year follow-up a telephone interview with patients in both groups was performed. The incidence of further ACL injury was identified through structured questions and the two groups were compared for the variables of graft rupture or further ACL injury, family history of ACL injury, International Knee Documentation Committee (IKDC) subjective score and activity level. There were 28 male and 14 female patients with a mean age of 25 years (13 to 42) at the time of first ACL injury. Subsequent further ACL injury was identified in ten patients (24%) in the bilateral ACL reconstruction study group and in nine patients (21%) in the unilateral ACL reconstruction control group (p = 0.794). The mean time from bilateral ACL reconstruction to further ACL injury was 54 months (6 to 103). There was no significant difference between the bilateral ACL reconstruction study group and the matched unilateral ACL reconstruction control group in incidence of further ACL injury (p = 0.794), family history of ACL injury (p = 0.595), IKDC activity level (p = 0.514), or IKDC subjective score (p = 0.824). After bilateral ACL reconstruction the incidence of graft rupture and subjective outcomes were equivalent to that after unilateral ACL reconstructions.

The incidence of secondary pathology after anterior cruciate ligament rupture in 5086 patients requiring ligament reconstruction.

We reviewed 5086 patients with a mean age of 30 years (9 to 69) undergoing primary reconstruction of the anterior cruciate ligament (ACL) in order to determine the incidence of secondary pathology with respect to the time between injury and reconstruction. There was an increasing incidence of medial meniscal tears and chondral damage, but not lateral meniscal tears, with increasing intervals before surgery. The chances of requiring medial meniscal surgery was increased by a factor of two if ACL reconstruction was delayed more than five months, and increased by a factor of six if surgery was delayed by > 12 months. The effect of delaying surgery on medial meniscal injury was also pronounced in the patients aged < 17 years, where a delay of five to 12 months doubled the odds of medial meniscal surgery (odds ratio (OR) 2.0, p = 0.001) and a delay of > 12 months quadrupled the odds (OR 4.3, p = 0.001). Increasing age was associated with a greater odds of chondral damage (OR 4.6, p = 0.001) and medial meniscal injury (OR 2.9, p = 0.001), but not lateral meniscal injury. The gender split (3251 men, 1835 women) revealed that males had a greater incidence of both lateral (34% (n = 1114) vs 20% (n = 364), p = 0.001) and medial meniscal tears (28% (n = 924) vs 25% (n = 457), p = 0.006), but not chondral damage (35% (n = 1152) vs 36% (n = 665), p = 0.565). We conclude that ideally, and particularly in younger patients, ACL reconstruction should not be delayed more than five months from injury.

The outcome at 15 years of endoscopic anterior cruciate ligament reconstruction using hamstring tendon autograft for 'isolated' anterior cruciate ligament rupture.

The purpose of this study was to report the outcome of 'isolated' anterior cruciate ligament (ACL) ruptures treated with anatomical endoscopic reconstruction using hamstring tendon autograft at a mean of 15 years (14.25 to 16.9). A total of 100 consecutive men and 100 consecutive women with 'isolated' ACL rupture underwent four-strand hamstring tendon reconstruction with anteromedial portal femoral tunnel drilling and interference screw fixation by a single surgeon. Details were recorded pre-operatively and at one, two, seven and 15 years post-operatively. Outcomes included clinical examination, subjective and objective scoring systems, and radiological assessment. At 15 years only eight of 118 patients (7%) had moderate or severe osteo-arthritic changes (International Knee Documentation Committee Grades C and D), and 79 of 152 patients (52%) still performed very strenuous activities. Overall graft survival at 15 years was 83% (1.1% failure per year). Patients aged < 18 years at the time of surgery and patients with > 2 mm of laxity at one year had a threefold increase in the risk of suffering a rupture of the graft (p = 0.002 and p = 0.001, respectively). There was no increase in laxity of the graft over time. ACL reconstructive surgery in patients with an 'isolated' rupture using this technique shows good results 15 years post-operatively with respect to ligamentous stability, objective and subjective outcomes, and does not appear to cause osteoarthritis.