Association of the apoptotic markers Apo1/Fas and cCK-18 and the adhesion molecule ICAM-1 with Type 1 diabetes mellitus in children and adolescents.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is characterized by immune and metabolic dysregulation. Apo1/Fas is implicated in maintaining homeostasis of the immune system. Cytokeratin-18 (cCK-18) is a predictive marker of liver disorders in T2DM. Intercellular adhesion molecule-1 (ICAM-1) is considered to increase susceptibility to diabetes mellitus. All three markers are associated with endothelial function, apoptosis and diabetes-related complications. The possible role of Apo1/Fas, cCK-18 and ICAM-1 was investigated in children and adolescents with T1DM. METHOD: Forty-nine (49) children and adolescents with T1DM and 49 controls were included in the study. Somatometric measurements were obtained and the Body Mass Index (BMI) of the participants was calculated. Biochemical parameters were measured by standard laboratory methods and Apo1/Fas, cCK-18 and ICAM-1 were measured using appropriate ELISA kits. The statistical analysis was performed using the IBM SPSS Statistics 23 program. RESULTS: Apo1/Fas (p = 0.001), cCK-18 (p < 0.001) and ICAM-1 (p < 0.001) were higher in patients with T1DM compared to the controls. Apo1Fas was negatively correlated with glucose (p = 0.042), uric acid (p = 0.026), creatinine (p = 0.022), total cholesterol (p = 0.023) and LDL (p = 0.005) in the controls. In children and adolescents with T1DM, Apo1/Fas was positively correlated with total cholesterol (p = 0.013) and LDL (p = 0.003). ICAM-1 was negatively correlated with creatinine (p = 0.019) in the controls, whereas in patients with T1DM it was negatively correlated with HbA1c (p = 0.05). CONCLUSIONS: Apo1/Fas, cCK-18 and ICAM-1 may be useful as serological markers for immune and metabolic dysregulation in children and adolescents with T1DM. Also, Apo1/Fas may have a protective role against metabolic complications in healthy children.

OUTER RETINAL MICROCAVITATIONS IN RETINITIS PIGMENTOSA : A Novel Optical Coherence Tomography Finding Common in RP1 -Related Retinopathy.

PURPOSE: To describe a novel optical coherence tomography (OCT) finding of outer retina microcavitations in RP1 -related retinopathy and other retinal degenerations. METHODS: Medical charts and OCT images of 28 patients with either autosomal dominant retinitis pigmentosa or autosomal recessive retinitis pigmentosa RP1 -related retinopathy were reviewed. Outer retina microcavitations were defined as hyporeflective OCT structures of at least 30 µ m in diameter between the ellipsoid zone and retinal pigment epithelium. Comparison was made based on the following metrics: (1) functional measures including best-corrected visual acuity and color discrimination errors on D-15 test; and (2) structural measures, including central subfield, average macular thickness, and preserved transfoveal ellipsoid zone width. Mann-Whitney tests were used for comparisons with significance set at P < 0.05. The specificity of microcavitations for RP1 -related retinopathy was estimated against 26 patients with non- RP1 retinitis pigmentosa. RESULTS: Among 15 included patients, microcavitations were found in at least one eye of all patients with arRP and 7/12 (58%) of patients with adRP. Patients with adRP and microcavitations were older at the time of examination (51 vs. 43 years of age; P = 0.04) and their eyes demonstrated worse best-corrected visual acuity (0.09 vs. 0 logMAR; P = 0.008), reduced central subfield (256 vs. 293 µ m; P = 0.01), average macular thickness (241 vs. 270 µ m; P = 0.02), and shorter transfoveal ellipsoid zone widths (1.67 vs. 4.98 mm; P < 0.0001). The finding of microcavitations showed a specificity of 0.92 for RP1 -related retinopathy. CONCLUSION: A novel OCT finding of outer retina microcavitations was commonly observed in patients with RP1 -related retinopathy. Eyes with outer retinal OCT microcavitations had worse visual function and more affected central retinal structure.

Safety and Efficacy of Adeno-Associated Viral Gene Therapy in Patients With Retinal Degeneration: A Systematic Review and Meta-Analysis.

Purpose: This systematic review evaluates the safety and efficacy of ocular gene therapy using adeno-associated virus (AAV). Methods: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched systematically for controlled or non-controlled interventional gene therapy studies using key words related to retinal diseases, gene therapy, and AAV vectors. The primary outcome measure was safety, based on ocular severe adverse events (SAEs). Secondary outcome measures evaluated efficacy of the therapy based on best corrected visual acuity (BCVA) and improvements in visual sensitivity and systemic involvement following ocular delivery. Pooling was done using a DerSimonian Laird random effects model. Risk of bias was assessed using the Cochrane Risk of Bias Tool, version 1. Results: Our search identified 3548 records. Of these, 80 publications met eligibility criteria, representing 28 registered clinical trials and 5 postmarket surveillance studies involving AAV gene therapy for Leber congenital amaurosis (LCA), choroideremia, Leber hereditary optic neuropathy (LHON), age-related macular degeneration (AMD), retinitis pigmentosa (RP), X-linked retinoschisis, and achromatopsia. Overall, AAV therapy vectors were associated with a cumulative incidence of at least one SAE of 8% (95% confidence intervals [CIs] of 5% to 12%). SAEs were often associated with the surgical procedure rather than the therapeutic vector itself. Poor or inconsistent reporting of adverse events (AEs) were a limitation for the meta-analysis. The proportion of patients with any improvement in BCVA and visual sensitivity was 41% (95% CIs of 31% to 51%) and 51% (95% CIs of 31% to 70%), respectively. Systemic immune involvement was associated with a cumulative incidence of 31% (95% CI = 21% to 42%). Conclusions: AAV gene therapy vectors appear to be safe but the surgical procedure required to deliver them is associated with some risk. The large variability in efficacy can be attributed to the small number of patients treated, the heterogeneity of the population and the variability in dosage, volume, and follow-up. Translational Relevance: This systematic review will help to inform and guide future clinical trials.

AAV2-Mediated Gene Therapy for Choroideremia: 5-Year Results and Alternate Anti-sense Oligonucleotide Therapy.

PURPOSE: To assess the long-term safety and efficacy of AAV2-REP1 in choroideremia (CHM) patients, and to test a potential antisense oligonucleotide therapy for CHM. DESIGN: Extended, prospective phase 1/2 clinical trial and laboratory investigation. METHODS: Five patients who received a single subfoveal injection of AAV2-REP1 were studied. The long-term safety was evaluated by ophthalmic examination, spectral domain optical coherence tomography, and fundus autofluorescence (FAF) for up to 5 years. Functional and structural changes were determined by different test modalities. Four antisense oligonucleotides (ASOs) were designed to treat the CHM c.1245-521A>G mutation, which was present in 2 patients within this trial. RESULTS: Subject P3 experienced a localized intraretinal immune response that resulted in a significant loss of preserved retinal pigment epithelium (RPE). P4 experienced an exacerbation of peripheral retinoschisis. P2 had a constant ≥15-letter best-corrected visual acuity (BCVA) gain in the treated eye, whereas P5 had ≥15-letter BCVA improvement once in the untreated eye. The preserved FAF areas declined more rapidly in the treated eyes compared to the untreated eyes (P = .043). A customized 25-mer ASO recovered 83.2% to 95.0% of the normal RNA and 57.5% of the normal protein in fibroblasts from 2 trial patients. CONCLUSIONS: Intraretinal inflammation triggered by AAV2-REP1 subretinal injection stabilized after 2 years but resulted in permanent damage to the retinal structure. Long-term progression of the disease was seen in both treated and untreated eyes, casting doubt as to the effectiveness of this approach in late-stage CHM. Alternative approaches such as ASO may have a therapeutic effect in a subgroup of CHM patients.

[Achalasia Update]. / Update Achalasie.

Achalasia Update Abstract. The neurodegenerative disease achalasia (obsolete: "cardiac spasm") is the second most common functional disease of the esophagus after reflux disease. It is associated with an extremely high level of suffering for the patient. Pathophysiologically, it is a combination of a lack of swallowing-reflex relaxation at the gastric entrance and disturbed peristalsis of the tubular esophagus. The gold standard in diagnostics is high-resolution manometry. The disease cannot be cured, the therapeutic spectrum that alleviates the disease includes pharmaceutical, endoscopic-interventional and surgical procedures.

[Curative Treatment of Esophageal Carcinoma - Disease, Diagnostics, Therapy in 2022]. / Kurative Therapie des Ösophaguskarzinomes.

Curative Treatment of Esophageal Carcinoma - Disease, Diagnostics, Therapy in 2022 Abstract. Surgical resection remains the gold standard for non-metastatic carcinoma of the lower and middle third of the esophagus. Locally advanced tumors (T3) are pretreated neoadjuvantly (radiochemotherapy) or perioperatively (chemotherapy). A differentiated primary staging and an interdisciplinary case presentation are of essential importance today. The individual risk assessment, the pre-habilitation and the individualized treatment play a major role. Clinically, the further advancement of access minimization - through laparoscopic/thoracoscopic and robot-assisted procedures and the associated reduction of access trauma - as well as the treatment of this entity in high volume centers are clearly in the foreground. For cervical carcinomas definitive radiotherapy is often the better alternative, both for tumor biological reasons and for reasons of the increase in complications during surgery.

Emotional intelligence scores in children and adolescents with subclinical hypothyroidism-correlation with serum serotonin and thyroid-stimulating hormone (TSH) concentrations.

INTRODUCTION: Thyroxine is essential for nervous system development. Subclinical hypothyroidism (SCH), also known as mild thyroid failure, is associated with impaired cognitive function in children and mood disorders in adults. Serotonin is also involved in brain development as well as in mood and behavior modulation. The possible interaction between thyroid function tests, serum serotonin concentrations, and emotional intelligence (EI) was studied. METHODS: A total of 224 schoolchildren from the Peloponnese, Greece, aged 11-19, were included in the study, of whom 26.3% had SCH. Emotional quotients (EQ), such as well-being, self-control, emotionality, and sociability, were assessed using the TEIQue-ASF questionnaire, and TSH, fT4, and serum serotonin concentrations were also evaluated. RESULTS: Children and adolescents with SCH had a lower EQ total score (p < 0.001), EQ well-being score (p = 0.025), EQ self-control score (p = 0.029), EQ emotionality score (p = 0.029), and EQ sociability score (p = 0.010) and lower serum serotonin concentrations (p < 0.001). CONCLUSIONS: Children and adolescents with SCH exhibited lower EI scores and lower serum serotonin concentrations when compared with age-matched healthy controls.

Association of the apoptotic marker APO1/Fas with children's predisposing factors for metabolic syndrome and with mean platelet volume.

BACKGROUND: Apoptosis antigen 1/FAS receptor (APO1/Fas) signaling in endothelial cells plays a significant role in angiogenesis while increased mean platelet volume (MPV) is an important marker for platelet activation. We investigated the possible correlation between APO1/Fas and both metabolic parameters and platelet activity (indicated by the MPV) in a healthy pediatric population. METHODS: One hundred and eighty-five children, aged 5-17 years old, were enrolled in the study. The participants were divided into subgroups according to their age and body mass index percentile (BMI%). APO1/Fas was measured by enzyme-linked immunosorbent assay (ELISA) and MPV by the MEK-6410K. RESULTS: Eighty-one children (43.8%) had excess weight, which was more prevalent in children ≤9 years of age. Sixty-five children (35.1%) exhibited a predisposition for metabolic syndrome. A negative correlation was found between APO1/Fas and predisposing factors for metabolic syndrome: Glucose, cholesterol, uric acid, low-density lipoprotein (LDL), and triglycerides. In contrast, a positive correlation was found between APO1/Fas and C-reactive protein (CRP). Receiver operating characteristic (ROC) analysis showed a predisposition to metabolic syndrome when APO1/Fas was <78.46 pg/mL. A negative correlation was also observed between APO1/Fas and MPV. MPV was also positively correlated with predisposing factors for metabolic syndrome: BMI%, glucose, cholesterol, uric acid, LDL, and negatively with high-density lipoprotein. CONCLUSIONS: APO1/Fas expression is associated with a lower predisposition to metabolic syndrome may be through endothelial homeostasis, the induction of apoptosis of cells involved in atherosclerosis, and platelet activity. It may also enhance CRP-mediated noninflammatory clearance of apoptotic cells. Early monitoring of all the components of metabolic syndrome in overweight children is important in order to prevent metabolic and cardiovascular complications.

[Results of pancreatic surgery from the perspective of patients: a cross-sectional study of the support group "Arbeitskreis der Pankreatektomierten e. V."] / Ergebnisse nach Pankreaseingriffen aus Sicht der Betroffenen: Versorgungsforschung der Selbsthilfegruppe "Arbeitskreis der Pankreatektomierten e. V.".

BACKGROUND: The support group "Arbeitskreis der Pankreatektomierten e. V. (AdP)" was founded in 1976 and is the largest group of individuals affected by pancreatic disease in Germany. Members of the AdP support patients with pancreatic disease. This patient-initiated, cross-sectional study intends to present the results of pancreatic surgery from the perspective of patients. METHODS: Since March the 3 rd, 2018, members of the AdP received a questionnaire with eleven categories of questions concerning their medical history. This data was gathered in a medical database and analysed. RESULTS: 625 members were operated upon, with 57.5 % receiving pancreaticoduodenectomy, 15.5 % distal pancreatectomy, 23.2 % total pancreatectomy, and 4.0 % another or unknown operation. 37.9 % were diagnosed with pancreatic cancer, 38.2 % with another type of pancreatic tumour, 25 % with pancreatitis, 4 % with autoimmune pancreatitis and 2.7 % with other rare entities.82 patients of 237 pancreatic cancer patients survived more than 5 years. 24.5 % of the 237 patients reported have a second primary malignancy and 13.9 % have close family members with pancreatic cancer.Weight loss after pancreatic surgery was dependant on the type of operation with the greatest after pancreatectomy (17.8 ±â€Š9.5 kg). The prevalence of diabetes was 54.1 %, the incidence of new onset perioperative diabetes 33.3 %. 91.5 % needed pancreatic enzyme replacement therapy, on average 189 417 IE/day. The reported quality of life was independent from type of surgery received. CONCLUSION: Following complex pancreatic surgery, patients are confronted with daily lifelong challenges. AdP members offering their shared experiences offer meaningful support to newly affected patients. Individuals affected by pancreatic disease could be an important but underutilised resource to studying these diseases.

Inner Retinal Morphology and Visual Outcomes in Idiopathic Epiretinal Membrane Surgery: A Retrospective Optical Coherence Tomography Study.

Purpose: Epiretinal membrane (ERM) is a common retinal finding for patients older than 50 years. Disorganization of the retinal inner layers (DRIL) has emerged as a novel predictor of poor visual acuity (VA) in eyes with inner retinal pathology. The aim of our study is to correlate preoperative DRIL with visual outcomes after ERM surgery. Methods: Medical records and optical coherence tomography (OCT) images of 81 pseudophakic patients who underwent treatment of idiopathic ERM were reviewed. Preoperative DRIL on OCT was correlated with VA at baseline and at 3 and 6 months after ERM surgery. DRIL was defined as the loss of distinction between the ganglion cell-inner plexiform layer complex, inner nuclear layer, and outer plexiform layer. DRIL severity was based on its extent within the central 2-mm region of a transfoveal B-scan (absent/mild: one-third horizontal width). Results: Review of preoperative OCT showed severe DRIL in 41% and absent/mild DRIL in 59%. Severe DRIL was associated with worse baseline VA (P < .001). Preoperative VA and DRIL status at baseline were both predictors of postoperative VA at follow-up time points (P < .001). Severe DRIL was associated with significantly less improvement in VA at 6 months (-0.23 logMAR for absent/mild vs -0.14 for severe DRIL). Conclusions: Presence of severe preoperative DRIL correlates with worse baseline VA in patients with ERM and reduced VA improvement at 6 months. DRIL can be a strong predictor of long-term poor visual outcomes in ERM surgery.

The Effect of Dietary Intervention With High-Oleocanthal and Oleacein Olive Oil in Patients With Early-Stage Chronic Lymphocytic Leukemia: A Pilot Randomized Trial.

AIM: Oleocanthal and oleacein (OC/OL) have important in vitro and in vivo antitumor properties; however, there is no data about their anticancer activity in humans. The aim of this pilot study was to test if patients at early stage of chronic lymphocytic leukemia (CLL) could adhere to and tolerate an intervention with high OC/OL extra virgin olive oil (EVOO) and if this intervention could lead to any changes in markers related to the disease. METHODS: A pilot dietary intervention (DI) was made in patients with CLL in Rai stages 0-II who did not follow any treatment (NCT04215367). In the first intervention (DI1), 20 CLL patients were included in a blind randomized study and were separated into two groups. One group (A) of 10 patients consumed 40 ml/day of high OC/OL-EVOO (416 mg/Kg OC and 284 mg/kg OL) for 3 months. A second group (B) of 10 patients consumed 40 ml/day of low OC/OL (82 mg/kg OC and 33 mg/kg OL) for 3 months. After a washout period of 9-12 months, a second intervention (DI2) only with High OC/OL-EVOO for 6 months was performed with 22 randomly selected patients (16 from the DI1 (8 from each group) and 6 new). Hematological, biochemical, and apoptotic markers were analyzed in the serum of the patients. In addition, cellular proliferation and apoptosis markers were studied in isolated proteins from peripheral blood mononuclear cells. RESULTS: The results of the DI1 showed beneficial effects on hematological and apoptotic markers only with High OC/OL-EVOO. During the DI2, a decrease in the white blood cell and lymphocyte count was observed (p ≤0.05), comparing 3 months before the intervention and 6 months after it. After 3 and 6 months of DI2, an increase (p ≤0.05) was observed in the apoptotic markers ccK18 and Apo1-Fas, and also in the cell cycle negative regulator p21, and also a decrease in the antiapoptotic protein Survivin, and in the cellular proliferation marker Cyclin D. CONCLUSIONS: This is the first clinical trial with High OC/OL-EVOO that indicates that it could be a promising dietary feature for the improvement of CLL inducing the apoptosis of their cancer cells and improving the metabolism of the patients. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT04215367, identifier: NCT04215367.

Adiponectin Signaling and Impaired GTPase Rab5 Expression in Adipocytes of Adolescents with Obesity.

INTRODUCTION: Abnormalities in adipose tissue AdipoR1; adaptor protein, phosphotyrosine interaction, PH domain, and leucine zipper containing 1 (APPL1); GTPase Rab5; adiponectin; leptin; and visfatin in adults with obesity have been associated with metabolic disturbances. OBJECTIVE: The objective of this study was to examine whether pediatric obesity disrupts elements of the adiponectin signaling pathway and GTPase Rab5 in adipose tissue. METHODS: Primary adipocyte cultures of subcutaneous abdominal tissue were obtained from 96 lean and 66 children and adolescents with obesity (AO). AdipoR1, APPL1, and GTPase Rab5 mRNA levels were measured by RT-PCR and their protein content by Western immunoblotting. Serum total and high-molecular-weight adiponectin, leptin, leptin soluble receptor (sOB-R), and visfatin were measured by ELISA. RESULTS: The mRNA expression and protein content of AdipoR1 and APPL1 did not differ significantly with obesity, age, or puberty. However, GTPase Rab5 protein was increased in the adipocytes of younger prepubertal children with obesity but decreased in AO. Leptin was increased in AO compared to lean adolescents (AL) and in older prepubertal lean (OPL) children and AL compared to younger prepubertal lean and obese children. sOB-R was higher in OPL children and in the AL and AO. Serum visfatin was increased in the younger prepubertal children and AO. CONCLUSIONS: In contrast to adults, obesity did not change the expression of AdipoR1 and APPL1 in cultured adipocytes from biopsies of subcutaneous abdominal adipose tissue of children and adolescents. Similar to adipose tissue studies in adults with obesity and metabolic dysfunction, the AO in our study showed reduced adipocyte GTPase Rab5 expression.

Quantification of RPE Changes in Choroideremia Using a Photoshop-Based Method.

Purpose: To develop a reliable and efficient method for quantifying the area of preserved retinal pigment epithelium (RPE), facilitating the evaluation of disease progression or response to therapy in choroideremia (CHM). Methods: The fundus autofluorescence images of CHM patients were captured at baseline and 1 year. A Photoshop-based method was developed to allow the reliable measurement of the RPE area. The results were compared with measurements generated by the Heidelberg Eye Explorer 2 (HEYEX2). The areas measured by two independent graders were compared to assess the test-retest reliability. Results: By using the Photoshop-based method, the area of the RPE measured from 64 eyes was seen to decrease significantly (P < 0.001) at a rate of 2.57 ± 3.22 mm2 annually, and a percentage of 8.39% ± 5.24%. The average standard deviations for Photoshop were less than that for HEYEX2 (0.5-1.1 in grader 1; 0.4-1.6 in grader 2), indicating less intragrader variability. The RPE decrease as determined by the Photoshop-based method showed excellent reliability with an intraclass correlation coefficient of 0.944 (95% confidence interval, 0.907-0.966). In Bland-Altman plots, the Photoshop method also exhibited better intergrader agreement. Conclusions: Photoshop-based quantification of preserved RPE area in patients with CHM is feasible and has better test-retest reliability compared with the HEYEX2 method. Translational Relevance: An accurate quantification method for longitudinal RPE change in CHM patients is an important tool for the evaluation of efficacy in any therapeutic trials.

The roles of triglyceride/high-density lipoprotein cholesterol ratio and uric acid as predisposing factors for metabolic syndrome in healthy children.

PURPOSE: To estimate the roles of triglyceride/high-density lipoprotein cholesterol (TG/HDL) ratio and uric acid in predisposition for metabolic syndrome (MetS) and its components in healthy children. METHODS: Anthropometric and biochemical analyses were performed on 110 children, aged 5 to 12 years, from the Greek county of Laconia. The children were studied as a whole population and in separate groups according to age and predisposition to MetS after taking into consideration International Diabetes Federation criteria, body mass index, and lipid profile. RESULTS: Seventeen percent of children exhibited predisposition to MetS, while 39.1% had TG/HDL ratio >1, and 3.64% had high level of uric acid. According to a receiver operating characteristic curve analysis, the relative probability for MetS predisposition sextupled when TG/HDL ratio was ≥1 (odds ratio [OR], 5.986; 95% confidence interval [CI], 1.968-18.205). Children in the total population and those aged < 9 years had a greater probability for increased low-density lipoprotein (LDL) cholesterol (OR, 3.614; 95% CI, 1.561-8.365) when TG/HDL ratio was ≥ 1. The TG/HDL ratio was positively correlated with body mass index (BMI) (P=0.035) in children without MetS, cholesterol in the total population (P=0.06) and children ≥9 years old (P=0.026), and with LDL in the total population and both age groups (P=0.001). The TG/HDL ratio was also positively correlated with alanine aminotransferase in the total population (P=0.033) and gamma-glutamyl transferase in most studied groups (P<0.001). Uric acid was positively correlated with waist circumference in the total population (P=0.043) and in those without MetS (P=0.027). It was also positively correlated with BMI, TG, cholesterol, and TG/HDL ratio and negatively correlated with HDL in most studied groups (P<0.005). CONCLUSION: The studied parameters correlated with MetS components and could be characterized as effective indexes for childhood MetS, regardless of age and predisposition to MetS.

Epidemiological analysis of management of severe odontogenic infections before referral to the emergency department.

PURPOSE: The aims of the present study are to present the epidemiology and management of patients hospitalized with odontogenic infections in a major Greek hospital from 2015 to 2016 and to find out whether the basic principles of management of odontogenic infections were followed before referral to the emergency department of the Oral and Maxillofacial Surgery Clinic (OMFSED). METHODS: A retrospective study of the patients hospitalized with odontogenic infections was performed, including management both prior and after referral to the OMFSED. RESULTS: During the two-year period from 2015 to 2016, 102 patients, 54 men (52.9%) and 48 women (47.1%) were hospitalized with severe odontogenic infections. The most common space involved in severe odontogenic infections was the submandibular (52.9%), and in 31.4% of the patients multiple spaces were involved. The lower third molars were the most common cause (36.5%). In 83 patients (81.4%) the tooth causing the infection had not received any treatment whatsoever and in all cases (100%) no decision for early incision and drainage prior to the referral to the OMFSED was made. CONCLUSION: The data presented reveal that the basic principles of management of odontogenic infections are not followed before referral of the patients to the OMFSED.

RETINAL PHENOTYPE IN A CASE OF LCHAD/TFP DEFICIENCY WITH LATE-STAGE DIAGNOSIS.

PURPOSE: To report the retinal phenotype of a rare case of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)/trifunctional protein (TFP) deficiency diagnosed in his late 40s with ocular findings of diffuse chorioretinal atrophy and bilateral retinoschisis. METHODS: An acylcarnitine profile assay revealed LCHAD/TFP deficiency in a 45-year-old man with a history of high myopia, bilateral decreased vision, episodic rhabdomyolysis, and peripheral neuropathy. Ocular findings were evaluated with spectral domain optical coherence tomography (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany) and color fundus photography. RESULTS: Spectral domain optical coherence tomography revealed severe bilateral macular retinoschisis. Subretinal fibrosis was noted in the left temporal macula with an associated lamellar macular hole. Fundus photographs demonstrated diffuse, symmetric chorioretinal atrophy characteristic of end-stage retinopathy, as previously reported in younger patients. Myopic staphylomas were evident in the posterior pole of both eyes. A trial of topical dorzolamide for 3 months resulted in no change in the retinal profile. CONCLUSION: We report the retinal phenotype of a patient with LCHAD/TFP deficiency diagnosed later in life. To date, this is the oldest patient reported with LCHAD/TFP-associated retinopathy. Macular retinoschisis may represent a feature of the end-stage retinopathy due to the progressive myopia. The diagnosis of LCHAD/TFP deficiency should be considered in adult patients with a history rhabdomyolysis, neuropathy, and retinopathy, as they would not have undergone routine newborn screening before the late 90s.

Two-Year Results After AAV2-Mediated Gene Therapy for Choroideremia: The Alberta Experience.

PURPOSE: To assess the safety of a recombinant adeno-associated viral vector expressing REP1 (rAAV2.REP1) in choroideremia subjects. METHODS: Design: Phase I clinical trial. PARTICIPANTS: Six adult male subjects, 30-42 years of age, with genetically confirmed choroideremia (CHM) were enrolled. The eye with the worse vision, for all subjects, received a single subfoveal injection of 0.1 mL rAAV2.REP1 containing 1011 genome particles. Subjects were followed up for 2 years thereafter. OUTCOME MEASURES: The primary outcome measure was safety, determined by the number of ocular and systemic adverse events assessed by ophthalmic examination, spectral-domain optical coherence tomography (SD-OCT), and short-wavelength autofluorescence (FAF). Secondary outcome measures were the change from baseline in best-corrected visual acuity (BCVA) in the treated eye compared to the untreated eye, changes in visual function using microperimetry, and the area of retinal pigment epithelium (RPE) preservation by FAF. RESULTS: One subject had an 8-ETDRS-letter BCVA loss from baseline measured at 24 months, while 1 subject had a ≥15-letter BCVA gain. A similar improvement was noted in the untreated eye of another subject throughout the follow-up period. Microperimetry sensitivity showed no improvement or significant change up to 2 years after vector administration. The area of preserved RPE as measured by FAF was noted to decline at a similar rate between the treated and untreated eyes. One subject experienced a serious adverse event: a localized intraretinal immune response, resulting in marked decline in visual function and loss of SD-OCT outer retinal structures. CONCLUSIONS: One serious adverse event was experienced in 6 subjects treated with a subfoveal injection of AAV2.REP1. The area of remaining functional RPE in the treated eye and untreated eye declined at the same rate over a 2-year period. Fundus autofluorescence area is a remarkably predictive biomarker and objective outcome measure for future studies of ocular gene therapy in CHM subjects.