Progressive Dystrophy Research Articles

Glycine Enhances Satellite Cell Proliferation, Cell Transplantation, and Oligonucleotide Efficacy in Dystrophic Muscle.

The need to distribute therapy evenly systemically throughout the large muscle volume within the body makes Duchenne muscular dystrophy (DMD) therapy a challenge. Cell and exon-skipping therapies are promising but have limited effects, and thus enhancing their therapeutic potency is of paramount importance to increase the accessibility of these therapies to DMD patients. In this study, we demonstrate that co-administered glycine improves phosphorodiamidate morpholino oligomer (PMO) potency in mdx mice with marked functional improvement and an up to 50-fold increase of dystrophin in abdominal muscles compared to PMO in saline. Glycine boosts satellite cell proliferation and muscle regeneration by increasing activation of mammalian target of rapamycin complex 1 (mTORC1) and replenishing the one-carbon unit pool. The expanded regenerating myofiber population then results in increased PMO uptake. Glycine also augments the transplantation efficiency of exogenous satellite cells and primary myoblasts in mdx mice. Our data provide evidence that glycine enhances satellite cell proliferation, cell transplantation, and oligonucleotide efficacy in mdx mice, and thus it has therapeutic utility for cell therapy and drug delivery in muscle-wasting diseases.

Nutritional intervention with cyanidin hinders the progression of muscular dystrophy

Muscular Dystrophies are severe genetic diseases due to mutations in structural genes, characterized by progressive muscle wasting that compromises patients’ mobility and respiratory functions. Literature underlined oxidative stress and inflammation as key drivers of these pathologies. Interestingly among different myofiber classes, type I fibers display a milder dystrophic phenotype showing increased oxidative metabolism. This work shows the benefits of a cyanidin-enriched diet, that promotes muscle fiber-type switch and reduced inflammation in dystrophic alpha-sarcoglyan (Sgca) null mice having, as a net outcome, morphological and functional rescue. Notably, this benefit is achieved also when the diet is administered in dystrophic animals when the signs of the disease are seriously evident. Our work provides compelling evidence that a cyanidin-rich diet strongly delays the progression of muscular dystrophies, paving the way for a combinatorial approach where nutritional-based reduction of muscle inflammation and oxidative stress facilitate the successful perspectives of definitive treatments.

Antisense-Mediated Skipping of Dysferlin Exons in Control and Dysferlinopathy Patient-Derived Cells.

Dysferlinopathies encompass a spectrum of progressive muscular dystrophies caused by the lack of dysferlin due to missense mutations in the dysferlin gene or mutations causing premature truncation of protein translation. Dysferlin is a modular protein, and dysferlins lacking one or more repetitive domains have been shown to retain functionality. As such, antisense-mediated exon skipping has been proposed as a therapy for dysferlinopathy. By skipping the mutated exon, the reading frame would be maintained, while the mutation would be bypassed, thus allowing production of an internally deleted, but partially functional, dysferlin. We previously showed that dysferlin exon skipping is feasible in control cell lines. We here evaluated exon skipping and dysferlin protein restoration in patient-derived cells requiring the skipping of exon 9, 29, 30, or 34. Exon 30 skipping was possible at high efficiency, but did not result in increased dysferlin. We discovered that the alleged exon 30 mutation was in fact a polymorphism and identified a splicing mutation in intron 28 as the disease-causing mutation. While exon skipping was feasible for each of the other cell lines, no increases in dysferlin protein could be detected by western blotting.

Characteristics of transcranial parenchymal sonography and correlation with psychiatric symptomatology in patients with myotonic dystrophy type 1 and 2

Introduction Myotonic dystrophy type 1 and 2 (dystrophia myotonica, DM) is an autosomal dominant genetically determined progressive muscular dystrophy associated with multiple organs involvement. Neuroimaging techniques allow visualization and quantification of pathoanatomic changes, while the parenchymal transcranial sonography (TCS) allows accurate visualization of deep brain structures (basal ganglia, raphe nuclei, and the chamber system). The aim Determining the basal ganglia echogenicity change (substantia nigra-SN, n. raphe-BR, n. ruber-NR, n. lentiformis-NL) and third ventricle diameter (DTV), by using TCS in DM1 and DM2 patients and correlating the ultrasonography results with the psychiatric clinical manifestation. Materials and methods TCS and neuropsychological testings (Scales: HAMD, FSS, DSS) were conducted on 163 patients with DM1 and DM2, age 30-62 years. Results Borderline statistical significance (p = 0.05) is determined by comparing the right SN surface in DM1 patients (0.14 ± 0.06 cm2) and is lower than the right SN in DM2 patients, average size 0.16 ± 0.07 cm2. BR hypoechogenicity in DM1 patients was more common in older (32–53 years) and in patients with depression (p Conclusion TCS is a practical, easily applicable, highly sensitive neuroimaging method of great importance in diagnosing and treatment planning of patients with DM1 and DM2.

Best's disease

Best's disease is an inherited macular dystrophy with autosomal dominant inheritance pattern, characterized by the presence of autofluorescent vitelliform deposition whose development is stereotyped from its manifestation to the fragmentation of the material and then to its resorption. Age at onset is between 7 and 12 years. Except in the presence of complications, patients are more often asymptomatic and the disease is discovered fortuitously. We report the case of 8 year-old only daughter with no particular past medical history. Ophthalmologic examination showed corrected visual acuity 7/10 in the left and right eyes, the examination of the anterior segment was normal, fundus examination showed macular yellowish-white stain (A, B). On fluorescein angiography, hyperfluorescence occurred early followed by a hypofluorescence. Macular imaging by optical coherence tomography (OCT) showed the presence of an empty optical space between the neuroretina and the pigment epithelium (C, D). Assessment was performed: electrooculogram was perturbed using Arden ratio of 146% in the right eye and 179% in the left eye. Electroretinogram, visual fields and color vision test were normal. Fundus examination of parents was normal. The diagnosis of previtelliform BEST's disease was made based on early hypofluorescence, OCT appearance and alteration of the electroretinogram. Differential diagnoses included: stargardt's disease, progressive dystrophy of the cones and X-linked retinoschisis. No treatment was proposed, only simple monitoring.

O.14B3GNT4 deficiency: a new α-dystroglycanopathy causing late-onset progressive brain atrophy and muscular dystrophy

Defects of α-dystroglycan glycosylation (dystroglycanopathies) account for 20 disorders presenting with either early onset brain and muscular dystrophy phenotype, or late onset purer muscular dystrophy. Here, we report a new dystroglycanopathy with an atypical phenotype of late-onset, progressive brain atrophy and muscular dystrophy. The proband is a 46-year-old man with consanguineous parents of Pakistani origin. He was born at term and had normal motor and cognitive milestones until age 8, when he started to fall and develop involuntary movements and spastic paresis of limbs. He was wheelchair bound by age 13 and speech deteriorated from age 25, until loss of language and cognitive skills at age 32. Cerebral MRI at age 16 showed mild changes of corpus callosum smallness and leukoencephalopathy, which at age 44 had developed into profound atrophy of the entire cerebrum. At age 38, CK was 620 U/l. The muscle biopsy showed severe dystrophic changes, upregulated glycosylation (IIH6 and VIA4 antibodies) in regenerating fibers, but loss of glycosylation in mature fibers. Muscle MRI showed fatty replacement, preferentially of hamstring muscles. No candidate genes were found in large NGS gene panels. Exome sequencing, specifically looking at glycosylation genes, revealed a homozygous p.G160W variant in the B3GNT4 gene, an acetylglucosaminyltransferase highly expressed in brain. Unaffected parents and a brother were heterozygous for this change. We developed a knock-in mouse model of the p.G160W variant. Homozygous mice showed muscle weakness and atrophy at 4 months. At age 6 months, muscle histology showed similar changes as seen in the patient. Brain abnormalities had not developed at this stage. The study demonstrates a new dystroglycanopathy, which unlike other forms has late-onset progressive brain involvement and muscular dystrophy. The muscular dystrophy was replicated in the knock-in mouse model, supporting the pathogenicity of the variant in this new disease gene.

GENE EDITING AND MOLECULAR THERAPY: P.285Effective gene editing of the human DYSF founder mutation c.1624delG in patient-derived cells and generation of analogous "humanized" mouse models for in vivo treatment

Dysferlinopathy, also known as limb-girdle muscular dystrophy type 2B (LGMD2B), is caused by mutations in DYSF. It is one of the most frequent of > 40 untreatable muscular dystrophies leading to progressive muscle degeneration and wheel-chair-dependency. We generated hiPSC from two patients carrying a founder frameshift mutation (c.1624delG) in DYSF exon 44 that results in a complete absence of dysferlin protein and developed various gene editing approaches to repair this mutation using CRISPR/Cas9. First, using mutation-specific sgRNAs in combination with the enhanced specificity Cas9 variant eSpCas9(1.1), we were able to restore the mutant sequence to its wild-type form via homology directed repair without introducing any silent mutations in the repair template. Second, we used Cas9-induced NHEJ, in particular the indel signature bias of specific sgRNAs, to restore the DYSF reading frame in patient-derived cells with a high efficiency. We could readily demonstrate rescue of the re-framed dysferlin protein by western blot after editing. In parallel, we generated two related transgenic mouse lines, one with the murine Dysf exon 44 exchanged for the human wild-type DYSF exon 44 and the other containing the human c.1624delG founder mutation within the human DYSF exon 44. The latter lacks dysferlin protein and recapitulates the progressive muscular dystrophy phenotype seen in LGMD2B patients. Using these models, we are assessing ways to re-create in vivo our DYSF editing approaches directly on the human sequence, utilizing genetic tools that can be applied to patient cells.

EP.79The impact of ventilation on non-ambulatory patients with DMD

Duchenne muscular dystrophy (DMD) is a severe progressive muscular dystrophy caused by mutations in the DMD gene, leading to the absence of a functional dystrophin protein. During disease progression patients develop respiratory decline, which leads to the need for ventilation, either non-invasive or invasive, in their late teens or early twenties. Also the ability to cough becomes more compromised during the course of the disease. This has a huge impact on daily life and is a burden for both patients and families. To get an insight into the effects of respiratory decline, use of ventilation, the burden and the areas on which it has the most impact, a survey has been held among non-ambulatory DMD patients. The survey was completed by 114 patients from 21 countries (age range: 11 to 54). On average ventilation (any form) was started around 17 years of age (n=101) and continuous ventilation around 20 years (n=49). BiPAP is most commonly used (68%). Also cough assists are frequently used (54%). Respiratory complications sometimes resulted in missing school or work days by both patients and parents. For the majority (85%) the use of ventilation led to an improvement of the quality of life by improving sleeping (77%) and reducing anxiety (58% of those who felt anxious before). For most patients (87%) it facilitated their participation in social activities to some extent. Patients on average give their life a rating of 68 on the EQ-5D scale. This is around 20 points lower than the healthy population. While in the general population a decrease in EQ-5D score is seen with ageing, the contrary is seen for DMD. Thereby the differences between the general and the DMD population diminish with age. The main conclusion of the respiratory survey is that ventilation has a major positive impact on the quality of life, both physically and socially.

Progressive Muscular Dystrophy (Duchenne Type) (Case Report)

Clinical findings of two brothers suffering from progressive muscular dystrophy pseudohypertrophic type according to Duchenne are reported. Literatures dealing with its clinical classification, biochemical disturbances, hypotheses of the pathogenesis, management of treatment, mode of action of A.T.P. and the pedigree have been briefly reported.
 Progressive Muscular Dystrophy is a progressive disease affecting voluntary muscles; It is characterized by a decreased strength in the affected muscles with rapid or slow gradual progression. About 45% of the patients gave a history that at least another member of the family is affected by the disease. Pseudohypertrophic form (Duchenne type) is usually inherited as a recessive factor, often sexlinked.

Clinical trial readiness to solve barriers to drug development in FSHD (ReSolve): protocol of a large, international, multi-center prospective study

BackgroundFacioscapulohumeral muscular dystrophy (FSHD) is a dominantly-inherited progressive muscular dystrophy caused by de-repression of the DUX4 gene, which causes disease by a toxic-gain-of-function. As molecularly targeted drugs move from preclinical testing into human trials, it is essential that we validate clinical trial tools and methodology to facilitate the drug development process.Methods/designThe primary goal of this study is to hasten drug development for FSHD by validating two novel clinical outcome assessments (COAs) and refining clinical trial strategies. We will perform an 18-month longitudinal study in 220 genetically confirmed and clinically affected participants using our FSHD Clinical Trial Research Network, comprised of 8 sites in the United States, and 3 collaborating sites in Europe. Visits occur at baseline and months 3, 12, and 18. At each visit we will collect: 1) a novel FSHD functional composite COA made up of 18 evaluator-administered motor tasks in the domains of shoulder/arm, hand, core/abdominal, leg, and balance function; and 2) electrical impedance myography as a novel muscle quality biomarker (US sites). Other COAs include 1) Domain 1 of the Motor Function Measure; 2) Reachable workspace; 3) orofacial strength using the Iowa Oral Performance Instrument; 4) lean muscle mass using dual-energy X-ray absorptiometry (DEXA); 5) strength as measured by quantitative myometry and manual muscle testing; and 6) the FSHD Health Index and other patient-reported outcomes. Plasma, DNA, RNA, and serum will be collected for future biomarker studies. We will use an industry standard multi-site training plan. We will evaluate the test-retest reliability, validity, and sensitivity to disease progression, and minimal clinically important changes of our new COAs. We will assess associations between demographic and genetic factors and the rate of disease progression to inform refinement of eligibility criteria for future clinical trials.DiscussionTo the best of our knowledge, this is the largest collaborative study of patients with FSHD performed in the US and Europe. The results of this study will enable more efficient clinical trial design. During the conduct of the study, relevant data will be made available for investigators or companies pursuing novel FSHD therapeutics.Trial registrationclinicaltrials.gov NCT03458832; Date of registration: 1/11/2018

Chart validation of an algorithm for identifying hereditary progressive muscular dystrophy in healthcare claims

BackgroundMuscular dystrophies (MDs) are a group of inherited conditions characterized by progressive muscle degeneration and weakness. The rarity and heterogeneity of the population with MD have hindered therapeutic developments as well as epidemiological and health outcomes research. The objective of the study was to develop and validate a case-finding algorithm utilizing administrative claims data to identify and characterize patients with MD.MethodsThis retrospective cohort study used medical chart validation to evaluate an ICD-9/10 coding algorithm in a large commercial claims database. Patients were identified who had ≥2 office visits with a diagnosis of hereditary progressive MDs from January 1, 2013 through December 31, 2016, were male, and younger than 18 years at the time of first MD diagnosis. Cases who met the algorithm were then validated against medical charts. Diagnoses of MD and specific type (Duchenne, Becker, or other MD) were confirmed by medical chart review by trained reviewers. Positive predictive value (PPV) and 95% confidence intervals (CI) were calculated using a 2 × 2 contingence table. Patient demographic, clinical, and health utilization characteristics were summarized using basic descriptive statistics.ResultsCharts were obtained and reviewed for 109 patients who met the algorithm. The PPV of the case-identifying algorithm for MD was 95% (95% CI 88–98%). Of the 103 confirmed MD cases, 87 patients (85%, 95% CI 76–91%) had Duchenne or Becker MD; 76 patients (74%, 95% CI 64–82%) had Duchenne MD, and 11 patients (11%, 95% CI 5–18%) had Becker MD. A total of 74 (67.9%) patients had ≥1 pediatric complex chronic condition (other than neurologic/neuromuscular disease); 54 (49.5%) had cardiovascular conditions; 14 (12.8%) had respiratory conditions; 50 (45.9%) had bone-related issues; 11 (10.1%) had impaired growth; and 6 (5.5%) had puberty delay.ConclusionsThe results of this study demonstrate that the case-finding algorithm accurately identified patients with MD, primarily Duchenne MD, within a large administrative database. The algorithm, which was constructed using a few items easily accessible from claims, can be used to facilitate epidemiological and health outcomes research in the Duchenne patient population.

Ions concentration in blood samples of SJL/J dystrophic mice strains using X-ray fluorescence spectrometry

Star This study proposes an investigation of ions in whole blood of the dystrophic animal model SJL/J (mice strain with dysferlin protein deficiency) and in the control group (C57BL/6J) using the Energy Dispersive X-ray Fluorescence (EDXRF) spectrometry technique. The comparison between control and dystrophic mice results shown an increase in blood for P, S, K and Fe (p < 0.05) while a decrease in Ca (p < 0.05). This elemental analysis will contribute to evaluate the best diagnostic, care and treatment procedures, for the Progressive Muscular Dystrophy.

A novel pathogenic variant in TNPO3 in a Hungarian family with limb-girdle muscular dystrophy 1F

Limb-girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous muscular diseases that predominantly affect the proximal muscles. Pathogenic variants in TNPO3 have been associated with a rare, autosomal dominant limb-girdle muscular dystrophy 1F (LGMD1F) in a large Italian-Spanish family and an isolated LGMD1F case. Here we present two individuals from a Hungarian family with an early-onset, slowly progressive muscular dystrophy. Both the female proband and her affected son had delayed early motor milestones including first walking at 14 months and 18 months, respectively. Both present with progressive weakness of facial, bulbar, axial, and distal muscles especially of the lower extremities. Electromyography indicated myogenic damage and muscle biopsy from the proband showed myopathic alterations with sarcoplasmic masses and signs of mitochondrial dysfunction. Exome sequencing of the female proband identified a novel c.2767delC p.(Arg923AspfsTer17) variant in TNPO3. Sanger sequencing confirmed the presence of the TNPO3 variant in the affected son; the unaffected son did not have the variant. The identification of the c.2767delC variant further supports the clinical significance of TNPO3 and expands the clinical spectrum of TNPO3-associated LGMD1F.

Alstrom syndrome: insulin resistance in young with congestive heart failure

Alstrom Hallgren syndrome is a rare ciliopathy first described in 1959. It is characterised by progressive cone-rod dystrophy leading to blindness, sensorineural hearing loss, childhood obesity and congestive heart failure. Its pathogenesis is related to development of insulin resistance, and type 2 diabetes mellitus. We report a case of a 20-year-old presenting with decompensated heart failure and had been blind since childhood who was eventually diagnosed as Alstrom syndrome based on clinical criteria.

Myotonic dystrophy: genetics and clinical polymorphism

Myotonic dystrophy is the most common form of hereditary progressive muscular dystrophy in adults. The disorder is characterized by progressive course, autosomal dominant inheritance and multisystem involvement (skeletal muscles, myocardium, endocrine system, eyes, etc.). The paper highlights a huge heterogeneity of clinical manifestations of myotonic type 1 and type 2, and reviews genetic aspects and current approaches to the diagnosis of myotonic dystrophy. We present our own clinical observation of myotonic dystrophy in a family, which demonstrates a rare combination of a classical form of myotonic dystrophy type 1, syringomyelia and proximal muscle weakness, and provides an classical example of the phenomenon of anticipation.

A case report of infant with robertsonian translocation

Robertsonian translocations carry reproductive risks that are dependent on the chromosomes involved and the sex of the carrier Robertsonian translocation (14:15)(q10;q10)4p is rare and account for only 0.6%. We describe a case with rob (14;15) in which the phenotype includes: Generalized hypotonia, respiratory distress, high arch palate, left ear-grooves abnormal, prominent nasal bridge, left impatent nasolacrimal duct, dysmorphic face. Chromosome analysis with peripheral blood was performed, while the karyotype was interpreted as 45,XX, der (14;15)(q10;q10)4p.out of two chromosome number 4, one Chromosome 4 has found deleted from 'p' arm small arm In wolf-hirschhorn Syndrome. Molecular studies associated with spinal muscular atrophy and progressive muscular dystrophy also had negative findings. We suggest that rob(14;15)(q10;q10)4p could be Related to clinical presentation like this case. Keywords: PGD, reproductive risks, Robertsonian translocation, Chromosomes, Down syndrome, Aneuploidy, Trisomy, Translocation (genetics), Mosaicism, Preimplantation diagnosis.

Діагностика та сучасні підходи до терапії прогресуючих м'язових дистрофій у дітей (лекція)

Діагностика та сучасні підходи до терапії прогресуючих м'язових дистрофій у дітей (лекція)

Metabolism responses to silver nanoparticles stresses during zebrafish embryogenesis

Silver nanoparticles (AgNPs) are widely used in medical, optoelectronic, new energy and other related fields on account of their broad-spectrum antibacterial properties. However, their biological effects on aquatic organism embryogenesis as well as potential molecular characters and mechanisms are still poorly understood. In this study, microarray analysis unveiled the altered expression of metabolic genes in AgNPs-stressed zebrafish embryos at 24 hpf (hour post fertilization). The enrichment in pathways for the down-regulated differentially expressed genes (DEGs) indicated that genes in the metabolic pathways, such as glycolysis/gluconeogenesis, tyrosine metabolism, and fatty acid metabolism, were over-enriched for the gene lists with differential expression in both AgNPs-exposed and AgNPs-injected embryos. It was found that the down-regulated expression of the genes in glycolysis and tyrosine metabolic pathways in AgNPs-stressed embryos at 24 hpf was followed by a compensatory increased expression in embryos at 72 hpf. AgNPs might influence transcriptional expression of the glycolysis and tyrosine genes differentially through their particle and ion portions separately. Additionally, decreased hexokinase & succinate de-hydrogenase activities in glycolysis pathway and high level of pyruvate were observed in the AgNPs stressed embryos, which was similar to the metabolic molecular characters observed in progressive muscular dystrophy patients. Moreover, the altered glycolysis metabolic activities were assumed to influence the muscle fibrils maintenance via regulating the concentration of glycolysis metabolites rather than cell apoptosis and proliferation in trunk muscle cells. Furthermore, the altered tyrosine metabolic activities might be another contributor to touch response defects parallel to the defective neural circuit formation in AgNPs-stressed embryos.

Molecular and Genetic Study of Limb-Girdle Muscular Dystrophy 2D in Patient Cohorts with Various Forms of Progressive Muscular Dystrophies

Limb-girdle muscular dystrophy 2D (LGMD 2D) is the most common form of sarcoglycanopathies, which include autosomal recessive LGMDs caused by various molecular defects in the genes encoding sarcoglycan family proteins (α, β, γ, and δ). LGMD 2D occurs owing to mutations in the SGCA gene that encodes α-sarcoglycan. In general, it is difficult to distinguish clinical features of LGMD 2D from ones of both other pseudohypertrophic LGMDs and Duchenne/Becker muscular dystrophy (D/BMD). In the present paper, the study of LGMD 2D based on the analysis of the frequency of recurrent SGCA gene variants (c.229C>T, c.271G>A, and c.850C>T) in three patient cohorts with progressive muscular dystrophy manifesting itself after a normal motor development period was conducted. No LGMD 2D patients were found within the cohort of patients with clinical diagnosis of Emery–Dreifuss muscular dystrophy. The percentage of LGMD 2D patients was no less than 1.9% in the patient cohort with clinical diagnosis of LGMD, while LGMD 2D accounted for no less than 0.6% in the patient cohort with clinical diagnosis of D/BMD. It is noteworthy that, in these two cohorts, the most common SGCA variant in the world, c.229C>T, and a variant found in only one Italian family, c.271G>A, account for almost the same number of affected chromosomes. Therefore, LGMD 2D patients from Russia differ from LGMD 2D patients from all over the world in the presence of two major variants of this gene (c.229C>T and c.271G>A). The information value of the test system for the detection of three SGCA gene variants (the capability to reveal at least one mutant allele) was on average rather high (70% in the group of patients with LGMD and 50% in the group of patients with D/BMD); therefore this test system could be recommended as the primary step of LGMD 2D molecular diagnostics in patients with the corresponding clinical features.

Trinucleotide repeat expansion length as a predictor of the clinical progression of Fuchs' Endothelial Corneal Dystrophy.

PurposeTo determine if CTG18.1 TNR expansion length prognosticates the clinical progression of Fuchs’ Endothelial Corneal Dystrophy (FECD).MethodsThis was a prospective cohort study. A total of 51 patients with newly diagnosed FECD were recruited and followed-up over a period of 12 years, from November 2004 to April 2016. Baseline clinical measurements included central corneal thickness (CCT), endothelial cell density (ECD) and CTG18.1 TNR expansion length from peripheral leukocytes, with yearly repeat measurements of CCT and ECD. A patient was defined to have experienced significant clinical progression and to have developed Threshold Disease if any of these criteria were fulfilled in either eye: a) CCT increased to >700μm, b) ECD decreased to <700 cells/mm2, or c) underwent keratoplasty for treatment of FECD.ResultsPatients were categorized as having at least one allele whose maximum allele length was equal to or greater than 40 repeats (L≥40, n = 22, 43.1%), or having both alleles shorter than 40 repeats (L<40). Threshold Disease rates at the 5-year time point were 87.5% for the L≥40 group and 47.8% for the L<40 group (p = 0.012). This difference narrowed and was no longer statistically significant at the 8-years (92.9% vs 78.9%, p = 0.278) and 10-years (92.9% vs 84.2%, p = 0.426) time points.ConclusionsL≥40 patients are at greater risk of FECD progression and development of Threshold Disease within the first 5 years following diagnosis.