Group Of Dystrophies Research Articles

Kronik Engelli Bireylerde Ortez Ve Yardımcı Cihaz Memnuniyetinin Araştırılması

Amaç: Bu çalışmanın amacı ortez/yardımcı cihaz tavsiye edilen kronik engelli bireylerin ortez kullanım memnuniyetlerinin araştırılması. Bununla birlikte tanı grupları ve serebral palsili bireylerin motor fonksiyon seviyeleri ile ortez kullanım memnuniyeti arasında ilişki olup olmadığının araştırılmasıdır. Gereç ve Yöntem: Çalışmaya 105 kronik engelli birey (64 serebral palsili, 13 spina bifida, 14 musküler distrofi ve 14 farklı nörolojik tanılı birey) ve aileleri dahil edildi. Yardımcı cihaz/ortez kullanımı, günlük kullanma süreleri ve eğer ortezlerini kullanmıyorlarsa nedenleri sorgulandı. Bireylerin ortez kullanım memnuniyetleri araştırmacılar tarafından literatüre dayanarak oluşturulmuş Ortez Kullanım Memnuniyet Anketi ile değerlendirildi. Bulgular: Serebral palsili bireylerin motor fonksiyon düzeyleri ile ortez kullanım memnuniyeti arasında ilişki olmadığı bulundu (p=0.779). Ortez Kullanım Memnuniyet Anketi toplam skoru ve günlük ortez kullanma süreleri arasında pozitif yönlü zayıf bir ilişki saptandı (r=0.242, p=0.015). Ortez Kullanım Memnuniyet Anketi toplam skoru ve ne kadar zamandır ortez kullanıldığına ait veriler arasında bir ilişki bulunmadı (p=0.811). Engelli bireylerin tanılarının (p=0.23) ve cihaz/ortez tipinin ortez kullanma memnuniyeti skorları ile ilişkili olmadığı saptandı (p=0.97). Sonuç: Sonuç olarak, kronik engelli bireylerde ortez/yardımcı cihaz günlük kullanım süresi arttıkça kullanım memnuniyetinin arttığı ve cihaz/ortez tipinin ortez kullanma memnuniyeti ile ilşkili olmadığı gözlemlendi. Ayrıca serebral palsili, spina bifida, musküler distrofi ve diğer tanı gruplarının ortez memnuniyetlerinin benzer olduğu görüldü.

Uncovering sleep in young males with Duchenne muscular dystrophy.

Sleep health in rare disease is often overlooked due to the complex nature of the disease. For males with Duchenne muscular dystrophy, sleep assessment is typically focused on pulmonary function and identification of sleep disordered breathing. Unfortunately for young boys with Duchenne muscular dystrophy, sleep assessment is often neglected, resulting in a dearth of knowledge on sleep health in this population. This study describes sleep quantity and quality in both younger (4-9 years) and older (10-17 years) males with Duchenne muscular dystrophy (n=19) and compares these characteristics with sleep characteristics of unaffected peers (n=17). This study was a longitudinal, observational study. Sleep measures were collected using the parent-proxy Children's Sleep Habits Questionnaire-Abbreviated version and objective sleep measures from actigraphy (sleep efficiency, awakenings, and awakening duration) over 30 days for all participants. Means and standard deviations were examined, and effect sizes were computed to quantify the magnitude of difference between the Duchenne muscular dystrophy and unaffected groups. Overall, boys with Duchenne muscular dystrophy were found to experience worse sleep than their unaffected peers as measured by parent report and actigraphy. Effect sizes of both measures demonstrated moderate to large magnitudes of difference in many of the sleep variables. Parents of boys with Duchenne muscular dystrophy reported higher scores (indicating worse sleep) in all subsections and total score of the Children's Sleep Habits Questionnaire - Abbreviated version. Actigraphy data indicated that the Duchenne muscular dystrophy group had lower percent sleep efficiency, more night awakenings and longer duration of night awakenings than their unaffected peers. Our findings offer a novel look into sleep in young boys with Duchenne muscular dystrophy. Both parent-report and actigraphy data indicate poor sleep health in this population compared with age-matched unaffected peers. Actigraphy was found to align with parent-report of sleep in this population, supporting the use of these two different ways to measure sleep in Duchenne muscular dystrophy. Results from this study should encourage clinicians and researchers alike to further explore sleep and its impact on disease in young boys with Duchenne muscular dystrophy.

Crystal structures of fukutin-related protein (FKRP), a ribitol-phosphate transferase related to muscular dystrophy

α-Dystroglycan (α-DG) is a highly-glycosylated surface membrane protein. Defects in the O-mannosyl glycan of α-DG cause dystroglycanopathy, a group of congenital muscular dystrophies. The core M3 O-mannosyl glycan contains tandem ribitol-phosphate (RboP), a characteristic feature first found in mammals. Fukutin and fukutin-related protein (FKRP), whose mutated genes underlie dystroglycanopathy, sequentially transfer RboP from cytidine diphosphate-ribitol (CDP-Rbo) to form a tandem RboP unit in the core M3 glycan. Here, we report a series of crystal structures of FKRP with and without donor (CDP-Rbo) and/or acceptor [RboP-(phospho-)core M3 peptide] substrates. FKRP has N-terminal stem and C-terminal catalytic domains, and forms a tetramer both in crystal and in solution. In the acceptor complex, the phosphate group of RboP is recognized by the catalytic domain of one subunit, and a phosphate group on O-mannose is recognized by the stem domain of another subunit. Structure-based functional studies confirmed that the dimeric structure is essential for FKRP enzymatic activity.

BiAb Mediated Restoration of the Linkage between Dystroglycan and Laminin-211 as a Therapeutic Approach for α-Dystroglycanopathies.

Patients with α-dystroglycanopathies, a subgroup of rare congenital muscular dystrophies, present with a spectrum of clinical manifestations that includes muscular dystrophy as well as CNS and ocular abnormalities. Although patients with α-dystroglycanopathies are genetically heterogeneous, they share a common defect of aberrant post-translational glycosylation modification of the dystroglycan alpha-subunit, which renders it defective in binding to several extracellular ligands such as laminin-211 in skeletal muscles, agrin in neuromuscular junctions, neurexin in the CNS, and pikachurin in the eye, leading to various symptoms. The genetic heterogeneity associated with the development of α-dystroglycanopathies poses significant challenges to developing a generalized treatment to address the spectrum of genetic defects. Here, we propose the development of a bispecific antibody (biAb) that functions as a surrogate molecular linker to reconnect laminin-211 and the dystroglycan beta-subunit to ameliorate sarcolemmal fragility, a primary pathology in patients with α-dystroglycan-related muscular dystrophies. We show that the treatment of LARGEmyd-3J mice, an α-dystroglycanopathy model, with the biAb improved muscle function and protected muscles from exercise-induced damage. These results demonstrate the viability of a biAb that binds to laminin-211 and dystroglycan simultaneously as a potential treatment for patients with α-dystroglycanopathy.

Genetic variability in Iranian limb-girdle muscular dystrophy type 2B patients: An evidence of a founder effect.

BackgroundDysferlinopathies are a group of autosomal recessive limb‐girdle muscular dystrophies (LGMDs) caused by mutations in DYSF (#603,009). This gene encodes a transmembrane protein called dysferlin. Since there are few reports on Iranian dysferlinopathy patients, we tried to identify the DYSF mutations in affected individuals of Iran.MethodsEight unrelated Iranian families have been selected for this study. Sanger sequencing followed by haplotype analysis was performed to identify individual variations in DYSF sequence. Identified variants were analyzed, and their pathogenicity was interpreted according to the recommendations of the American College of Medical Genetics and Genomics.ResultsWe identified two new mutations in DYSF, the first one is a nonsense mutation c.2419C > T (p.Gln807*), which eliminates downstream part of the protein. Another novel mutation is c. (1,053 + 1_1,054‐1)_(1,397 + 1_1,398‐1)del, which causes deletion of the DNA segment from exon 12 to exon 15.ConclusionTwo of the other six families are from the same ethnicity and share the same mutation and haplotype patterns, suggesting a founder mutation. Genetic analysis of dysferlinopathy can prevent a wrong diagnosis of myositis for these patients.

A new patient‐derived iPSC model for dystroglycanopathies validates a compound that increases glycosylation of α‐dystroglycan

Dystroglycan, an extracellular matrix receptor, has essential functions in various tissues. Loss of α‐dystroglycan‐laminin interaction due to defective glycosylation of α‐dystroglycan underlies a group of congenital muscular dystrophies often associated with brain malformations, referred to as dystroglycanopathies. The lack of isogenic human dystroglycanopathy cell models has limited our ability to test potential drugs in a human‐ and neural‐specific context. Here, we generated induced pluripotent stem cells (iPSCs) from a severe dystroglycanopathy patient with homozygous FKRP (fukutin‐related protein gene) mutation. We showed that CRISPR/Cas9‐mediated gene correction of FKRP restored glycosylation of α‐dystroglycan in iPSC‐derived cortical neurons, whereas targeted gene mutation of FKRP in wild‐type cells disrupted this glycosylation. In parallel, we screened 31,954 small molecule compounds using a mouse myoblast line for increased glycosylation of α‐dystroglycan. Using human FKRP‐iPSC‐derived neural cells for hit validation, we demonstrated that compound 4‐(4‐bromophenyl)‐6‐ethylsulfanyl‐2‐oxo‐3,4‐dihydro‐1H‐pyridine‐5‐carbonitrile (4BPPNit) significantly augmented glycosylation of α‐dystroglycan, in part through upregulation of LARGE1 glycosyltransferase gene expression. Together, isogenic human iPSC‐derived cells represent a valuable platform for facilitating dystroglycanopathy drug discovery and therapeutic development.

Analysis of the functional capacity outcome measures for myotonic dystrophy.

ObjectivesDefining clinically relevant outcome measures for myotonic dystrophy type 1 (DM1) that can be valid and feasible for different phenotypes has proven problematic. The Outcome Measures for Myotonic Dystrophy (OMMYD) group proposed a battery of functional outcomes: 6‐minute walk test, 30 seconds sit and stand test, timed 10 m walk test, timed 10 m walk/run test, and nine‐hole peg test. This, however, required a large‐scale investigation,MethodsA cohort of 213 patients enrolled in the natural history study, PhenoDM1, was analyzed in cross‐sectional analysis and subsequently 98 patients were followed for longitudinal analysis. We aimed to assess: (1) feasibility and best practice; (2) intra‐session reliability; (3) validity; and (4) behavior over time, of these tests.ResultsOMMYD outcomes proved feasible as 96% of the participants completed at least one trial for all tests and more than half (n = 113) performed all three trials of each test. Body mass index and disease severity associate with functional capacity. There was a significant difference between the first and second trials of each test. There was a moderate to strong correlation between these functional outcomes and muscle strength, disease severity and patient‐reported outcomes. All outcomes after 1 year detected a change in functional capacity except the nine‐hole peg test.ConclusionsThese tests can be used as a battery of outcomes or independently based on the shown overlapping psychometric features and strong cross‐correlations. Due to the large and heterogeneous sample of this study, these results can serve as reference values for future studies.

Quality of life in adults with muscular dystrophy

BackgroundMuscle weakness is a defining characteristic of Muscular Dystrophy (MD); however, yet while speculated, objective measures of muscle weakness has not been reported in relation to quality of life in adults with MD.Objectives1) compare the self-reported QoL of adults with Duchenne MD (DMD), Beckers MD (BMD), Limb-Girdle MD (LGMD) and Fascioscapulohumeral MD (FSHD, and a non-MD (CTRL) group; 2) present and compare between groups measures of Impairment (Muscle Strength and Activities of Daily Living) and Perception (Fatigue, Pain and Self-Efficacy); and 3) identify associations between QoL domains and measures of Impairment and Perception (See above).MethodsSeventy-Five males, including MD classifications DMD, BMD, LGMD, FSHD and CTRL, completed measures for QoL, Knee-Extension Maximal Voluntary Contraction (KEMVC), Fatigue, Pain, Self-Efficacy and Activities of Daily Living (ADL).ResultsQoL was lower across many domains in MD than CTRL. FSHD scored lower than DMD for mental wellbeing domains. KEMVC associated with Physical-Function domain for BMD. Pain, Self-Efficacy and ADLs associated with QoL domains, with Fatigue the most consistently associated.ConclusionThe present study identified differences between MD classifications within self-perceptions of mental-health. Muscle weakness is a defining feature of MD; however, it doesn’t define QoL in adults with MD. A greater understanding of mental wellbeing, independence, and management of fatigue and pain, are required to improve QoL for adults with MD.

REPARATIVE RHABDOMYOGENESIS IN MICE WITH DYSF MUTATION

Dysferlinopathies are a group of muscular dystrophies with autosomal-recessive inheritance caused by mutations in DYSF gene. Dysferlin is a 237 kDa transmembrane protein responsible for reparation of the sarcolemma. It has calcium-sensitive C2 domains and after dysferlin binding with calcium ions the first one activates vesicles fusion and patch mechanism repair. There are number of knockout animal strains with dysferlin gene mutations. Bla/J mice have the ETn retrotransposon inserted in intron 4 of the DYSF gene of wild-type mice - C57Bl/6. The pathogenesis ascertainment of dysferlinopathies is important not only for revealing of physiological function of dysferlin, but its deficiency influence on reparative regeneration of skeletal muscles. In this paper the description of main pathohistological processes in skeletal muscle that take place in mice with dysferlinopathy after acute myotoxic injury is present. This article reviews quantitative evaluation of main pathomorphological processes in reparative regeneration: alteration (necrotized muscle fibers ratio), proliferation (Ki-67-positive myonuclei ratio), differentiation (mean cros-sectional area, percentage of centrinucleated muscle fibers, myo-genin-positive nuclei ratio, slow/fast muscle fibers ratio). It was identified that dysferlin-deficient mice have increased alteration level with more necrotized muscle fibers (35,1% (29,4%; 42,9%) in Bla/J vs. 25,8% (17,9%; 37,4%) in C57Bl/6 on 2 day after alteration, p

Frequency of reported pain in adult males with muscular dystrophy.

IntroductionThe purpose of this study was to present and compare pain between adult males with Duchenne (DMD), Becker’s (BMD), Limb-Girdle (LGMD) Facioscapulohumeral (FSHD) forms of Muscular Dystrophy (MD), and healthy controls (CTRL), using three different methods of assessment.MethodsPain was assessed using 1) a whole body visual analogue scale (VAS) of pain, 2) a generalised body map and 3) a localised body map.ResultsAll types of MD reported more VAS pain than CTRL, with 97% of all MD participants reporting pain; however, no differences were reported between types of MD. The generalised body map approach identified more frequent pain in the shoulders of FSHD (93%) than other groups (13–43%), hips of DMD (87%) and LGMD (75%) than other groups (0–29%), and legs of all MD (64–78%) than CTRL (25%). The localised body map approach identified common areas of frequent pain across types of MD, posterior distal leg and distal back, as well as condition specific regions of frequent pain, for example posterior trapezius in FSHD, and anterior hip pain in DMD and LGMD.ConclusionsUsing a single pain value (VAS), increased pain was reported by adults with MD compared to CTRL, with no clear differences between different MD groups, suggesting pain is symptomatic of MD. The use of the generalised body map approach, and to an even greater extent the localised body map approach, identified specific areas of frequent pain relevant to each individual condition. These results indicate that whist the commonly used generalised approach can be used to identify broad anatomical regions, the localised approach provides a more comprehensive understanding of pain, reflective of clinical assessment, and should be utilised in future research.

The roles of dystroglycan in the nervous system: insights from animal models of muscular dystrophy.

ABSTRACTDystroglycan is a cell membrane protein that binds to the extracellular matrix in a variety of mammalian tissues. The α-subunit of dystroglycan (αDG) is heavily glycosylated, including a special O-mannosyl glycoepitope, relying upon this unique glycosylation to bind its matrix ligands. A distinct group of muscular dystrophies results from specific hypoglycosylation of αDG, and they are frequently associated with central nervous system involvement, ranging from profound brain malformation to intellectual disability without evident morphological defects. There is an expanding literature addressing the function of αDG in the nervous system, with recent reports demonstrating important roles in brain development and in the maintenance of neuronal synapses. Much of these data are derived from an increasingly rich array of experimental animal models. This Review aims to synthesize the information from such diverse models, formulating an up-to-date understanding about the various functions of αDG in neurons and glia of the central and peripheral nervous systems. Where possible, we integrate these data with our knowledge of the human disorders to promote translation from basic mechanistic findings to clinical therapies that take the neural phenotypes into account.

X-linked juvenile retinoschisis: phenotypic and genetic characterization

Juvenile X-linked retinoschisis (XLRS, MIM#312700) belongs to a group of the vitreoretinal dystrophies. We aimed to describe the phenotype-genotype correlation of three XLRS cases in juveniles with different novel mutations from the Lithuanian population. The patients demonstrated macular retinoschisis and typical cyst-like cavities on spectral-domain optical coherence tomography (SD-OCT) images. The mean central foveal thickness was 569.7 µm. Two patients presented with peripheral retinoschisis. Flash electroretinogram demonstrated a reduced b/a ratio (<1.0) in all patients. RS1 (NM_000330.3) gene coding exons Sanger sequencing was performed. RS1 c.599G>T (p.R200L) mutation was detected in one case, showing to be pathogenic in silico analysis. c. (92_97) insC (p.W33fs) mutation was identified for another patient, indicating the variant is possibly damaging in silico analysis. The third case was identified with a pathogenic mutation c.422C>G (p.R141H), HGMD CM981753. These are the first cases of XLRS in the Lithuanian population confirmed by molecular genotyping. Presented patients had a different genotype but similar phenotypic traits.

Relationships between muscle size, strength, and physical activity in adults with muscular dystrophy.

BackgroundMuscular dystrophy (MD) is characterized by progressive muscle wasting and weakness, yet few comparisons to non‐MD controls (CTRL) of muscle strength and size in this adult population exist. Physical activity (PA) is promoted to maintain health and muscle strength within MD; however, PA reporting in adults with MD is limited to recall data, and its impact on muscle strength is seldom explored.MethodsThis study included 76 participants: 16 non‐MD (CTRL, mean age 35.4), 15 Duchenne MD (DMD, mean age 24.2), 18 Becker's MD (BMD, mean age 42.4), 13 limb‐girdle MD (LGMD, mean age 43.1), and 14 facioscapulohumeral MD (mean age 47.7). Body fat (%) and lean body mass (LBM) were measured using bioelectrical‐impedance. Gastrocnemius medialis (GM) anatomical cross‐sectional area (ACSA) was determined using B‐mode ultrasound. Isometric maximal voluntary contraction (MVC) was assessed during plantar flexion (PFMVC) and knee extension (KEMVC). PA was measured for seven continuous days using triaxial accelerometry and was expressed as daily average minutes being physically active (TPAmins) or average daily percentage of waking hours being sedentary (sedentary behaviour). Additionally, 10 m walk time was assessed.ResultsMuscular dystrophy groups had 34–46% higher body fat (%) than CTRL. DMD showed differences in LBM with 21–28% less LBM than all other groups. PFMVC and KEMVC were 36–75% and 24–92% lower, respectively, in MD groups than CTRL. GM ACSA was 47% and 39% larger in BMD and LGMD, respectively, compared with CTRL. PFMVC was associated with GM ACSA in DMD (P = 0.026, R = 0.429) and CTRL (P = 0.015, R = 0.553). MD groups were 14–38% more sedentary than CTRL groups, while DMD were more sedentary than BMD (14%), LGMD (8%), and facioscapulohumeral MD (14%). Sedentary behaviour was associated with LBM in DMD participants (P = 0.021, R = −0.446). TPAmins was associated with KEMVC (P = 0.020, R = 0.540) in BMD participants, while TPAmins was also the best predictor of 10 m walk time (P < 0.001, R 2 = 0.540) in ambulant MD, revealed by multiple linear regression.ConclusionsQuantified muscle weakness and impaired 10 m walking time is reported in adults with MD. Muscle weakness and 10 m walk time were associated with lower levels of TPA in adults with MD. Higher levels of sedentary behaviour were associated with reduced LBM in DMD. These findings suggest a need for investigations into patterns of PA behaviour, and relevant interventions to reduce sedentary behaviour and encourage PA in adults with MD regardless of impairment severity.

Two-Year Longitudinal Changes in Lower Limb Strength and Its Relation to Loss in Function in a Large Cohort of Patients With Duchenne Muscular Dystrophy.

The main objective of this study was to examine the effect of disease on strength in two functionally important lower limb muscles for a period of 2 yrs in children with Duchene muscular dystrophy. Seventy-seven Duchene muscular dystrophy children participated in this study. Plantar flexors, knee extensors, strength, and performance on timed tests (6-min walk, 4-stairs, 10-m walk, supine-up) were assessed yearly for 2 yrs. Multivariate normal regression was used to assess changes in strength over time in the Duchene muscular dystrophy group. Spearman correlations were computed to examine relationship between strength and function. Normalized plantar flexor and knee extensor strength showed a significant decrease (P < 0.05) over 2 yrs, with larger declines in knee extensor. At baseline, knee extensor strongly correlated with performance on timed tests. However, plantar flexor strength was found to be a stronger predictor of loss in ambulatory function. Modest correlations (r = 0.19-0.34) were found between the decline in strength and functional performance over 2 yrs. This study describes the loss of lower limb strength in a large cohort of Duchene muscular dystrophy children for 2 yrs. The findings support that lower limb strength alone cannot account for the decline in performance on functional tests, and the role of other contributing factors, such as compensatory strategies, should be considered.

Choroidal structural analysis and vascularity index in retinal dystrophies

To assess choroidal structural changes in patients with retinal dystrophies using choroidal vascularity index (CVI), a novel optical coherence tomography (OCT) based tool. This retrospective study included 26 patients with retinal dystrophies (17 with retinitis pigmentosa, four with Stargardt disease, three with cone-rod dystrophy, one each with Best disease and Bietti crystalline dystrophy) and 32 healthy controls. Subfoveal OCT images were used for analysis. Mean CVI was compared between retinal dystrophy and control group, as well as among the retinal dystrophy subgroups. Mean CVI in eyes with retinal dystrophies was 52±9% and it was significantly lower compared to that in normal eyes (70±3%, p<0.001). The differences among subgroups of retinal dystrophy were not statistically significant (p=0.084). All types of retinal dystrophy were associated with lower CVI (all p<0.001), after adjusting for age, gender, visual acuity and duration of symptoms. Older age was also shown to be independently associated with lower CVI (p=0.012). Gender, visual acuity (VA) and duration of symptoms did not significantly affect CVI. Decreased choroidal vascularity was seen in eyes with retinal dystrophies. (CVI) may be a helpful tool in monitoring choroidal involvement in retinal dystrophies.

CDP-glycerol inhibits the synthesis of the functional O-mannosyl glycan of α-dystroglycan

α-Dystroglycan (α-DG) is a highly glycosylated cell-surface laminin receptor. Defects in the O-mannosyl glycan of an α-DG with laminin-binding activity can cause α-dystroglycanopathy, a group of congenital muscular dystrophies. In the biosynthetic pathway of functional O-mannosyl glycan, fukutin (FKTN) and fukutin-related protein (FKRP), whose mutated genes underlie α-dystroglycanopathy, sequentially transfer ribitol phosphate (RboP) from CDP-Rbo to form a tandem RboP unit (RboP-RboP) required for the synthesis of the laminin-binding epitope on O-mannosyl glycan. Both RboP- and glycerol phosphate (GroP)-substituted glycoforms have recently been detected in recombinant α-DG. However, it is unclear how GroP is transferred to the O-mannosyl glycan or whether GroP substitution affects the synthesis of the O-mannosyl glycan. Here, we report that, in addition to having RboP transfer activity, FKTN and FKRP can transfer GroP to O-mannosyl glycans by using CDP-glycerol (CDP-Gro) as a donor substrate. Kinetic experiments indicated that CDP-Gro is a less efficient donor substrate for FKTN than is CDP-Rbo. We also show that the GroP-substituted glycoform synthesized by FKTN does not serve as an acceptor substrate for FKRP and that therefore further elongation of the outer glycan chain cannot occur with this glycoform. Finally, CDP-Gro inhibited the RboP transfer activities of both FKTN and FKRP. These results suggest that CDP-Gro inhibits the synthesis of the functional O-mannosyl glycan of α-DG by preventing further elongation of the glycan chain. This is the first report of GroP transferases in mammals.

Indications and techniques of corneal transplantation in a referral center in Colombia, South America (2012-2016).

To describe the indications and techniques of corneal grafting in a tertiary institution in a middle-sized city in Colombia. A retrospective review of surgical reports and medical records of patients undergoing keratoplasty from January 2012 to December of 2016. A total of 346 eyes from 316 patients were included. The first three indications for keratoplasty were: bullous keratopathy (BK) with 46.2% of the cases, active infectious keratitis (22.3%) and the group of corneal dystrophies and degenerations, including Fuchs' endothelial dystrophy (9%). Keratoconus was in the sixth place (4.9%). 73.3% of the procedures were penetrating keratoplasties (n = 255), 21.7% posterior lamellar (n = 75) and 3.5% anterior lamellar (n = 12). While in 2012, 25 cases of endothelial grafts were performed, only 13 were done in 2016. BK was the first cause of keratoplasty with almost half of the cases, and keratoconus was relegated to sixth place with less than 5%. In comparison, in a study from eye banks from the US, BK was the second and keratoconus was the third indication for corneal grafts. The frequency of endothelial lamellar techniques in our institution decreased from 2012 to 2016. This could have been related to both the long time that the patients had to be on a waiting list, which made them unsuitable candidates for this technique, due to stromal fibrosis, and to the fact that surgeons of our institution had less experience with posterior endothelial grafting than with penetrating keratoplasties.

Fixation behavior in macular dystrophy assessed by microperimetry

PurposeTo investigate the fixation behavior in macular dystrophy using microperimetry.MethodsThis retrospective study included patients with macular dystrophy and unilateral macular pucker. Macular dystrophic eyes were compared based on fixation within or outside of the atrophic region. The normal fellow eyes in patients with unilateral macular pucker formed the control group. Clinical and demographic characteristics of age, sex, best-corrected visual acuity, spherical equivalent, and fixation behavior (which included foveal mean sensitivity (MS), fixation MS, MS improvement, stability, centrality, and eccentric distance of fixation) were analyzed. A total of 58 patients were recruited, comprising 29 eyes of 29 patients in the macular dystrophy group and 29 eyes of 29 patients in the control group.ResultsCompared to the control group, patients with macular dystrophy had significantly poorer visual acuity, foveal MS, fixation MS, stability, and centrality, and more eccentric preferred retinal locations (PRLs). In macular dystrophy, the PRLs were most common on the superior side (48.3%). Compared to fixation in the atrophic region, PRLs out of the atrophic lesion gained more MS (7.41 vs. 0.89 dB, p = 0.001), although with less stable fixation (10.0 vs. 47.4%, p = 0.044). By multivariate linear regression, eccentric distance was found to be significantly associated with MS improvement (p = 0.023).ConclusionsThe commonest location of PRLs in macular dystrophy is anatomically superior to the lesion. The dystrophic eye can gain better sensitivity by using PRLs outside the atrophic area.

TRAPPC11 and GOSR2 mutations associate with hypoglycosylation of \u03b1-dystroglycan and muscular dystrophy

BackgroundTransport protein particle (TRAPP) is a supramolecular protein complex that functions in localizing proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in muscle disease by virtue of homozygous and compound heterozygous deleterious mutations being identified in individuals with limb girdle muscular dystrophy and congenital muscular dystrophy. It remains unclear how this protein leads to muscle disease. Furthermore, a role for this protein, or any other membrane trafficking protein, in the etiology of the dystroglycanopathy group of muscular dystrophies has yet to be found. Here, using a multidisciplinary approach including genetics, immunofluorescence, western blotting, and live cell analysis, we implicate both TRAPPC11 and another membrane trafficking protein, GOSR2, in α-dystroglycan hypoglycosylation.Case presentationSubject 1 presented with severe epileptic episodes and subsequent developmental deterioration. Upon clinical evaluation she was found to have brain, eye, and liver abnormalities. Her serum aminotransferases and creatine kinase were abnormally high. Subjects 2 and 3 are siblings from a family unrelated to subject 1. Both siblings displayed hypotonia, muscle weakness, low muscle bulk, and elevated creatine kinase levels. Subject 3 also developed a seizure disorder. Muscle biopsies from subjects 1 and 3 were severely dystrophic with abnormal immunofluorescence and western blotting indicative of α-dystroglycan hypoglycosylation. Compound heterozygous mutations in TRAPPC11 were identified in subject 1: c.851A>C and c.965+5G>T. Cellular biological analyses on fibroblasts confirmed abnormal membrane trafficking. Subject 3 was found to have compound heterozygous mutations in GOSR2: c.430G>T and c.2T>G. Cellular biological analyses on fibroblasts from subject 3 using two different model cargo proteins did not reveal defects in protein transport. No mutations were found in any of the genes currently known to cause dystroglycanopathy in either individual.ConclusionRecessive mutations in TRAPPC11 and GOSR2 are associated with congenital muscular dystrophy and hypoglycosylation of α-dystroglycan. This is the first report linking membrane trafficking proteins to dystroglycanopathy and suggests that these genes should be considered in the diagnostic evaluation of patients with congenital muscular dystrophy and dystroglycanopathy.

T131. Electrophisiological evolution of retinitis pigmentosa

Retinitis pigmentosa (RP) is a group of hereditary retinal dystrophies, with a prevalence of 1/4000 inhabitants. It is an incapacitating entity that initially presents with nocturnal vision affectation and progressive decrease of the peripheral visual field, whose symptoms range from childhood to adulthood. Depending on the moment in which the electrophysiological tests are performed, the findings can be very variable. From early phases, when the symptoms are imperceptible or in healthy carriers, to those with an evolved retinosis that affects the entire retina. Objective: To present the findings of the neurophysiological tests in the different times of the evolution of the disease. Material and Methods: Patients diagnosed with RP derived from our unit, we performed Visual Evoked Potentials Pattern (PEV-P), Ganzfeld Electroretinogram (ERG-G) and Multifocal Electrorretinogram (ERG-MF).The results of the tests are exposed in three stages of the disease: preclinical (P): asymptomatic patients, with nictalopia without clear campimetric affectation and healthy carriers, established peripheral retinopathy (RPE): peripheral vision deficit and evolved retinopathy (RE): visual commitment below the 10th central of the visual field. Our observations in patients in phase P: normal PEV-P, ERG-G with alterations of scotopic responses and ERG-MF with lower response density in peripheral rings. In phase RPE: PEV-P normal or slightly altered, ERG-G practically abolished and ERG-MF with only conservation of responses in central rings. In phase RE: PEV-P altered, ERG-G abolished and ERG-MF with only discrete central response or affected diffusely. Neurophysiological tests are not only determinant in the diagnosis, during the different phases of the disease they contribute to assess their evolution and predict prognosis in patients affected with RP.