CORIN KneeTec DeepDishTM: Functional outcomes after a follow-up of 12 months and comparison with the STRYKER Triathlon PS.

Several competing concepts of anteroposterior stabilization have been developed for total knee arthroplasty (TKA), with an overall great success despite some differences in terms of clinical or radiological outcomes. The CORIN KneeTec DeepDish TM is a novel mobile-bearing implant, stabilized with an ultra-congruent deep-dish poly- ethylene insert. The aim of the present study was to report clinical and radiological outcomes of a series of patients who received the KneeTec DeepDish TM after a follow-up of 12 months, and to compare them to those of a comparable series of patients who received the STRYKER Triathlon ® posterior- stabilized. This was a retrospective comparative cohort study (level of evidence III). Demographic data, radiographic data and range of motion (ROM), as well the International Knee Society score and Oxford Knee Score were collected pre-operatively, and after a follow-up of 12 months. 106 KneeTec DeepDish TM and 80 Triathlon ® PS were evaluated at follow-up. Patients who received the KneeTec DeepDish TM had significant improvement in ROM, radiographic and clinical outcomes. There were no significant differences between the cohorts in terms of ROM, radiographic and clinical outcomes, as well as antero-posterior stability. This study is the first to report the 12-month outcomes of the CORIN KneeTec DeepDish TM. The novel KneeTec DeepDish TM achieved comparable ROM, radiographic and clinical outcomes to the Triathlon ® PS after 12 months. Further studies will be necessary to evaluate the mid- to long-term outcomes of the KneeTec DeepDish TM .

Novel PXDN biallelic variants in patients with microphthalmia and anterior segment dysgenesis.

Microphthalmia, anophthalmia, and anterior segment dysgenesis are severe ocular developmental defects. There is a wide genetic heterogeneity leading to these ocular malformations. By using whole genome, exome and targeted sequencing in patients with ocular developmental anomalies, six biallelic pathogenic variants (including five novel variants) were identified in the PXDN gene in four families with microphthalmia and anterior segment dysgenesis. Only 11 different mutations (11 families) have been described in this gene to date. The phenotype of these patients is variable in severity, ranging from cataract and developmental glaucoma to complex microphthalmia. Interestingly, two unrelated patients of our series presented with an ocular phenotype including aniridia and microspherophakia. However, despite various phenotypic presentations and types of mutations, no genotype-phenotype correlation could be made. Thus, this work improves our knowledge of the recessive phenotype associated with biallelic variants in this gene and highlights the importance of screening PXDN in patients with anterior segment dysgenesis with or without microphthalmia.

Recessive and Dominant De Novo ITPR1 Mutations Cause Gillespie Syndrome.

Gillespie syndrome (GS) is a rare variant form of aniridia characterized by non-progressive cerebellar ataxia, intellectual disability, and iris hypoplasia. Unlike the more common dominant and sporadic forms of aniridia, there has been no significant association with PAX6 mutations in individuals with GS and the mode of inheritance of the disease had long been regarded as uncertain. Using a combination of trio-based whole-exome sequencing and Sanger sequencing in five simplex GS-affected families, we found homozygous or compound heterozygous truncating mutations (c.4672C>T [p.Gln1558(∗)], c.2182C>T [p.Arg728(∗)], c.6366+3A>T [p.Gly2102Valfs5(∗)], and c.6664+5G>T [p.Ala2221Valfs23(∗)]) and de novo heterozygous mutations (c.7687_7689del [p.Lys2563del] and c.7659T>G [p.Phe2553Leu]) in the inositol 1,4,5-trisphosphate receptor type 1 gene (ITPR1). ITPR1 encodes one of the three members of the IP3-receptors family that form Ca(2+) release channels localized predominantly in membranes of endoplasmic reticulum Ca(2+) stores. The truncation mutants, which encompass the IP3-binding domain and varying lengths of the modulatory domain, did not form functional channels when produced in a heterologous cell system. Furthermore, ITPR1 p.Lys2563del mutant did not form IP3-induced Ca(2+) channels but exerted a negative effect when co-produced with wild-type ITPR1 channel activity. In total, these results demonstrate biallelic and monoallelic ITPR1 mutations as the underlying genetic defects for Gillespie syndrome, further extending the spectrum of ITPR1-related diseases.

[When everything is frozen, start moving again: the FIT@CHUV program]. / Quand tout est gelé, se remettre à bouger†: programme FIT@CHUV.

The adolescent's painful functional disorders deserve management by a specialized interdisciplinary team. In recent years, intensive interdisciplinary physical therapy (IIPT) programs have developed in a hospital environment in Europe and around the world. While the short-term objective is often to restore trust between the patient and the therapists by relieving parents of the need to coordinate a network of multidisciplinary practitioners. These programs have proven to be effective in the medium and long term in improving the patient's clinical performance and for the benefits associated with restoring normal life for the family. Finally, these programs can have a positive impact in a cost-benefit approach when considering these often long and complex care arrangements.

Les troubles fonctionnels douloureux chroniques de l'adolescent méritent une prise en charge interdisciplinaire spécialisée. Depuis quelques années, des programmes de thérapie physique intensive interdisciplinaire (intensive interdisciplinary physical therapy, IIPT) se sont développés dans un environnement hospitalier en Europe et dans le monde. Si l'objectif à court terme est souvent de remettre les patients en mouvement, un autre objectif est de restaurer une confiance entre le patient et les professionnels de la santé en soulageant notamment les parents de la coordination d'un réseau de praticiens multidisciplinaires. Ces programmes ont montré leur efficacité à moyen et long termes sur l'amélioration clinique du patient et sur les bénéfices associés à la reprise d'une vie normale pour la famille. Enfin, ces programmes peuvent avoir un impact positif en termes de coût/bénéfice dans ces prises en charge souvent longues et complexes.

Submicroscopic deletions at 13q32.1 cause congenital microcoria.

Congenital microcoria (MCOR) is a rare autosomal-dominant disorder characterized by inability of the iris to dilate owing to absence of dilator pupillae muscle. So far, a dozen MCOR-affected families have been reported worldwide. By using whole-genome oligonucleotide array CGH, we have identified deletions at 13q32.1 segregating with MCOR in six families originating from France, Japan, and Mexico. Breakpoint sequence analyses showed nonrecurrent deletions in 5/6 families. The deletions varied from 35 kbp to 80 kbp in size, but invariably encompassed or interrupted only two genes: TGDS encoding the TDP-glucose 4,6-dehydratase and GPR180 encoding the G protein-coupled receptor 180, also known as intimal thickness-related receptor (ITR). Unlike TGDS which has no known function in muscle cells, GPR180 is involved in the regulation of smooth muscle cell growth. The identification of a null GPR180 mutation segregating over two generations with iridocorneal angle dysgenesis, which can be regarded as a MCOR endophenotype, is consistent with the view that deletions of this gene, with or without the loss of elements regulating the expression of neighboring genes, are the cause of MCOR.

Global radiological score for femoral cementless revision stem.

PURPOSE: The purpose of this study was to evaluate the outcomes of total hip arthroplasty (THA) revision with cementless stems using a numeric global radiological score (GRxS) that summarizes two previously validated scores: secondary bone stock (SBS) and osseointegration-secondary stability (O-SS). METHOD: One hundred fifty cases of THA were evaluated at a mean follow-up of 6.5 ± 3.7 years. The GRxS combines the SBS, which evaluated cortical bone thickness, bone density and bone defects in each Gruen zone and the O-SS, which evaluated the location and extent of a single radiolucent line. To calculate the GRxS, the SBS and O-SS were each expressed on a 10-point scale and given equal weighing. The final result was a number out of 20. The GRxS was used to assign a radiological grade to each THA case: very good (20), good (18-15), average (13-12), or poor (≤ 10). The numerical mean (Nm) was calculated for each grade. The inter- and intra-observer reproducibility was evaluated. RESULTS: The inter-observer reproducibility was good (0.8) and the intra-observer reproducibility was very good (0.9). The GRxS was considered very good in 46 cases (Nm 20), good in 57 cases (Nm 16.6), average in 25 cases and poor in 22 cases. There was a significant relationship between the GRxS and the Harris Hip and Postel Merle d'Aubigné scores (p < 0.0001), and the initial bone stock (p = 0.0001). CONCLUSIONS: The GRxS is reliable and reproducible. This information can be used by surgeons to adapt the surgical technique to bone characteristics (especially during revision cases) and to compare the outcomes of different implant designs.

[Together we are stronger: management of complex functional disorders during adolescence]. / L'union fait la force :traitement des troubles fonctionnels complexes à l'adolescence.

Functional disorder during adolescence is a very complex problem too often limited to a psychological origin. Its pathogenesis remains unclear but it definitively associates individual and environmental factors. Recent data show anatomo-functional evidence of neural networks of the brain that is involved in pain and its psychological representation as well as the representation of pain in the body. We describe a holistic approach to manage functional disorders that include the family and promote adolescent centered care in order to reach a rapid and optimal rehabilitation.

Le trouble fonctionnel de l'adolescent est une pathologie complexe trop souvent réduite à un abord exclusivement psychologique. Sa genèse est encore insuffisamment comprise, mais elle associe certainement des facteurs individuels et environnementaux. Les données récentes montrent qu'il existe un support anatomo-fonctionnel au sein des réseaux neuronaux cérébraux impliqués dans la douleur et sa représentation psychique et corporelle. A l'instar des réseaux neuronaux, il s'agit souvent aussi d'une difficulté de travailler en réseau interdisciplinaire. Nous proposons ici une approche holistique de ces troubles, incluant les familles et plaçant l'adolescent au centre d'une prise en charge qui vise une réhabilitation rapide.

Assessment of fixation in cementless femoral revision of total hip arthroplasty: comparison of the Engh score versus radiolucent line measurement.

PURPOSE: To assess osseointegration and stability of a primary cementless femoral stem, many scoring systems have been developed, but none of them have taken into account only the radiolucent line. The purposes of this study were (1) to compare the results between the Engh score to assess osseointegration and stability of the cementless stem with results of a score called the O-SS score (osseointegration-secondary stability), which takes into account the radiolucent line, (2) to verify the relationship between these two scores and the functional results, and (3) to verify if there is a relationship between the O-SS score and secondary subsidence or a pedestal. METHODS: A clinical and radiological evaluation was performed in a group of 100 hip prosthesis revisions comparing the results obtained by Engh score and O-SS score for which reproducibility was analysed. RESULTS: Inter-observer reproducibility was estimated to be average at 0.5 and intra-observer reproducibility good at 0.7. The correlation with the Engh score was good at r = 0.59 (p < 0.0001). For the 80 cases assessed O-SS score as very good/good, Harris hip score was at 83.7 versus 78.25 for the 20 cases assessed as average/poor (p = 0.07). For the 73 cases with assessed Engh score as very good/good, this score was at 82.8 versus 82.14 for the 27 cases assessed as average/poor. No correlation between the O-SS score and secondary subsidence (p = 0.2) or pedestal (p = 0.2) was noticed. CONCLUSION: The evaluation of the clear radiolucent line alone, extent and location, is a sufficient condition to assess osseointegration and secondary stability of a cementless femoral stem.

Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations.

Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal dystrophy. Through a combination of ciliome resequencing and Sanger sequencing, we identified IFT140 mutations in six MSS families and in a family with the clinically overlapping Jeune syndrome. IFT140 is one of the six currently known components of the intraflagellar transport complex A (IFT-A) that regulates retrograde protein transport in ciliated cells. Ciliary abundance and localization of anterograde IFTs were altered in fibroblasts of affected individuals, a result that supports the pivotal role of IFT140 in proper development and function of ciliated cells.

Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6.

Spontaneous pathologic arterial calcifications in childhood can occur in generalized arterial calcification of infancy (GACI) or in pseudoxanthoma elasticum (PXE). GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE. However, the genetic basis in subsets of both disease phenotypes remains elusive. We hypothesized that GACI and PXE are in a closely related spectrum of disease. We used a standardized questionnaire to retrospectively evaluate the phenotype of 92 probands with a clinical history of GACI. We obtained the ENPP1 genotype by conventional sequencing. In those patients with less than two disease-causing ENPP1 mutations, we sequenced ABCC6. We observed that three GACI patients who carried biallelic ENPP1 mutations developed typical signs of PXE between 5 and 8 years of age; these signs included angioid streaks and pseudoxanthomatous skin lesions. In 28 patients, no disease-causing ENPP1 mutation was found. In 14 of these patients, we detected pathogenic ABCC6 mutations (biallelic mutations in eight patients, monoallelic mutations in six patients). Thus, ABCC6 mutations account for a significant subset of GACI patients, and ENPP1 mutations can also be associated with PXE lesions in school-aged children. Based on the considerable overlap of genotype and phenotype of GACI and PXE, both entities appear to reflect two ends of a clinical spectrum of ectopic calcification and other organ pathologies, rather than two distinct disorders. ABCC6 and ENPP1 mutations might lead to alterations of the same physiological pathways in tissues beyond the artery.

Surgical management of the infected reversed shoulder arthroplasty: a French multicenter study of reoperation in 32 patients.

BACKGROUND: In a retrospective multicenter study, we evaluated the efficiency and outcomes of the different therapeutic options for infection after reversed shoulder arthroplasty. METHODS: Thirty-two patients were reoperated on for infection after reversed shoulder arthroplasty between 1996 and 2011. The mean age was 71 (55-83) years. The involved implants were primary prostheses in 23 cases and revision prostheses in 9 cases. The average preoperative Constant score was 34 (11-69). Six of these patients needed 2 successive procedures. A total of 38 procedures were performed: débridement (13), 1-stage (5) or 2-stage revision (14), or implant removal (6). At last follow-up (mean, 36 months; range, 12-137 months), every patient had clinical, biologic, and radiographic evaluation. RESULTS: Infections were largely caused by coagulase-negative staphylococci (56%) and Propionibacterium acnes (59%). The complication rate was 26%. At last follow-up, 26 patients were free of infection (81%). The final Constant score was 46 (12-75). After débridement with implant retention, the mean Constant score was 51 (29-75), but the healing rate was only 54%. Implant revision (1 or 2 stage) led to better functional results than implant removal (46 vs. 25; P = .001), with similar healing rates (73% and 67%, respectively). Patients with low initial impairment (Constant score > 30) were not significantly improved by surgical treatment. CONCLUSION: Débridement is the less aggressive option but exposes patients to healing failure. It should be proposed as a first treatment attempt. Revision of the implant is technically challenging but preserves shoulder function, with no higher rate of residual infection compared with implant removal.

Bone stock in revision femoral arthroplasty: a new evaluation.

PURPOSE: The purpose of this study was to finalize a method allowing a qualitative and numerical evaluation of the bone stock and to confirm its reproducibility, to verify the relationship between the secondary bone stock value and the functional results, and to determine the main factors influencing the value of the bone stock. METHODS: A clinical and radiological evaluation was performed in a group of 150 revisions of total hip replacements according to a new method taking into account cortical bone thickness, bone density and bone defects. RESULTS: Interobserver reproducibility was evaluated at an average of 0.6 and intra-observer reproducibility was considered good at 0.8. Between the initial bone stock and at the last follow-up, no significant difference was noticed. For secondary bone stock considered as "very good or good", the gain was +38.1 points versus +29.9 points for patients evaluated as "average or poor" (p < 0.0001). Between the initial bone stock assessment and at last follow-up, a significant relation was found in numerical values for the global type of primary fixation and in the presence of osteopenia (p < 0.0001). CONCLUSIONS: Deficient secondary bone stock can result in less favourable functional results. The numerical scores confirm the importance of strategic choices during surgery in order to manage bone stock preservation.

Genetic characterization of congenital tufting enteropathy: epcam associated phenotype and involvement of SPINT2 in the syndromic form.

Congenital tufting enteropathy (CTE) is a rare and severe enteropathy recently ascribed to mutations in the epcam gene. Here we establish SPINT2, previously ascribed to congenital sodium diarrhea, as a second gene associated with CTE and report molecular and immunohistochemistry data in 57 CTE patients. Inclusion criteria were early onset diarrhea and intestinal insufficiency with the typical histological CTE abnormalities. The clinical phenotype was registered, the entire coding regions of epcam and SPINT2 sequenced, and immunostaining of EpCAM and SPINT2 performed on intestinal biopsies. An epcam mutation was involved in 41 patients (73 %) who mainly displayed isolated digestive symptoms. Mutations severely affected gene expression since the EpCAM signal on intestinal tissues was either undetectable or low and irregular. Twelve other patients (21 %) carried mutations in SPINT2, and were phenotypically characterized by systematic association with keratitis (p < 10(-4)) and, for half of them, with choanal atresia (p < 10(-4)). Dependency on parenteral nutrition (PN) was comparable in patients with epcam or SPINT2 mutations, but the frequent epcam mutation c.556-14A>G (abnormal splicing) was significantly associated with a better outcome (p = 0.032) with milder PN dependency to weaning in some cases. Finally, four patients (7 %) with isolated digestive symptoms had no detectable epcam or SPINT2 mutation. Two candidate genes, Elf3 and Claudin7, were excluded from this population. Our study allows us to separate CTE patients into at least three genetic classes, each with specific phenotypes. The genetics approach raises the question of the distinction between two congenital enteropathies. Our findings should help improve the diagnosis of CTE, guide toward strategies of long-term PN management, and limit indications for intestinal transplantation to life-threatening PN complications.

[From congenital glaucoma to chronic open angle glaucoma in adulthood: a clinical and genetic continuum]. / Du glaucome congénital au glaucome chronique de l'adulte: un continuum clinique et génétique.

Congenital glaucoma, a true hydrocephalus of the eye, is defined by ocular hypertension resulting in buphthalmos in children up to three years old, the elasticity of the eye wall allowing its expansion. Juvenile glaucoma in teenagers and chronic glaucoma in adults do not alter the external aspect of the eye, as the eyeball has lost its elasticity. However, chronic ocular hypertension always causes ischemic excavation of the optic nerve head, leading to insidious amputation of the visual field and, potentially, blindness. Like most ophthalmological disorders, the different types of glaucoma have been shown to be genetically determined, and alterations in several genes have been identified. These altered genes can be expressed more or less early in life, suggesting a role of modifier genes. The role of CYP1B1 alterations in classic primary congenital glaucoma is well known, as is the role of PITX2, FOXC1, PAX6 and LOXC1 alterations in secondary congenital glaucoma due to iridogoniodysgenesis, and of MYOC alterations in the genesis of chronic glaucoma in adulthood. An outbred family carrying CYP1B1 mutations in the compound heterozygous state includes two sibs with primary congenital glaucoma and two others who developed chronic glaucoma in adulthood.

TMEM126A, encoding a mitochondrial protein, is mutated in autosomal-recessive nonsyndromic optic atrophy.

Nonsyndromic autosomal-recessive optic neuropathies are rare conditions of unknown genetic and molecular origin. Using an approach of whole-genome homozygosity mapping and positional cloning, we have identified the first gene, to our knowledge, responsible for this condition, TMEM126A, in a large multiplex inbred Algerian family and subsequently in three other families originating from the Maghreb. TMEM126A is conserved in higher eukaryotes and encodes a transmembrane mitochondrial protein of unknown function, supporting the view that mitochondrial dysfunction may be a hallmark of inherited optic neuropathies including isolated autosomal-recessive forms.

Articulated bipolar vs. non-articulated conventional spacers: A comparative study of results from two-stage treatment of chronic septic arthritis in prosthetic or native hips.

INTRODUCTION: Infection is a serious complication of 0.2-0.7% of primary total hip arthroplasties (THA) and 1-22% of prosthetic revisions. The objective of our study was to compare two types of spacers (unipolar versus bipolar) for two-stage revisions of periprosthetic hip infections. The primary hypothesis was that bipolar spacers have fewer mechanical complications than unipolar spacers. The secondary hypothesis was that bipolar spacers decrease the rate of septic revisions and promote primary prosthesis reimplantation. MATERIAL AND METHOD: This retrospective, monocentric, multi-operator study was carried out between January 2012 and July 2018, including patients operated on for septic arthritis of the native or prosthetic hip (two-stage procedure). The patients were divided into two groups: group A, including the articulated spacers and group B, including the unipolar spacers. We studied the complications of the spacers and the course of the infection over a minimum of two years. Functional status was assessed by the Postel Merle d'Aubigné (PMA) score, the Harris Hip Score (HHS) and pre- and postoperative patient satisfaction scores. RESULTS: We collected data for 39 hips from 37 patients (mean age 63, 22 men and 14 women: 16 patients in group A, 21 in group B). We found no mechanical complications in group A versus 12 (52%) in group B. At 2 years, 93.8% of patients in group A no longer had any signs indicative of an active infection, compared with 71.4% in group B. In group A, the median PMA score increased from 5.5 (4-10.5) to 13.5 (12.5-15.5) and the HHS score from 27.5 (17-41.5) to 79 (64.5-89.5), postoperatively. In the final group B, the PMA score increased from 7 (6-9) to 14 (12-16) and the HHS score from 24 (11-41) to 72 (48-82) postoperatively. CONCLUSION: The use of articulated spacers in THA or septic THA two-stage revision significantly reduces the occurrence of mechanical complications in the short term, as well as the pain between the two procedures. LEVEL OF PROOF: IV.

De novo design by pharmacophore-based searches in fragment spaces.

De novo ligand design supports the search for novel molecular scaffolds in medicinal chemistry projects. This search can either be based on structural information of the targeted active site (structure-based approach) or on similarity to known binders (ligand-based approach). In the absence of structural information on the target, pharmacophores provide a way to find topologically novel scaffolds. Fragment spaces have proven to be a valuable source for molecular structures in de novo design that are both diverse and synthetically accessible. They also offer a simple way to formulate custom chemical spaces. We have implemented a new method which stochastically constructs new molecules from fragment spaces under consideration of a three dimensional pharmacophore. The program has been tested on several published pharmacophores and is shown to be able to reproduce scaffold hops from the literature, which resulted in new chemical entities.

Experimental assessment of the effective friction at the base of granular chute flows on a smooth incline.

We report on direct measurements of the basal force components for granular material flowing down a smooth incline. We investigate granular flows for a large range of inclination angles from θ=13.4^{∘} to 83.6° and various gate openings of the chute. We find that the effective basal friction coefficient µ_{B}, obtained from the ratio of the longitudinal force to the normal one, exhibits a systematic increase with increasing slope angle and a significant weakening with increasing particle holdup H (the depth-integrated particle volume fraction). At low angles, the basal friction is slightly less than or equal to tanθ. The deviation from tanθ can be interpreted as a contribution from the sidewall to the overall friction. At larger angles, the basal friction µ_{B} saturates at an asymptotic value that is dependent on the gate opening of the chute. Importantly, our data confirm the outcomes of recent discrete numerical simulations. First, for steady and fully developed flows as well as for moderately accelerated ones, the variation of the basal friction can be captured through a unique dimensionless number, the Froude number Fr, defined as Fr=U[over ¯]/(gHcosθ)^{1/2}, where U[over ¯] is the mean flow velocity. Second, the mean velocity scales with the particle holdup H with a power exponent close to 1/4, contrasting with the Bagnold scaling (U[over ¯]∼H^{3/2}).

Confirmation of FZD5 implication in a cohort of 50 patients with ocular coloboma.

Defects in optic fissure closure can lead to congenital ocular coloboma. This ocular malformation, often associated with microphthalmia, is described in various clinical forms with different inheritance patterns and genetic heterogeneity. In recent times, the identification of an increased number of genes involved in numerous cellular functions has led to a better understanding in optic fissure closure mechanisms. Nevertheless, most of these genes are also involved in wider eye growth defects such as micro-anophthalmia, questioning the mechanisms controlling both extension and severity of optic fissure closure defects. However, some genes, such as FZD5, have only been so far identified in isolated coloboma. Thus, to estimate the frequency of implication of different ocular genes, we screened a cohort of 50 patients affected by ocular coloboma by using targeted sequencing of 119 genes involved in ocular development. This analysis revealed seven heterozygous (likely) pathogenic variants in RARB, MAB21L2, RBP4, TFAP2A, and FZD5. Surprisingly, three out of the seven variants detected herein were novel disease-causing variants in FZD5 identified in three unrelated families with dominant inheritance. Although molecular diagnosis rate remains relatively low in patients with ocular coloboma (14% (7/50) in this work), these results, however, highlight the importance of genetic screening, especially of FZD5, in such patients. Indeed, in our series, FZD5 variants represent half of the genetic causes, constituting 6% (3/50) of the patients who benefited from a molecular diagnosis. Our findings support the involvement of FZD5 in ocular coloboma and provide clues for screening this gene during current diagnostic procedures.

Spectrum of SPATA7 mutations in Leber congenital amaurosis and delineation of the associated phenotype.

Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration. It may present as a congenital stationary cone-rod dystrophy (LCA type I) or a progressive yet severe rod-cone dystrophy (LCA type II). Twelve LCA genes have been identified, three of which account for Type I and nine for LCA type II. All proteins encoded by these genes but two are preferentially expressed in the retina and are responsible for non-syndromic LCA only. By contrast LCA5 and CEP290 are widely expressed and mutations in this latter result in a variety of phenotypes from non-syndromic retinal degeneration to pleiotropic disorders including senior-Loken (SNLS) and Joubert syndromes (JBTS). Recently, mutations in the widely expressed gene SPATA7 were reported to cause LCA or juvenile retinitis pigmentosa. The purpose of this study was i) to determine the level of expression of two major alternative SPATA7 transcripts in a large range of tissues and ii) to assess the involvement of this novel gene in a large cohort of unrelated patients affected with LCA (n = 134). Here, we report high SPATA7expression levels in retina, brain and testis with differential expression of the two transcripts. SPATA7 mutations were identified in few families segregating non-syndromic LCA (n = 4/134). Six different mutations were identified, four of which are novel; All affected both SPATA7 transcripts. The clinical evaluation of patients suggested that SPATA7 mutations account for the rod-cone dystrophy type of the disease.