Spinocerebellar ataxia 27B (SCA27B), a frequent late-onset cerebellar ataxia.

Genetic cerebellar ataxias are still a diagnostic challenge, and yet not all of them have been identified. Very recently, in early 2023, a new cause of late-onset cerebellar ataxia (LOCA) was identified, spinocerebellar ataxia 27B (SCA27B). This is an autosomal dominant ataxia due to a GAA expansion in intron 1 of the FGF14 gene. Thanks to the many studies carried out since its discovery, it is now possible to define the clinical phenotype, its particularities, and the progression of SCA27B. It has also been established that it is one of the most frequent causes of LOCA. The core phenotype of the disease consists of slowly progressive late-onset ataxia with cerebellar syndrome, oculomotor disorders including downbeat nystagmus, and episodic symptoms such as diplopia. Therapeutic approaches have been proposed, including acetazolamide, and 4-aminopyridine, the latter with a better benefit/tolerance profile.

Megalencephaly secondary to a novel germline missense variant p.Asp322Tyr in AKT3 associated with growth hormone deficiency and central hypothyroidism: A case report.

Germline gain of function variations in the AKT3 gene cause brain overgrowth syndrome with megalencephaly and diffuse bilateral cortical malformations. Here we report a child with megalencephaly, who is a carrier of a novel heterozygous missense variant in the AKT3 gene NM_005465.7:c.964G>T,p.Asp322Tyr. The phenotype of this patient is associated with pituitary deficiencies diagnosed at 2 years of age: growth hormone (GH) deficiency responsible for growth delay and central hypothyroidism. After 6 months of GH treatment, intracranial hypertension was noted, confirmed by the observation of papilledema and increased intracranial pressure, requiring the initiation of acetazolamide treatment and the discontinuation of GH treatment. This is the second reported patient described with megalencephaly and AKT3 gene variant associated with GH deficiency . Other endocrine disorders have also been reported in few cases with hypothyroidism and hypoglycemia. Pituitary deficiency may be a part of the of megalencephaly phenotype secondary to germline variant in the AKT3 gene. Special attention should be paid to growth in these patients and search for endocrine deficiency is necessary in case of growth retardation or hypoglycemia.

ENPP1 homozygous stop-loss variant causing generalized arterial calcifications of infancy: About a severe neonatal clinical case.

Generalized Arterial Calcifications of Infancy (GACI) is an extremely rare autosomal recessive genetic condition, mostly due to pathogenic variations in the ENPP1 gene (GACI1, MIM #208000, ENPP1, MIM #173335). To date 46 likely pathogenic or pathogenic distinct variations in ENPP1 have been described, including nonsense, frameshift, missense, splicing variations, and large deletions. Here we report a case of GACI in a male newborn with a homozygous stop-loss variant in ENPP1 treated in Nancy Regional University Maternity Hospital. Based on proband main clinical signs, clinical exome sequencing was performed and showed a deletion of one nucleotide leading to frameshift and stop-loss (NM_006208.3 (ENPP1):c.2746del,p.(Thr916Hisfs*23)). Clinical presentation is characterized by primary neonatal arterial hypertension resulting in hypertrophic cardiomyopathy decompensated by three cardiogenic shocks and a neonatal deep right sylvian stroke. The child died at 24 days of life. This is the first report of a pathogenic stop-loss variant in ENPP1. It is an opportunity to remind clinicians of GACI disease, a rare and severe etiology in neonates with severe hypertension, and possibility of bisphosphonates therapy.

Extracellular miR-6723-5p could serve as a biomarker of limbal epithelial stem/progenitor cell population.

BACKGROUND: Dysfunction or loss of limbal stem cells can result in limbal stem cell deficiency (LSCD), a disease that cause corneal opacity, pain, and loss of vision. Cultivated limbal epithelial transplantation (CLET) can be used to restore stem cell niche homeostasis and replenish the progenitor pool. Transplantation has been reported with high success rate, but there is an unmet need of prognostic markers that correlate with clinical outcomes. To date, the progenitor content in the graft is the only parameter that has been retrospectively linked to success. METHODS: In this study, we investigate extracellular micro RNAs (miRNAs) associated with stem/progenitor cells in cultivated limbal epithelial cells (cLECs). Using micro RNA sequencing and linear regression modelling, we identify a miRNA signature in cultures containing high proportion of stem/progenitor cells. We then develop a robust RNA extraction workflow from culture media to confirm a positive miRNA correlation with stem/progenitor cell proportion. RESULTS: miR-6723-5p is associated with cultures containing high proportion of stem/progenitor cells, and is detected in the basal layer of corneal epithelium. CONCLUSIONS: These results indicate that miR-6723-5p could potentially serve as a stem/progenitor cell marker in cLECs.

[Systematic karyotyping before ICSI: A necessary procedure? Analysis of case studies in the Nancy University Hospital Fertility Centre]. / Le caryotype avant ICSI, une procédure à abandonner ? Étude de pratiques au centre d'AMP du CHRU de Nancy.

INTRODUCTION: A constitutional karyotype is often assayed for the couple before ICSI management. The objective of this study was to assess the prevalence of chromosomal abnormality in an infertile population, the impact on the care of couples and its cost. METHODS: A single-center retrospective study was carried out at the Fertility Center of the University Hospital of Nancy, including all infertile couples who underwent a karyotype analysis from June 2009 to December 2016. RESULTS: 1252 couples were included. 7.9% had at least one abnormal karyotype. A change in care affected 22% of these couples, i.e. 1.7% of the total population. 9% of couples with karyotype abnormality underwent PGD. In the male population, the percentage of abnormal spermograms is significantly higher in the group with karyotype abnormality compared to the control group (85.7% vs. 46.5%, P<0.001). DISCUSSION: The constitutional karyotype, due to its high economic and human cost, and limited interest, is a screening method for chromosomal abnormalities that has no place systematically before performing IVF. The future lies in the restriction of the indications for prescribing the karyotype as well as in the realization of PGS in targeted situations.

Patient education program at the forefront of cancer-associated thrombosis care.

INTRODUCTION: Treatment of cancer-associated thrombosis (CAT) requires specific approaches, although it is well codified in most cases. Current national and international (International Initiative on Cancer and Thrombosis, ITAC) Clinical Practice Guidelines (CPG) recommend the use of low-molecular-weight heparin (LMWH) over 6 months as first treatment option, and anticoagulation should be maintained thereafter as long as cancer is active. Since compliance improves when patients understand their disease and related treatments, we created a dedicated patient education program (PEP) for CAT, aiming to improve quality of care. METHODS: Retrospective analysis of all patients who voluntarily joined the PEP for CAT from 2014 to 2020. RESULTS: In total, 182 cancer patients (median age, 64.9 years) were included, 53.3% with metastatic disease. A total of 528 PEP sessions (median, 3 per patient) were delivered. After PEP completion, the rate of self-injections or those performed at home by a relative had increased from 49.1% to 59.8% (P=0.05). Quality of life had improved significantly (P=0.025) and 90.0% of patients reported adhering to anticoagulant therapy. CONCLUSION: Implementation of a structured and personalized PEP for CAT is feasible, allowing to improve cancer patient empowerment, adherence to CAT treatment and quality of life. The Groupe francophone et cancer (GFTC) members aim at facilitating access to CAT-PEP for both patients and caregivers and use of the multi-language ITAC-CPG mobile app (free access: www.itaccme.com) to improve the care and quality of life of patients with CAT.

[Diffuse large B-cell lymphoma: a revolutionary treatment based on genetically-modified immune cells called CAR T cells]. / Le lymphome diffus à grandes cellules B : nouveau traitement révolutionnaire par des cellules immunitaires génétiquement modifiées appelées «CART cells¼.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Firstline immunochemotherapy cures approximatively 60 % of patients. The prognosis of patients with refractory disease or with relapsed disease within the first two years after the end of treatment is highly unfavourable. Since June 2019, a new third-line treatment with CAR T cells (chimeric antigen receptor T cells) seems to completely modify the prognosis of these patients. A significant proportion of long-lasting complete responses is obtained with this revolutionary treatment. Quick specialized intervention is required for the unique side effects of this therapy.

Le lymphome B diffus à grandes cellules (LBDGC) est le type histologique de lymphome non Hodgkinien le plus fréquent. Le traitement de première ligne par immunochimiothérapie ne permet de guérir qu'environ 60 % des patients. Les patients présentant une maladie réfractaire à une première ligne de traitement ou en rechute dans les deux premières années suivant le traitement présentent un mauvais pronostic. Disponible depuis juin 2019, un nouveau traitement de 3ème ligne sous forme d'immunothérapie par CAR T cells (acronyme anglais de «chimeric antigen receptor T cells¼) semble modifier complètement le pronostic de ces patients, avec l'obtention d'une proportion importante de réponses complètes de longue durée. Les effets indésirables spécifiques liés à ce traitement demandent une prise en charge rapide et spécialisée.

[Management of mycosis fungoide : focus on brentuximab vedotin]. / Comment je traite le mycosis fongoïde : à propos du brentuximab védotine, une nouvelle arme thérapeutique.

Recently, brentuximab vedotin (BV) (Adcetris®) obtained the reimbursement in Belgium for the treatment of the primary cutaneous NKT-cell lymphomas mycosis fungoides (MF), large cell anaplastic lymphoma and lymphomatoid papulosis type A. BV is a monoclonal antibody directed against the CD30 expressed on tumoral T cells. The inhibition of this pathway releases the process of apoptosis leading to the cell death of the tumoral cells. BV is reimbursed after the use of another systemic treatment without success and if the number of CD30 positive atypical T-cells is larger than 10 %. BV is administered intravenously every 3 weeks with a dosing of 1,8 mg/kg with a maximum of 16 courses. The response rates exceed 75 %. In some instances, interesting treatment responses have been observed with BV in CD30 negative patients. The principal adverse effects are neutropenia and peripheral neuropathy. Two patients are presented with longstanding multi-resistant MF that were successfully treated with BV.

Récemment, le brentuximab védotine (BV) (Adcetris®) a obtenu le remboursement en Belgique pour le traitement du lymphome cutané primitif de type mycosis fongoïde (MF), du lymphome anaplasique à larges cellules et de la papulose lymphomatoïde de type A. Le BV est un anticorps monoclonal dirigé contre le CD30 exprimé par les cellules T tumorales. L'inhibition de cette voie de signalisation induit un processus d'apoptose et conduit à la mort cellulaire. Le BV est remboursé après l'échec d'un autre traitement systémique et lorsque le nombre de cellules T atypiques exprimant le CD30 en immunohistochimie excède 10 % de la population totale sur une biopsie cutanée. Le BV est administré par voie intraveineuse toutes les 3 semaines à la posologie de 1,8 mg/kg, avec un maximum de 16 cures. Les taux de réponse globale excèdent 75 %. Certains patients négatifs pour le CD30 ont également montré une réponse thérapeutique intéressante. Les principaux effets indésirables du BV sont la neutropénie et la neuropathie périphérique. Les cas de deux patients avec un MF de longue date et multi-résistant, ayant répondu favorablement au BV, sont présentés dans cet article.

Patients' perception of the open-space operating hall for cataract surgery.

PURPOSE: To assess the perception of patients undergoing cataract surgery under topical anesthesia in an open-space operating hall. METHODS: The study was set in the department of ophthalmology, Cochin Paris Descartes University Hospital, in a newly built open-space operating hall dedicated to ophthalmic surgery. It was a prospective study of consecutive patients undergoing cataract surgery by 11 surgeons. Our population study comprised 250 patients operated in an open-space operating hall with 3 surgical areas. Only first-eye standard cataract surgeries performed under topical anesthesia were included. Responses to a face-to-face questionnaire administered by a single interviewer to patients before their discharge on the day of their surgery were analyzed. RESULTS: Fifty-two patients (21%) knew beforehand that their procedure would take place in an open-space operating hall, 118 (47%) realized that they were in such an environment on the occasion of their surgery and 80 (32%) did not notice. Conversations and noises unrelated to their own surgeries were overheard respectively by 15 (6%) and 37 (15%) patients. Of the 250 patients, 237 (95%) did not report any discomfort associated with the fact that their procedure had been performed in an open-space operating hall. CONCLUSIONS: Cataract surgery performed in an open-space setting did not seem to affect the patients' comfort during the procedure.

[An illustrative case of the POEMS syndrome]. / Cas clinique. Un cas illustratif de POEMS syndrome.

POEMS syndrome is a rare and invalidating entity characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and dermatoses. The diagnosis of this condition is often late and challenging due to the heterogeneity of clinical forms. The light chains secreted by the clonal plasmocytes cause overproduction of VEGF (Vascular Endothelial Growth Factor) responsible for the appearance of the clinical manifestations of POEMS. The diagnostic approach is based on different clinical and biological criteria. Patients with a solitary plasmacytoma are candidates for radiotherapy treatment. Patients with diffuse bone involvement or bone marrow infiltration are best treated by systemic drugs. The response to treatment may take several months before clinical and biological improvement. Early diagnosis and dedicated management limit the clinico-functional impact of POEMS.

Le POEMS syndrome est une entité rare et invalidante caractérisée par une polyneuropathie, une organomégalie, une endocrinopathie, une gammapathie monoclonale et des atteintes dermatologiques. Le diagnostic de cette infection est souvent tardif et représente un véritable défi au vu de l'hétérogénéité des formes cliniques. Les chaînes légères sécrétées par les plasmocytes clonaux entraînent une surproduction de VEGF (Vascular Endothelial Growth Factor) responsable de la plupart des manifestations cliniques du POEMS. La démarche diagnostique repose, en pratique, sur des critères cliniques dont les principaux sont la polyneuropathie et la gammapathie monoclonale. Le bilan d'extension reprend le dosage du VEGF, l'électrophorèse et l'mmunofixation des protéines sériques. Un bilan radiologique permet d'objectiver des lésions osseuses ostéosclérotiques ou des adénopathies et l'électromyogramme la polyneuropathie. Les patients qui souffrent d'un plasmocytome en l'absence d'une infiltration médullaire de plasmocytes clonaux sont des candidats au traitement par radiothérapie. Les patients avec une atteinte osseuse diffuse ou une localisation médullaire recevront un traitement systémique. La réponse au traitement peut prendre plusieurs mois avant une amélioration clinique et biologique. Un diagnostic précoce et une prise en charge spécifique limitent l'impact clinico-fonctionnel du POEMS.

How to treat venous thromboembolism (TVE) in cancer patients: ten years of multidisciplinary team meetings (MDTM) at Saint-Louis Hospital.

BACKGROUND: - The management of venous thromboembolism (VTE) is particularly challenging in patients with cancer who undergo complex treatment protocols. Cancer patients often have comorbidities which may affect the efficacy and safety of anticoagulant treatments. Coordinated multidisciplinary management of these complex cases can help optimize delivery of individualized anticoagulant treatment. AIMS: - To describe the multidisciplinary team meeting (MDTM) for the management of VTE in cancer patients at our institution and to document outcomes in these patients. METHODS: - Bi-monthly MDTMs attended by different physicians and nurses were established at Saint-Louis Hospital in 2008. We performed a retrospective analysis of all cases discussed between September 2008 and January 2018. RESULTS: - Over a 10-year period, 520 patients were discussed a total of 551 times. Their mean age was 63 years with 278 (53%) women. The most frequent primary cancer sites were breast (23%), genitourinary (21 %), hematological (20%), digestive (15%), and lung (9%). Fifty-two percent of patients had metastatic cancer, and 54% of them were receiving chemotherapy. The optimal treatment for pulmonary embolism (17%), deep vein thrombosis (16%), catheter-related thrombosis (20%) or combined events (46%) was discussed. Twenty-three patients (4.4%) were discussed for one VTE recurrence and 4 (0.8%) for 2 recurrences. CONCLUSIONS: - A dedicated MDTM for the management of VTE in cancer patients allows to discuss a wide range of clinical scenarios and contributes to optimal adherence to evidence-based clinical practices guidelines. The MDTM evaluation was successfully carried out within a short time-frame of VTE diagnosis and helped optimize individualized treatment plans.

Drug-drug interaction (DDI) with direct oral anticoagulant (DOAC) in patients with cancer.

Cancer-associated thrombosis (CAT) is the second leading cause of death in cancer patients after tumor progression. The treatment of CAT is challenging because of a high risk of VTE recurrence, a high risk of bleeding, common presence of comorbidities, poly-medication, and potential drug-drug interactions (DDI). Since 2018, direct oral anticoagulants (DOACs) represent a promising therapeutic alternative and have been recently included into the 2019 update of the International Initiative on Thrombosis and Cancer (ITAC-CME) clinical practice guidelines for management of CAT. However, pharmacokinetic studies suggest that concomitant treatment with P-gp or CYP3A4 inhibitors will result in an increased exposure to rivaroxaban and apixaban, but the clinical relevance of these studies is unknown. In addition, there is an important inter-individual variability in drug absorption, distribution, metabolism and elimination, even more in cancer patients. Overall, the risk of pharmacokinetic DDI should be estimated based on several individual (patient age, renal and liver function, number of comedications) and diseases-related factors, including inflammation, sarcopenia, and low body weight. In this context, DDI with clinical implications could be expected with anti-neoplastic agents or supportive care treatments, especially with drugs known to be moderate or strong inhibitors/inducers of CYP3A4 and P-gp. Consequently, in the presence of potential DDIs through CYP3A4, and/or P-gp, LMWHs remain the first-line anticoagulant of choice for the long-term treatment of CAT. Multidisciplinary consultation meetings and therapeutic patient education should be emphasized in the complex management of CAT.

[Uveitis: Diagnosis and work-up]. / Uvéites, éléments d'orientation diagnostique.

Uveitis is an inflammation of the uveal tissue: iris, ciliary body and choroid. The annual incidence of uveitis in France is low (17/100,000), but visual and therapeutic consequences may be severe. Etiologic investigation is thus a fundamental step in the management of any uveitis. The history plays an important role in the initial evaluation; it must be methodic. The ophthalmologic examination seeks to classify the uveitis by type (granulomatous or not), location (anterior, intermediate or posterior), severity, duration and recurrence. Systemic signs often orient the diagnosis toward a specific cause. The diagnostic approach to uveitis relies on the history, ophthalmologic examination and evaluation of possible extraocular manifestations. Ancillary testing must be prescribed based on the clinical differential diagnosis, without which their yield is very low.

Correction to: Pupillometry as an indicator of L-DOPA dosages in Parkinson's disease patients.

Unfortunately, original article has been published without acknowledgement section.

[Induced drug uveitis and drug side effects in ophthalmology]. / Uvéite médicamenteuse et effets indésirables des médicaments en ophtalmologie.

Ocular drug side effects are very varied and can affect all the structures of the eye. The purpose of this review is to help clinicians: (i) to evoke this drug-induced toxicity yearly in the course of an unexplained ocular injury, before its damage become irreversible, (ii) to be able to recognize induced paradoxical ocular inflammation, mimicking an inflammatory pathology flare-up, especially in patient under anti-TNF regimen and (iii) to propose a more in-depth knowledge on recently described ocular toxicities from targeted cancer therapy, mainly the tyrosine kinase inhibitors.

Riboflavin induces Metarhizium spp. to produce conidia with elevated tolerance to UV-B, and upregulates photolyases, laccases and polyketide synthases genes.

AIMS: The effect of nutritional supplementation of two Metarhizium species with riboflavin (Rb) during production of conidia was evaluated on (i) conidial tolerance (based on germination) to UV-B radiation and on (ii) conidial expression following UV-B irradiation, of enzymes known to be active in photoreactivation, viz., photolyase (Phr), laccase (Lac) and polyketide synthase (Pks). METHODS AND RESULTS: Metarhizium acridum (ARSEF 324) and Metarhizium robertsii (ARSEF 2575) were grown either on (i) potato dextrose agar medium (PDA), (ii) PDA supplemented with 1% yeast extract (PDAY), (iii) PDA supplemented with Rb (PDA+Rb), or (iv) PDAY supplemented with Rb (PDAY+Rb). Resulting conidia were exposed to 866·7 mW m-2 of UV-B Quaite-weighted irradiance to total doses of 3·9 or 6·24 kJ m-2 . Some conidia also were exposed to 16 klux of white light (WL) after being irradiated, or not, with UV-B to investigate the role of possible photoreactivation. Relative germination of conidia produced on PDA+Rb (regardless Rb concentration) or on PDAY and exposed to UV-B was higher compared to conidia cultivated on PDA without Rb supplement, or to conidia suspended in Rb solution immediately prior to UV-B exposure. The expression of MaLac3 and MaPks2 for M. acridum, as well as MrPhr2, MrLac1, MrLac2 and MrLac3 for M. robertsii was higher when the isolates were cultivated on PDA+Rb and exposed to UV-B followed by exposure to WL, or exposed to WL only. CONCLUSIONS: Rb in culture medium increases the UV-B tolerance of M. robertsii and M. acridum conidia, and which may be related to increased expression of Phr, Lac and Pks genes in these conidia. SIGNIFICANCE AND IMPACT OF THE STUDY: The enhanced UV-B tolerance of Metarhizium spp. conidia produced on Rb-enriched media may improve the effectiveness of these fungi in biological control programs.

Epidemiology of meningiomas.

Although they represent about a third of all the tumors of the central nervous system, knowledge concerning meningioma epidemiology (including incidence data and exploration of the risk factors) remains scarce compared to that of gliomas. A limited number of cancer registries worldwide only record malignant brain tumors, however their completeness and accuracy have been questioned. Even if comparisons are made difficult due to differences in methodologies, available annual incidence rates (sex- and age-standardized, generally on US or World standard population), provided by population-based registries range from 1.3/100,000 to 7.8/100,000 for cerebral meningiomas. An increase in the incidence of primary brain tumors in general and of meningiomas in particular has been observed during the past decades in several countries. It has been suggested that this trend could be artefactual and could be the resultant of an ageing population, improvement in health access and in diagnostic procedures, changes in coding classification for tumors recorded in registries, and/or an increase in the rate of histological confirmation, even in the elderly. All these factors are likely to play a role but they might not fully explain the increase in incidence, observed in most age groups. In addition to intrinsic risk factors (gender, ethnic groups, allergic conditions, familial and personal history, genetic polymorphisms), some exogenous risk factors have been suspected to play a role in the etiology of meningiomas and their changes with time is likely to impact incidence trends. A causal link has been established only for ionising radiation but the role of many other factors have been hypothesised: electromagnetic fields, nutrition, pesticides, hormonal as well as reproductive factors. Considering the serious or even lethal potentiality of some meningiomas and the apparent rise in their incidence, all practitioners involved in neuro-oncology should feel concerned today of the necessity to better assess their public health burden and to study their epidemiological features.

Pupillometry as an indicator of L-DOPA dosages in Parkinson's disease patients.

Dopamine was shown to induce mydriasis by excitation of alpha-adrenergic receptors at the dilator pupillae muscle. Pupilla diameter may thus serve as an indirect measure of peripheral pharmacokinetics of L-DOPA and dopamine. The aim of this study is to evaluate the effect of L-DOPA dosage on pupillometric parameters in Parkinson's disease (PD) patients. Sixteen PD patients and 14 healthy control subjects (CS) were studied. The statistical analysis revealed significant differences between CS and PD patients for the mean maximum and minimum pupil diameters (p = 0.017, p = 0.028, respectively), with higher values found in PD. Moreover, a significant dose-response relationship was found between the maximum pupil diameter and both the morning L-DOPA dose (R 2 = 0.78) and the total daily L-DOPA dose (R 2 = 0.93). A sigmoid-shaped curve best describes the dose-response relationship, with a ceiling effect at about 400 mg L-DOPA daily dose. In conclusion, measuring pupillometric parameters represents a sensitive tool for non-invasive evaluation of the peripheral effect of L-DOPA, especially with daily doses below 400 mg L-DOPA.