HIDEA syndrome: A new case report highlighting similarities with ROHHAD syndrome.

Context: ROHHAD syndrome presents a significant resemblance to HIDEA syndrome. The latter is caused by biallelic loss-of-function variants in the P4HTM gene and encompasses hypotonia, intellectual disabilities, eye abnormalities, hypoventilation, and dysautonomia. We report the first patient identified with HIDEA syndrome from our ROHHAD cohort. Clinical case: Our patient was a 21-month-old girl who had a history of severe respiratory infections requiring intensive care, hypotonia, abnormal eye movements, and rapid weight gain. Polysomnography identified severe central hypoventilation. During her follow-up, a significant psychomotor delay and the absence of language were gradually observed. The prolactin levels were initially increased. Hypothermia was reported at 4 years. Exome sequencing identified a new homozygous truncating P4HTM variant. Discussion: Our patient met the diagnosis criteria for ROHHAD, which included rapid weight gain, central hypoventilation appearing after 1.5 years of age, hyperprolactinemia suggesting hypothalamic dysfunction, and autonomic dysfunction manifesting as strabismus and hypothermia. However, she also presented with severe neurodevelopmental delay, which is not a classic feature of ROHHAD syndrome. HIDEA syndrome presents similarities with ROHHAD, including hypoventilation, obesity, and dysautonomia. To date, only 14% of endocrinological disturbances have been reported in HIDEA patients. Better delineation of both syndromes is required to investigate the eventual involvement of P4HTM, a regulator of calcium dynamics and gliotransmission, in ROHHAD patients. Conclusion: In the case of clinical evidence of ROHHAD in a child with abnormal neurological development or eye abnormalities, we suggest that the P4HTM gene be systematically interrogated in addition to the analysis of the PHOX2B gene. A better delineation of the natural history of HIDEA is required to allow further comparisons between features of HIDEA and ROHHAD. The clinical similarities could potentially orient some molecular hypotheses in the field of ROHHAD research.

Homologous recombination repair deficiency (HRD) testing in newly diagnosed advanced-stage epithelial ovarian cancer: A Belgian expert opinion.

Ovarian cancer (OC) has a poor prognosis as most patients present with non-specific symptoms and the disease is mostly diagnosed at advanced stages. Approximately 90% of cases are classified as epithelial OC (EOC), a category comprising histologically and molecularly distinct tumours. Identifying reliable biomarkers and employing personalised therapies in OC subgroups is crucial for battling the disease. EOCs are often characterised by homologous recombination repair deficiency (HRD), frequently caused by inactivation of the breast cancer susceptibility (BRCA) genes. These findings have led to the development of poly- (adenosine diphosphate [ADP])- ribose polymerase inhibitors (PARPi), which are synthetically lethal to HRD tumour cells. Both patients with HRD and non-HRD tumours can benefit from PARPi therapy in the recurrent setting. Moreover, recent phase III trials in patients with newly diagnosed advanced-stage OC have demonstrated greater clinical benefit from PARPi in treating HRD than non-HRD tumours. These findings offer new opportunities for the use of PARPi as maintenance therapy after first-line chemotherapy based on the presence of HRD. In the current article, we provide recommendations for HRD testing and treatment of patients with newly diagnosed advanced-stage EOC.

[Heredity and cancer]. / Hérédité et cancer.

A personal or family history of cancer has now become the primary cause of genetic consultations. In recent years, various genes have been identified that are associated with a more or less marked genetic predisposition to the development of cancers. The syndrome associated with the hereditary risk of breast and ovarian cancer and the Lynch syndrome are the most frequent ones, but there are many other, much less common, situations associated with familial cancer risk. In most cases, there are clear recommendations regarding the indications for genetic testing and the follow-up of patients identified as having a predisposition to cancer. At the CHU of Liège, we currently perform more than 1.400 oncogenetic consultations per year and we maintain a positivity rate of genetic tests performed in this indication higher than 10%. In this way, we allow a multidisciplinary care of patients with a high oncological risk and participate in a prevention and surveillance activity. We also pay increasing attention to the hereditary risk associated with pediatric cancers and to patients with multiple cancers, especially when these develop at an early age. Finally, the oncogenetic consultation must consider the psychological, ethical and legal aspects of a diagnosis that involves the patient and his or her future, but also the whole family.

Une histoire personnelle ou familiale de cancer est aujourd'hui devenue la première cause de consultation en génétique. Au cours de ces dernières années, en effet, différents gènes associés à une prédisposition génétique plus ou moins marquée au développement de pathologies cancéreuses ont été identifiés. Le syndrome de prédisposition héréditaire au cancer du sein et de l'ovaire (HBOC : Hereditary Breast and/or Ovarian Cancer) et le syndrome de Lynch sont les plus fréquents. Mais il existe une multitude d'autres situations beaucoup moins fréquentes associées à un risque familial de cancer. Dans la plupart des cas, des recommandations claires existent quant à l'indication des tests génétiques et quant au suivi proposé au patient chez qui une prédisposition au cancer est identifiée. Au CHU de Liège, nous réalisons actuellement plus de 1.400 consultations d'oncogénétique par an et nous maintenons un taux de positivité des tests génétiques réalisés dans cette indication supérieur à 10 %. De cette façon, nous permettons une prise en charge multidisciplinaire des patients avec un haut risque oncologique et participons à une activité de prévention et de surveillance. Nous portons une attention croissante aux enfants et adolescents présentant un cancer, d'une part, et aux adultes ayant présenté de multiples cancers, d'autre part, particulièrement lorsque ceux-ci se développent à un âge précoce. Enfin, la consultation d'oncogénétique doit tenir compte des aspects psychologiques, éthiques et légaux, liés à un diagnostic qui implique le patient et son avenir, mais également l'ensemble de la famille.

[Current and new therapeutic options in inborn errors of metabolism]. / Actualités thérapeutiques dans les erreurs innées du métabolisme.

Inborn errors of metabolism (IEM) represent a vast group of orphan genetic disorders associated with enzyme deficiencies, substrates accumulation and products depletion. For several decades, the cornerstone of life-saving therapies in IEM was based on extreme manipulations of the nutritional intakes. Such outstanding dietary engineering is still relevant today, but new therapeutic avenues have emerged last years, based on better pathophysiological understanding and technological advances. In this paper, we summarize current and new therapeutic options in the field of IEM.

Les erreurs innées du métabolisme (EIM) représentent un groupe de conditions génétiques associées à une déficience enzymatique causant une accumulation du substrat en amont de la réaction et une déficience du produit en aval. Pendant des décennies, la pierre angulaire du traitement de ces affections a été basée sur des régimes drastiquement restrictifs. Ces manipulations diététiques extrêmes sont encore aujourd'hui d'actualité, mais l'arsenal thérapeutique s'est considérablement élargi ces dernières années, basé sur de meilleures connaissances physiopathologiques et sur des progrès technologiques et pharmacologiques. Dans cet article, nous résumons les différentes stratégies et nouveautés thérapeutiques dans le domaine des erreurs innées du métabolisme.

[(S)un (M)ay (A)rise on SMA : the hope of a region without spinal muscular atrophy]. / (S)un (M)ay (A)rise on SMA : l'espoir d'une région sans amyotrophie spinale.

The treatment of spinal muscular atrophy (SMA) has considerably changed over the last 3 years. Several approaches that aim to increase the deficient SMN protein have demonstrated an efficacy that is inversely correlated with disease duration. In this context, newborn screening (NBS) is increasingly considered as the next step in several countries or regions. In 2018, we initiated a pilot study for NBS of SMA in French- and German-speaking Belgium. We aim to evaluate the feasibility, the efficacy, and the cost-effectiveness of such a program. Initially covering the region of Liege, the program was recently extended to the whole Southern Belgium and currently covers about 55.000 newborns per year. On June 1st 2019, 35.000 newborns had been screened and 5 affected babies were identified and referred to neuromuscular centers for early treatment. A full evaluation of the program will take place after three years to consider the inclusion of SMA screening in the publically-funded NBS program in Southern Belgium.

La prise en charge de l'amyotrophie spinale antérieure (SMA) a considérablement évolué au cours des trois dernières années. Les différents essais visant à augmenter la production de la protéine SMN déficitaire dans la SMA ont systématiquement montré une efficacité inversement proportionnelle à la durée de la maladie. Dès lors, l'implémentation d'un programme de dépistage néonatal s'est rapidement imposée comme une évidence médico-économique dans de nombreux pays. Dans ce contexte, nous avons initié un programme de dépistage néonatal pour la SMA en Belgique francophone et germanophone. En 2018, une étude pilote de trois ans visant à évaluer la faisabilité, l'efficacité et la rentabilité du screening a été initiée au sein du centre de dépistage de Liège. L'étude a récemment été étendue à l'ensemble de la Fédération Wallonie-Bruxelles (FWB) pour couvrir environ 55.000 naissances annuelles. Au 1er juin 2019, 35.000 bébés ont été dépistés et cinq nouveau-nés atteints de SMA ont été identifiés. Tous ont été immédiatement référés pour assurer leur prise en charge dans un centre de référence pour les maladies neuromusculaires. Une évaluation complète du programme aura lieu à l'issue de la phase pilote, afin d'envisager que la SMA soit reconnue comme maladie officielle du programme de dépistage néonatal en FWB.

[Study of cancer risks associated with Lynch syndrome in the Liège region]. / Etude des risques oncologiques associés au syndrome de Lynch en région liégeoise.

Lynch syndrome is a hereditary predisposition to several cancers. The goals of our study were to know the different mutations in our Lynch population, to evaluate the prevalence of cancers in this population and to determine the mean age of onset of those cancers. This retrospective study includes proven carriers of a MMR mutation diagnosed either by the CHU of Liège or either by the CHC Saint-Joseph in Liège, Belgium. We noted a clear majority of MSH2 mutations (50 %) in the Lynch families recorded in Liège, which is different from the main literature. In our study population (106 subjects), 65 % of subjects were affected by at least one cancer. Prevalences for colorectal and endometrial cancers are, respectively, 50 % and 27.5 %. We found no difference in the mean age of onset of cancers compared to literature. We discuss the follow-up of Lynch patients and the interest of additional exams such as hysteroscopy and cystoscopy.

Le syndrome de Lynch est un syndrome de prédisposition héréditaire à un certain nombre de cancers. Les objectifs de notre étude sont de connaître la répartition des différentes mutations dans la population Lynch prise en charge dans nos centres, d'évaluer la prévalence des cancers présentés par les patients Lynch de cette population et de déterminer l'âge moyen d'apparition de ces cancers. Cette étude rétrospective inclut les porteurs confirmés d'une mutation MMR ayant été diagnostiqués, soit par le CHU de Liège, soit par le CHC Saint-Joseph à Liège. Nous avons constaté une nette majorité de mutations MSH2 (50 %) parmi les familles Lynch répertoriées à Liège, ce qui est différent de ce qui est décrit dans la littérature. Dans notre population d'étude (106 sujets), 65 % des sujets ont présenté au moins un cancer. Les prévalences du cancer colorectal et de l'endomètre sont, respectivement, de 50 % et 27.5 %. Nous n'avons pas trouvé de différence dans les âges moyens de présentation des cancers par rapport à la littérature existante. Nous discutons du suivi des patients porteurs d'un syndrome de Lynch et de la place d'examens supplémentaires comme l'hystéroscopie et la cystoscopie.

[Hereditary diffuse gastric cancer : case serie of 8 patients from a single family and literature review]. / Cancer gastrique diffus héréditaire. Série de 8 patients appartenant à une même famille et revue de la littérature.

Hereditary diffuse gastric cancer is a form of gastric cancer associated, in about 40 % of cases, with a germline mutation of the CDH1 gene. The management of patients with a pathogenic mutation of this gene is based on total prophylactic gastrectomy because, until proven otherwise, endoscopic monitoring is insufficient. We report a series of eight patients with pathogenic CDH1 mutation who underwent total prophylactic gastrectomy in our centre.

Le cancer gastrique diffus héréditaire est une forme de cancer gastrique associé, dans 40 % des cas environ, à une mutation germinale du gène CDH1. La prise en charge des patients porteurs d'une mutation pathogène de ce gène repose sur la gastrectomie totale prophylactique car, jusqu'à preuve du contraire, la surveillance endoscopique est insuffisante. Nous rapportons une série de huit patients porteurs d'une mutation pathogène de CDH1 ayant bénéficié d'une gastrectomie totale prophylactique dans notre centre. Mots-clés : Gastrectomie prophylactique - Cancer gastrique diffus héréditaire - Mutation CDH1.

Genetic assessment and folate receptor autoantibodies in infantile-onset cerebral folate deficiency (CFD) syndrome.

INTRODUCTION: Cerebral folate deficiency (CFD) syndromes are defined as neuro-psychiatric conditions with low CSF folate and attributed to different causes such as autoantibodies against the folate receptor-alpha (FR) protein that can block folate transport across the choroid plexus, FOLR1 gene mutations or mitochondrial disorders. High-dose folinic acid treatment restores many neurologic deficits. STUDY AIMS AND METHODS: Among 36 patients from 33 families the infantile-onset CFD syndrome was diagnosed based on typical clinical features and low CSF folate. All parents were healthy. Three families had 2 affected siblings, while parents from 4 families were first cousins. We analysed serum FR autoantibodies and the FOLR1 and FOLR2 genes. Among three consanguineous families homozygosity mapping attempted to identify a monogenetic cause. Whole exome sequencing (WES) was performed in the fourth consanguineous family, where two siblings also suffered from polyneuropathy as an atypical finding. RESULTS: Boys (72%) outnumbered girls (28%). Most patients (89%) had serum FR autoantibodies fluctuating over 5-6 weeks. Two children had a genetic FOLR1 variant without pathological significance. Homozygosity mapping failed to detect a single autosomal recessive gene. WES revealed an autosomal recessive polynucleotide kinase 3´phosphatase (PNKP) gene abnormality in the siblings with polyneuropathy. DISCUSSION: Infantile-onset CFD was characterized by serum FR autoantibodies as its predominant pathology whereas pathogenic FOLR1 gene mutations were absent. Homozygosity mapping excluded autosomal recessive inheritance of any single responsible gene. WES in one consanguineous family identified a PNKP gene abnormality that explained the polyneuropathy and also its contribution to the infantile CFD syndrome because the PNKP gene plays a dual role in both neurodevelopment and immune-regulatory function. Further research for candidate genes predisposing to FRα-autoimmunity is suggested to include X-chromosomal and non-coding DNA regions.

Innovative PCR without DNA extraction for African sickle cell disease diagnosis.

OBJECTIVES: Hemoglobin (Hb) disorders consist of thalassemia and Hb structural variants, of which the major forms are associated with severe anemia and/or vascular occlusion. Current diagnostic techniques are highly accurate and mostly based on isoelectric focusing, high-performance liquid chromatography or mass spectrometry, which often require advanced laboratory equipment. In sub-Saharan Africa, the Hb disorders are mainly associated to the pathological variants hemoglobin S (HbS) and HbC. Unfortunately, until now, it is not easy to get a diagnosis of these disorders in this area. In this study, we tested the performance of a new molecular diagnostic tests on qualified samples. METHODS: The Human Hb S/C Lamp assay is a new polymerase chain reaction test able to detect HbS, HbC and HbA alleles without DNA extraction, directly on fresh or frozen blood samples, or on dried blood spots (DBS). In this study, we compared the genotyping of 248 blood samples (56 whole blood and 192 DBS) with this LAMP assay to the routine diagnostic methods performed in the genetics lab at the university hospital of Liège. RESULTS: Our results show that the LAMP method can detect HbS and HbC with an accuracy of 100%. Moreover, this test can be used for the neonatal screening because we did not observe any interference with fetal Hb. DISCUSSION: To our knowledge, this method is the only molecular assay that can be performed directly on dried blood cards without DNA extraction, lowering handling, turnaround time and costs.

A next-generation newborn screening pilot study: NGS on dried blood spots detects causal mutations in patients with inherited metabolic diseases.

The range of applications performed on dried blood spots (DBS) widely broadened during the past decades to now include next-generation sequencing (NGS). Previous publications provided a general overview of NGS capacities on DBS-extracted DNA but did not focus on the identification of specific disorders. We thus aimed to demonstrate that NGS was reliable for detecting pathogenic mutations on genomic material extracted from DBS. Assuming the future implementation of NGS technologies into newborn screening (NBS), we conducted a pilot study on fifteen patients with inherited metabolic disorders. Blood was collected from DBS. Whole-exome sequencing was performed, and sequences were analyzed with a specific focus on genes related to NBS. Results were compared to the known pathogenic mutations previously identified by Sanger sequencing. Causal mutations were readily characterized, and multiple polymorphisms have been identified. According to variant database prediction, an unexplained homozygote pathogenic mutation, unrelated to patient's disorder, was also found in one sample. While amount and quality of DBS-extracted DNA are adequate to identify causal mutations by NGS, bioinformatics analysis revealed critical drawbacks: coverage fluctuations between regions, difficulties in identifying insertions/deletions, and inconsistent reliability of database-referenced variants. Nevertheless, results of this study lead us to consider future perspectives regarding "next-generation" NBS.

New perspective on maintenance therapies for platinum- sensitive recurrent ovarian cancer in women with germline and somatic mutations in BRCA1 and BRCA2 genes.

Ovarian cancer (OC) is the seventh most common cancer in women. Although women diagnosed with OC are usually treated frontline with platinum-based chemotherapy, most of them relapse once treatment is halted. Therefore, maintenance therapies have been developed to secure the response and delay further chemotherapy. There are two established maintenance therapies for women affected by platinum-sensitive recurrent OC: bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor, and olaparib, an inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerase (PARPi). Loss-of-function mutations in genes in the homologous recombination pathway, especially BRCA1 and BRCA2, predict higher rates of platinum sensitivity, better overall survival (OS), and better response to PARPi in women with OC. Among patients with platinum-sensitive recurrent OC, a BRCA mutation is the first genetically defined predictive marker for targeted therapy, since these patients are most likely to benefit from treatment with a PARPi, such as olaparib. In patients with platinum-sensitive recurrent OC without a BRCA mutation, bevacizumab currently seems to be the best maintenance option. Women with OC are progressively more routinely screened for germline BRCA mutations, and the implication of somatic BRCA mutations is increasingly being recognized in OC. Therefore, the recommendations should be updated to reflect the importance of both types of mutations. Together, these data highlight the fact that treatment of recurrent OC can be optimized using genomic contributions to individualize therapy and to improve treatment response.

GPR101 Mutations are not a Frequent Cause of Congenital Isolated Growth Hormone Deficiency.

Patients with Xq26.3 microduplication present with X-linked acrogigantism (X-LAG) syndrome, an early-childhood form of gigantism due to marked growth hormone (GH) hypersecretion from mixed GH-PRL adenomas and hyperplasia. The microduplication includes GPR101, which is upregulated in patients' tumor tissue. The GPR101 gene codes for an orphan G protein coupled receptor that is normally highly expressed in the hypothalamus. Our aim was to determine whether GPR101 loss of function mutations or deletions could be involved in patients with congenital isolated GH deficiency (GHD). Taking advantage of the cohort of patients from the GENHYPOPIT network, we studied 41 patients with unexplained isolated GHD. All patients had Sanger sequencing of the GPR101 gene and array comparative genome hybridization (aCGH) to look for deletions. Functional studies (cell culture with GH secretion measurements, cAMP response) were performed. One novel GPR101 variant, c.589 G>T (p.V197L), was seen in the heterozygous state in a patient with isolated GHD. In silico analysis suggested that this variant could be deleterious. Functional studies did not show any significant difference in comparison with wild type for GH secretion and cAMP response. No truncating, frameshift, or small insertion-deletion (indel) GPR101 mutations were seen in the 41 patients. No deletion or other copy number variation at chromosome Xq26.3 was found on aCGH. We found a novel GPR101 variant of unknown significance, in a patient with isolated GH deficiency. Our study did not identify GPR101 abnormalities as a frequent cause of GH deficiency.

[Cancer therapy-induced cardiotoxicity]. / La cardiotoxicité des traitements anti-cancéreux.

The incidence of cancer is raising and the treatments are increasingly aggressive. Consequently, physicians are regularly facing side effects of cytotoxic therapies. Cancer- therapy-induced cardiotoxicity is a serious complication because it can be fatal and causes a temporary or permanent cessation of the treatment. In this article, we summarize the mechanisms, the monitoring and the multidisciplinary management of patients with cancer-therapy induced cardiotoxicity.

Les cancers sont de plus en plus fréquents et leurs traitements de plus en plus agressifs. En conséquence, les médecins se trouvent régulièrement confrontés aux effets secondaires des traitements cytotoxiques. La cardiotoxicité induite par les traitements anti-cancéreux est une complication gravissime, car elle peut être mortelle et provoque un arrêt temporaire, voire définitif, des traitements. Dans cet article, nous décrivons les mécanismes, le dépistage et la prise en charge multidisciplinaire de la cardiotoxicité des agents anti-cancéreux.

[A Familial Non Medullary Thyroid Carcinoma (FNMTC) : a clinical and genetic update]. / Cancer thyroïdien familial non médullaire: actualités cliniques et génétiques.

The syndrome of Familial Non Medullary Thyroid Carcinoma (FNMTC) includes two or more patients with an isolated non-medullary thyroid cancer (papillary, follicular, anaplastic) within the same family. To diagnose FNMTC, the clinician must exclude a syndromic presentation such as the syndromes of Cowden, Gardner or Werner, and the Carney Complex. Up to now, a hundred families with FNMTC have been genetically studied, including forms with (Ch19p13.2) or without oxyphilia (Ch2q21), in association with a multinodular goiter (Ch14q32), or with a renal cancer (Ch1q21). Several candidate genes of susceptibility have been proposed: SRGAP1, NKX2-1, FOXE1 and HABP2. So far, it is considered that familial cases represent less than 5 % of thyroid cancers. Although rare, these cases represent a unique opportunity to improve our understanding of thyroid cancer. The identification of candidate genes will enrich our knowledge of thyroid cancer pathophysiology. Based on the literature and our experience of the follow-up of eight families with FNMTC, we discuss epidemiological, clinical, pathological and genetic aspects of FNMTC with a view to improve the diagnosis and treatment of this disease.

Le syndrome de «Familial Non Medullary Thyroid Carcinoma¼ (FNMTC) suppose l'existence, au sein d'une même famille, de deux ou plusieurs patients avec un cancer thyroïdien non médullaire isolé (papillaire, folliculaire, anaplasique). Le diagnostic de FNMTC est retenu après exclusion d'une présentation syndromique comme celle liée aux syndromes de Cowden, Gardner, ou Werner et au Complexe de Carney. Une centaine de familles de FNMTC ont été bien caractérisées sur le plan génétique, incluant des formes papillaires avec (Ch19p13.2) ou sans oxyphilie (Ch2q21, 6q22), en association avec un goitre multinodulaire (14q32), ou avec un cancer rénal (Ch1q21). Plusieurs gènes de susceptibilité ont été proposés : SRGAP1, NKX2-1, FOXE1, et HABP2. On estime que les cas familiaux représentent moins de 5 % des cancers thyroïdiens. Bien que minoritaires, ils représentent une occasion exceptionnelle d'approfondir notre compréhension de la tumorigenèse du cancer thyroïdien et d'identifier des gènes candidats pouvant participer à leur physiopathologie. A partir d'une revue de la littérature et de notre expérience sur le suivi de huit familles avec FNMTC, nous discutons des aspects épidémiologiques, cliniques, pathologiques et génétiques permettant d'aboutir à un meilleur diagnostic et à une prise en charge de ce syndrome oncologique.

[PHARMACOGENOMICS AND PERSONALIZED MEDICINE: TOWARDS A SYSTEMATIC GENOMIC SCREENING?]. / PHARMACOGÉNOMIQUE ET MÉDECINE PERSONNALISÉE : VERS UN SCREENING SYSTÉMATIQUE DE LA POPULATION ?

Recent advances in medical genomics open new perspectives for personalized medicine through the identification of genetic variants that influence drug response and/or the risk of side effects. Today, the clinical applications of pharmacogenetics remain scarce as a consequence of the cost and turn-around-time of genetic tests. However, a few tests are recommended, for instance before the prescription of some anti-cancer agents or the anti-retroviral agent abacavir. In the future, we will probably move either towards rapid targeted tests or towards a large screening, before any diagnosis, of all the genetic factors influencing the therapeutic response. In that case, physicians will have to consult the patient genomic data before drug prescription in order to personalize the choice of the therapeutic agent or its dosage. However, such a genomic approach brings economical and ethical questions and will require further progress in our capacity to interpret and store the personal genomic data without compromising their confidentiality.

[BREAST CANCER: FROM TARGETED THERAPY TO PRECISION MEDICINE]. / CANCER DU SEIN : DE LA THÉRAPIE CIBLÉE À LA MÉDECINE PERSONNALISÉE.

The authors review the principles of systemic therapy in breast cancer. They analyze the degree of treatment individualization in our current approach. New technologies allow the detection of genomic alterations in cancer cells. Unfortunately, we do not know yet how to best use this knowledge for routine patient care. Most genomic alterations are rare events complicating further drug development. Temporal and spatial heterogeneity in tumors also has to be taken into account. An intense international collaboration is ongoing to try and demonstrate that precision medicine will really improve treatment outcome.

Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies.

BACKGROUND: Auto-antibodies against folate receptor alpha (FRα) at the choroid plexus that block N(5)-methyltetrahydrofolate (MTHF) transfer to the brain were identified in catatonic schizophrenia. Acoustic hallucinations disappeared following folinic acid treatment. Folate transport to the CNS prevents homocysteine accumulation and delivers one-carbon units for methyl-transfer reactions and synthesis of purines. The guanosine derivative tetrahydrobiopterin acts as common co-factor for the enzymes producing dopamine, serotonin and nitric oxide. METHODS: Our study selected patients with schizophrenia unresponsive to conventional treatment. Serum from these patients with normal plasma homocysteine, folate and vitamin B12 was tested for FR autoantibodies of the blocking type on serial samples each week. Spinal fluid was analyzed for MTHF and the metabolites of pterins, dopamine and serotonin. The clinical response to folinic acid treatment was evaluated. RESULTS: Fifteen of 18 patients (83.3%) had positive serum FR auto-antibodies compared to only 1 in 30 controls (3.3%) (χ(2)=21.6; p<0.0001). FRα antibody titers in patients fluctuated over time varying between negative and high titers, modulating folate flux to the CNS, which explained low CSF folate values in 6 and normal values in 7 patients. The mean±SD for CSF MTHF was diminished compared to previously established controls (t-test: 3.90; p=0.0002). A positive linear correlation existed between CSF MTHF and biopterin levels. CSF dopamine and serotonin metabolites were low or in the lower normal range. Administration of folinic acid (0.3-1mg/kg/day) to 7 participating patients during at least six months resulted in clinical improvement. CONCLUSION: Assessment of FR auto-antibodies in serum is recommended for schizophrenic patients. Clinical negative or positive symptoms are speculated to be influenced by the level and evolution of FRα antibody titers which determine folate flux to the brain with up- or down-regulation of brain folate intermediates linked to metabolic processes affecting homocysteine levels, synthesis of tetrahydrobiopterin and neurotransmitters. Folinic acid intervention appears to stabilize the disease process.

Clinical, cytogenetic and molecular characterization of two cases of mosaic ring chromosome 13.

The occurrence of mosaic ring chromosome 13 is rare. The mechanism of ring chromosome formation is usually associated with loss of genetic material. We report 2 cases of mosaic ring chromosome 13, resulting in deletion of 13qter. The first patient, a 15 year-old boy, presented a delayed psychomotor development, mental retardation, dysmorphic features and bleeding disorders associated with a de novo terminal 13q34 deletion. The second case was a foetus of 31 weeks with prenatal diagnosis of severe malformation such as holoprosencephaly, congenital cardiac defects, gastro-intestinal abnormalities with intrauterine growth retardation, the molecular analysis showed a de novo deletion encompassing the region 13q31.3-q34.

[Are we genetically predisposed to addictions?]. / Existe-t-il une prédisposition génétique aux addictions ?

Is free will the rule in front of drugs, alcohol or gambling? Would interindividual genetic variations influence our behaviour to such a point that addiction susceptibility would be enhanced or decreased? Addiction predisposition is a complex trait, involving numerous predisposition genes and also environment. Heritability of this trait is 50%, meaning a similar contribution of genes and environment in the setting of this trait. Some genes of the dopaminergic system and some others specific for various drugs metabolism have been associated to addictions. The growth of those findings into promising pilot treatments seems a good future coming in.

[Complex diseases: the importance of genetics]. / Les maladies complexes: l'importance de la génétique.

Complex diseases usually harbour hereditary factors linked with multiple susceptibility genes. The additive effects of genetic and environmental factors are responsible for the pathology. The impact of heredity has been demonstrated through family studies, but also, and mostly, through the study of adopted people and twins. Recently, genome wide association studies (GWAS) allowed the identification of many susceptibility genes for most complex diseases. However, a large part of the heritability is still missing, probably because of insufficient exploration of rare genetic variants and/or epigenetic factors. The ultimate goal of these genetic studies is the definition of an individual risk leading to specific preventive measures (model "predict and prevent"), but this purpose remains very remote for the majority of complex diseases.