Modified cued recall test in the French population with Down syndrome: A retrospective medical records analysis.

BACKGROUND: Adults with Down syndrome (DS) are at increased risk of developing Alzheimer's disease (AD) due to genetic predisposition. Identification of patients with AD is difficult since intellectual disabilities (ID) may confound diagnosis. The objective of this study was to evaluate the ability of the French version of the modified cued recall test (mCRT) to distinguish between subjects with and without AD in the adult DS population. METHODS: This was a retrospective, single-centre, medical records study including data between March 2014 and July 2020. Adults aged ≥30 years with DS who had at least one mCRT record available were eligible. Age, sex and ID level were extracted, and subjects were attributed to three groups: patients with AD, patients with co-occurring conditions that may impact cognitive function and subjects without AD. mCRT scores, adjusted by sex, age and ID level, were compared between groups. The optimal cut-off value to distinguish between patients with and without AD was determined using the receiver operating characteristic curve. The impact of age and ID level on mCRT scores was assessed. RESULTS: Overall, 194 patients with DS were included: 12 patients with AD, 94 patients with co-occurring conditions and 88 healthy subjects. Total recall scores were significantly lower (P < 0.0001) in patients with AD compared with healthy subjects. The optimal cut-off value to discriminate between patients with AD and healthy subjects was 22, which compares well with the cut-off value of 23 originally reported for the English version of the mCRT. Patients aged 30-44 years had higher mCRT total recall scores compared with patients aged ≥45 years (P = 0.0221). Similarly, patients with mild ID had higher mCRT scores compared with patients with severe ID (P < 0.0001). INTERPRETATION: The mCRT is a sensitive tool that may help in the clinical diagnosis of AD in subjects with DS. Early recognition of AD is paramount to deliver appropriate interventions to this vulnerable population.

Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia.

Anophthalmia and microphthalmia (AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and different genes have been demonstrated to be causative of syndromic and non-syndromic forms of AM. We screened seven AM genes [GDF6 (growth differentiation factor 6), FOXE3 (forkhead box E3), OTX2 (orthodenticle protein homolog 2), PAX6 (paired box 6), RAX (retina and anterior neural fold homeobox), SOX2 (SRY sex determining region Y-box 2), and VSX2 (visual system homeobox 2 gene)] in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21% of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition eight gene deletions (five SOX2, two OTX2 and one RAX) were identified using a semi-quantitative multiplex polymerase chain reaction (PCR) [quantitative multiplex PCR amplification of short fluorescent fragments (QMPSF)]. The causative genetic defect was identified in 21% of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling.

What can we learn from old microdeletion syndromes using array-CGH screening?

Most microdeletion syndromes identified before the implementation of array-comparative genomic hybridization (array-CGH) were presumed to be well-defined clinical entities. However, the introduction of whole-genome screening led not only to the description of new syndromes but also to the recognition of a broader spectrum of features for well-known syndromes. Here, we report on 10 patients presenting with mental retardation associated with atypical features not suggestive of a known microdeletion and a normal standard karyotype. Array-CGH analyses revealed five microdeletions in the DiGeorge region, three microdeletions in the Williams-Beuren region and two microdeletions in the Smith-Magenis region. Reevaluation in these patients confirmed that the diagnosis remained difficult on clinical grounds and emphasized that well-known genomic disorders can have a phenotype that is heterogeneous and more variable than originally thought. The widespread use of array-CGH shows that such patients may be more readily achieved on the basis of genotype rather than phenotype.

2q23.1 microdeletion identified by array comparative genomic hybridisation: an emerging phenotype with Angelman-like features?

BACKGROUND: Genome-wide screening of patients with mental retardation using array comparative genomic hybridisation (CGH) has identified several novel imbalances. With this genotype-first approach, the 2q22.3q23.3 deletion was recently described as a novel microdeletion syndrome. The authors report two unrelated patients with a de novo interstitial deletion mapping in this genomic region and presenting similar "pseudo-Angelman" phenotypes, including severe psychomotor retardation, speech impairment, epilepsy, microcephaly, ataxia, and behavioural disabilities. METHODS: The microdeletions were identified by array CGH using oligonucleotide and bacterial artificial chromosome (BAC) arrays, and further confirmed by fluorescence in situ hybridisation (FISH) and semi-quantitative polymerase chain reaction (PCR). RESULTS: The boundaries and sizes of the deletions in the two patients were different but an overlapping region of about 250 kb was defined, which mapped to 2q23.1 and included two genes: MBD5 and EPC2. The SIP1 gene associated with the Mowat-Wilson syndrome was not included in the deleted genomic region. DISCUSSION: Haploinsufficiency of one of the deleted genes (MBD5 or EPC2) could be responsible for the common clinical features observed in the 2q23.1 microdeletion syndrome, and this hypothesis needs further investigation.

De novo subtelomeric deletion additional to an inherited apparently balanced reciprocal translocation.

OBJECTIVE: We describe the analysis of an apparently balanced inherited reciprocal translocation in a fetus presenting with multiple congenital abnormalities, characterize the structural chromosome rearrangement, and report an unexpected additional imbalance to the inherited rearrangement. METHODS: DNA microarray was used to screen for genomic imbalance in subtelomeric and interstitial critical regions. High-resolution comparative genomic hybridization was used to screen for genomic imbalance at a genome-wide level. Fluorescence in situ hybridization using whole-chromosome painting and specific probes was used to characterize the inherited translocation, and the size of the de novoadditional deletion. RESULTS: An unexpected additional deletion was found in 7qter on derivative 10 of the inherited maternal reciprocal translocation t(7;10)(q11.23; p14). CONCLUSIONS: We show the usefulness of genome-wide and specific molecular cytogenetic techniques to explore apparently balanced rearrangements.

Changes in aortic blood flow induced by passive leg raising predict fluid responsiveness in critically ill patients.

INTRODUCTION: Esophageal Doppler provides a continuous and non-invasive estimate of descending aortic blood flow (ABF) and corrected left ventricular ejection time (LVETc). Considering passive leg raising (PLR) as a reversible volume expansion (VE), we compared the relative abilities of PLR-induced ABF variations, LVETc and respiratory pulsed pressure variations (DeltaPP) to predict fluid responsiveness. METHODS: We studied 22 critically ill patients in acute circulatory failure in the supine position, during PLR, back to the supine position and after two consecutive VEs of 250 ml of saline. Responders were defined by an increase in ABF induced by 500 ml VE of more than 15%. RESULTS: Ten patients were responders and 12 were non-responders. In responders, the increase in ABF induced by PLR was similar to that induced by a 250 ml VE (16% versus 20%; p = 0.15). A PLR-induced increase in ABF of more than 8% predicted fluid responsiveness with a sensitivity of 90% and a specificity of 83%. Corresponding positive and negative predictive values (PPV and NPV, respectively) were 82% and 91%, respectively. A DeltaPP threshold value of 12% predicted fluid responsiveness with a sensitivity of 70% and a specificity of 92%. Corresponding PPV and NPV were 87% and 78%, respectively. A LVETc of 245 ms or less predicted fluid responsiveness with a sensitivity of 70%, and a specificity of 67%. Corresponding PPV and NPV were 60% and 66%, respectively. CONCLUSION: The PLR-induced increase in ABF and a DeltaPP of more than 12% offer similar predictive values in predicting fluid responsiveness. An isolated basal LVETc value is not a reliable criterion for predicting response to fluid loading.

One-year outcome following biological or mechanical valve replacement for infective endocarditis.

BACKGROUND: Nearly half of patients require cardiac surgery during the acute phase of infective endocarditis (IE). We describe the characteristics of patients according to the type of valve replacement (mechanical or biological), and examine whether the type of prosthesis was associated with in-hospital and 1-year mortality. METHODS AND RESULTS: Among 5591 patients included in the International Collaboration on Endocarditis Prospective Cohort Study, 1467 patients with definite IE were operated on during the active phase and had a biological (37%) or mechanical (63%) valve replacement. Patients who received bioprostheses were older (62 vs 54years), more often had a history of cancer (9% vs 6%), and had moderate or severe renal disease (9% vs 4%); proportion of health care-associated IE was higher (26% vs 17%); intracardiac abscesses were more frequent (30% vs 23%). In-hospital and 1-year death rates were higher in the bioprosthesis group, 20.5% vs 14.0% (p=0.0009) and 25.3% vs 16.6% (p<.0001), respectively. In multivariable analysis, mechanical prostheses were less commonly implanted in older patients (odds ratio: 0.64 for every 10years), and in patients with a history of cancer (0.72), but were more commonly implanted in mitral position (1.60). Bioprosthesis was independently associated with 1-year mortality (hazard ratio: 1.298). CONCLUSIONS: Patients with IE who receive a biological valve replacement have significant differences in clinical characteristics compared to patients who receive a mechanical prosthesis. Biological valve replacement is independently associated with a higher in-hospital and 1-year mortality, a result which is possibly related to patient characteristics rather than valve dysfunction.

[Descriptive study of the patients admitted to an intensive care unit during the heat wave of August 2003 in France]. / Etude descriptive des patients admis en réanimation pour coup de chaleur au cours de la canicule d'août 2003.

INTRODUCTION: Several thousands of deaths were attributed to heat stroke during August 2003 in France. To date, only a very few studies have analyzed the prognosis in the intensive care unit (ICU) of the most severely hyperthermic patients. METHOD: Descriptive observational study of the patients admitted to the intensive care unit at the Lariboisière hospital in Paris, for heat stroke defined by an elevated core body temperature above 40 degrees C with central nervous system dysfunction, in the absence of other etiologies explaining the hyperthermia. RESULTS: In the Lariboisière hospital, an elevation in the ICU (+143%) and hospital mortality rate (+191%) were registered during August 2003, in comparison with August 2002. Fifteen patients (10 men, 5 women, median age: 57 years) were admitted to the ICU for heat stroke between the 4th and 14th of August 2003. Seven of them (47%) died. On admission, the occurrence of a pre-hospital cardiac arrest, the presence of coagulation abnormalities (reduction in prothrombin time and in platelet count) or of an elevation in plasma lactate concentration were significantly associated with the risk of death in the ICU. Conversely, age, body temperature, coma depth on admission and convulsions were not predictive of death. Neurological after effects (cerebellar syndrome, polyneuropathy and residual brain damage) were noted in 50% of the survivors. DISCUSSION: Although it is possible that heat alone precipitated the death of very sick people, our study clearly showed that young and valid patients died of heat stroke and suggests the possible increase in the 2003 death rate secondary to the heat wave. Moreover, it is still difficult at the moment to really appreciate the long-term consequences for survivors who presented serious neurological after effects. CONCLUSION: The August 2003 heat wave resulted in an elevation of the hospital and ICU death rates in the Lariboisière hospital in Paris. Despite adequate cooling and supportive therapies, the mortality of patients admitted to the ICU for heat stroke remained elevated and the neurological after effects severe. These preliminary results should be confirmed by larger cohort studies.

Properties and characteristics of an indirect Bis-GMA/barium-glass polymer ceramic restorative system.

Although porcelain has predictably served the dental profession for more than 200 years, this class of restorative material has presented a number of clinically undesirable characteristics. As a result, during the past several years, major efforts have been made to enhance the mechanical and physical characteristics of polymers to better mimic porcelain for specific clinical applications. In recent years, Bis-GMA/barium-glass polymer systems have been developed to offer dental professionals a versatile restorative alternative to porcelain. This article details the material properties and clinical characteristics of one such system for the esthetic restoration of anterior and posterior teeth.

Chromosome 22q13.3 deletion syndrome with a de novo interstitial 22q13.3 cryptic deletion disrupting SHANK3.

BACKGROUND: The 22q13.3 deletion syndrome (or Phelan-McDermid syndrome, MIM 606232) is characterized by developmental delay, absent or severely delayed speech, neonatal hypotonia, autistic behavior, normal to accelerated growth, and minor dysmorphic facial features. Among the three genes in the minimal critical region (from the centromere to the telomere: SHANK3, ACR and RABL2B), the defect in the SHANK3 gene is considered to be the cause of the neurobehavioral symptoms. OBJECTIVE: We describe the molecular characterization of a de novo interstitial del(22)(q13.3q13.3) disrupting the SHANK3 gene in a child with a phenotype compatible with the 22q13.3 deletion syndrome. METHODS: Clinical work-up included clinical histories, physical, neurological, and ophthalmological examinations, and imaging of the brain. Commercially available MLPA for subtelomeric analysis, FISH specific probes and quantitative real-time PCR were used to characterize the rearrangement. RESULTS: Subtelomere analysis by MLPA showed a discrepancy between P036B and P070 kits (MCR Holland): the P070 MLPA 22q probe (targeting the ARSA gene) showed a deletion but the P036B one (targeting the RABL2B gene) showed a normal result. FISH analysis using LSI TUPLE1/LSI ARSA (Vysis) probes confirmed deletion of ARSA, whereas FISH with N25/N85A3 (Cytocell) probes, targeting the SHANK3 locus was normal. Supplemented FISH analysis using BAC clones allowed us to specify the centromeric breakpoint region of the interstitial deletion between clones RP11-354I12 and RP11-232E17, at less than 2 Mb from the telomere. Quantitative real-time PCR of exon 5, 22 and 24 and intron 9 of SHANK3 showed that the telomeric breakpoint occurred between intron 9 and exon 22. CONCLUSIONS: These data highlight the difficulty of performing an appropriate test aimed at looking for cryptic 22q13.3 deletion. Furthermore, the molecular characterization of this interstitial 22q13.3 deletion contributes to the clinical and genetic delineation of the 22q13.3 deletion syndrome.

Familial CHARGE syndrome because of CHD7 mutation: clinical intra- and interfamilial variability.

CHARGE syndrome (OMIM #214800) is a multiple malformation syndrome with distinctive diagnostic criteria, usually because of CHD7 (chromodomain helicase DNA binding 7) haploinsufficiency. Familial occurrence of CHARGE syndrome is rare. We report six patients from two Caucasian families (both with one parent and two children) affected by mild to severe CHARGE syndrome. Direct sequencing of the CHD7 gene was performed in these two unrelated families. A mutation in exon 8 (c.2501C>T - p.S834F) in first chromodomain was found in family A and a nonsense mutation in exon 2 (c.469C>T - p.R157X) in family B. Both mutations are de novo in the parents. In family A, the elder son had bilateral cleft lip and palate, esophageal atresia with fistula, complex heart defect and vertebral abnormalities, while the younger had a posterior coloboma. Their mother had asymptomatic vestibular dysfunction and retinal coloboma, identified after the molecular diagnosis of her children. In family B, both affected children had severe expression of CHARGE syndrome. The father carrying the mutation only had asymmetric anomaly of the pinnae. These familial reports describe the intrafamilial variability of CHARGE syndrome, and underline the presence of CHD7 mutations in patients who do not fit the 'classical clinical criteria' for CHARGE syndrome.

MEFV analysis is of particularly weak diagnostic value for recurrent fevers in Western European Caucasian patients.

OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal-recessive disorder characterized by recurrent attacks of fever, with abdominal, thoracic, or articular pain. FMF is particularly common in Mediterranean populations, while other populations are rarely affected. MEFV gene analysis provides the only objective diagnostic criterion for FMF. However, the spectrum of MEFV mutations, which was first established in classically affected populations, remains insufficiently studied in other populations. The purpose of this study was to assess involvement of MEFV in the phenotype of western European Caucasian patients with a clinical diagnosis of FMF. METHODS: Mutation analysis was performed in 208 Caucasian patients from western Europe, by screening for the most common MEFV mutations in exons 2, 3, 5, and 10, and by sequencing the promoter region and the whole MEFV coding sequence in 21 of these patients. RESULTS: None of the patients carried 2 mutated alleles. Only 2 patients carried 1 mutated allele. CONCLUSION: FMF-like syndromes in western European Caucasian populations cannot be explained by MEFV mutations. These results should be helpful in avoiding laborious and costly MEFV molecular analyses that, at the population level, seem to be of poor diagnostic value in the case of western European Caucasian patients, and rather should prompt a search for other causes in those patients.