Neonatal screening for congenital hypothyroidism: Time to lower the TSH threshold in France.

Neonatal screening for congenital hypothyroidism (CH) is based on the measurement of thyroid-stimulating hormone (TSH) in whole dried blood samples on filter paper in all newborns. The objective of screening for CH is to prevent mental retardation, which is irreversible in the event of a late diagnosis, by setting up prompt treatment (before day 15) with levothyroxine. The threshold value of TSH on filter paper on day 3 is 17 mIU/L in France in the GSP method (GSP, Genetic Screening Processor, Perkin Elmer): It is one of the highest thresholds used in the world. In many countries, the TSH threshold is between 6 and 12 mIU/L. Studies have found that a threshold of > 17 mIU/L may miss as much as 30% of cases of CH, with 30-80% of these being permanent CH. Recent studies suggest that mild CH (currently missed by the French TSH threshold) is associated with cognitive consequences if left untreated. An inverse relationship between TSH at screening (below the current threshold) and cognitive development at preschool or school age has been shown. These studies advocate for the evaluation of a lowering of the threshold of TSH on filter paper in France: (a) to determine the number of CH diagnoses with the new threshold and whether these "new cases" would be transitory or permanent; and (b) to analyze the cost-effectiveness of the strategy.

An Unusual Compound Heterozygosity for Hb O-Arab (HBB: c.364G>A) and Hb D-Los Angeles (HBB: c.364G>C).

We report a newborn with a compound heterozygosity for Hb O-Arab (HBB: 364G>A) and Hb D-Los Angeles (HBB: 364G>C). To the best of our knowledge, the combination of these two hemoglobin (Hb) variants has not been identified and reported before. The variants of the proband and parents were identified by high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE). DNA analysis was performed to confirm the variants. The levels of Hb variants of the proband were determined post-partum, at 3 months and 1 year after birth. Blood count analysis after 1 year revealed that the proband had a mild microcytic anemia. Furthermore, HPLC and CE analysis revealed an equal distribution of Hb D-Los Angeles compared to Hb O-Arab at the age of 1 year. The follow-up of the patient, suggested that the Hb combination is clinically silent or mild.

Chronic Diarrhea in L-Amino Acid Decarboxylase (AADC) Deficiency: A Prominent Clinical Finding Among a Series of Ten French Patients.

Aromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive inborn error of metabolism, affecting catecholamines and serotonin biosynthesis. Cardinal signs consist in psychomotor delay, hypotonia, oculogyric crises, dystonia, and extraneurological symptoms. PATIENTS AND METHODS: We present a retrospective descriptive multicentric study concerning ten French children with a biochemical and molecular confirmed diagnosis of AADC deficiency. RESULTS: Clinical presentation of most of our patients was consistent with the previous descriptions from the literature (hypotonia (nine children), autonomic signs (nine children), sleep disorders (eight children), oculogyric crises (eight children), motor disorders like hypertonia and involuntary movements (seven children)). We described however some phenotypic particularities. Two patients exhibited normal intellectual abilities (patients already described in the literature). We also underlined the importance of digestive symptoms like diarrhea, which occurred in five among the ten patients. We report in particular two children with chronic diarrhea, complicated by severe failure to thrive. Vanillactic acid (VLA) elevation in urines of one of these two patients led to suspect the diagnosis of AADC deficiency, as in two other patients from our population. CONCLUSION: Some symptoms like chronic diarrhea were atypical and have been poorly described in the literature up to now. Diagnosis of the AADC deficiency is sometimes difficult because of the phenotypic heterogeneity of the disease and VLA elevation in urines should suggest the diagnosis.

[Neonatal eucapnic pH at birth: Application in a cohort of 5392 neonates]. / Le pH eucapnique néonatal à la naissance : application à une cohorte de 5392 nouveau-nés.

OBJECTIVE: To apply a newly concept of neonatal eucapnic pH at birth [pH euc (n)] and compare its contribution towards conventional criteria of severe metabolic acidosis. METHODS: Analysis of a cohort of 5392 neonates from 2010 to 2014 in a level 1 maternity. clinical data (birth weight, gestational age, mode of delivery, APGAR score) were collected from archived files. Biological data were collected from umbilical cord blood, consisting of pH, PCO2, Base deficit, lactate. Eucapnic pH and eucapnic base deficit were calculated from pH and PCO2 with the Henderson-Hasselbalch equation applied in the Charles-Racinet diagram and/or with an Excel spreadsheet. RESULTS: Data set the prevalence of neonatal acidemia<7.00 to 0.62 %. The current cohort shows 32 cases of severe neonatal metabolic acidosis according to ACOG-AAP (2014) criteria and 26/29 cases according to McLennan (2015) criteria, of which 80 % were born by cesarean section or instrumental delivery. In 55 % of cases, calculated eucapnic pH at birth did not confirm the severity of metabolic acidosis based on a threshold set at 7.11. Five cases were transferred in neonatalogy only on clinical considerations of poor neonatal adaptation but not on biological consideration (pH euc<7.11 was equally distributed between transferred and non-transferred neonates, P=0.76; the same distribution was observed with the pH, P=0.20) and followed normal outcome. DISCUSSION AND CONCLUSION: The pH determination provides information only on the degree of acidemia and not on respiratory and/or metabolic components. Moreover, hypercapnia always present at birth is not included in the instructions to determine a metabolic acidosis (The American College of Obstetricians and Gynecologists, 2014; MacLennan et al., 2015). The new concept of neonatal eucapnic pH at birth accounts for only the metabolic component. We feel it should fine tune indications for cerebral hypothermia and thus improve its effectiveness. From a medicolegal perspective, for cases of cerebral palsy, it often allows to refute metabolic acidosis in perpartum events, often wrongfully being linked to generate cerebral injuries.

Don't forget methylmalonic acid quantification in symptomatic exclusively breast-fed infants.

Vitamin B12 deficiency can lead to serious haematological and neurological signs in infants. The reported clinical cases of vitamin B12 deficiency were found in exclusively breast-fed infants whose asymptomatic mothers were diagnosed later with pernicious anaemia. For the infants, the diagnosis required urinary methylmalonic acid quantification (grossly elevated in these two cases) and treatment rapidly improved the clinical signs. These cases underline the serious consequences of vitamin B12 deficiency in infants and the helpful role of early methylmalonic acid quantification for diagnosis.

[Diagnosis of neonatal metabolic acidosis by eucapnic pH determination]. / Diagnostic de l'acidose métabolique à la naissance par la détermination du pH eucapnique.

UNLABELLED: The identification of a metabolic acidosis is a key criterion for establishing a causal relationship between fetal perpartum asphyxia and neonatal encephalopathy and/or cerebral palsy. The diagnostic criteria currently used (pH and base deficit or lactatemia) are imprecise and non-specific. OBJECTIVE: The study aimed to determine among a low-risk cohort of infants born at term (n = 867), the best diagnostic tool of metabolic acidosis in the cordonal from the following parameters: pH, blood gases and lactate values at birth. MATERIALS AND METHODS: The data were obtained from arterial blood of the umbilical cord by a blood gas analyser. The parameter best predicting metabolic analysis was estimated from the partial correlations established between the most relevant parameters. RESULTS: The results showed a slight change in all parameters compared to adult values: acidemia (pH: 7.28 ± 0.01), hypercapnia (56.5 ± 1.59 mmHg) and hyperlactatemia (3.4 ± 0.05 mmol/L). From partial correlation analysis, pCO(2) emerged to be the main contributor of acidemia, while lactatemia was shown to be non-specific for metabolic acidosis. Seven cases (0.81 %) showed a pH less than 7.00 with marked hypercapnia. The correction of this respiratory component by EISENBERG's method led to the eucapnic pH, classifying six out of seven cases as exclusive respiratory acidosis. DISCUSSION AND CONCLUSION: It has been demonstrated that the criteria from ACOG-AAP for defining a metabolic acidosis are incomplete, imprecise and generating errors in excess. The same is true for lactatemia, whose physiological significance has been completely revised, challenging the misconception of lactic acidosis as a specific marker of hypoxia. It appeared that eucapnic pH was the best way for obtaining a reliable diagnosis of metabolic acidosis. We proposed to adopt a simple decision scheme for determining whether a metabolic acidosis has occurred in case of acidemia less than 7.00.

Novel mutations in pyridoxine-dependent epilepsy.

PURPOSE: Pyridoxine-Dependent Epilepsy (PDE) is a rare autosomal recessive disease with neonatal seizures resistant to conventional anti-epileptic drugs. This metabolic disease has to be diagnosed early and treated to improve outcome. We report on two new mutations that open new prenatal prospects and suggest a new diagnostic procedure. CASE REPORT: We describe PDE in a neonate carrying two novel mutations in the ALDH7A1 gene: c.[852_856delCTTAG] + [1230C > A]; p.[(Phe410Leu)] + p.[(Leu285CysfsX26)]. This case also illustrates that diagnosis could have been made without any pyridoxine withdrawal, thanks to the measurement of biomarkers. The patient was successfully treated with pyridoxine supplementation and currently shows normal neurological development.

SPR-imaging based assays on an oligonucleotide-array to analyze DNA lesions recognition and excision by repair proteins.

An original oligonucleotide-array, coupled with SPR-imaging detection, has been developed to study biological interactions between DNA base lesions and DNA repair enzymes. This bioanalytical tool constitutes an efficient screening platform to quantify DNA repair activities and to search for new DNA repair inhibitors.

Rapid perceptual integration of facial expression and emotional body language.

In our natural world, a face is usually encountered not as an isolated object but as an integrated part of a whole body. The face and the body both normally contribute in conveying the emotional state of the individual. Here we show that observers judging a facial expression are strongly influenced by emotional body language. Photographs of fearful and angry faces and bodies were used to create face-body compound images, with either matched or mismatched emotional expressions. When face and body convey conflicting emotional information, judgment of facial expression is hampered and becomes biased toward the emotion expressed by the body. Electrical brain activity was recorded from the scalp while subjects attended to the face and judged its emotional expression. An enhancement of the occipital P1 component as early as 115 ms after presentation onset points to the existence of a rapid neural mechanism sensitive to the degree of agreement between simultaneously presented facial and bodily emotional expressions, even when the latter are unattended.

[A very high level in a cardiac troponin I assay]. / Une valeur de troponine I cardiaque particulièrement élevée.

Cardiac troponin I (TnIc) is a very sensitive and also a specific marker of myocardial injuries. We report here, the clinical case of a patient with a particularly important and brutal increase of the troponin during a myocardial infarction. A 64-year-old man was admitted to hospital. He had a myocardial infarction associated to a cardiac necrosis and important cytolysis. The troponin assay was normal when the patient was hospitalized. The angioplasty coronary reperfusion brought about a massive troponin Ic release in systemic circulation: the assay made 10 hours after the appearance of the symptoms shows us an exceptional TnIc concentration that is greater than 4000 microg/L (baseline: 1,5 microg/L). This might be the highest value ever reported.

Evaluation of the leucocyte contamination of plateletpheresis concentrates collected on Trima separators: a review of three years of use at fixed sites and mobile units.

The Trima separator, manufactured by the Gambro, was introduced at the end of 1997 and the first separators were tested in France in early 1998. They are now routinely used on our Grenoble site for the collection of platelets and plasma. The aim of this paper is to evaluate the residual contamination of leucocytes of platelet products routinely collected on the Trima separator in a French blood transfusion center (ETS). Two separators are used at the fixed site and two separators are used for mobile collection (500 km/week). After a preliminary period of validation on site, 3237 plateletpheresis concentrates were collected by four separators qualified for fixed site or mobile unit use. An analysis taking into account the separator site (fixed or mobile) fails to reveal any significant difference for means or non-conformity percentages (data available).