Novel partial loss-of-function variants in the tyrosyl-tRNA synthetase 1 (YARS1) gene involved in multisystem disease.

Cytoplasmic aminoacyl-tRNA synthetases (ARSs) are emerging as a cause of numerous rare inherited diseases. Recently, biallelic variants in tyrosyl-tRNA synthetase 1 (YARS1) have been described in ten patients of three families with multi-systemic disease (failure to thrive, developmental delay, liver dysfunction, and lung cysts). Here, we report an additional subject with overlapping clinical findings, heterozygous for two novel variants in tyrosyl-tRNA synthetase 1 (NM_003680.3(YARS1):c.176T>C; p.(Ile59Thr) and NM_003680.3(YARS1):c.237C>G; p.(Tyr79*) identified by whole exome sequencing. The p.Ile59Thr variant is located in the highly conserved aminoacylation domain of the protein. Compared to subjects previously described, this patient presents a much more severe condition. Our findings support implication of two novel YARS1 variants in these disorders. Furthermore, we provide evidence for a reduced protein abundance in cells of the patient, in favor of a partial loss-of-function mechanism.

Comparative analysis of perinatal and postnatal factors, and general movement in extremely preterm infants.

STUDY AIM: To describe general movement in extremely premature infants and examine correlations with risk factors for antenatal, perinatal, and postnatal morbidity. STUDY TYPE: Prospective, single-center study. Nineteen patients were followed up. METHODOLOGY: The infants' general movement was analyzed using video recordings. Qualitative and quantitative assessments were performed during the writhing movement (WM) period and fidgety movement (FM) period. The quality of the general movements (GMs) and the scores achieved were then correlated with antenatal, perinatal, and postnatal factors. RESULTS: Infants' motor activity fluctuated during the WM period, especially in extremely premature infants where poor repertoire is often observed. No correlations were found between WMs and obstetric factors. Gestational age correlated with WMs' quality (p=0.023). WMs correlated with factors of postnatal morbidity such as chronic lung disease (CLD) (p=0.034) and nosocomial infections (p=0.05). At 3 months corrected age, the spontaneous movement quality are correlated with neurological explorations such as US brain (p=0.032), MRI (p=0.039), EEG (p=0.036), and neurological follow-up assessments (p=0.015). CONCLUSION: Prudence must be used when performing the analysis of general movement in extremely preterm infants. WMs may be influenced by perinatal morbidity, and possibly by the severe brain immaturity of these infants. WMs correlate with CLD and nosocomial infections. Analysis of general movement in infants of 3 months corrected age is a valuable means to detect neurological disorders.

Longitudinal follow-up of a cohort of 350 singleton infants born at less than 32 weeks of amenorrhea: neurocognitive screening, academic outcome, and perinatal factors.

OBJECTIVE: To analyse the incidence of neurodevelopmental disorders at the age 6-10 years, in children born at less than 32 weeks of amenorrhea, and to identify the perinatal and neonatal factors associated with adverse neurodevelopmental outcomes at this age. STUDY DESIGN: Longitudinal prospective trial in a French university and tertiary perinatal care centre. A total of 350 preterm singletons born in hospital at less than 32 weeks of amenorrhea between 1997 and 2001 were included. Children were invited for examination to screen for neurocognitive disorders between 4 and 8 years of age and re-contacted when they were between 6 and 10 years of age to evaluate school results. Three profiles of neurocognitive outcome were defined (normal, minor disorder, or major disorder) and correlated with maternal, antenatal, perinatal, and neonatal factors. RESULTS: The survival rate of our cohort was 80.8% (283/350) and the proportion of survivors followed-up was 71.4% (202/283). There were 137 children (68%) with normal profiles, 29 (14%) with minor disorders, and 36 (18%) with major disorders. For those born at less than 28 weeks of amenorrhea, the survival rate was 62.7% (64/102) and the proportion of survivors followed-up was 78.1% (50/64). Among these children, 24 (48.0%) had normal outcomes, 8 (16.0%) suffered from minor disorders, and 18 (36.0%) had major disorders. The three principal independent risk factors for major or minor disorders at school age were gestational age less than 28 weeks of amenorrhea (adjusted odds ratio: 1.28 [95% confidence interval: 1.06-1.56]), chronic lung disease at birth (adjusted odds ratio: 2.92 [95% confidence interval: 1.15-7.42]), and an abnormal electroencephalogram before discharge (adjusted odds ratio: 2.61 [95% confidence interval: 1.10-6.18]). Moreover, abnormal brain ultrasonography was identified as an independent risk factor for occurrence of major disorders (adjusted odds ratio: 2.98 [95% confidence interval: 1.31-6.71]). CONCLUSION: Very preterm infants remain at high risk for long-term neurodevelopmental disorders. Several neonatal factors, particularly chronic lung disease, seem to be important determinants of long-term outcome.

Evaluation of a tool to screen at preschool age for minor cognitive disorders liable to affect schooling among children born premature.

PURPOSE: To evaluate a detection tool designed to help paediatricians identify, at preschool age, minor neurocognitive disorders that interfere with normal schooling. METHODS: One hundred-and-fourteen preterm singletons born between 1997 and 2001 at less than 32 weeks of amenorrhoea, in a tertiary perinatal care center, were invited to visit us for a medical examination and a rapid neurocognitive assessment (BREV) when they were aged between 4 and 8 years and were re-contacted at 6-10 years of age to evaluate their current schooling situation. Results of BREV and schooling parameters were compared. RESULTS: Mean gestational age was 29 weeks and mean birth weight was 1,164 g. Fifteen children (13.2%) showed abnormal results on BREV testing and had unusual schooling histories. Among the 68 children with normal BREV, 65 (95.6%) had achieved normal schooling. The sensitivity of the BREV test in this population for detection of minor disorders interfering with schooling was thus 83.3% (95% CI = 57.7-95.6) and the predictive value of a negative test was 95.6% (95% CI = 86.8-98.9). For the 57 children (50%) assessed before the age of 5 years, the sensitivity and the predictive value of a negative test were both 100%. CONCLUSION: Our survey shows that the BREV test can, in a population of preschool children who were born premature, screen for minor neurocognitive disorders that impact schooling parameters. BREV assessment, used in the setting of follow-up of premature infants, would identify children in need of early remedial education before schooling under-attainment or failure developed.

Neuropsychological screening of a group of preterm twins: comparison with singletons.

OBJECTS: Perform neuropsychological screening of a group of preterm twins without major brain pathology and compare it with a control group of similarly preterm children born as singletons. MATERIALS AND METHODS: Twenty-three preterm twins born at fewer than 32 weeks of gestation were tested for rapid evaluation of cognitive functions at the age of 4 years. The tests evaluated language, non-verbal performances, learning and attention deficit disorders. Cognitive profiles were established. Links between perinatal factors, clinical follow-up and cognitive outcome were investigated. Their cognitive outcome was then compared with the cognitive outcome of 31 preterm singletons with the same gestational periods. CONCLUSION: The twins' neuropsychological outcome was not more marked than that of the singletons. Birth weight discordance and chorionicity were the only predictive perinatal factors with worse outcome in the twin population.