Distinct Clinical Courses and Shortened Lifespans in Childhood-Onset DNA Polymerase Gamma Deficiency.

Background and Objectives: DNA polymerase subunit gamma (POLG) deficiency is likely the most frequent cause of nuclear-encoded mitochondrial disorders. POLG-related disorders reportedly constitute a spectrum of overlapping phenotypes from infancy to late adulthood. We retrospectively reviewed natural histories for 40 children carrying biallelic pathogenic POLG variants. Methods: The patients were identified by the French coordinating center for mitochondrial disorders (CARAMMEL), making this a large monocentric series on childhood-onset POLG deficiency. Results: Three patterns of clinical course and survival were observed, distinguished by main category of symptoms: neurologic, hepatic, and gastrointestinal. A total of 24 patients needed urgent neurointensive care for tonic-clonic seizures, myoclonic epilepsy, and status epilepticus, occasionally precipitated by valproate administration. Other neurologic symptoms included dystonia, cerebellar ataxia, and peripheral neuropathy. We report 6 POLG-deficient patients with polyradiculoneuropathy mimicking subacute Guillain-Barré syndrome and provide postgadolinium MRI evidence of diffuse cranial nerve root and cauda equina enhancement, suggesting these disorders have an inflammatory component. Children presenting with enteral nervous system involvement had vomiting, gastroparesis, and chronic intestinal pseudo-obstruction. They had later ages of onset and lived much longer. Primarily, hepatic presentations had the earliest onset and shortest survivals. Secondary hepatic failure was frequently precipitated by valproate administration given before diagnosis to patients with focal impaired awareness seizures or absence of seizures. These POLG deficiencies were often fatal, with age at death ranging from 3 months to 10 years, with a significant difference in survival between the 3 clinical forms; 6 of the 40 children did survive. No genotype-phenotype correlations were found for the 3 clinical course types. Discussion: The study demonstrates the prevalence of neurologic presentation and the extent of central, peripheral, and autonomous nervous system involvement in 60% of patients. Most of the patients with early onset and rapidly fatal hepatic failure did not live long enough to develop neurologic symptoms. The study revealed a new clinical form of POLG deficiency presenting with neurodigestive symptoms with longer lifespan. We also propose that POLG deficiency should be considered in children presenting with unexplained polyradiculoneuropathy, demyelinating neuropathy, and elevated CSF protein. Finally, valproate administration remains a notable cause of avoidable death in POLG-deficient patients.

Clinical and molecular characterization of patients with YWHAG-related epilepsy.

OBJECTIVE: YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy. METHODS: We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients. RESULTS: The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001). SIGNIFICANCE: This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype-phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling.

Assessment of Multiple Dimensions of Psychological Well-Being in Swiss Youth Born with a Unilateral Cleft Lip and Palate.

OBJECTIVE: This study examines the psychological well-being of Swiss youths born with a unilateral cleft lip and palate (UCLP), in a multi-dimensional and clinical perspective. DESIGN: Retrospective cross-sectional study. SETTING: Self-report questionnaires completed by youths born with UCLP, followed at a specialized cleft clinic in Switzerland, and by peers without UCLP, recruited in schools of the Vaud county, Switzerland. PARTICIPANTS: Youths aged 7.5 to 16, born with UCLP (clinical group, n = 41, 29.2% female) or without UCLP (control group, n = 56, 49.0% female). OUTCOME MEASURES: Adverse life events (ALE; Adverse Life Events), behavioral and emotional symptoms (Strengths and Difficulties Questionnaire and Post-Traumatic Checklist Scale), bodily self-esteem (Body Esteem Scale), quality of life (Kidscreen-27), emotion regulation (Cognitive Emotion Regulation Questionnaire), social support (Sarason's Social Support Questionnaire). RESULTS: Most outcomes showed no significant group-difference. Compared to matched peers, youths with UCLP reported lower psychological quality of life and social support satisfaction, along with positive factors of fewer ALE and lower non-adaptive emotion regulation. In youths with UCLP, higher scores for ALE were associated with higher total scores for behavioral and emotional symptoms. Higher scores for bodily self-esteem were associated with higher scores for satisfaction of social support and adaptive emotion regulation. CONCLUSIONS: Youths with UCLP show globally similar psychological well-being as matched peers. We observed some vulnerabilities but also protective factors, which support the need for psychological perspective within multidisciplinary care. The relationships between dimensions suggest specific targets that may have an impact in context of intervention.

Bullying in Swiss Youth Born with a Unilateral Cleft lip and Palate by Self- and Parent-Report.

OBJECTIVE: This study aimed to gain a better understanding of bullying as victims and aggressors in youths born with unilateral cleft lip and palate (UCLP). DESIGN: This is an observational study comparing youths with UCLP (ages 8-16) and their parents with a control group (CG) of children in state schools and their parents. PARTICIPANTS: Forty-one youths (43% female; mean age 12.4 ± 2.3 years) and their parents (n = 40) composed the UCLP group and 56 youths (47% female; mean age 12.4 ± 1.2 years) and their parents (n = 33) were in the CG. MAIN OUTCOME MEASURE: The Olweus Bully/Victim questionnaire self- and parent-report was used to assess victims and aggressors involved in bullying behaviors. RESULTS: About 30% of all youths reported being a frequent victim of bullying at least 2-3 times a month and an additional 32.3% were bullied 1-2 times in the last 2-3 months. For the total sample, parents significantly (P < .05) underestimated any bullying, both as a victim (youths 62.5% vs parents 45.7%) and as an aggressor (youths 53.1% vs parents 37.1%). There were no significant group differences in experiencing any bullying between the youths with UCLP (52.5%) and the CG youths (69.6%) or in its perception by their parents (43.2% and 48.5%, respectively). There were no group differences between the combinations of victim and aggressor. CONCLUSIONS: While there were no differences in bullying prevalence in our sample between youths with UCLP and their peers, this study highlights differences in bullying perceptions between parents and their children.

Normal intellectual skills in patients with Rhombencephalosynapsis.

OBJECTIVES: Rhombencephalosynapsis (RES) is a very rare cerebellar malformation. Neurodevelopmental outcome of apparently isolated RES remains poorly documented and standardized cognitive assessment, reported in only nine published cases so far, is lacking. Prenatal counselling is challenging considering the uncertain prognosis of isolated RES. The aim of this study was to focus on cognitive and motor outcome of isolated RES with a clinical description of six new cases and a detailed review of the literature. METHODS: A single-centre retrospective study of all RES patients over a 15-year period. Ataxia and fine motor skills were scored using a five-grade scale, according to the degree of disturbance of daily living. Intelligence Quotient (IQ) was established according to age-related Weschler Intelligence Scales. A systematic literature review included published cases with relevant outcome data. RESULTS: Six new cases of apparently isolated RES were reported, including three diagnosed in prenatal settings. The onset age for walking was delayed in four patients. Three patients had head shaking and three had a strabismus. One patient had a mild motor disability, one had subtle ataxia that did not impair daily life and four patients had a normal neurological examination at the last visit. Intellectual abilities were normal in all patients (full IQ score from 90 to 142), although three had ADHD. All received standard schooling. Based on these six new cases, as well as cases from 12 publications in the literature, a total of 28 patients with non-syndromic RES were analysed. Concerning motor outcome, 72% had no complaint or minimal impairment, 16% moderate and 12% severe impairment. Concerning cognitive outcome, 68% had normal cognitive skills, 18% borderline intellectual functioning and 14% moderate to severe disability.

[New features in the management of labio-maxillo-palatal clefts at the CHUV]. / Nouveautés dans la prise en charge des fentes labio-maxillo-palatines au CHUV.

The labio-maxillofacial cleft (LMFC) penalizes the child from birth by its aesthetic, functional, psychological and social repercussions. The prognosis is conditioned by a multidisciplinary care that starts from the antenatal period to continue until the end of growth. The treatment is long and complex. This explains the multiplicity of techniques and the variability of schedules according to the teams. The purpose of this article is to describe the protocol of management of the LMFC within the multi-disciplinary team in Lausanne and to emphasize the novelties in both surgical and organizational plan.

La fente labio-maxillo-palatine (FLMP) pénalise l'enfant dès sa naissance par ses retentissements esthétiques, fonctionnels, psychologiques et sociaux. Le pronostic est conditionné par une prise en charge multidisciplinaire qui commence dès la période anténatale pour se poursuivre jusqu'à la fin de la croissance. Le traitement est long et complexe. Ceci explique la multiplicité des techniques et la variabilité des calendriers selon les équipes. Le but de cet article est de décrire le protocole de prise en charge des FLMP au sein de l'équipe pluridisciplinaire lausannoise et en mettant l'accent sur les nouveautés tant sur le plan chirurgical qu'organisationnel.

Effect of desipramine on patients with breathing disorders in RETT syndrome.

Objective: Rett Syndrome (RTT) is a severe neurodevelopmental condition with breathing disorders, affecting around one in 10,000 female births. Desipramine, a noradrenaline reuptake inhibitor, reduced the number of apneas in Mecp2-deficient mice, a model of RTT. We planned a phase 2 trial to test its efficacy and its safety on breathing patterns in 36 girls with RTT. Methods: The trial was a 6-month, multicenter, randomized, double-blind, placebo-controlled study registered with ClinicalTrials.gov, number NCT00990691. Girls diagnosed according to clinical examination and confirmed by genotyping were randomly assigned in a 1:1:1 ratio to receive 2-3 mg/kg Desipramine per day (high Desipramine), 1-2 mg/kg Desipramine per day (low Desipramine), or a placebo. The primary outcome was the change of apnea hypopnea index (AHI), defined by the number of apnea and hypopnea events per hour, assessed at 6 months from baseline. Intention-to-treat analysis was applied. Results: The median change in AHI from baseline to 6 months was -31 (IQR: -37 to -11) for the high Desipramine, -17.5 (IQR: -31 to 13) for the low Desipramine, and -13 (IQR:-31 to 0) for the placebo group. We did not find any significant difference in these changes between the groups (P = 0.781). A significant inverse correlation between Desipramine plasma concentration and AHI (r = -0.44; P = 0.0002) was underlined. Interpretation: This first clinical trial of desipramine did not show clinical efficacy. Although required further studies, the significant correlation between Desipramine concentrations and improvement of AHI provided additional and relevant reasons to test the noradrenergic pathway in RTT.