Programme Hospitalier Recherche Clinique, Institut Pasteur, Inserm, French Public Health Agency.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5–37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden’s Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.

Aim: To estimate the re‐hospitalization rate of extremely preterm children during infancy and associated factors after the recent improvement in survival rates. Method: The cohort included all children born before 29 wk of gestation in nine French regions in 1997. All admissions between discharge from initial hospitalization and 9 mo after birth were considered. Factors studied included the child's characteristics at birth and during neonatal hospitalization, risk factors for infection after discharge and parents' socio‐demographic characteristics. Adjusted odds ratios (aOR) for re‐hospitalization for all reasons and for respiratory disorders were obtained from logistic regression models. Results: Of the 376 children, 178 were re‐admitted at least once (47.3%; 95% CI: 42.3–52.4). Fifty‐five percent of the hospitalized children were admitted at least once for respiratory disorders. The re‐hospitalization rate was higher for children who had had chronic lung disease (aOR: 2.2; 95% CI: 1.3–3.7), those initially discharged between August and October (aOR: 2.5; 95% CI: 1.2–5.1) or between November and January (aOR: 3.2; 95% CI: 1.5–6.8), and children living with other children under six (aOR: 3.4; 95 %CI: 1.6–7.5). Re‐hospitalizations were associated with neither gestational age nor the duration of neonatal hospitalization. Adjusted odds ratios for re‐hospitalization for respiratory tract disorders were very similar to those for the overall hospitalizations. Conclusion: Infants born before 29 wk have a very high risk of re‐hospitalization. The associated factors can help define high‐risk groups at discharge from the neonatal unit who need special surveillance.

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