De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females.

PURPOSE: MED12 is a subunit of the Mediator multiprotein complex with a central role in RNA polymerase II transcription and regulation of cell growth, development, and differentiation. This might underlie the variable phenotypes in males carrying missense variants in MED12, including X-linked recessive Ohdo, Lujan, and FG syndromes. METHODS: By international matchmaking we assembled variant and clinical data on 18 females presenting with variable neurodevelopmental disorders (NDDs) and harboring de novo variants in MED12. RESULTS: Five nonsense variants clustered in the C-terminal region, two splice variants were found in the same exon 8 splice acceptor site, and 11 missense variants were distributed over the gene/protein. Protein truncating variants were associated with a severe, syndromic phenotype consisting of intellectual disability (ID), facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. De novo missense variants were associated with a less specific, but homogeneous phenotype including severe ID, autistic features, limited speech and variable other anomalies, overlapping both with females with truncating variants as well as males with missense variants. CONCLUSION: We establish de novo truncating variants in MED12 as causative for a distinct NDD and de novo missense variants as causative for a severe, less specific NDD in females.

Hypnotherapy or transcendental meditation versus progressive muscle relaxation exercises in the treatment of children with primary headaches: a multi-centre, pragmatic, randomised clinical study.

Many children suffer from headaches. Since stress may trigger headaches, effective techniques to cope with stress are needed. We investigated the effectiveness of two mind-body techniques, transcendental meditation (TM) or hypnotherapy (HT), and compared them with progressive muscle relaxation (PMR) exercises (active control group). Children (9-18 years) suffering from primary headaches more than two times per month received either TM (N = 42), HT (N = 45) or PMR (N = 44) for 3 months. Primary outcomes were frequency of headaches and ≥ 50% reduction in headaches at 3 and 9 months. Secondary outcomes were adequate relief, pain coping, anxiety and depressive symptoms, somatisation and safety of treatment. Groups were comparable at baseline. Headache frequency was significantly reduced in all groups from 18.9 days per month to 12.5 and 10.5 at respectively 3 and 9 months (p < 0.001), with no significant differences between the groups. Clinically relevant headache reduction (≥ 50%) was observed in 41% and 47% of children at 3 and 9 months respectively, with no significant differences between the groups. No differences were observed in secondary outcome measures between the intervention groups. No adverse events were reported.Conclusion: All three techniques reduced primary headache in children and appeared to be safe.Trial registration: NTR 2955, 28 June 2011 ( www.trialregister.nl ) What is Known: • Stress may be an important trigger for both tension type headache and migraine in children. • Good data are lacking on the effect of transcendental meditation, hypnotherapy or progressive muscle relaxation as possible stress-reducing therapies in children with primary headaches. What is New: • Three non-pharmacological techniques, i.e., transcendental meditation, hypnotherapy and progressive muscle relaxation exercises, all result in a clinically significant reduction of headaches and use of pain medication. • No large differences between the three techniques were found, suggesting that children can choose either one of the three techniques based on personal preferences.