Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy

Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1−/− mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.

Paediatric orthopaedics through paintings

Purpose Some famous artistic representations created throughout the centuries can reveal a hidden or mysterious diagnosis of some diseases and these paintings have always drawn the attention of physicians interested in art. Artistic illustration of a child with a malformation or disability can reflect the characteristic appearance of a disease and its historic perspective. Some articles have revealed the definite diagnosis of a child with achondroplasia through portraits of dwarfs and some studies have discussed the secret diagnosis of a crippled child with Pes Equinovarus or poliomyelitis. In this study, we aim to introduce some paintings that reveal musculoskeletal diseases related to paediatric orthopaedics. Methods Paintings painted since the Renaissance were reviewed and collected via web searches. Artistic paintings depicting children with suspected paediatric orthopaedic diseases were analyzed in this study. Results Paintings in which artists have depicted children with achondroplasia, poliomyelitis and clubfoot were found. Conclusion The investigation of a drawing depicting a disabled child may encourage an orthopaedic surgeon to introduce an analytical approach using visual cues. These paintings may also enhance the observational skills of paediatric orthopaedic surgeons, give information about the historical process of a disease and demonstrate the impact of the disease at the time the painting was painted.