Unravelling the Clinical Co-Morbidity and Risk Factors Associated with Agenesis of the Corpus Callosum.

Agenesis of the Corpus Callosum (ACC) can result in multiple neurological deficits including social and behavioural issues. However, the underlying aetiology, clinical co-morbidity and the contributing risk factors remain elusive, resulting in inaccurate prognosis and delayed therapy. The main objective of this study was to comprehensively describe the epidemiology and clinical co-morbidity associated with patients diagnosed with ACC. The secondary objective was to identify the factors that contribute towards increased risk for ACC. For this, we analysed 22 years (1998-2020) of clinical data across the whole of Wales, UK collected through the Congenital Anomaly Register & Information Service (CARIS) and Public Health Wales (PHW). Our results demonstrate that complete ACC (84.1%) was the prevalent subtype, in comparison to partial ACC. Further, ventriculomegaly/hydrocephalus (26.37%) and ventricular septal defect (21.92%) were identified to be the most prevalent neural malformation (NM) and congenital heart disorder (CHD) in our cohort. Although 12.7% of subjects with ACC had both an NM and CHD, we found no significant association between them (χ2 (1, n = 220) = 3.84, p = 0.33). We found socioeconomic deprivation and increased maternal age contributed towards an increased risk for ACC. To the best of our knowledge, this study for the first time defines the clinical phenotypes and the factors that contribute to ACC within the Welsh population. These findings will be of value to both patients and healthcare professionals, who may take preventative or remedial measures.

The association of neurodevelopmental abnormalities, congenital heart and renal defects in a tuberous sclerosis complex patient cohort.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterised by the presence of benign tumours throughout multiple organs including the brain, kidneys, heart, liver, eyes, lungs and skin, in addition to neurological and neuropsychiatric complications. Intracardiac tumour (rhabdomyoma), neurodevelopmental disorders (NDDs) and kidney disorders (KD) are common manifestations of TSC and have been linked with TSC1 and TSC2 loss-of-function mutations independently, but the dynamic relationship between these organ manifestations remains unexplored. Therefore, this study aims to characterise the nature of the relationship specifically between these three organs' manifestations in TSC1 and TSC2 mutation patients. METHODS: Clinical data gathered from TSC patients across South Wales registered with Cardiff and Vale University Health Board (CAV UHB) between 1990 and 2020 were analysed retrospectively to evaluate abnormalities in the heart, brain and kidney development. TSC-related abnormalities such as tumour prevalence, location and size were analysed for each organ in addition to neuropsychiatric involvement and were compared between TSC1 and TSC2 mutant genotypes. Lastly, statistical co-occurrence between organ manifestations co-morbidity was quantified, and trajectories of disease progression throughout organs were modelled. RESULTS: This study found a significantly greater mutational frequency at the TSC2 locus in the cohort in comparison to TSC1. An equal proportion of male and female patients were observed in this group and by meta-analysis of previous studies. No significant difference in characterisation of heart involvement was observed between TSC1 and TSC2 patients. Brain involvement was seen with increased severity in TSC2 patients, characterised by a greater prevalence of cortical tubers and communication disorders. Renal pathology was further enhanced in TSC2 patients, marked by increased bilateral angiomyolipoma prevalence. Furthermore, co-occurrence of NDDs and KDs was the most positively correlated out of investigated manifestations, regardless of genotype. Analysis of disease trajectories revealed a more diverse clinical outcome for TSC2 patients: however, a chronological association of rhabdomyoma, NDD and KD was most frequently observed for TSC1 patients. CONCLUSIONS: This study marks the first empirical investigation of the co-morbidity between congenital heart defects (CHD), NDDs, and KDs in TSC1 and TSC2 patients. This remains a unique first step towards the characterisation of the dynamic role between genetics, heart function, brain function and kidney function during the early development in the context of TSC.

What is new in migraine management in children and young people?

For this narrative review, we found recent publications on the use and effectiveness of old therapies including nutraceuticals, such as riboflavin, vitamin D, magnesium, melatonin and talking therapies. Recent large trials of established conventional pharmaceuticals such as propranolol, pizotifen, topiramate and amitriptyline for childhood migraine have failed, but the use of a quasi-placebo in future trials could help. We reviewed the evidence for angiotensin antagonists including candesartan in adults, but found a lack of evidence for their use in children. There have been new developments in pharmaceuticals recently, including a more selective 5-HT1F agonist, lasmiditan, an effective acute treatment with no vasoconstrictor activity in adults, currently being tested in children. Also, a number of new calcitonin gene-related peptide (CGRP) antibodies and antagonists, with proven efficacy in acute treatment and/or prevention of migraine in adults, are undergoing trials in children. Peripheral nerve blocks and botulinum toxin are gaining popularity in adult practice, but we really need more good quality evidence for their effectiveness in children. Finally, electroceuticals, that is, therapeutic electric devices, are now marketed for acute and or preventative treatment, including an external trigeminal nerve stimulator (e-TNS), a non-invasive vagal nerve stimulator (nVNS), a single-pulse transcranial magnetic stimulator (sTMS) and a remote electrical neuromodulation device (REN). At the moment, evidence for their effectiveness in children is still lacking. So, there has been much progress, but mostly for adults. We are in urgent need of more migraine trials in children.

Untreated recurrent acute necrotising encephalopathy associated with RANBP2 mutation, and normal outcome in a Caucasian boy.

Acute necrotising encephalopathy (ANE) is a rare encephalitis-like syndrome usually reported in East Asia. This clinical syndrome tends to be triggered by viral febrile illness with rapid deterioration to seizures, coma and a generally poor outcome. Diagnosis is usually made on Magnetic Resonance Imaging (MRI). Its epidemiology is unknown largely due to under-recognition. Recurrent ANE has recently been associated with a newly discovered autosomal dominant mutation RAN-binding protein 2 now termed ANE1. There had been reports encouraging the use of empirical corticosteroids as treatment for this condition. However, there have not been any clinical trials to date. Here we report an unusual case of a Caucasian toddler who had suffered two episodes of ANE, but did not receive any specific treatment and has normal physical and cognitive outcome at 1 year follow up. He has this missense mutation in the gene of the RAN-binding protein 2 as have his mother and brother who are both well. This case adds to the worldwide literature and expands on the spectrum of outcomes in order to bring about better recognition in the Caucasian population.

A genetic cause for neonatal encephalopathy: incontinentia pigmenti with NEMO mutation.

UNLABELLED: Incontinentia pigmenti (IP) is not generally recognized as a cause of neonatal encephalopathy. A full-term infant developed a rash and encephalopathy with lesions in the basal ganglia and periventricular white matter 3 days after a normal delivery. Typical skin changes of IP were confirmed by histology and mutation analysis of the NFkappaB essential modulator (NEMO) gene. CONCLUSION: The mechanism of brain injury appears to be increased apoptosis after inflammation and this condition should be included in differential diagnosis of neonatal encephalopathy if skin lesions are present.