Missense variants in cause myo-tubulinopathies.

Tubulinopathies encompass a wide spectrum of disorders resulting from variants in genes encoding α- and β-tubulins, the key components of microtubules. While previous studies have linked or dominantly inherited missense variants to neurodegenerative phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, hereditary spastic ataxia, and more recently, an isolated report of congenital myopathy, the full phenotypic and genotypic spectrum of -related disorders remains incompletely characterised. In this multi-centre study, we identified 13 novel missense variants in 31 individuals from 19 unrelated families.

Development and Validation of a Stakeholder-Driven, Self-Contained Electronic Informed Consent Platform for Trio-Based Genomic Research Studies.

Background: Increasingly long and complex informed consents have yielded studies demonstrating comparatively low participant and with traditional face-to-face approaches. In parallel, interest in electronic consents for clinical and research genomics has steadily increased, yet limited data are available for trio-based genomic discovery studies. We describe the design, development, implementation, and validation of an electronic iConsent application for trio-based genomic research deployed to support genomic studies of cerebral palsy.

Opportunities and challenges for paediatricians requesting funded genomic tests for children.

Genomic diagnosis for children with childhood syndromes can inform treatment, management and reproductive planning. Shortages in the clinical genetics workforce mean that practices are changing, with paediatricians likely requesting initial genomic investigations and clinical genetics services reserved for particularly complex cases or post-test genetic counselling. In Australia, paediatricians can request funded genomic testing for patients, yet ordering rates are less than a quarter predicted.

Speech, Language and Non-verbal Communication in CLN2 and CLN3 Batten Disease.

CLN2 and CLN3 diseases, the most common types of Batten disease (also known as neuronal ceroid lipofuscinosis), are childhood dementias associated with progressive loss of speech, language and feeding skills. Here we delineate speech, language, non-verbal communication and feeding phenotypes in 33 individuals (19 females) with a median age of 9.5 years (range 3-28 years); 16 had CLN2 and 17 CLN3 disease; 8/15 (53%) participants with CLN2 and 8/17 (47%) participants with CLN3 disease had speech and language impairments prior to genetic diagnosis.

Clinical Actionability of Genetic Findings in Cerebral Palsy: A Systematic Review and Meta-Analysis.

Importance: Single gene variants can cause cerebral palsy (CP) phenotypes, yet the impact of genetic diagnosis on CP clinical management has not been systematically evaluated.

Objective: To evaluate how frequently genetic testing results would prompt changes in care for individuals with CP and the clinical utility of precision medicine therapies.

Data Sources: Published pathogenic or likely pathogenic variants in OMIM genes identified with exome sequencing in clinical (n = 1345) or research (n = 496) cohorts of CP were analyzed.

The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses.

Purpose: Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial Flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples.

Methods: A total of 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized to either exome + mitochondrial DNA (mtDNA) sequencing or genome sequencing.

Kawasaki Disease and Respiratory Viruses: Ecological Spatiotemporal Analysis.

Background: Kawasaki disease is an uncommon vasculitis affecting young children. Its etiology is not completely understood, although infections have been frequently postulated as the triggers. Respiratory viruses, specifically, have often been implicated as causative agents for Kawasaki disease presentations.

Development and validation of a stakeholder-driven, self-contained electronic informed consent platform for trio-based genomic research studies.

Increasingly long and complex informed consents have yielded studies demonstrating comparatively low participant and with traditional face-to-face approaches. In parallel, interest in electronic consents for clinical and research genomics has steadily increased, yet limited data are available for trio-based genomic discovery studies. We describe the design, development, implementation, and validation of an electronic iConsent application for trio-based genomic research deployed to support genomic studies of cerebral palsy.

Early administration of umbilical cord blood cells following brief high tidal volume ventilation in preterm sheep: a cautionary tale.

Background: Umbilical cord blood (UCB) cells are a promising treatment for preterm brain injury. Access to allogeneic sources of UCB cells offer the potential for early administration to optimise their therapeutic capacities. As preterm infants often require ventilatory support, which can contribute to preterm brain injury, we investigated the efficacy of early UCB cell administration following ventilation to reduce white matter inflammation and injury.

The Temporal Relationship between Blood-Brain Barrier Integrity and Microglial Response following Neonatal Hypoxia Ischemia.

Blood-brain barrier (BBB) dysfunction and neuroinflammation are key mechanisms of brain injury. We performed a time-course study following neonatal hypoxia-ischemia (HI) to characterize these events. HI brain injury was induced in postnatal day 10 rats by single carotid artery ligation followed by hypoxia (8% oxygen, 90 min).

Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations.

This study aimed to determine the diagnostic yield of singleton exome sequencing and subsequent research-based trio exome analysis in children with a spectrum of brain malformations seen commonly in clinical practice. We recruited children ≤ 18 years old with a brain malformation diagnosed by magnetic resonance imaging and consistent with an established list of known genetic causes. Patients were ascertained nationally from eight tertiary paediatric centres as part of the Australian Genomics Brain Malformation Flagship.

Distinct manifestations and potential mechanisms of seizures due to cortical versus white matter injury in children.

Purpose: To study seizure manifestations and outcomes in children with cortical versus white matter injury, differences potentially explaining variability of epilepsy in children with cerebral palsy.

Methods: In this population-based retrospective cohort study, MRIs of children with cerebral palsy due to ischemia or haemorrhage were classified according to presence or absence of cortical injury. MRI findings were then correlated with history of neonatal seizures, seizures during childhood, epilepsy syndromes, and seizure outcomes.

Neuroprotective Action of Tacrolimus before and after Onset of Neonatal Hypoxic-Ischaemic Brain Injury in Rats.

(1) Background: Neonatal brain injury can lead to permanent neurodevelopmental impairments. Notably, suppressing inflammatory pathways may reduce damage. To determine the role of neuroinflammation in the progression of neonatal brain injury, we investigated the effect of treating neonatal rat pups with the immunosuppressant tacrolimus at two time points: before and after hypoxic-ischaemic (HI)-induced injury.

Clinical actionability of genetic findings in cerebral palsy.

Background And Objectives: Single gene mutations are increasingly recognized as causes of cerebral palsy (CP) phenotypes, yet there is currently no standardized framework for measuring their clinical impact. We evaluated Pathogenic/Likely Pathogenic (P/LP) variants identified in individuals with CP to determine how frequently genetic testing results would prompt changes in care.

Methods: We analyzed published P/LP variants in OMIM genes identified in clinical (n = 1,345 individuals) or research (n = 496) cohorts using exome sequencing of CP patients.

Intrathecal magnesium delivery for Mg++-insensitive NMDA receptor activity due to GRIN1 mutation.

Background: Mutations in the NMDA receptor are known to disrupt glutamatergic signaling crucial for early neurodevelopment, often leading to severe global developmental delay/intellectual disability, epileptic encephalopathy, and cerebral palsy phenotypes. Both seizures and movement disorders can be highly treatment-refractory.

Results: We describe a targeted ABA n-of-1 treatment trial with intrathecal MgSO, rationally designed based on the electrophysiologic properties of this gain of function mutation in the GRIN1 NMDA subunit.

Redefining cerebral palsies as a diverse group of neurodevelopmental disorders with genetic aetiology.

Cerebral palsy is a clinical descriptor covering a diverse group of permanent, non-degenerative disorders of motor function. Around one-third of cases have now been shown to have an underlying genetic aetiology, with the genetic landscape overlapping with those of neurodevelopmental disorders including intellectual disability, epilepsy, speech and language disorders and autism. Here we review the current state of genomic testing in cerebral palsy, highlighting the benefits for personalized medicine and the imperative to consider aetiology during clinical diagnosis.