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Purpose To describe a series of children with extensive PNF or treatment refractory PLGG treated on a compassionate basis with trametinib. Methods We report on six patients with NF‐1 treated with trametinib on a compassionate basis at British Columbia Children's Hospital since 2017. Data were collected retrospectively from the patient record. RAPNO and volumetric criteria were used to evaluate the response of intracranial and extracranial lesions, respectively. Results Subjects were 21 months to 14 years old at the time of initiation of trametinib therapy and 3/6 subjects are male. Duration of therapy was 4–28 months at the time of this report. All patients had partial response or were stable on analysis. Two patients with life‐threatening PNF had a partial radiographic response in tandem with significant clinical improvement and developmental catch up. One subject discontinued therapy after 6 months due to paronychia and inadequate response. The most common adverse effect (AE) was grade 1–2 paronychia or dermatitis in 5/6 patients. There were no grade 3 or 4 AEs. At the time of this report, five patients remain on therapy. Conclusion Trametinib is an effective therapy for advanced PNF and refractory PLGG in patients with NF‐1 and is well tolerated in children. Further data and clinical trials are required to assess tolerance, efficacy and durability of response, and length of treatment required in such patients., Here, we report on response to Trametinib, a MEK inhibitor in children with NF‐1. Our experience presented in this report demonstrates that Trametinib is an effective therapy for advanced, life‐threatening PNF, and treatment‐refractory PLGG in patients with NF‐1 and is well tolerated in children.

The phenotype of recurrent ∼600 kb microdeletion and microduplication on proximal 16p11.2 is characterized by a spectrum of neurodevelopmental impairments including developmental delay and intellectual disability, epilepsy, autism and psychiatric disorders which are all subject to incomplete penetrance and variable expressivity. A variety of brain MRI abnormalities were reported in patients with 16p11.2 rearrangements, but no systematic correlation has been studied among patients with similar brain anomalies, their neurodevelopmental and clinical phenotypes. We present three patients with the proximal 16p11.2 microduplication exhibiting significant developmental delay, anxiety disorder and other variable clinical features. Our patients have abnormal brain MRI findings of cerebral T2 hyperintense foci (3/3) and ventriculomegaly (2/3). The neuroradiological or neurological findings in two cases prompted an extensive diagnostic work-up. One patient has exhibited neurological regression and progressive vision impairment and was diagnosed with juvenile neuronal ceroid-lipofuscinosis. We compare the clinical course and phenotype of these patients in regard to the clinical significance of the cerebral lesions and the need for MRI surveillance. We conclude that in all three patients the lesions were not progressive, did not show any sign of malignant transformation and could not be correlated to specific clinical features. We discuss potential etiologic mechanisms that may include overexpression of genes within the duplicated region involved in control of cell proliferation and complex molecular mechanisms such as the MAPK/ERK pathway. Systematic studies in larger cohorts are needed to confirm our observation and to establish the prevalence and clinical significance of these neuroanatomical abnormalities in patients with 16p11.2 duplications.

Diagnosis of mitochondrial disease is often a challenge because of the extreme heterogeneity of the clinical phenotype and the variety of underlying gene defects. Insight into the range of clinical phenotypes associated with a particular mitochondrial DNA mutation will facilitate better recognition of patients at risk by focused gene testing. We present a family affected by the mitochondrial m.13513G>A (p.D393N, ND5) mutation, illustrating a previously unreported degree of clinical heterogeneity, varying from mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) in a 10-year-old female, to a fatal neonatal course with metabolic acidosis and hypotonia in a younger sister, to absence of medical problems in the mother. The mutation loads ranging from 66% in the deceased neonate to 30% in the female with MELAS and 7% in the asymptomatic mother, correlated with severity of the clinical phenotype. The importance of proactive collection and storage of appropriate samples during the diagnostic work-up of an acutely ill or deceased neonate, allowing subsequent mitochondrial investigations, is hereby illustrated.

Objective [ ] The association of chorioamnionitis and non-cystic white matter injury, a common brain injury in premature newborns, remains controversial. Our objectives were to determine the association of chorioamnionitis and postnatal risk factors with white matter injury, and the effects of chorioamnionitis on early brain development, using advanced MR imaging. Methods [ ] Ninety-two preterm newborns (24-32 weeks gestation) were studied at a median age of 31.9 weeks and again at 40.3 weeks gestation. Histopathological chorioamnionitis and white matter injury were scored using validated systems. Measures of brain metabolism (N-acetylaspartate/choline and lactate/choline) on magnetic resonance spectroscopy, and microstructure (average diffusivity and fractional anisotropy) on diffusion tensor imaging were calculated from predefined brain regions. Results [ ] Thirty-one newborns (34%) were exposed to histopathological chorioamnionitis, and 26 (28%) had white matter injury. Histopathological chorioamnionitis was not associated with an increased risk of white matter injury (relative risk: 1.2; P=0.6). Newborns with postnatal infections and hypotension requiring therapy were at higher risk of white matter injury (P0.1). In contrast, white matter injury was associated with lower N-acetylaspartate/choline (–8.9%; P=0.009) and lower white matter fractional anisotropy (–11.9%; P=0.01). Interpretation [ ] Histopathological chorioamnionitis does not appear to be associated with an increased risk of white matter injury on magnetic resonance imaging or with abnormalities of brain development. In contrast, postnatal infections and hypotension are associated with an increased risk of white matter injury in the premature newborn. Final published version [ ] Ann Neurol. 2009 Aug;66(2):155-64. URL: http://www3.interscience.wiley.com/journal/76507645/home

Detailed neurological, speech and language, psychological, and neuroimaging studies were carried out in eight children with the diagnosis of congenital ocular motor apraxia. The neurological examination showed clinical evidence of cerebellar vermis abnormality (hypotonia and truncal ataxia) in all cases. Neuroimaging studies suggested that the site of neuropathological disturbance of congenital ocular motor apraxia was the inferior vermis. Half of the subjects had associated speech apraxia. The most likely location of brain disturbance, which was responsible for the speech apraxia, was also an as yet undefined area of the vermis. Psychological testing consistently revealed visual-spatial difficulties. These may have been secondary to cerebellar pathology or to developmentally inappropriate sensory input caused by the abnormal saccades. Children with speech apraxia appear to be slightly more affected neurologically than those with normal speech.

Now that transgenic strains of Xenopus laevis and X. tropicalis can be generated efficiently and with genomic sequence resources available for X. tropicalis, early amphibian development can be studied using integrated biochemical and genetic approaches. However, housing large numbers of animals generated during genetic screens or produced as novel transgenic lines presents a considerable challenge. We describe a method for cryopreserving Xenopus sperm that should facilitate low maintenance, long-term storage of male gametes. By optimising the cryoprotectant, the rates of cooling and thawing, and conditions for fertilisation, sperm from the equivalent of one-eighth of a X. laevis testis or of two X. tropicalis testes have been cryopreserved and used to fertilise eggs of both species after thawing. Sperm undergo a substantial loss of viability during a freeze-thaw cycle, but sufficient survive to fertilise eggs. Gametes of mutagenised frogs are being stored in connection with a screen for developmental mutations.

Computerized tomography (CT) of the brain was performed in 10 of 11 consecutive infants with neonatal lupus erythematosus (NLE) (five boys and six girls). Ten of the 11 infants had brain neurosonography. Nine of 10 infants had abnormal CT scans. There was diffuse, markedly reduced attenuation of the cerebral white matter in four infants studied in the first week of life, and also in an infant 5 weeks of age. Patchy reduced subcortical white matter attenuation was observed in another 5-week-old infant. Basal ganglia calcifications were present in two infants at 2 months of age, one of whom also had mild ventriculomegaly. A patient with macrocephaly studied at 4 months of age had enlarged ventricles and subarachnoid spaces consistent with benign macrocephaly of infancy. Cerebral ultrasound examination was abnormal in all five infants studied in the first week of life and in one infant at 2 months of age. Findings included subependymal cysts (4), echogenic white matter (3), and echogenic lenticulostriate vessels (3). Apart from one case of macrocephaly, there was no clinical evidence of neurologic disease and the subsequent development of these infants has been normal. Subclinical central nervous system (CNS) disease in NLE is likely to be a transient phenomenon that resolves as maternal antibodies are cleared from the infant's circulation. It is important to be aware of these neuroimaging abnormalities to avoid misdiagnosis of congenital viral infection in a newborn with multisystem NLE. The potential for neurologic sequelae is uncertain.