Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood.

Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5'- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.

Vertebral Artery Dissection Causing Stroke After Trampoline Use.

OBJECTIVES: The aim of this study was to report a case of a 4-year-old boy who had been playing on the trampoline and presented to the emergency department (ED) with vomiting and ataxia, and had a vertebral artery dissection with subsequent posterior circulation infarcts. METHODS: This study is a chart review. RESULTS: The patient presented to the emergency department with a 4-day history of vomiting and gait unsteadiness. A computed tomography scan of his head revealed multiple left cerebellar infarcts. Subsequent magnetic resonance imaging/magnetic resonance angiogram of his head and neck demonstrated multiple infarcts involving the left cerebellum, bilateral thalami, and left occipital lobe. A computed tomography angiogram confirmed the presence of a left vertebral artery dissection. CONCLUSIONS: Vertebral artery dissection is a relatively common cause of stroke in the pediatric age group. Trampoline use has been associated with significant risk of injury to the head and neck. Patients who are small and/or young are most at risk. In this case, minor trauma secondary to trampoline use could be a possible mechanism for vertebral artery dissection and subsequent strokes. The association in this case warrants careful consideration because trampoline use could pose a significant risk to pediatric users.

Methylmalonic aciduria as a biochemical marker for mitochondrial DNA depletion syndrome in patients with developmental delay and movement disorders: a case series.

Background: Mitochondrial DNA (mtDNA) depletion syndromes (MDDS) are genetically and clinically variable disorders resulting from a reduction in mtDNA content in the cells, tissues, and organ systems, leading to symptoms related to energy deficits. Deficiency of the mitochondrial succinyl-CoA ligase/synthetase enzyme secondary to pathogenic variations in the SUCLG1 and SUCLA2 genes is a subtype of MDDS that presents with neurological manifestations and a specific biochemical profile. Methods: This cross-sectional series describes five patients with MDDS secondary to pathogenic variations in the SUCLG1 and SUCLA2 genes from two tertiary care centers in Canada and India. Clinical data concerning the course, investigations, and outcome were gathered through chart reviews. Results: All subjects presented in early infancy with neurological manifestations, including movement disorder, psychomotor regression, developmental delay, hearing loss, behavioral issues, or a combination thereof. Elevated methylmalonic acid metabolites, an abnormal acylcarnitine profile, and lactic acidemia were noted in the biochemical profile of each patient (n = 5/5, 100%). Molecular genetic testing disclosed the presence of pathogenic homozygous mutations in four subjects and compound heterozygosity in one subject. Conclusion: MDDS associated with SUCLG1 and SUCLA2 genes can be detected biochemically by the presence of methylmalonic aciduria besides the elevation of lactate, C3, C4DC, and C5-OH acylcarnitine. Conducting metabolic workups including MMA and acylcarnitine profiles in patients with heterogeneity of clinical symptoms associated with the presence of this biochemical marker may potentially reduce the time to diagnosis and management.

Altered activation and functional asymmetry of exner's area but not the visual word form area in a child with sudden-onset, persistent mirror writing.

Mirror writing is often produced by healthy children during early acquisition of literacy, and has been observed in adults following neurological disorders or insults. The neural mechanisms responsible for involuntary mirror writing remain debated, but in healthy children, it is typically attributed to the delayed development of a process of overcoming mirror invariance while learning to read and write. We present an unusual case of sudden-onset, persistent mirror writing in a previously typical seven-year-old girl. Using her dominant right hand only, she copied and spontaneously produced all letters, words and sentences, as well as some numbers and objects, in mirror image. Additionally, she frequently misidentified letter orientations in perceptual assessments. Clinical, neuropsychological, and functional neuroimaging studies were carried out over sixteen months. Neurologic and ophthalmologic examinations and a standard clinical MRI scan of the head were normal. Neuropsychological testing revealed average scores on most tests of intellectual function, language function, verbal learning and memory. Visual perception and visual reasoning were average, with the exception of below average form constancy, and mild difficulties on some visual memory tests. Activation and functional connectivity of the reading and writing network was assessed with fMRI. During a reading task, the VWFA showed a strong response to words in mirror but not in normal letter orientation - similar to what has been observed in typically developing children previously - but activation was atypically reduced in right primary visual cortex and Exner's Area. Resting-state connectivity within the reading and writing network was similar to that of age-matched controls, but hemispheric asymmetry between the balance of motor-to-visual input was found for Exner's Area. In summary, this unusual case suggests that a disruption to visual-motor integration rather than to the VWFA can contribute to sudden-onset, persistent mirror writing in the absence of clinically detectable neurological insult.

Magnetic resonance imaging in the diagnosis of white matter signal abnormalities.

Background White matter abnormalities (WMAs) pose a diagnostic challenge when trying to establish etiologic diagnoses. During childhood and adult years, genetic disorders, metabolic disorders and acquired conditions are included in differential diagnoses. To assist clinicians and radiologists, a structured algorithm using cranial magnetic resonance imaging (MRI) has been recommended to aid in establishing working diagnoses that facilitate appropriate biochemical and genetic investigations. This retrospective pilot study investigated the validity and diagnostic utility of this algorithm when applied to white matter signal abnormalities (WMSAs) reported on imaging studies of patients seen in our clinics. Methods The MRI algorithm was applied to 31 patients selected from patients attending the neurometabolic/neurogenetic/metabolic/neurology clinics at a tertiary care hospital. These patients varied in age from 5 months to 79 years old, and were reported to have WMSAs on cranial MRI scans. Twenty-one patients had confirmed WMA diagnoses and 10 patients had non-specific WMA diagnoses (etiology unknown). Two radiologists, blinded to confirmed diagnoses, used clinical abstracts and the WMSAs present on patient MRI scans to classify possible WMA diagnoses utilizing the algorithm. Results The MRI algorithm displayed a sensitivity of 100%, a specificity of 30.0% and a positive predicted value of 74.1%. Cohen's kappa statistic for inter-radiologist agreement was 0.733, suggesting "good" agreement between radiologists. Conclusions Although a high diagnostic utility was not observed, results suggest that this MRI algorithm has promise as a clinical tool for clinicians and radiologists. We discuss the benefits and limitations of this approach.