ZSCAN10 deficiency causes a neurodevelopmental disorder with characteristic oto-facial malformations.

Neurodevelopmental disorders are major indications for genetic referral and have been linked to more than 1500 loci including genes encoding transcriptional regulators. The dysfunction of transcription factors often results in characteristic syndromic presentations; however, at least half of these patients lack a genetic diagnosis. The implementation of machine learning approaches has the potential to aid in the identification of new disease genes and delineate associated phenotypes. Next generation sequencing was performed in seven affected individuals with neurodevelopmental delay and dysmorphic features. Clinical characterization included reanalysis of available neuroimaging datasets and 2D portrait image analysis with GestaltMatcher. The functional consequences of ZSCAN10 loss were modelled in mouse embryonic stem cells (mESCs), including a knockout and a representative ZSCAN10 protein truncating variant. These models were characterized by gene expression and western blot analyses, chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR) and immunofluorescence staining. Zscan10 knockout mouse embryos were generated and phenotyped. We prioritized bi-allelic ZSCAN10 loss-of-function variants in seven affected individuals from five unrelated families as the underlying molecular cause. RNA-sequencing analyses in Zscan10-/- mESCs indicated dysregulation of genes related to stem cell pluripotency. In addition, we established in mESCs the loss-of-function mechanism for a representative human ZSCAN10 protein truncating variant by showing alteration of its expression levels and subcellular localization, interfering with its binding to DNA enhancer targets. Deep phenotyping revealed global developmental delay, facial asymmetry and malformations of the outer ear as consistent clinical features. Cerebral MRI showed dysplasia of the semicircular canals as an anatomical correlate of sensorineural hearing loss. Facial asymmetry was confirmed as a clinical feature by GestaltMatcher and was recapitulated in the Zscan10 mouse model along with inner and outer ear malformations. Our findings provide evidence of a novel syndromic neurodevelopmental disorder caused by bi-allelic loss-of-function variants in ZSCAN10.

Dynamic assessment of scapholunate ligament status by real-time magnetic resonance imaging: an exploratory clinical study.

OBJECTIVE: Clinical-standard MRI is the imaging modality of choice for the wrist, yet limited to static evaluation, thereby potentially missing dynamic instability patterns. We aimed to investigate the clinical benefit of (dynamic) real-time MRI, complemented by automatic analysis, in patients with complete or partial scapholunate ligament (SLL) tears. MATERIAL AND METHODS: Both wrists of ten patients with unilateral SLL tears (six partial, four complete tears) as diagnosed by clinical-standard MRI were imaged during continuous active radioulnar motion using a 1.5-T MRI scanner in combination with a custom-made motion device. Following automatic segmentation of the wrist, the scapholunate and lunotriquetral joint widths were analyzed across the entire range of motion (ROM). Mixed-effects model analysis of variance (ANOVA) followed by Tukey's posthoc test and two-way ANOVA were used for statistical analysis. RESULTS: With the increasing extent of SLL tear, the scapholunate joint widths in injured wrists were significantly larger over the entire ROM compared to those of the contralateral healthy wrists (p<0.001). Differences between partial and complete tears were most pronounced at 5°-15° ulnar abduction (p<0.001). Motion patterns and trajectories were altered. Complete SLL deficiency resulted in complex alterations of the lunotriquetral joint widths. CONCLUSION: Real-time MRI may improve the functional diagnosis of SLL insufficiency and aid therapeutic decision-making by revealing dynamic forms of dissociative instability within the proximal carpus. Static MRI best differentiates SLL-injured wrists at 5°-15° of ulnar abduction.

Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities.

Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In light of the partially overlapping phenotype between RALA- and RALGAPA1-associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies.

De novo missense variants in RRAGC lead to a fatal mTORopathy of early childhood.

PURPOSE: Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase heterodimer. One component of the Rag heterodimer is RagC (Ras-related GTP-binding protein C), which is encoded by the RRAGC gene. METHODS: Genetic testing via trio exome sequencing was applied to identify the underlying disease cause in 3 infants with dilated cardiomyopathy, hepatopathy, and brain abnormalities, including pachygyria, polymicrogyria, and septo-optic dysplasia. Studies in patient-derived skin fibroblasts and in a HEK293 cell model were performed to investigate the cellular consequences. RESULTS: We identified 3 de novo missense variants in RRAGC (NM_022157.4: c.269C>A, p.(Thr90Asn), c.353C>T, p.(Pro118Leu), and c.343T>C, p.(Trp115Arg)), which were previously reported as occurring somatically in follicular lymphoma. Studies of patient-derived fibroblasts carrying the p.(Thr90Asn) variant revealed increased cell size, as well as dysregulation of mTOR-related p70S6K (ribosomal protein S6 kinase 1) and transcription factor EB signaling. Moreover, subcellular localization of mTOR was decoupled from metabolic state. We confirmed the key findings for all RRAGC variants described in this study in a HEK293 cell model. CONCLUSION: The above results are in line with a constitutive overactivation of the mTORC1 pathway. Our study establishes de novo missense variants in RRAGC as cause of an early-onset mTORopathy with unfavorable prognosis.

Classical homocystinuria presenting with transient basal ganglia pathology and dystonia.

Classical homocystinuria is caused by pathogenic variants in the CBS gene leading to a deficiency of the vitamin B6-dependent enzyme cystathionine beta synthase. The disease is typically associated with high blood homocysteine concentrations. Clinical features include developmental delay/intellectual disability, psychiatric problems, thromboembolism, lens dislocation, and marfanoid habitus. We report on a child with classical homocystinuria presenting with acute episodes of dystonia and symmetrical basal ganglia abnormalities mimicking a mitochondrial disease. After starting treatment with vitamin B6, homocysteine levels rapidly normalized and dystonic episodes did not re-occur. Moreover, brain-imaging findings almost completely disappeared. The case illustrates that homocystinuria should be considered as a treatable differential diagnosis of dystonia.

Real-time MRI: a new tool of radiologic imaging in small children.

Real-time MRI (rt-MRI) in children is a new imaging technique that combines the advantages of US - at frame rates of up to 50 images per second - with the quality and features of MRI. Although still subject of research, it has become a standard tool in the diagnostic portfolio of two pediatric radiology departments in Germany. Based on ultrashort acquisition times, any detrimental effects of macroscopic movements of the child and the physiological movements of the organs are negligible. Especially in pediatric brain imaging, rt-MRI has already proven its value. With suitable indications, rt-MRI can reduce anesthesia and sedation examinations in children below 6 years of age by 40% due to its very short examination time and its robustness to motion. There is a high level of acceptance among parents and referrers when diagnostic possibilities and limitations are communicated correctly. CONCLUSION: Completely new diagnostic possibilities arise in the imaging of the moving lung, the beating heart, joint movements, and speaking and swallowing, as demonstrated in this video-backed review. WHAT IS KNOWN: • MRI in moving children has been burdened with severe artifacts. • Gross motion usually has to be handled by sedation and periodic motion of the heart and lungs has to be compensated with time-consuming techniques until now. WHAT IS NEW: • Real-time MRI allows image acquisition with up to 50 frames per second similar to ultrasound frame rate. • Real-time MRI proofs to be very promising for imaging children, reducing examination time and sedation rate drastically.

First experience with real-time magnetic resonance imaging-based investigation of respiratory influence on cardiac function in pediatric congenital heart disease patients with chronic right ventricular volume overload.

BACKGROUND: Congenital heart disease (CHD) is often associated with chronic right ventricular (RV) volume overload. Real-time magnetic resonance imaging (MRI) enables the analysis of cardiac function during free breathing. OBJECTIVE: To evaluate the influence of respiration in pediatric patients with CHD and chronic RV volume overload. METHODS AND MATERIALS: RV volume overload patients (n=6) and controls (n=6) were recruited for cardiac real-time MRI at 1.5 tesla during free breathing. Breathing curves from regions of interest reflecting the position of the diaphragm served for binning images in four different tidal volume classes, each in inspiration and expiration. Tidal volumes were estimated from these curves by data previously obtained by magnetic resonance-compatible spirometry. Ventricular volumes indexed to body surface area and Frank-Starling relationships referenced to the typical tidal volume indexed to body height (TTVi) were compared. RESULTS: Indexed RV end-diastolic volume (RV-EDVi) and indexed RV stroke volume (RV-SVi) increased during inspiration (RV-EDVi/TTVi: RV load: + 16 ± 4%; controls: + 22 ± 13%; RV-SVi/TTVi: RV load: + 21 ± 6%; controls: + 35 ± 17%; non-significant for comparison). The increase in RV ejection fraction during inspiration was significantly lower in RV load patients (RV load: + 1.1 ± 2.2%; controls: + 6.1 ± 1.5%; P=0.01). The Frank-Starling relationship of the RV provided a significantly reduced slope estimate in RV load patients (inspiration: RV load: 0.75 ± 0.11; controls: 0.92 ± 0.02; P=0.02). CONCLUSION: In pediatric patients with CHD and chronic RV volume overload, cardiac real-time MRI during free breathing in combination with respiratory-based binning indicates an impaired Frank-Starling relationship of the RV.

Comparison of cardiac volumetry using real-time MRI during free-breathing with standard cine MRI during breath-hold in children.

BACKGROUND: Cardiac real-time magnetic resonance imaging (RT-MRI) provides high-quality images even during free-breathing. Difficulties in post-processing impede its use in clinical routine. OBJECTIVE: To demonstrate the feasibility of quantitative analysis of cardiac free-breathing RT-MRI and to compare image quality and volumetry during free-breathing RT-MRI in pediatric patients to standard breath-hold cine MRI. MATERIALS AND METHODS: Pediatric patients (n = 22) received cardiac RT-MRI volumetry during free breathing (1.5 T; short axis; 30 frames per s) in addition to standard breath-hold cine imaging in end-expiration. Real-time images were binned retrospectively based on electrocardiography and respiratory bellows. Image quality and volumetry were compared using the European Cardiovascular Magnetic Resonance registry score, structure visibility rating, linear regression and Bland-Altman analyses. RESULTS: Additional time for binning of real-time images was 2 min. For both techniques, image quality was rated good to excellent. RT-MRI was significantly more robust against artifacts (P < 0.01). Linear regression revealed good correlations for the ventricular volumes. Bland-Altman plots showed a good limit of agreement (LoA) for end-diastolic volume (left ventricle [LV]: LoA -0.1 ± 2.7 ml/m2, right ventricle [RV]: LoA -1.9 ± 3.4 ml/m2), end-systolic volume (LV: LoA 0.4 ± 1.9 ml/m2, RV: LoA 0.6 ± 2.0 ml/m2), stroke volume (LV: LoA -0.5 ± 2.3 ml/m2, RV: LoA -2.6 ± 3.3 ml/m2) and ejection fraction (LV: LoA -0.5 ± 1.6%, RV: LoA -2.1 ± 2.8%). CONCLUSION: Compared to standard cine MRI with breath hold, RT-MRI during free breathing with retrospective respiratory binning offers good image quality, reduced image artifacts enabling fast quantitative evaluations of ventricular volumes in clinical practice under physiological conditions.

Spirometry-based reconstruction of real-time cardiac MRI: Motion control and quantification of heart-lung interactions.

PURPOSE: To test the feasibility of cardiac real-time MRI in combination with retrospective gating by MR-compatible spirometry, to improve motion control, and to allow quantification of respiratory-induced changes during free-breathing. METHODS: Cross-sectional real-time MRI (1.5T; 30 frames/s) using steady-state free precession contrast during free-breathing was combined with MR-compatible spirometry in healthy adult volunteers (n = 4). Retrospective binning assigned images to classes that were defined by electrocardiogram and spirometry. Left ventricular eccentricity index as an indicator of septal position and ventricular volumes in different respiratory phases were calculated to assess heart-lung interactions. RESULTS: Real-time MRI with MR-compatible spirometry is feasible and well tolerated. Spirometry-based binning improved motion control significantly. The end-diastolic epicardial eccentricity index increased significantly during inspiration (1.04 ± 0.04 to 1.19 ± 0.05; P < .05). During inspiration, right ventricular end-diastolic volume (79 ± 17 mL/m2 to 98 ± 18 mL/m2 ), stroke volume (41 ± 8 mL/m2 to 59 ± 11 mL/m2 ) and ejection fraction (53 ± 3% to 60 ± 1%) increased significantly, whereas the end-systolic volume remained almost unchanged. Left ventricular end-diastolic volume, left ventricular stroke volume, and left ventricular ejection fraction decreased during inspiration, whereas the left ventricular end-systolic volume increased. The relationship between stroke volume and end-diastolic volume (Frank-Starling relationship) based on changes induced by respiration allowed for a slope estimate of the Frank-Starling curve to be 0.9 to 1.1. CONCLUSION: Real-time MRI during free-breathing combined with MR-compatible spirometry and retrospective binning improves image stabilization, allows quantitative image analysis, and importantly, offers unique opportunities to judge heart-lung interactions.

Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder.

PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. RESULTS: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. CONCLUSION: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.

Choline transporter-like 1 deficiency causes a new type of childhood-onset neurodegeneration.

Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutations (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protein 1. Clinical features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and bowel incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia nigra were seen in two individuals. The Asp517Metfs*19 and Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultrastructural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of other phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance.

Biallelic mutation of human SLC6A6 encoding the taurine transporter TAUT is linked to early retinal degeneration.

We previously reported that inactivation of the transmembrane taurine transporter (TauT or solute carrier 6a6) causes early retinal degeneration in mice. Compatible with taurine's indispensability for cell volume homeostasis, protein stabilization, cytoprotection, antioxidation, and immuno- and neuromodulation, mice develop multisystemic dysfunctions (hearing loss; liver fibrosis; and behavioral, heart, and skeletal muscle abnormalities) later on. Here, by genetic, cell biologic, in vivo1H-magnetic resonance spectroscopy and molecular dynamics simulation studies, we conducted in-depth characterization of a novel disorder: human TAUT deficiency. Loss of TAUT function due to a homozygous missense mutation caused panretinal degeneration in 2 brothers. TAUTp.A78E still localized in the plasma membrane but is predicted to impact structural stabilization. 3H-taurine uptake by peripheral blood mononuclear cells was reduced by 95%, and taurine levels were severely reduced in plasma, skeletal muscle, and brain. Extraocular dysfunctions were not yet detected, but significantly increased urinary excretion of 8-oxo-7,8-dihydroguanosine indicated generally enhanced (yet clinically unapparent) oxidative stress and RNA oxidation, warranting continuous broad surveillance.-Preising, M. N., Görg, B., Friedburg, C., Qvartskhava, N., Budde, B. S., Bonus, M., Toliat, M. R., Pfleger, C., Altmüller, J., Herebian, D., Beyer, M., Zöllner, H. J., Wittsack, H.-J., Schaper, J., Klee, D., Zechner, U., Nürnberg, P., Schipper, J., Schnitzler, A., Gohlke, H., Lorenz, B., Häussinger, D., Bolz, H. J. Biallelic mutation of human SLC6A6 encoding the taurine transporter TAUT is linked to early retinal degeneration.

Cardiometabolic risk factor clustering in patients with deficient branched-chain amino acid catabolism: A case-control study.

Classical organic acidemias (OAs) result from defective mitochondrial catabolism of branched-chain amino acids (BCAAs). Abnormal mitochondrial function relates to oxidative stress, ectopic lipids and insulin resistance (IR). We investigated whether genetically impaired function of mitochondrial BCAA catabolism associates with cardiometabolic risk factors, altered liver and muscle energy metabolism, and IR. In this case-control study, 31 children and young adults with propionic acidemia (PA), methylmalonic acidemia (MMA) or isovaleric acidemia (IVA) were compared with 30 healthy young humans using comprehensive metabolic phenotyping including in vivo 31 P/1 H magnetic resonance spectroscopy of liver and skeletal muscle. Among all OAs, patients with PA exhibited abdominal adiposity, IR, fasting hyperglycaemia and hypertriglyceridemia as well as increased liver fat accumulation, despite dietary energy intake within recommendations for age and sex. In contrast, patients with MMA more frequently featured higher energy intake than recommended and had a different phenotype including hepatomegaly and mildly lower skeletal muscle ATP content. In skeletal muscle of patients with PA, slightly lower inorganic phosphate levels were found. However, hepatic ATP and inorganic phosphate concentrations were not different between all OA patients and controls. In patients with IVA, no abnormalities were detected. Impaired BCAA catabolism in PA, but not in MMA or IVA, was associated with a previously unrecognised, metabolic syndrome-like phenotype with abdominal adiposity potentially resulting from ectopic lipid storage. These findings suggest the need for early cardiometabolic risk factor screening in PA.

NAXE Mutations Disrupt the Cellular NAD(P)HX Repair System and Cause a Lethal Neurometabolic Disorder of Early Childhood.

To safeguard the cell from the accumulation of potentially harmful metabolic intermediates, specific repair mechanisms have evolved. APOA1BP, now renamed NAXE, encodes an epimerase essential in the cellular metabolite repair for NADHX and NADPHX. The enzyme catalyzes the epimerization of NAD(P)HX, thereby avoiding the accumulation of toxic metabolites. The clinical importance of the NAD(P)HX repair system has been unknown. Exome sequencing revealed pathogenic biallelic mutations in NAXE in children from four families with (sub-) acute-onset ataxia, cerebellar edema, spinal myelopathy, and skin lesions. Lactate was elevated in cerebrospinal fluid of all affected individuals. Disease onset was during the second year of life and clinical signs as well as episodes of deterioration were triggered by febrile infections. Disease course was rapidly progressive, leading to coma, global brain atrophy, and finally to death in all affected individuals. NAXE levels were undetectable in fibroblasts from affected individuals of two families. In these fibroblasts we measured highly elevated concentrations of the toxic metabolite cyclic-NADHX, confirming a deficiency of the mitochondrial NAD(P)HX repair system. Finally, NAD or nicotinic acid (vitamin B3) supplementation might have therapeutic implications for this fatal disorder.

Age-related apparent diffusion coefficients of lumbar vertebrae in healthy children at 1.5 T.

BACKGROUND: Diffusion-weighted magnetic resonance imaging with apparent diffusion coefficient (ADC) calculation is important for detecting bone marrow pathologies. OBJECTIVE: To investigate age-related differences of lumbar vertebral body ADC to establish normal values for healthy children. MATERIALS AND METHODS: Forty-nine healthy children without any history of oncological or hematological diseases (10.2±4.7 years, range: 0-20 years) were included in this retrospective study. All magnetic resonance imaging (MRI) examinations were performed at 1.5 T and with similar scan parameters. The diffusion-weighted sequences were performed with b values of 50, 400 and 800 s/mm2. ADC values were measured by placing regions of interest at three different levels within each lumbar vertebral body (L1 to L5). ADC values were analyzed for different age groups (0-2 years, 3-6 years, 7-11 years, 12-14 years, 15-20 years), for each vertebral and intravertebral level. RESULTS: The mean ADC of the whole study group was 0.60±0.09 × 10-3 mm2/s. Children between the ages of 12 and 14 years had significantly higher ADC compared to the other age groups (P≤0.0003). ADC values were significantly higher in the 1st lumbar vertebral body compared to the other levels of the lumbar spine (P<0.005) with the exception of L5, and in the upper third of the vertebral bodies compared to the middle or lower thirds (P≤0.003). CONCLUSION: The age-, vertebral- and intravertebral level-dependent differences in ADC suggest a varying composition and cellularity in different age groups and in different locations.

Gadolinium Brain Deposition after Macrocyclic Gadolinium Administration: A Pediatric Case-Control Study.

Purpose To determine whether signal intensity (SI) in T1 sequences as a potential indicator of gadolinium deposition increases after repeated administration of the macrocyclic gadolinium-based contrast agents (GBCAs) gadoteridol and gadoterate meglumine in a pediatric cohort. Materials and Methods This retrospective case-control study of children with brain tumors who underwent nine or more contrast material-enhanced brain magnetic resonance (MR) imaging studies from 2008 to 2015 was approved by the local ethics board. Informed consent was obtained for MR imaging. Twenty-four case patients aged 5-18 years and appropriate control patients with nonpathologic MR neuroimaging findings (and no GBCA administration), matched for age and sex, were inculded. SI was measured on unenhanced T1-weighted MR images for the following five regions of interest (ROIs): the dentate nucleus (DN), pons, substantia nigra (SN), pulvinar thalami, and globus pallidus (GP). Paired t tests were used to compare SI and SI ratios (DN to pons, GP to thalamus) between case patients and control patients. Pearson correlations between relative signal changes and the number of GBCA administrations and total GBCA dose were calculated. Results The mean number of GBCA administrations was 14.2. No significant differences in mean SI for any ROI and no group differences were found when DN-to-pons and GP-to-pulvinar ratios were compared (DN-to-pons ratio in case patients: mean, 1.0083 ± 0.0373 [standard deviation]; DN-to-pons ratio in control patients: mean, 1.0183 ± 0.01917; P = .37; GP-to-pulvinar ratio in case patients: mean, 1.1335 ± 0.04528; and GP-to-pulvinar ratio in control patients: mean, 1.1141 ± 0.07058; P = .29). No correlation was found between the number of GBCA administrations or the total amount of GBCA administered and signal change for any ROI. (Number of GBCA applications: DN: r = -0.254, P = .31; pons: r = -0.097, P = .65; SN: r = -0.194, P = .38; GP: r = -0.175, P = .41; pulvinar: r = -0.067, P = .75; total amount of administered GBCA: DN: r = 0.091, P = .72; pons: r = 0.106, P = .62; SN: r = -0.165, P = .45; GP: r = 0.111, P = .61; pulvinar: r = 0.173, P = .42.) Conclusion Multiple intravenous administrations of these macrocyclic GBCAs in children were not associated with a measurable increase in SI in T1 sequences as an indicator of brain gadolinium deposition detectable by using MR imaging. Additional imaging and pathologic studies are needed to confirm these findings. © RSNA, 2017 Online supplemental material is available for this article.

Screening for non-alcoholic fatty liver disease in children and adolescents with type 1 diabetes mellitus: a cross-sectional analysis.

The liver is intensely involved in glucose metabolism and is thereby closely related to diabetes pathophysiology. Adult patients with type 1 diabetes mellitus (DM) are at an increased risk for non-alcoholic fatty liver disease (NAFLD). Here, we studied the prevalence of NAFLD in a cohort of children and adolescents with type 1 DM in a tertiary care paediatric diabetes centre in Germany. We screened 93 children and adolescents with type 1 DM using ultrasound, laboratory investigations, and liver stiffness measurements (Fibroscan® [FS] and acoustic radiation force imaging [ARFI]). Of these, 82 (88.1%) had completely normal results in all examined aspects. Only one patient (1.1%) fulfilled the criteria as potential NAFLD with ALT > twice the upper limit of normal. Ten of the 93 patients (10.8%) showed any mild abnormality in at least one examined category including ALT, conventional ultrasounds and liver stiffness measurements. However, none of these ten fulfilled the NAFLD case definition criteria. Therefore, these slightly abnormal results were judged to be unspecific or at least of unknown significance in terms of NAFLD indication. CONCLUSION: Compared to data from the general population, our results do not indicate a significantly increased prevalence of NAFLD in this cohort, and advocate against the systematic screening for NAFLD in paediatric type 1 DM. What is Known: • Non-alcoholic fatty liver disease (NAFLD) is common in adults with type 1 DM, and paediatric patients with type 1 DM in Egypt and Saudi Arabia. What is New: • Our results do not indicate a significantly increased prevalence of NAFLD in a cohort of children and adolescents with type 1 DM from Germany compared to prevalence data from the general population. • This finding advocates against the systematic screening for NAFLD in paediatric type 1 DM in western countries.

EARS2 mutations cause fatal neonatal lactic acidosis, recurrent hypoglycemia and agenesis of corpus callosum.

Mitochondrial aminoacyl tRNA synthetases are essential for organelle protein synthesis. Genetic defects affecting the function of these enzymes may cause pediatric mitochondrial disease. Here, we report on a child with fatal neonatal lactic acidosis and recurrent hypoglycemia caused by mutations in EARS2, encoding mitochondrial glutamyl-tRNA synthetase 2. Brain ultrasound revealed agenesis of corpus callosum. Studies on patient-derived skin fibroblasts showed severely decreased EARS2 protein levels, elevated reactive oxygen species (ROS) production, and altered mitochondrial morphology. Our report further illustrates the clinical spectrum of the severe neonatal-onset form of EARS2 mutations. Moreover, in this case the live-cell parameters appeared to be more sensitive to mitochondrial dysfunction compared to standard diagnostics, which indicates the potential relevance of fibroblast studies in children with mitochondrial diseases.