Neurocognitive outcome in patients with hypertyrosinemia type I after long-term treatment with NTBC

Objective  

The implementation of NTBC into treatment of hypertyrosinemia type I (HT I) greatly improved survival by prevention of acute liver failure and hepatocellular carcinoma. However, there are first reports of cognitive impairment in patients with elevated plasma tyrosine concentrations.     

VLCAD enzyme activity determinations in newborns identified by screening: a valuable tool for risk assessment

Tandem mass spectrometry-based newborn screening correctly identifies individuals with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). However, a great number of healthy individuals present with identical acylcarnitine profiles during catabolism in the first three days of life. We routinely perform an enzyme activity assay as confirmation analysis in newborns identified by screening. Whereas VLCAD residual activities of less than 10% are clearly diagnostic and indicate patients at risk of clinical disease, the clinical relevance of higher residual activities is unclear. In this study we assess the molecular basis in 34 individuals with residual activities of 10-50%. We identify two pathogenic mutations in patients that result in residual activities as high as 22%, while individuals with residual activities of 25-50% either present with a heterozygous or no mutation in the VLCAD gene. In addition, confirmed heterozygous parents present with residual activities as low as 32%.     

Capsule endoscopy: comparison of two different reading modes

Purpose  

Capsule endoscopy (CE) is a very useful tool for the evaluation of the small intestine, but it is time consuming. The aim of this study was to compare evaluation times and detection rates in two different reading modes (single view at a speed of 10 frames per second (fps) and four images simultaneously, i.e., quadview mode at a speed of 20 fps) to find the optimum setting mode for evaluation of CE videos.     

Cyclin E1 controls proliferation of hepatic stellate cells and is essential for liver fibrogenesis in mice

Liver fibrogenesis is associated with the transition of quiescent hepatocytes and hepatic stellate cells (HSCs) into the cell cycle. Exit from quiescence is controlled by E-type cyclins (cyclin E1 [CcnE1] and cyclin E2 [CcnE2]). Thus, the aim of the current study was to investigate the contribution of E-type cyclins for liver fibrosis in man and mice. Expression of CcnE1, but not of its homolog, CcnE2, was induced in fibrotic and cirrhotic livers from human patients with different etiologies and in murine wild-type (WT) livers after periodical administration of the profibrotic toxin, CCl(4) . To further evaluate the potential function of E-type cyclins for liver fibrogenesis, we repetitively treated constitutive CcnE1(-/-) and CcnE2(-/-) knock-out mice with CCl(4) to induce liver fibrosis. Interestingly, CcnE1(-/-) mice were protected against CCl(4) -mediated liver fibrogenesis, as evidenced by reduced collagen type I α1 expression and the lack of septum formation. In contrast, CcnE2(-/-) mice showed accelerated fibrogenesis after CCl(4) treatment. We isolated primary HSCs from WT, CcnE1(-/-) , and CcnE2(-/-) mice and analyzed their activation, proliferation, and survival in vitro. CcnE1 expression in WT HSCs was maximal when they started to proliferate, but decreased after the cells transdifferentiated into myofibroblasts. CcnE1(-/-) HSCs showed dramatically impaired survival, cell-cycle arrest, and strongly reduced expression of alpha smooth muscle actin, indicating deficient HSC activation. In contrast, CcnE2-deficient HSCs expressed an elevated level of CcnE1 and showed enhanced cell-cycle activity and proliferation, compared to WT cells. Conclusions: CcnE1 and CcnE2 have antagonistic roles in liver fibrosis. CcnE1 is indispensable for the activation, proliferation, and survival of HSCs and thus promotes the synthesis of extracellular matrix and liver fibrogenesis. (HEPATOLOGY 2012;56:1140-1149).     

Why Do Patients with Partial Epilepsy Improve Their IQ After Training to Self-Regulate Slow Cortical Potentials?

In patients with epilepsy, not only seizures but also cognitive, emotional, and social functioning are of increasing interest in research (Kelley, Jacobs, &; Lowenstein, 2009 Kelley , M. S. , Jacobs , M. P. , &; Lowenstein , D. H. , for the NINDS Epilepsy Benchmark Stewards . ( 2009 ). The NINDS epilepsy research benchmarks . Epilepsia , 50 , 579 – 582 . doi: doi:10.1111/j.1528-1167.2008.01813.x  [Google Scholar]). As a decrease in cognitive functions over the course of the illness is usually reported, we wanted to explore changes in Intelligence Scores observed after a neurofeedback treatment in patients with drug-resistant epilepsies. In a controlled study that compared the outcome of three different interventions (training to regulate slow cortical potentials, N = 34; training to regulate breath rate and the amount of carbon dioxide in the end tidal volume of the exhaled air, N = 11; modification of drug regime, N = 25), pre- and postmeasurements of a short version of the Wechsler Intelligence Scale were applied. The interval between the two assessments was more than 12 months, with a mean of 61 weeks. Mean age of the patients was 35, with a range from 17 to 57. The highly significant 7-point increment of IQ only after training of slow cortical potentials was not related to clinical (e.g., seizure reduction) or neuropsychological (e.g., attention and memory) variables. Instead, it was related to psychophysiological measures: IQ change was inversely related to the Latency of the P300 component of event-related brain potentials and directly related to the Latency of the P2 component and the increase of N2 Amplitude during training. We conclude that regulation training of slow cortical potentials improves IQ in patients with refractory partial epilepsy, which might be related to an improved ability for controlled allocation of cognitive resources.     

Homozygous dystroglycan mutation associated with a novel muscle–eye–brain disease-like phenotype with multicystic leucodystrophy

Defects in dystroglycan post-translational modification result in congenital muscular dystrophy with or without additional eye and brain involvement, are referred to as secondary dystroglycanopathies and have been associated with mutations in 11 different genes encoding glycosyltransferases or associated proteins. However, only one patient with a mutation in the dystroglycan encoding gene DAG1 itself has been described before. We here report a homozygous novel DAG1 missense mutation c.2006G>T predicted to result in the amino acid substitution p.Cys669Phe in the β-subunit of dystroglycan in two Libyan siblings. The affected girls presented with a severe muscle–eye–brain disease-like phenotype with distinct additional findings of macrocephaly and extended bilateral multicystic white matter disease, overlapping with the cerebral findings in patients with megalencephalic leucoencephalopathy with subcortical cysts. This novel clinical phenotype observed in our patients further expands the clinical spectrum of dystroglycanopathies and suggests a role of DAG1 not only for dystroglycanopathies but also for some forms of more extensive and multicystic leucodystrophy.