Mutations in SYNGAP1 Cause Intellectual Disability,Autism, and a Specific Form of Epilepsy by Inducing Haploinsufficiency

De novo mutations in SYNGAP1, which codes for a RAS/RAP GTP‐activating protein, cause nonsyndromic intellectual disability (NSID). All disease‐causing point mutations identified until now in SYNGAP1 are truncating, raising the possibility of an association between this type of mutations and NSID. Here, we report the identification of the first pathogenic missense mutations (c.1084T>C [p.W362R], c.1685C>T [p.P562L]) and three novel truncating mutations (c.283dupC [p.H95PfsX5], c.2212_2213del [p.S738X], and (c.2184del [p.N729TfsX31]) in SYNGAP1 in patients with NSID. A subset of these patients also showed ataxia, autism, and a specific form of generalized epilepsy that can be refractory to treatment. All of these mutations occurred de novo, except c.283dupC, which was inherited from a father who is a mosaic. Biolistic transfection of wild‐type SYNGAP1 in pyramidal cells from cortical organotypic cultures significantly reduced activity‐dependent phosphorylated extracellular signal‐regulated kinase (pERK) levels. In contrast, constructs expressing p.W362R, p.P562L, or the previously described p.R579X had no significant effect on pERK levels. These experiments suggest that the de novo missense mutations, p.R579X, and possibly all the other truncating mutations in SYNGAP1 result in a loss of its function. Moreover, our study confirms the involvement of SYNGAP1 in autism while providing novel insight into the epileptic manifestations associated with its disruption.     

Comparison of 3T and 7T Susceptibility-Weighted Angiography of the Substantia Nigra in Diagnosing Parkinson Disease

BACKGROUND AND PURPOSE:Standard neuroimaging fails in defining the anatomy of the substantia nigra and has a marginal role in the diagnosis of Parkinson disease. Recently 7T MR target imaging of the substantia nigra has been useful in diagnosing Parkinson disease. We performed a comparative study to evaluate whether susceptibility-weighted angiography can diagnose Parkinson disease with a 3T scanner.MATERIALS AND METHODS:Fourteen patients with Parkinson disease and 13 healthy subjects underwent MR imaging examination at 3T and 7T by using susceptibility-weighted angiography. Two expert blinded observers and 1 neuroradiology fellow evaluated the 3T and 7T images of the sample to identify substantia nigra abnormalities indicative of Parkinson disease. Diagnostic accuracy and intra- and interobserver agreement were calculated separately for 3T and 7T acquisitions.RESULTS:Susceptibility-weighted angiography 7T MR imaging can diagnose Parkinson disease with a mean sensitivity of 93%, specificity of 100%, and diagnostic accuracy of 96%. 3T MR imaging diagnosed Parkinson disease with a mean sensitivity of 79%, specificity of 94%, and diagnostic accuracy of 86%. Intraobserver and interobserver agreement was excellent at 7T. At 3T, intraobserver agreement was excellent for experts, and interobserver agreement ranged between good and excellent. The less expert reader obtained a diagnostic accuracy of 89% at 3T.CONCLUSIONS:Susceptibility-weighted angiography images obtained at 3T and 7T differentiate controls from patients with Parkinson disease with a higher diagnostic accuracy at 7T. The capability of 3T in diagnosing Parkinson disease might encourage its use in clinical practice. The use of the more accurate 7T should be supported by a dedicated cost-effectiveness study.

Parkinson disease (PD) is a common neurodegenerative disease whose pathologic substrate is nigrostriatal dopaminergic degeneration due to the neuronal loss in the pars compacta of the substantia nigra (SN).¹On the basis of the correlation between MR signal intensity at conventional field strengths and Perls staining for iron distribution, the medial portion of the midbrain with lower MR signal is attributed to the pars reticulata of the substantia nigra, and the lateral region (with higher MR signal), to the substantia nigra pars compacta.² However, Perls staining and T2WI signal hypointensity do not match precisely,³ and the hypointense area on T2WI does not match the substantia nigra pars reticulata.⁴ Moreover, conventional MR imaging techniques, including segmented inversion recovery ratio imaging,⁵ fail to distinguish the inner structure of the substantia nigra.⁶ More advanced and recently proposed SN-derived biomarkers such as relaxometry,^7,8 DTI,⁹ and neuromelanin imaging¹⁰ are currently not yet accepted in evaluating patients with PD in clinical practice.¹¹Recently, by using high-resolution 3D susceptibility-weighted angiography (SWAN),¹² the ultra-high-field (UHF) anatomy of the SN with its inner organization has been described¹³ as a 3-layer structure of different signal intensities along the posterior-anterior axis of the midbrain, resembling the dorsal and ventral components of the substantia nigra pars compacta and the substantia nigra pars reticulata, respectively. By using calbindin immunostaining, one can distinguish calbindin-positive (matrix) and calbindin-negative structures (nigrosomes)¹⁴ within the substantia nigra. In a recent MR imaging study at 7T,¹⁵ nigrosome 1, the largest and highly attenuated cluster of calbindin-negative neurons within the substantia nigra pars compacta ventralis, corresponded to the round hyperintense area observed in the intermediate and lateral portion of the substantia nigra pars compacta.¹⁶In patients with PD the 3-layer organization and the hyperintense lateral spot within the SN (nigrosome 1) are lost, and this radiologic sign distinguishes patients with PD from healthy subjects (HS) on an individual basis with high accuracy.¹³The diagnostic gain provided by 7T imaging is a prerequisite for the clinical acceptance of UHF, but until now, 7T MR imaging examinations have been confined to the research environment. The neuroimaging-based diagnosis of PD might constitute an important addition to the clinical diagnosis of extrapyramidal disorders. Therefore, the diagnostic role of SWI performed with a clinical MR imaging scanner at 3T has been tested recently,^17,18 with promising results. A direct comparison of 3T and 7T evaluation of the SN is mentioned in a pilot experience including 2 patients with PD.¹⁵Here, we describe a comparative study with a case control design that prospectively evaluates the diagnostic accuracy of SWAN at 3T and 7T.     

Bacteriophage T4 polynucleotide kinase triggers degradation of mRNAs

The bacteriophage T4-encoded RegB endoribonuclease is produced during the early stage of phage development and targets mostly (but not exclusively) the Shine-Dalgarno sequences of early genes. In this work, we show that the degradation of RegB-cleaved mRNAs depends on a functional T4 polynucleotide kinase/phosphatase (PNK). The 5'-OH produced by RegB cleavage is phosphorylated by the kinase activity of PNK. This modification allows host RNases G and E, with activity that is strongly stimulated by 5'-monophosphate termini, to attack mRNAs from the 5'-end, causing their destabilization. The PNK-dependent pathway of degradation becomes effective 5 min postinfection, consistent with our finding that several minutes are required for PNK to accumulate after infection. Our work emphasizes the importance of the nature of the 5' terminus for mRNA stability and depicts a pathway of mRNA degradation with 5'- to 3'-polarity in cells devoid of 5'-3' exonucleases. It also ascribes a role for T4 PNK during normal phage development.     

Adrenocortical dysfunction in liver disease: a systematic review

In patients with cirrhosis, adrenal insufficiency (AI) is reported during sepsis and septic shock and is associated with increased mortality. Consequently, the term "hepato-adrenal syndrome" was proposed. Some studies have shown that AI is frequent in stable cirrhosis as well as in cirrhosis associated with decompensation other than sepsis, such as bleeding and ascites. Moreover, other studies showed a high prevalence in liver transplant recipients immediately after, or some time after, liver transplantation. The effect of corticosteroid therapy in critically ill patients with liver disease has been evaluated in some studies, but the results remain controversial. The 250-μg adreno-cortico-tropic-hormone stimulation test to diagnose AI in critically ill adult patients is recommended by an international task force. However, in liver disease, there is no consensus on the appropriate tests and normal values to assess adrenal function; thus, standardization of normal ranges and methodology is needed. Serum total cortisol assays overestimate AI in patients with cirrhosis, so that direct free cortisol measurement or its surrogates may be useful measurements to define AI, but further studies are needed to clarify this. In addition, the mechanisms by which liver disease leads to adrenal dysfunction are not sufficiently documented. This review evaluates published data regarding adrenal function in patients with liver disease, with a particular focus on the potential limitations of these studies as well as suggestions for future studies.