SUMMARY1. Sympathetic vasomotor nerves play a major role in determining the level of arterial blood pressure and the distribution of cardiac output. The present review will discuss briefly the central regulatory mechanisms that control the sympathetic outflow to the cardiovascular system in the short and long term.2. In the short term, the sympathetic vasomotor outflow is regulated by: (i) homeostatic feedback mechanisms, such as the baroreceptor or chemoreceptor reflexes; or (ii) feed-forward mechanisms that evoke cardiovascular changes as part of more complex behavioural responses.3. The essential central pathways that subserve the baroreceptor reflex and, to a lesser extent, other cardiovascular reflexes, have been identified by studies in both anaesthetized and conscious animals. A critical component of these pathways is a group of neurons in the rostral ventrolateral medulla that project directly to the spinal sympathetic outflow and that receive inputs from both peripheral receptors and higher centres in the brain. 4. Much less is known about the central pathways subserving feed-forward or 'central command' responses, such as the cardiovascular changes that occur during exercise or that are evoked by a threatening or alerting stimulus. However, recent evidence indicates that the dorsomedial hypothalamic nucleus is a critical component of the pathways mediating the cardiovascular response to an acute alerting stimulus.5. Long-term sustained changes in sympathetic vasomotor activity occur under both physiological conditions (e.g. a change in salt intake) and pathophysiological conditions (e.g. heart failure). There is evidence that the paraventricular nucleus in the hypothalamus is a critical component of the pathways mediating these changes.6. Understanding the central mechanisms involved in the long-term regulation of sympathetic activity and blood pressure is a major challenge for the future. As a working hypothesis, a model is presented of the postulated central mechanisms that result in sustained changes in sympathetic vasomotor activity that are evoked by different types of chronic stimulation.

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ObjectiveDetermining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past 2 decades, the etiology of most speech disorders in children remains unexplained. To test the hypothesis that speech disorders have a genetic etiology, we performed genetic analysis of children with severe speech disorder, specifically childhood apraxia of speech (CAS).MethodsPrecise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment analyses were conducted on high-confidence gene candidates.ResultsThirty-four probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified highly plausible pathogenic single nucleotide (n = 10; CDK13, EBF3, GNAO1, GNB1, DDX3X, MEIS2, POGZ, SETBP1, UPF2, ZNF142) or copy number (n = 1; 5q14.3q21.1 locus) variants in novel genes or loci for CAS. Testing of parental DNA was available for 9 probands and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated genes were highly coexpressed in the developing human brain.ConclusionWe identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous. Highly penetrant variants implicate shared pathways in broad transcriptional regulation, highlighting the key role of transcriptional regulation in normal speech development. CAS is a distinctive, socially debilitating clinical disorder, and understanding its molecular basis is the first step towards identifying precision medicine approaches.

PRKACA and PRKACB code for two catalytic subunits (Ca and Cb) of cAMP-dependent protein kinase (PKA), a pleiotropic holoenzyme that regulates numerous fundamental biological processes such as metabolism, development, memory, and immune response. We report seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense variants in PRKACA or PRKACB. Three affected individuals were found with the same PRKACA variant, and the other four had different PRKACB mutations. In most cases, the mutations arose de novo, and two individuals had offspring with the same condition. Nearly all affected individuals and their affected offspring shared an atrioventricular septal defect or a common atrium along with postaxial polydactyly. Additional features included skeletal abnormalities and ectodermal defects of variable severity in five individuals, cognitive deficit in two individuals, and various unusual tumors in one individual. We investigated the structural and functional consequences of the variants identified in PRKACA and PRKACB through the use of several computational and experimental approaches, and we found that they lead to PKA holoenzymes which are more sensitive to activation by cAMP than are the wild-type proteins. Furthermore, expression of PRKACA or PRKACB variants detected in the affected individuals inhibited hedgehog signaling in NIH 3T3 fibroblasts, thereby providing an underlying mechanism for the developmental defects observed in these cases. Our findings highlight the importance of both Ca and Cb subunits of PKA during human development.Protein kinase A (PKA) can be found as an inactive tetrameric holoenzyme formed by the association of two catalytic (C) subunits with a regulatory (R) subunit dimer. Activation is achieved through binding of two molecules of cyclic AMP (cAMP) to each R-subunit and subsequent unleashing of the C-subunits to engage substrates. PRKACA

In humans, disruption of nonsense-mediated decay (NMD) has been associated with neurodevelopmental disorders (NDDs) such as autism spectrum disorder and intellectual disability. However, the mechanism by which deficient NMD leads to neurodevelopmental dysfunction remains unknown, preventing development of targeted therapies. Here we identified novel proteincoding UPF2 (UP-Frameshift 2) variants in humans with NDD, including speech and language deficits. In parallel, we found that mice lacking Upf2 in the forebrain (Upf2 fb-KO mice) show impaired NMD, memory deficits, abnormal long-term potentiation (LTP), and social and communication deficits. Surprisingly, Upf2 fb-KO mice exhibit elevated expression of immune genes and brain inflammation. More importantly, treatment with two FDA-approved anti-Johnson et al.

Familial adult myoclonic epilepsy 1 (FAME1), first recognised in Japanese families, was recently shown to be caused by a TTTCA repeat insertion in intron 4 of SAMD12 on chromosome 8. We performed whole genome sequencing on two families with FAME, one of Sri Lankan origin and the other of Indian origin, and identified a TTTCA repeat insertion in SAMD12 in both families. Haplotype analysis revealed that both families shared the same core ancestral haplotype reported in Japanese and Chinese families with FAME1. Mutation dating, based on the length of shared haplotypes, estimated the age of the ancestral haplotype to be ~670 generations, or 17,000 years old. Our data extend the geographic range of this repeat expansion to Southern Asia and potentially implicate an even broader regional distribution given the age of the variant. This finding suggests patients of Asian ancestry with suspected FAME should be screened for the SAMD12 TTTCA expansion.

1. A large proportion of sympathetic preganglionic neurones contain nitric oxide synthase.The purpose of this study was to determine the effects of facilitation and inhibition of nitric oxide synthesis within the lower thoracic spinal cord (which contains the majority of renal preganglionic neurones) on renal sympathetic nerve activity (rSNA).2. In anaesthetized rabbits, rSNA was recorded before and after intrathecal injection (50 /sl of 0-5 M solution) of either L-arginine, a precursor of nitric oxide, or NW-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, into the lower thoracic spinal cord. Spinal cord sections were also stained for the presence of NADPH diaphorase, a marker of nitric oxide synthesizing neurones. 3. A high density of NADPH diaphorase-containing neurones was found within the intermediolateral cell column of the lower thoracic spinal cord. 4. Intrathecal injection of L-arginine and L-NAME resulted in a large increase (113 + 25%) and decrease (43 + 8%), respectively, in rSNA. In contrast, injection of the inactive isomers D-arginine and D-NAME had no significant effect on rSNA. 5. The results indicate that endogenous nitric oxide in the lower thoracic spinal cord (1) has a potent excitatory action on renal sympathetic preganglionic neurones, and (2) helps to maintain the tonic activity of renal sympathetic nerves under resting conditions.

Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10−10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10−4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.