A simple blood test expedites the diagnosis of GLUT1 deficiency syndrome

published_or_final_versio

Dexamethasone stimulates expression of C-type Natriuretic Peptide in chondrocytes

BACKGROUND: Growth of endochondral bones is regulated through the activity of cartilaginous growth plates. Disruption of the physiological patterns of chondrocyte proliferation and differentiation – such as in endocrine disorders or in many different genetic diseases (e.g. chondrodysplasias) – generally results in dwarfism and skeletal defects. For example, glucocorticoid administration in children inhibits endochondral bone growth, but the molecular targets of these hormones in chondrocytes remain largely unknown. In contrast, recent studies have shown that C-type Natriuretic Peptide (CNP) is an important anabolic regulator of cartilage growth, and loss-of-function mutations in the human CNP receptor gene cause dwarfism. We asked whether glucocorticoids could exert their activities by interfering with the expression of CNP or its downstream signaling components. METHODS: Primary mouse chondrocytes in monolayer where incubated with the synthetic glucocorticoid Dexamethasone (DEX) for 12 to 72 hours. Cell numbers were determined by counting, and real-time PCR was performed to examine regulation of genes in the CNP signaling pathway by DEX. RESULTS: We show that DEX does influence expression of key genes in the CNP pathway. Most importantly, DEX significantly increases RNA expression of the gene encoding CNP itself (Nppc). In addition, DEX stimulates expression of Prkg2 (encoding cGMP-dependent protein kinase II) and Npr3 (natriuretic peptide decoy receptor) genes. Conversely, DEX was found to down-regulate the expression of the gene encoding its receptor, Nr3c1 (glucocorticoid receptor), as well as the Npr2 gene (encoding the CNP receptor). CONCLUSION: Our data suggest that the growth-suppressive activities of DEX are not due to blockade of CNP signaling. This study reveals a novel, unanticipated relationship between glucocorticoid and CNP signaling and provides the first evidence that CNP expression in chondrocytes is regulated by endocrine factors

Deterministic Concurrency: A Clock-Synchronised Shared Memory Approach

International audienceSynchronous Programming (SP) is a universal computational principle that provides deterministic concurrency. The same input sequence with the same timing always results in the same externally observable output sequence, even if the internal behaviour generates uncertainty in the scheduling of concurrent memory accesses. Consequently, SP languages have always been strongly founded on mathematical semantics that support formal program analysis. So far, however, communication has been constrained to a set of primitive clock-synchronised shared memory (csm) data types, such as data-flow registers, streams and signals with restricted read and write accesses that limit modularity and behavioural abstractions. This paper proposes an extension to the SP theory which retains the advantages of deterministic concurrency, but allows communication to occur at higher levels of abstraction than currently supported by SP data types. Our approach is as follows. To avoid data races, each csm type publishes a policy interface for specifying the admissibility and precedence of its access methods. Each instance of the csm type has to be policy-coherent, meaning it must behave deterministically under its own policy-a natural requirement if the goal is to build deterministic systems that use these types. In a policy-constructive system, all access methods can be scheduled in a policy-conformant way for all the types without deadlocking. In this paper, we show that a policy-constructive program exhibits deterministic concurrency in the sense that all policy-conformant interleavings produce the same input-output behaviour. Policies are conservative and support the csm types existing in current SP languages. Technically, we introduce a kernel SP language that uses arbitrary policy-driven csm types. A big-step fixed-point semantics for this language is developed for which we prove determinism and termination of constructive programs

New mutations of SCN4A cause a potassium-sensitive normokalemic periodic paralysis

BACKGROUND: Periodic paralysis is classified into hypokalemic (hypoPP) and hyperkalemic (hyperPP) periodic paralysis according to variations of blood potassium levels during attacks. OBJECTIVE: To describe new mutations in the muscle sodium channel gene SCN4A that cause periodic paralysis. METHODS: A thorough clinical, electrophysiologic, and molecular study was performed of four unrelated families who presented with periodic paralysis. RESULTS: The nine affected members had episodes of muscle weakness reminiscent of both hyperPP and hypoPP. A provocative test with potassium chloride was positive in two patients. However, repeated and carefully performed tests of blood potassium levels during attacks resulted in normal potassium levels. Remarkably, two patients experienced hypokalemic episodes of paralysis related to peculiar provocative factors (corticosteroids and thyrotoxicosis). Similarly to hyperPP, electromyography in nine patients revealed increased compound muscle action potentials after short exercise and a delayed decline during rest after long exercise as well as myotonic discharges in one patient. With use of molecular genetic analysis of the gene SCN4A, three new mutations were found affecting codon 675. They resulted in an amino acid substitution of a highly conserved arginine (R) to either a glycine (G), a glutamine (Q), or a tryptophan (W). Interestingly, hypoPP is caused by both mutations affecting nearby codons as well as the change of an arginine into another amino acid. CONCLUSION: A potassium-sensitive and normokalemic type of periodic paralysis caused by new SCN4A mutations at codon 675 is reported

Triheptanoin dramatically reduces paroxysmal motor disorder in patients with GLUT1 deficiency

Objective:&nbsp;On the basis of our previous work with triheptanoin, which provides key substrates to the Krebs cycle in the brain, we wished to assess its therapeutic effect in patients with glucose transporter type 1 deficiency syndrome (GLUT1-DS) who objected to or did not tolerate ketogenic diets. Methods:&nbsp;We performed an open-label pilot study with three phases of 2 months each (baseline, treatment and withdrawal) in eight patients with GLUT1-DS (7&ndash;47 years old) with non-epileptic paroxysmal manifestations. We used a comprehensive patient diary to record motor and non-motor paroxysmal events. Functional&nbsp;31P-NMR spectroscopy was performed to quantify phosphocreatine (PCr) and inorganic phosphate (Pi) within the occipital cortex during (activation) and after (recovery) a visual stimulus. Results:&nbsp;Patients with GLUT1-DS experienced a mean of 30.8 (&plusmn;27.7) paroxysmal manifestations (52% motor events) at baseline that dropped to 2.8 (&plusmn;2.9, 76% motor events) during the treatment phase (p=0.028). After withdrawal, paroxysmal manifestations recurred with a mean of 24.2 (&plusmn;21.9, 52% motor events; p=0.043). Furthermore, brain energy metabolism normalised with triheptanoin, that is, increased Pi/PCr ratio during brain activation compared to the recovery phase (p=0.021), and deteriorated when triheptanoin was withdrawn. Conclusions:&nbsp;Treatment with triheptanoin resulted in a 90% clinical improvement in non-epileptic paroxysmal manifestations and a normalised brain bioenergetics profile in patients with GLUT1-DS. Trial registration number:&nbsp;NCT02014883.</p

Female predominance and transmission distortion in the long-QT syndrome

BACKGROUND: Congenital long-QT syndrome is a disorder resulting in ventricular arrhythmias and sudden death. The most common forms of the long-QT syndrome, types 1 and 2, are caused by mutations in the potassium-channel genes KCNQ1 and KCNH2, respectively. Although inheritance of the long-QT syndrome is autosomal dominant, female predominance has often been observed and has been attributed to an increased susceptibility to cardiac arrhythmias in women. We investigated the possibility of an unbalanced transmission of the deleterious trait. METHODS: We investigated the distribution of alleles for the long-QT syndrome in 484 nuclear families with type 1 disease and 269 nuclear families with type 2 disease, all with fully genotyped offspring. The families were recruited in five European referral centers for the long-QT syndrome. Mutation segregation, sex ratio, and parental transmission were analyzed after correction for single ascertainment. RESULTS: Classic mendelian inheritance ratios were not observed in the offspring of either female carriers of the long-QT syndrome type 1 or male and female carriers of the long-QT syndrome type 2. Among the 1534 descendants, the proportion of genetically affected offspring was significantly greater than that expected according to mendelian inheritance: 870 were carriers of a mutation (57%), and 664 were noncarriers (43%, P<0.001). Among the 870 carriers, the allele for the long-QT syndrome was transmitted more often to female offspring (476 [55%]) than to male offspring (394 [45%], P=0.005). Increased maternal transmission of the long-QT syndrome mutations to daughters was also observed, possibly contributing to the excess of female patients with autosomal dominant long-QT syndrome. CONCLUSIONS: Positive selection of the mutated alleles that cause the long-QT syndrome leads to transmission distortion, with increased proportions of mutation carriers among the offspring of affected families. Alleles for the long-QT syndrome are more often transmitted to daughters than to sons