Nomenclature of Genetically Determined Myoclonus Syndromes: Recommendations of the International Parkinson and Movement Disorder Society Task Force

Genetically determined myoclonus disorders are a result of a large number of genes. They have wide clinical variation and no systematic nomenclature. With next‐generation sequencing, genetic diagnostics require stringent criteria to associate genes and phenotype. To improve (future) classification and recognition of genetically determined movement disorders, the Movement Disorder Society Task Force for Nomenclature of Genetic Movement Disorders (2012) advocates and renews the naming system of locus symbols. Here, we propose a nomenclature for myoclonus syndromes and related disorders with myoclonic jerks (hyperekplexia and myoclonic epileptic encephalopathies) to guide clinicians in their diagnostic approach to patients with these disorders. Sixty‐seven genes were included in the nomenclature. They were divided into 3 subgroups: prominent myoclonus syndromes, 35 genes; prominent myoclonus syndromes combined with another prominent movement disorder, 9 genes; disorders that present usually with other phenotypes but can manifest as a prominent myoclonus syndrome, 23 genes. An additional movement disorder is seen in nearly all myoclonus syndromes: ataxia (n = 41), ataxia and dystonia (n = 6), and dystonia (n = 5). However, no additional movement disorders were seen in related disorders. Cognitive decline and epilepsy are present in the vast majority. The anatomical origin of myoclonus is known in 64% of genetic disorders: cortical (n = 34), noncortical areas (n = 8), and both (n = 1). Cortical myoclonus is commonly seen in association with ataxia, and noncortical myoclonus is often seen with myoclonus‐dystonia. This new nomenclature of myoclonus will guide diagnostic testing and phenotype classification. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

<Emphasis Type="Italic">Vegf-A</Emphasis> mRNA transfection as a novel approach to improve mouse and human islet graft revascularisation

Aims/hypothesis

The initial avascular period following islet transplantation seriously compromises graft function and survival. Enhancing graft revascularisation to improve engraftment has been attempted through virus-based delivery of angiogenic triggers, but risks associated with viral vectors have hampered clinical translation. In vitro transcribed mRNA transfection circumvents these risks and may be used for improving islet engraftment.

Methods

Mouse and human pancreatic islet cells were transfected with mRNA encoding the angiogenic growth factor vascular endothelial growth factor A (VEGF-A) before transplantation under the kidney capsule in mice.

Results

At day 7 post transplantation, revascularisation of grafts transfected with Vegf-A (also known as Vegfa) mRNA was significantly higher compared with non-transfected or Gfp mRNA-transfected controls in mouse islet grafts (2.11- and 1.87-fold, respectively) (vessel area/graft area, mean?±?SEM: 0.118?±?0.01 [n?=?3] in Vegf-A mRNA transfected group (VEGF) vs 0.056?±?0.01 [n?=?3] in no RNA [p?<?0.05] vs 0.063?±?0.02 [n?=?4] in Gfp mRNA transfected group (GFP) [p?<?0.05]); EndoC-bH3 grafts (2.85- and 2.48-fold. respectively) (0.085?±?0.02 [n?=?4] in VEGF vs 0.030?±?0.004 [n?=?4] in no RNA [p?<?0.05] vs 0.034?±?0.01 [n?=?5] in GFP [p?<?0.05]); and human islet grafts (3.17- and 3.80-fold, respectively) (0.048?±?0.013 [n?=?3] in VEGF vs 0.015?±?0.0051 [n?=?4] in no RNA [p?<?0.01] vs 0.013?±?0.0046 [n?=?4] in GFP [p?<?0.01]). At day 30 post transplantation, human islet grafts maintained a vascularisation benefit (1.70- and 1.82-fold, respectively) (0.049?±?0.0042 [n?=?8] in VEGF vs 0.029?±?0.0052 [n?=?5] in no RNA [p?<?0.05] vs 0.027?±?0.0056 [n?=?4] in GFP [p?<?0.05]) and a higher beta cell volume (1.64- and 2.26-fold, respectively) (0.0292?±?0.0032 μl [n?=?7] in VEGF vs 0.0178?±?0.0021 μl [n?=?5] in no RNA [p?<?0.01] vs 0.0129?±?0.0012 μl [n?=?4] in GFP [p?<?0.001]).

Conclusions/interpretation

Vegf-A mRNA transfection before transplantation provides a promising and safe strategy to improve engraftment of islets and other cell-based implants.

     

Short-term pituitary desensitization to LH-RH after pulsatile LH-RH in the ovariectomized rat: an in vivo experiment

The development of acute insensitivity of pituitary LH secretion to LH-RH after a short exposure to LH-RH is described. In the first experiment, ovariectomized (OVX), phenobarbital-pretreated rats were given pulses of LH-RH (1.25 or 6.25 ng/100 g body weight (b.w.), intravenously). In rats given 1.25 ng at time 0, 6.25 ng at 60 min, 1.25 ng at 80 min and 1.25 ng at 120 min, there was a substantial increase in plasma LH after the first two injections, no increase after the third injection and a relatively small increase after the fourth one. In other rats treated identically but not given a 1.25-ng dose at 80 min, the plasma LH rise in response to the 1.25-ng dose at 120 min was comparable to that seen after the 1.25-ng dose given at time 0. If the 1.25-ng LH-RH pulses given at times 0 and 80 min were replaced by a rat pituitary extract, the plasma LH rise in response to the 1.25-ng dose at 120 min was comparable to that seen after administration of pituitary extract. In the second experiment, OVX phenobarbital-pretreated rats were given 1.25 ng LH-RH/100 g b.w. at t = 0. They were then divided into three groups, each receiving 1.25, 3.75 or 6.25 ng LH-RH/100 g b.w. at t = 60 min. Each of these three groups was again divided into three groups which received 1.25 ng LH-RH/100 g b.w. at 80, 100 or 120 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

A model for breast cancer screening

A model for breast cancer screening has been developed. When the appropriate screening policy is specified, the model reproduces the detection rates and the incidence of interval cancers as observed in the recent screening projects in Utrecht and Nijmegen, the Netherlands. The model-predicted mortality rate reduction is in accordance with the results of the Kopparberg/Osterg?tland randomized trial in Sweden. Key parameters of the model are the duration of the preclinical stages and the sensitivity of mammography. The average duration is approximately 2 years at age 40 and increases to approximately 5 years at age 70. The sensitivity is high (approximately 95%) for tumors larger than 1 cm. The model is used in the prospective evaluation of effects and costs of various screening policies.     

Phenobarbital enhances pituitary LH release induced by LRH pulses in the ovariectomized rat

In the ovariectomized (OVX) rat, the plasma LH response was measured to a pulse of LRH (1.25 or 5 ng/100 g body weight, ia) given before and 1 h after ip administration of phenobarbital (80 mg/kg body weight). The LH response to the LRH pulses was increased 1 h after phenobarbital. In a second experiment, the pituitary LH content of OVX rats was measured 1 h after administration of phenobarbital or saline. No difference in pituitary LH content was found. It is concluded that in the OVX rat, phenobarbital increases the response to a pulse of LRH, presumably by suppressing endogenous pulsatile LRH. This, together with results of earlier experiments, further supports the hypothesis that under conditions where endogenous pulsatile LRH is present, there is always a certain degree of pituitary desensitization or refractoriness and that the removal of this endogenous LRH leads to recovery of pituitary sensitivity to LRH.     

Is on-line monitoring of renal function possible?

Summary Twenty patients who had undergone open heart surgery were studied in order to determine whether measurement of the combined urinary sodium and potassium concentration can be used to monitor renal function.The clearances of creatinine and the free water demonstrated a significant statistical correlation with the combined urinary sodium and potassium concentration. We conclude that measurement of the combined sodium and potassium concentration in the urine can be used as an indicator of renal function. Thus, measurement of the electrical conductivity in the urine might be suitable as an on-line monitor of renal function during surgery or in the intensive care unit.