Intrathecal magnesium delivery for Mg++-insensitive NMDA receptor activity due to GRIN1 mutation

Abstract Background Mutations in the NMDA receptor are known to disrupt glutamatergic signaling crucial for early neurodevelopment, often leading to severe global developmental delay/intellectual disability, epileptic encephalopathy, and cerebral palsy phenotypes. Both seizures and movement disorders can be highly treatment-refractory. Results We describe a targeted ABA n-of-1 treatment trial with intrathecal MgSO4, rationally designed based on the electrophysiologic properties of this gain of function mutation in the GRIN1 NMDA subunit. Conclusion Although the invasive nature of the trial necessitated a short-term, non-randomized, unblinded intervention, quantitative longitudinal neurophysiologic monitoring indicated benefit, providing class II evidence in support of intrathecal MgSO4 for select forms of GRIN disorders

Consensus-based guidelines for the provision of palliative and end-of-life care for people living with epidermolysis bullosa

Abstract Background Inherited epidermolysis bullosa (EB) is a cluster of rare, genetic skin and mucosal fragility disorders with multi-system and secondary effects, in which blistering and erosions occur in response to friction/mechanical trauma. Considering the incurable and potentially life-limiting nature of the condition and the challenges posed by its symptoms, a palliative approach to EB-related care is necessary. However, knowledge and experience related to the provision of EB palliative care is minimal. Evidence-based, best care guidelines are needed to establish a base of knowledge for practitioners to prevent or ease suffering while improving comfort at all stages of the illness, not just the end of life. Methods This consensus guideline (CG) was begun at the request of DEBRA International, an international organization dedicated to improvement of care, research, and dissemination of knowledge for EB patients, and represents the work of an international panel of medical experts in palliative care and EB, people living with EB, and people who provide care for individuals living with EB. Following a rigorous, evidence-based guideline development process, the author panel identified six clinical outcomes based on the results of a survey of people living with EB, carers, and medical experts in the field, as well as an exhaustive and systematic evaluation of literature. Recommendations for the best clinical provision of palliative care for people living with EB for each of the outcomes were reached through panel consensus of the available literature. Results This article presents evidence-based recommendations for the provision of palliative healthcare services that establishes a base of knowledge and practice for an interdisciplinary team approach to ease suffering and improve the quality of life for all people living with EB. Any specific differences in the provision of care between EB subtypes are noted. Conclusions Because there is yet no cure for EB, this evidence-based CG is a means of optimizing and standardizing the IDT care needed to reduce suffering while improving comfort and overall quality of life for people living with this rare and often devastating condition

6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis

Fru-2,6-P(2) (fructose 2,6-bisphosphate) is a signal molecule that controls glycolysis. Since its discovery more than 20 years ago, inroads have been made towards the understanding of the structure–function relationships in PFK-2 (6-phosphofructo-2-kinase)/FBPase-2 (fructose-2,6-bisphosphatase), the homodimeric bifunctional enzyme that catalyses the synthesis and degradation of Fru-2,6-P(2). The FBPase-2 domain of the enzyme subunit bears sequence, mechanistic and structural similarity to the histidine phosphatase family of enzymes. The PFK-2 domain was originally thought to resemble bacterial PFK-1 (6-phosphofructo-1-kinase), but this proved not to be correct. Molecular modelling of the PFK-2 domain revealed that, instead, it has the same fold as adenylate kinase. This was confirmed by X-ray crystallography. A PFK-2/FBPase-2 sequence in the genome of one prokaryote, the proteobacterium Desulfovibrio desulfuricans, could be the result of horizontal gene transfer from a eukaryote distantly related to all other organisms, possibly a protist. This, together with the presence of PFK-2/FBPase-2 genes in trypanosomatids (albeit with possibly only one of the domains active), indicates that fusion of genes initially coding for separate PFK-2 and FBPase-2 domains might have occurred early in evolution. In the enzyme homodimer, the PFK-2 domains come together in a head-to-head like fashion, whereas the FBPase-2 domains can function as monomers. There are four PFK-2/FBPase-2 isoenzymes in mammals, each coded by a different gene that expresses several isoforms of each isoenzyme. In these genes, regulatory sequences have been identified which account for their long-term control by hormones and tissue-specific transcription factors. One of these, HNF-6 (hepatocyte nuclear factor-6), was discovered in this way. As to short-term control, the liver isoenzyme is phosphorylated at the N-terminus, adjacent to the PFK-2 domain, by PKA (cAMP-dependent protein kinase), leading to PFK-2 inactivation and FBPase-2 activation. In contrast, the heart isoenzyme is phosphorylated at the C-terminus by several protein kinases in different signalling pathways, resulting in PFK-2 activation