 Hello, good morning, we are Alfonso Yalzaba Lampilar Rodriguez Pombo, two of the authors of the article entitled a novel regulatory defect in the branched chain of alpha-keto acid, the hydrogenase complex, due to a mutation in the BPM1K gene causes a mild variant phenotype of maple syrup healing disease. In our work that we describe is a heteroteoan reported involvement of the phosphatase Pp2Cm in the MSUD condition of a 21 years old female patient. Now we are located in the city of Autónoma de Madrid, close to the center of the diagnostic of the disease molecular, where part of this research was done. But the story started in 1919 when a new bone female was detected in the neonatal screening as having increased amounts of branched chain amino acids in her blood. Continuando nos anos con o ámbito clínico e bioquímico de esta patienta, nos próximos minutos tentaremos mostrar que a pequena parte de esta pesquisa que era constantes ámbitos clínicos e bioquímicos fez posible a identificación de esta novela reportada, a regulatoria de defecto, corroborando que, also for our now diseases, as MSUD, something new can appear. MSUD is an inborn error caused by the deficient activity of the BCKDH complex. The blockage of this complex leads to an accumulation of branched amino acids and the respective keto acids in cells body fluids. This is manifested as different clinical phenotypes running from the most ever form seen in 70% of patients with MSUD to mild forms that present during early development. BCKDH, amito-quantally located complex occupies a strategic point in the catabolic pathway of branched amino acids. The other activity is controlled by phosphorylation of the E1FSU unit, catalyzed by a specific kinase. Phosphorylation leads to an inactive form of the complex. The unphosphorylated active state is regained via the activity of a specific protein phosphatase PP2CM. Several reports have actually described PP2CM as a protein phosphatase with an essential role in the activation of stress signaling pathways and other functions related to development and or cardiac function. To date, only described mutations that count MSUD have only been found in the genes encoding for the catalytist's units. Now we will try to show the traits from the patient to the analysis of the impact of the PPM1K gene mutation on the MSUD phenotype and specific aspects of the stress signaling. We present a patient selected as mild variant form of MSUD based on indirect biochemical and clinical variables such as BCKDH activity, metabolite levels at diagnostic, protein tolerance and clinical outcomes and for which non-local type changes were found in any of the MSUD related non-gens. We used a copy number map obtained from the patient's SNIPA-RAID data set to investigate possible genomic rearrangements. SNIPA-RAID analysis revealed a complete copy-neutral loss of heterothegocity for chromosome 4. We saw it for genes mapping at this chromosome and potentially related to BCA metabolism. PP2CM encoded by PPM1K gene maps to chromosome 4 at position 4Q22.1 and was selected as a good candidate. We sequenced the complete coding region of PPM1K and identified anomosicos nucleotide change C417-418 del TA. Parents' DNA sequencing together with the SNIPA-RAID results suggested paternal UPD for chromosome 4. Next question to be answered was if this defective PP2CM protein was irresponsible of the loss of functionality of the BCKDH complex in the patient. To add it as question, we transfected patient fibroblast with wild type PPM1K cDNA and measured the BCKDH activity. We observed a true fall increase over basal BCKDH activity. The maximum recovery achieved was 35% of contraactivity. Since the suspected deficiency was around 20% as determined by immunofluorescence, we didn't observe a 100% recovery. Taking into account the discreet involvement of PP2C family in the critical signaling pathways related with human disease, is the RNBCA metabolism responsible of the pathogenesis in this patient? We explored the impact of PP2CM deficiency on metabolic stress variables such as rose content, mapkinesis activation or cell cycle progression. Our data confirms the effective PP2CM to be associated with a significantly increased rose concentration and the selective induction of the stress-activated mapkinesis P38 and YUNC, supporting the idea of its importance in cell survival. However, whereas cardiac function seems to be compromised in several PP2CM deficient animal models, no hard pathology has been seen in the present PP2CM deficiency patient. At this point, we could argue that in our patient, BCAA and BCKA have always been under tight dietary control, thus possibly masking any potential effect. Therefore, the question about if the aberrant BCAA metabolism represents the link between phosphatase effect and activation of stress signals is still open. Dear colleagues, we encourage you to send us a feedback via e-mail and have a happy reading.