Magnetic resonance spectroscopy in MELAS syndrome: correlation with CSF and plasma metabolite levels and change after glutamine supplementation.

PURPOSE: MELAS syndrome is a genetic disorder caused by mitochondrial DNA mutations. We previously described that MELAS patients had increased CSF glutamate and decreased CSF glutamine levels and that oral glutamine supplementation restores these values. Proton magnetic resonance spectroscopy (1H-MRS) allows the in vivo evaluation of brain metabolism. We aimed to compare 1H-MRS of MELAS patients with controls, the 1H-MRS after glutamine supplementation in the MELAS group, and investigate the association between 1H-MRS and CSF lactate, glutamate, and glutamine levels. METHODS: We conducted an observational case-control study and an open-label, single-cohort study with single-voxel MRS (TE 144/35 ms). We assessed the brain metabolism changes in the prefrontal (PFC) and parieto-occipital) cortex (POC) after oral glutamine supplementation in MELAS patients. MR spectra were analyzed with jMRUI software. RESULTS: Nine patients with MELAS syndrome (35.8 ± 3.2 years) and nine sex- and age-matched controls were recruited. Lactate/creatine levels were increased in MELAS patients in both PFC and POC (0.40 ± 0.05 vs. 0, p < 0.001; 0.32 ± 0.03 vs. 0, p < 0.001, respectively). No differences were observed between groups in glutamate and glutamine (Glx/creatine), either in PFC (p = 0.930) or POC (p = 0.310). No differences were observed after glutamine supplementation. A positive correlation was found between CSF lactate and lactate/creatine only in POC (0.85, p = 0.003). CONCLUSION: No significant metabolite changes were observed in the brains of MELAS patients after glutamine supplementation. While we found a positive correlation between lactate levels in CSF and 1H-MRS in MELAS patients, we could not monitor treatment response over short periods with this tool. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04948138; initial release 24/06/2021; first patient enrolled on 1/07/2021. https://clinicaltrials.gov/ct2/show/NCT04948138.

High-dose oral glutamine supplementation reduces elevated glutamate levels in cerebrospinal fluid in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome.

BACKGROUND AND PURPOSE: Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous disorder caused by mitochondrial DNA mutations. There are no disease-modifying therapies, and treatment remains mainly supportive. It has been shown previously that patients with MELAS syndrome have significantly increased cerebrospinal fluid (CSF) glutamate and significantly decreased CSF glutamine levels compared to controls. Glutamine has many metabolic fates in neurons and astrocytes, and the glutamate-glutamine cycle couples with many metabolic pathways depending on cellular requirements. The aim was to compare CSF glutamate and glutamine levels before and after dietary glutamine supplementation. It is postulated that high-dose oral glutamine supplementation could reduce the increase in glutamate levels. METHOD: This open-label, single-cohort study determined the safety and changes in glutamate and glutamine levels in CSF after 12 weeks of oral glutamine supplementation. RESULTS: Nine adult patients with MELAS syndrome (66.7% females, mean age 35.8 ± 3.2 years) were included. After glutamine supplementation, CSF glutamate levels were significantly reduced (9.77 ± 1.21 vs. 18.48 ± 1.34 µmol/l, p < 0.001) and CSF glutamine levels were significantly increased (433.66 ± 15.31 vs. 336.31 ± 12.92 µmol/l, p = 0.002). A side effect observed in four of nine patients was a mild sensation of satiety. One patient developed mild and transient elevation of transaminases, and another patient was admitted for an epileptic status without stroke-like episode. DISCUSSION: This study demonstrates that high-dose oral glutamine supplementation significantly reduces CSF glutamate and increases CSF glutamine levels in patients with MELAS syndrome. These findings may have potential therapeutic implications in these patients. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT04948138. Initial release 24 June 2021, first patient enrolled 1 July 2021. https://clinicaltrials.gov/ct2/show/NCT04948138.

Understanding the ecosystem of patients with lysosomal storage diseases in Spain: a qualitative research with patients and health care professionals.

BACKGROUND: Lysosomal Storage Diseases (LSDs) are a group of Rare Diseases (RDs) caused by lysosomal enzyme deficiencies. Patients with LSDs suffer from a wide range of symptoms with a strong impact in their daily routines. In this study we aimed to explore the impact of the disease on the lives of patients with four LSDs, as well as how they experience Patient Journey from diagnosis to follow up. Unmet Needs (UNs) perceived by patients and clinicians were assessed to have a better understanding of which initiatives could improve LSDs management and especially those that could result in an improvement of patients' quality of life. METHODS: Qualitative research was the research methodology selected for the study. It provides plentiful and holistic insights into people's views and actions. The study was conducted through in-depth face-to-face semi-structured interviews. RESULTS: In total, 20 patients and 25 Health Care Professionals (HCPs) from different Spanish regions were interviewed. Patients perceived that the highest impact of the LSDs was on their daily routines, specifically on their emotional side, their work/school environment, their family and their social life. Regarding the Patient Journey experience, the worst perceived stage was the pre-diagnosis, where patients only reported negative perceptions, being the delay in diagnosis and misdiagnosis the most commented issues. On the contrary, the follow-up stage was the one with less negative perceptions. Overall, patients and HCPs agreed on the priority UNs, such as accelerating diagnosis, reducing bureaucracy for the treatment access and a more coordinated attention for the patients, not only among different physicians but also with other professionals such as genetic counselors or social workers. CONCLUSIONS: Our data shows that there are still UNs to be addressed from the perspective of patients and HCPs. The main UN is accelerating diagnosis, which could be achieved by medical awareness and education, according to clinicians. A more comprehensive disease management was another main point to be worked on to improve LSD-patient experience and quality of life.