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.
High‐dose oral glutamine supplementation for 12 weeks significantly reduces cerebrospinal fluid (CSF) glutamate and increases CSF glutamine levels in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes (MELAS) syndrome. This decrease in CSF glutamate levels could reduce glutamate‐mediated excitotoxicity. These findings may have potential therapeutic implications in patients with MELAS syndrome.
Acute hepatic porphyria (AHP) comprises a group of rare genetic diseases characterized by neurovisceral crises that are manifested by abdominal pain and neurological and/or psychological symptoms ...that interfere with the ability to lead a normal life. Our objective was to determine the burden of the disease in one year and the health-related quality of life (HRQoL) in patients with AHP.
28 patients were analyzed. The mean age was 36.6±10.2 years, 89.3% were women, and the average number of crises was 1.9±1.5. The average annual cost per patient was €38,255.40. 80.2% of the costs was direct medical costs, 17.5% was associated with loss of productivity and 2.3% was direct non-medical costs. 85.9% of the total cost corresponded to the crises. The intercrisis period accounted for the remaining 14.1%. The global index of the EQ-5D-5L (HRQoL) was 0.75±0.24. The dimensions of pain/discomfort, anxiety/depression and daily activities were the most affected. Leisure, travel/vacations and household activities were the most affected daily activities. 53.6% of patients required a caregiver due to AHP. 92.9% did not present overload and 7.1% presented extreme overload.
Patients with AHP are associated with a high economic impact and an affected HRQoL in the pain/discomfort dimension, with a negative impact on the performance of daily activities and a risk of psychiatric diseases.
Objective:
Describe the characteristics and prevalence of headache in patients with mitochondrial diseases (MDs), as well as sleep quality, trying to observe possible associations. To assess whether ...these patients are more likely to suffer headaches in relation to poorer quality of sleep.
Background:
Sleep disorders and headache are considered to be common in MDs. We present the largest sample analyzed to date.
Methods:
Observational, descriptive, cross-sectional study that analyzed a database of 232 patients with MDs, including age, sex, genotype, phenotype, presence and characteristics of headache. All patients fulfilled the Epworth Sleepiness Scale (ESS), the Pittsburgh Sleep Quality Index (PSQI) and, in migraine, the Migraine Disability Assessment questionnaire (MIDAS). Headache was divided into two groups: migraine headache, according to criteria of the International Classification of Headache Disorders (ICHD-III beta), and non-migraine headache.
Results:
A total of 203 cases were analyzed, 124 women (61%) and 79 men (39%). Average age was 46 years. Most frequent DNA mutation was m.3243 A > G in MITL1 gene (33%). Most frequent phenotype was MELAS syndrome: 28 patients (13.8%). Ninety-two patients (45.3%), reported headache, 44 fulfilling migraine criteria (21.7%). Headache was more frequent in MELAS syndrome (p < 0.01). Statistically significant differences were found in the number of disabling episodes per month in patients with migraine (p < 0.001). Patients with headache scored higher in Epworth (p = 0.01) and Pittsburgh scales (p < 0.001).
Conclusions:
A higher prevalence of migraine is observed in patients with mitochondrial diseases, independent of genotype and phenotype. MD-associated migraine tends to be chronic and more disabling. A higher frequency of headache, not specifically migraine, has also been observed in patients with MELAS syndrome. Mitochondrial dysfunction could be one of the pathophysiological mechanisms of migraine and a factor of chronification and severity. Poor sleep quality could also be associated with headache in patients with MDs. Assessment of headache and sleep disturbances should be part of the routine workup of patients with mitochondrial disease.
Trial registration:
N/A.
Porphobilinogen deaminase (PBGD) haploinsufficiency (acute intermittent porphyria, AIP) is characterized by neurovisceral attacks associated with high production, accumulation and urinary excretion ...of heme precursors, δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). The estimated clinical penetrance for AIP is extremely low (<1%), therefore it is likely that other factors may play an important role in the predisposition to developing attacks. Fasting is a known triggering factor. Given the increased prevalence of insulin resistance in patients and the large urinary loss of succinyl-CoA to produce ALA and PBG, we explore the impact of reduced availability of energy metabolites in the severity of AIP pathophysiology. Classic studies found clinical improvement in patients affected by AIP associated with the administration of glucose and concomitant insulin secretion, or after hyperinsulinemia associated with diabetes. Molecular studies have confirmed that glucose and insulin administration induces a repressive effect on hepatic ALA Synthase, the first and regulatory step of the heme pathway. More recently, the insulin-mimicking α-lipoic acid has been shown to improve glucose metabolism and mitochondrial dysfunction in a hepatocyte cell line transfected with interfering RNA targeting PBGD. In AIP mice, preventive treatment with an experimental fusion protein of insulin and apolipoprotein A-I improved the disease by promoting fat mobilization in adipose tissue, increasing the metabolite bioavailability for the TCA cycle and inducing mitochondrial biogenesis in the liver. In this review, we analyze the possible mechanisms underlying abnormal hepatocellular carbohydrate homeostasis in AIP.
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.
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.
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.
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.
Mitochondrial disorders (MD) comprise a group of heterogeneous clinical disorders for which non-invasive diagnosis remains a challenge. Two protein biomarkers have so far emerged for MD detection, ...FGF-21 and GDF-15, but the identification of additional biomarkers capable of improving their diagnostic accuracy is highly relevant. Previous studies identified Gelsolin as a regulator of cell survival adaptations triggered by mitochondrial defects. Gelsolin presents a circulating plasma isoform (pGSN), whose altered levels could be a hallmark of mitochondrial dysfunction. Therefore, we investigated the diagnostic performance of pGSN for MD relative to FGF-21 and GDF-15. Using ELISA assays, we quantified plasma levels of pGSN, FGF-21, and GDF-15 in three age- and gender-matched adult cohorts: 60 genetically diagnosed MD patients, 56 healthy donors, and 41 patients with unrelated neuromuscular pathologies (non-MD). Clinical variables and biomarkers’ plasma levels were compared between groups. Discrimination ability was calculated using the area under the ROC curve (AUC). Optimal cut-offs and the following diagnostic parameters were determined: sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios, and efficiency. Comprehensive statistical analyses revealed significant discrimination ability for the three biomarkers to classify between MD and healthy individuals, with the best diagnostic performance for the GDF-15/pGSN combination. pGSN and GDF-15 preferentially discriminated between MD and non-MD patients under 50 years, whereas FGF-21 best classified older subjects. Conclusion: pGSN improves the diagnosis accuracy for MD provided by FGF-21 and GDF-15.
Tuberous sclerosis (TS) is a condition whose manifestations in childhood have been extensively described, but whose presentation in adults is less well known. This study describes the clinical and ...genetic characteristics, therapeutic management and quality of life of a cohort of adult patients with TS. A comparative study of the characteristics of patients diagnosed in childhood and adulthood is also carried out. This observational, retrospective, cross-sectional study included a large cohort of adult patients (greater than or equai to 16 years old) followed for 5 years in a specific rare diseases unit. Fifty-seven patients with a diagnosis of tuberous sclerosis were included, more than 50% of whom were diagnosed as adults. The mean age of the patients was 42 years (20-86). The central nervous system was the main area affected (97%), followed by the skin (80.7%) and kidneys (73%). The most frequent genetic alteration was a mutation in the TSC2 gene (47.7%). Among patients diagnosed in adulthood, there was less neurological involvement, with less frequency of epileptic seizures (30.8% vs 60.79% of patients diagnosed in childhood) and astrocytomas (3.8% vs 53.6%), less intellectual disability (11.5% vs 71.4%) and less expressiveness of the condition. 42% of patients were treated with mTOR pathway inhibitors, and presence of an angiomyolipoma was the main indication. In a quality-of-life analysis, the means of the summary indices were below the scores of the average Spanish population: (47.42 (SD + or - 9.82) on the physical health scale, 45.61 (SD + or - 7.99) on the mental health scale) versus 50 (SD + or - 10) for the general population. Up to 50% of adult patients with TS were diagnosed in adulthood, and the condition is less severe with less frequent epileptic seizures and intellectual disability. 42% require treatment with mTOR inhibitors, in most cases due to the presence of AMLs. The quality of life of adult patients with TS is diminished compared to the general population.
Hyperammonaemia is a metabolic derangement that may cause severe neurological damage and even death due to cerebral oedema, further complicating the prognosis of its triggering disease. In small ...children it is a rare condition usually associated to inborn errors of the metabolism. As age rises, and especially in adults, it may be precipitated by heterogeneous causes such as liver disease, drugs, urinary infections, shock, or dehydration. In older patients, it is often overlooked, or its danger minimized. This protocol was drafted to provide an outline of the clinical measures required to normalise ammonia levels in patients of all ages, aiming to assist clinicians with no previous experience in its treatment. It is an updated protocol developed by a panel of experts after a review of recent publications. We point out the importance of frequent monitoring to assess the response to treatment, the nutritional measures that ensure not only protein restriction but adequate caloric intake and the need to avoid delays in the use of specific pharmacological therapies and, especially, extrarenal clearance measures. In this regard, we propose initiating haemodialysis when ammonia levels are >200−350 µmol/L in children up to 18 months of age and >150−200 µmol/L after that age.
Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is a progressive and disabling disease characterized by a deficiency of the enzyme N-acetylgalactosamine-6-sulphate sulphatase. Its clinical ...presentation is very heterogeneous and poorly understood in adults. Thirty-three patients from nine reference centres participated in the study. The median age was 32 (interquartile range IQR: 20.5-40.5) years. The phenotype was classical in 54.5% of patients, intermediate in 33.3% of patients, and non-classical in 12.1% of patients. The most common clinical manifestation was bone dysplasia, with a median height of 118 (IQR: 106-136) cm. Other frequent clinical manifestations were hearing loss (75.7%), ligamentous laxity (72.7%), odontoid dysplasia (69.7%), limb deformities that required orthopaedic aids (mainly hip dysplasia and genu valgus) (63.6%), and corneal clouding (60.6%). In addition, 36.0% of patients had obstructive sleep apnoea/hypopnoea syndrome and 33.3% needed non-invasive ventilation. Cervical surgery and varisation osteotomy were the most common surgical interventions (36.4% each). Almost 80% of patients had mobility problems and 36.4% used a wheelchair at all times. Furthermore, 87.9% needed help with self-care, 33.3% were fully dependent, and 78.8% had some degree of pain. HRQoL according to the health assessment questionnaire was 1.43 (IQR: 1.03-2.00) in patients with the non-classical phenotype, but 2.5 (IQR: 1.68-3.00) in those with the classical phenotype. Seven patients were initiated on enzyme replacement therapy (ERT), but two of them were lost to follow-up. Lung function improved in four patients and slightly worsened in one patient. The distance achieved in the six-minute walk test increased in the four patients who could perform it. HRQoL was better in patients treated with elosulfase alfa, with a median (IQR) of 1.75 (1.25-2.34) versus 2.25 (1.62-3.00) in patients not treated with ERT. The study provides real-world data on patients with MPS IVA. Limited mobility, difficulties with self-care, dependence, and pain were common, together with poor HRQoL. The severity and heterogeneity of clinical manifestations require the combined efforts of multidisciplinary teams.
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