Management of seizures in patients with primary mitochondrial diseases: consensus statement from the InterERNs Mitochondrial Working Group.

BACKGROUND AND PURPOSE: Primary mitochondrial diseases (PMDs) are common inborn errors of energy metabolism, with an estimated prevalence of one in 4300. These disorders typically affect tissues with high energy requirements, including heart, muscle and brain. Epilepsy may be the presenting feature of PMD, can be difficult to treat and often represents a poor prognostic feature. The aim of this study was to develop guidelines and consensus recommendations on safe medication use and seizure management in mitochondrial epilepsy. METHODS: A panel of 24 experts in mitochondrial medicine, pharmacology and epilepsy management of adults and/or children and two patient representatives from seven countries was established. Experts were members of five different European Reference Networks, known as the Mito InterERN Working Group. A Delphi technique was used to allow the panellists to consider draft recommendations on safe medication use and seizure management in mitochondrial epilepsy, using two rounds with predetermined levels of agreement. RESULTS: A high level of consensus was reached regarding the safety of 14 out of all 25 drugs reviewed, resulting in endorsement of National Institute for Health and Care Excellence guidelines for seizure management, with some modifications. Exceptions including valproic acid in POLG disease, vigabatrin in patients with γ-aminobutyric acid transaminase deficiency and topiramate in patients at risk for renal tubular acidosis were highlighted. CONCLUSIONS: These consensus recommendations describe our intent to improve seizure control and reduce the risk of drug-related adverse events in individuals living with PMD-related epilepsy.

Elevated cholesterol in ATAD3 mutants is a compensatory mechanism that leads to membrane cholesterol aggregation.

Aberrant cholesterol metabolism causes neurological disease and neurodegeneration, and mitochondria have been linked to perturbed cholesterol homeostasis via the study of pathological mutations in the ATAD3 gene cluster. However, whether the cholesterol changes were compensatory or contributory to the disorder was unclear, and the effects on cell membranes and the wider cell were also unknown. Using patient-derived cells, we show that cholesterol perturbation is a conserved feature of pathological ATAD3 variants that is accompanied by an expanded lysosome population containing membrane whorls characteristic of lysosomal storage diseases. Lysosomes are also more numerous in Drosophila neural progenitor cells expressing mutant Atad3, which exhibit abundant membrane-bound cholesterol aggregates, many of which co-localize with lysosomes. By subjecting the Drosophila Atad3 mutant to nutrient restriction and cholesterol supplementation, we show that the mutant displays heightened cholesterol dependence. Collectively, these findings suggest that elevated cholesterol enhances tolerance to pathological ATAD3 variants; however, this comes at the cost of inducing cholesterol aggregation in membranes, which lysosomal clearance only partly mitigates.

Øyesykdom ved dystrophia myotonica type 1.

Myotonic dystrophy type 1 is one of the most common genetic neuromuscular diseases in adults. The disease not only affects the musculoskeletal system, but is multisystemic, and ocular involvement with cataract formation is a frequent additional finding. To avoid recurrence of secondary opacification that is difficult to treat, the cataract should not be treated with traditional lens replacement. This clinical review article presents ophthalmological findings in cases of myotonic dystrophy type 1 and describes a new surgical method for cataracts in this patient group.

Serum neurofilament as a predictor of 10-year grey matter atrophy and clinical disability in multiple sclerosis: a longitudinal study.

BACKGROUND: The predictive value of serum neurofilament light chain (sNfL) on long-term prognosis in multiple sclerosis (MS) is still unclear. OBJECTIVE: Investigate the relation between sNfL levels over a 2-year period in patients with relapsing-remitting MS, and clinical disability and grey matter (GM) atrophy after 10 years. METHODS: 85 patients, originally enrolled in a multicentre, randomised trial of ω-3 fatty acids, participated in a 10-year follow-up visit. sNfL levels were measured by Simoa quarterly until month 12, and then at month 24. The appearance of new gadolinium-enhancing (Gd+) lesions was assessed monthly between baseline and month 9, and then at months 12 and 24. At the 10-year follow-up visit, brain atrophy measures were obtained using FreeSurfer. RESULTS: Higher mean sNfL levels during early periods of active inflammation (Gd+ lesions present or recently present) predicted lower total (ß=-0.399, p=0.040) and deep (ß=-0.556, p=0.010) GM volume, lower mean cortical thickness (ß=-0.581, p=0.010) and higher T2 lesion count (ß=0.498, p=0.018). Of the clinical outcomes, higher inflammatory sNfL levels were associated with higher disability measured by the dominant hand Nine-Hole Peg Test (ß=0.593, p=0.004). Mean sNfL levels during periods of remission (no Gd+ lesions present or recently present) did not predict GM atrophy or disability progression. CONCLUSION: Higher sNfL levels during periods of active inflammation predicted more GM atrophy and specific aspects of clinical disability 10 years later. The findings suggest that subsequent long-term GM atrophy is mainly due to neuroaxonal degradation within new lesions.

Mitochondrial disease caused by the m.3243A>G mutation / Mitokondriesykdom forårsaket av m.3243A>G-mutasjonen.

Mitochondrial disease is among the most commonly occurring metabolic disorders and is relevant for many medical specialties. This clinical review article discusses one of the most common mutations causing mitochondrial disease, namely m.3243A>G. The mutation can lead to diabetes mellitus, hearing loss, cardiac and muscle involvement, encephalopathy and epilepsy, gastric and intestinal problems and visual impairment, frequently in combination. Better knowledge of mitochondrial disease caused by the m.3243A>G mutation would improve both the diagnosis and treatment of patients who may suffer from a serious and life-threatening disease.

Research priorities for mitochondrial disorders: Current landscape and patient and professional views.

Primary mitochondrial disorders encompass a wide range of clinical presentations and a spectrum of severity. They currently lack effective disease-modifying therapies and have a high mortality and morbidity rate. It is therefore essential to know that competitively funded research designed by academics meets the core needs of people with mitochondrial disorders and their clinicians. Priority setting partnerships are an established collaborative methodology that brings patients, carers and families, charity representatives and clinicians together to try to establish the most pressing and unanswered research priorities for a particular disease. We developed a web-based questionnaire, requesting all patients affected by primary mitochondrial disease, their carers and clinicians to pose their research questions. This yielded 709 questions from 147 participants. These were grouped into overarching themes including basic biology, causation, health services, clinical management, social impacts, prognosis, prevention, symptoms, treatment and psychological impact. Following the removal of "answered questions", the process resulted in a list of 42 discrete, answerable questions. This was further refined by web-based ranking by the community to 24 questions. These were debated at a face-to-face workshop attended by a diverse range of patients, carers, charity representatives and clinicians to create a definitive "Top 10 of unanswered research questions for primary mitochondrial disorders". These Top 10 questions related to understanding biological processes, including triggers of disease onset, mechanisms underlying progression and reasons for differential symptoms between individuals with identical genetic mutations; new treatments; biomarker discovery; psychological support and optimal management of stroke-like episodes and fatigue.

Serum biomarkers in primary mitochondrial disorders.

The aim of this study was to explore the utility of the serum biomarkers neurofilament light chain, fibroblast growth factor 21 and growth and differentiation factor 15 in diagnosing primary mitochondrial disorders. We measured serum neurofilament light chain, fibroblast growth factor 21 and growth and differentiation factor 15 in 26 patients with a genetically proven mitochondrial disease. Fibroblast growth factor 21 and growth and differentiation factor 15 were measured by enzyme-linked immunosorbent assay and neurofilament light chain with the Simoa assay. Neurofilament light chain was highest in patients with multi-systemic involvement that included the central nervous system such as those with the m.3242A>G mutation. Mean neurofilament light chain was also highest in patients with epilepsy versus those without [49.74 pg/ml versus 19.7 pg/ml (P = 0.015)], whereas fibroblast growth factor 21 and growth and differentiation factor 15 levels were highest in patients with prominent myopathy, such as those with single-mitochondrial DNA deletion. Our results suggest that the combination of neurofilament light chain, fibroblast growth factor 21 and growth and differentiation factor 15 is useful in the diagnostic evaluation of mitochondrial disease. Growth and differentiation factor 15 and fibroblast growth factor 21 identify those with muscle involvement, whereas neurofilament light chain is a clear marker for central nervous system involvement independent of underlying mitochondrial pathology. Levels of neurofilament light chain appear to correlate with the degree of ongoing damage suggesting, therefore, that monitoring neurofilament light chain levels may provide prognostic information and a way of monitoring disease activity.

Using urine to diagnose large-scale mtDNA deletions in adult patients.

OBJECTIVE: The aim of this study was to evaluate if urinary sediment cells offered a robust alternative to muscle biopsy for the diagnosis of single mtDNA deletions. METHODS: Eleven adult patients with progressive external ophthalmoplegia and a known single mtDNA deletion were investigated. Urinary sediment cells were used to isolate DNA, which was then subjected to long-range polymerase chain reaction. Where available, the patient`s muscle DNA was studied in parallel. Breakpoint and thus deletion size were identified using both Sanger sequencing and next generation sequencing. The level of heteroplasmy was determined using quantitative polymerase chain reaction. RESULTS: We identified the deletion in urine in 9 of 11 cases giving a sensitivity of 80%. Breakpoints and deletion size were readily detectable in DNA extracted from urine. Mean heteroplasmy level in urine was 38% ± 26 (range 8 - 84%), and 57% ± 28 (range 12 - 94%) in muscle. While the heteroplasmy level in urinary sediment cells differed from that in muscle, we did find a statistically significant correlation between these two levels (R = 0.714, P = 0.031(Pearson correlation)). INTERPRETATION: Our findings suggest that urine can be used to screen patients suspected clinically of having a single mtDNA deletion. Based on our data, the use of urine could considerably reduce the need for muscle biopsy in this patient group.

Natural Variation of Vitamin D and Neurofilament Light Chain in Relapsing-Remitting Multiple Sclerosis.

Background: High serum levels of 25-hydroxyvitamin D (25(OH)D) have been found among patients with a favorable disease course in relapsing-remitting MS (RRMS), indicating that this may limit clinical deterioration. Clinical deterioration in RRMS correlates with increasing serum levels of neurofilament light chain (NfL). Objectives: To examine the association between physiological variations in serum 25(OH)D and NfL levels in RRMS patients before and during disease modifying therapy (DMT). Material and Methods: Serum 25(OH)D and NfL concentrations were measured in 85 newly diagnosed RRMS patients enrolled in a 24-month randomized double-blinded placebo-controlled trial of ω-3 fatty acid supplementation without vitamin D. Patients were without DMT until interferon ß-1a (IFN-ß) initiation at study month 6. Longitudinal serum measurements and brain magnetic resonance imaging (MRI) were obtained. Associations between 25(OH)D and NfL levels were analyzed with linear regression models for the whole study period and the periods before and during IFN-ß treatment. Analyses with adjustment for inflammatory MRI disease activity were also performed. Results: No significant associations were found between variations in 25(OH)D and NfL levels during the whole study period (p = 0.95), or the periods without (p = 0.78) or with (p = 0.33) IFN-ß therapy. Patients with inflammatory MRI disease activity had significantly higher serum NfL levels than patients without inflammatory MRI disease activity [mean (SD) difference 12.6 (2.0) pg/mL, p < 0.01]. Adjustment for this did not change the relationship between 25(OH)D and NfL concentrations. Conclusion: Natural variations in serum 25(OH)D values do not seem to be associated with alterations in serum NfL concentrations in RRMS patients.