OBJECTIVETo investigate the safety and efficacy of escalating doses of the semi-synthetic triterpenoid omaveloxolone in patients with mitochondrial myopathy.
METHODSIn cohorts of 8–13, 53 ...participants were randomized double-blind to 12 weeks of treatment with omaveloxolone 5, 10, 20, 40, 80, or 160 mg, or placebo. Outcome measures were change in peak cycling exercise workload (primary), in 6-minute walk test (6MWT) distance (secondary), and in submaximal exercise heart rate and plasma lactate (exploratory).
RESULTSNo differences in peak workload or 6MWT were observed at week 12 with omaveloxolone treatment vs placebo for all omaveloxolone dose groups. In contrast, omaveloxolone 160 mg reduced heart rate at week 12 by 12.0 ± 4.6 bpm (SE) during submaximal exercise vs placebo, p = 0.01, and by 8.7 ± 3.5 bpm (SE) vs baseline, p = 0.02. Similarly, blood lactate was 1.4 ± 0.7 mM (SE) lower vs placebo, p = 0.04, and 1.6 ± 0.5 mM (SE) lower vs baseline at week 12, p = 0.003, with omaveloxolone 160 mg treatment. Adverse events were generally mild and infrequent.
CONCLUSIONSOmaveloxolone 160 mg was well-tolerated, and did not lead to change in the primary outcome measure, but improved exploratory endpoints lowering heart rate and lactate production during submaximal exercise, consistent with improved mitochondrial function and submaximal exercise tolerance. Therefore, omaveloxolone potentially benefits patients with mitochondrial myopathy, which encourages further investigations of omaveloxolone in this patient group.
CLINICALTRIALS.GOV IDENTIFIERNCT02255422.
CLASSIFICATION OF EVIDENCEThis study provides Class II evidence that, for patients with mitochondrial myopathy, omaveloxolone compared to placebo did not significantly change peak exercise workload.
Optimizing individualized clinical care in heterogeneous rare disorders, such as primary mitochondrial disease (PMD), will require gaining more comprehensive and objective understanding of the ...patient experience by longitudinally tracking quantifiable patient-specific outcomes and integrating subjective data with clinical data to monitor disease progression and targeted therapeutic effects.
Electronic surveys of patient (and caregiver) reported outcome (PRO) measures were administered in REDCap within clinical domains commonly impaired in patients with PMD in the context of their ongoing routine care, including quality of life, fatigue, and functional performance. Descriptive statistics, group comparisons, and inter-measure correlations were used to evaluate system feasibility, utility of PRO results, and consistency across outcome measure domains. Real-time tracking and visualization of longitudinal individual-level and cohort-level data were facilitated by a customized data integration and visualization system, MMFP-Tableau.
An efficient PRO electronic capture and analysis system was successfully implemented within a clinically and genetically heterogeneous rare disease clinical population spanning all ages. Preliminary data analyses demonstrated the flexibility of this approach for a range of PROs, as well as the value of selected PRO scales to objectively capture qualitative functional impairment in four key clinical domains. High inter-measure reliability and correlation were observed. Between-group analyses revealed that adults with PMD reported significantly worse quality of life and greater fatigue than did affected children, while PMD patients with nuclear gene disorders reported lower functioning relative to those with an mtDNA gene disorder in several clinical domains.
Incorporation of routine electronic data collection, integration, visualization, and analysis of relevant PROs for rare disease patients seen in the clinical setting was demonstrated to be feasible, providing prospective and quantitative data on key clinical domains relevant to the patient experience. Further work is needed to validate specific PROs in diverse PMD patients and cohorts, and to formally evaluate the clinical impact and utility of harnessing integrated data systems to objectively track and integrate quantifiable PROs in the context of rare disease patient clinical care.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Glutamatergic neurotransmission governs excitatory signaling in the mammalian brain, and abnormalities of glutamate signaling have been shown to contribute to both epilepsy and hyperkinetic movement ...disorders. The etiology of many severe childhood movement disorders and epilepsies remains uncharacterized. We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein. Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose of Review
Primary mitochondrial disease encompasses an impressive range of inherited energy deficiency disorders having highly variable molecular etiologies as well as clinical onset, ...severity, progression, and response to therapies of diverse multi-system manifestations. Significant progress has been made in primary mitochondrial disease diagnostic approaches, clinical management, therapeutic options, and preventative strategies that are tailored to major mitochondrial disease phenotypes and subclasses.
Recent Findings
The extensive phenotypic pleiotropy of individual mitochondrial diseases from an organ-based perspective is reviewed. Improved consensus on standards for mitochondrial disease patient care are being complemented by emerging therapies that target specific molecular subtypes of mitochondrial disease. Reproductive counseling options now include pre-implantation genetic diagnosis at the time of in vitro fertilization for familial mutations in nuclear genes and some mtDNA disorders. Mitochondrial replacement technologies have promise for some mtDNA disorders, although practical and societal challenges remain to allow their further research evaluation and clinical utilization.
Summary
A dramatic improvement has occurred in recent years in the recognition, understanding, treatment options, and preventative strategies for primary mitochondrial disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Introduction
Primary mitochondrial disease is caused by either mitochondrial or nuclear DNA mutations that impact the function of the mitochondrial respiratory chain. Individuals with mitochondrial ...disorders have comorbid conditions that may increase their risk for poor bone health. The objective of this retrospective electronic medical record (EMR) review was to examine risk factors for poor bone health in children and adults with primary mitochondrial disease.
Methods
Eighty individuals with confirmed clinical and genetic diagnoses of primary mitochondrial disease at the Children’s Hospital of Philadelphia (CHOP) were included in this study. Risk factors and bone health outcomes were collected systematically, including: anthropometrics (low BMI), risk-conferring co-morbidities and medications, vitamin D status, nutrition, immobility, fracture history, and, where available, dual energy x-ray absorptiometry (DXA) bone mineral density (BMD) results.
Results
Of patients 73% (
n
= 58) had at least one risk factor and 30% (
n
= 24) had four or more risk factors for poor bone health. The median number of risk factors per participant was 2, with an interquartile interval (IQI 0–4). In the subset of the cohort who were known to have sustained any lifetime fracture (
n
= 11), a total of 16 fractures were reported, six of which were fragility fractures, indicative of a clinically significant decrease in bone strength.
Conclusions
The prevalence of risk factors for poor bone health in primary mitochondrial disease is high. As part of supportive care, practitioners should address modifiable risk factors to optimize bone health, and have a low threshold to evaluate clinical symptoms that could suggest occult fragility fracture.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose of Review
The groundwork for mitochondrial medicine was laid 30 years ago with identification of the first disease-causing mitochondrial DNA (mtDNA) mutations in 1988. Three decades later, ...mutations in nearly 300 genes involving every possible mode of inheritance within both nuclear and mitochondrial genomes are now recognized to collectively comprise the largest class of inherited metabolic disease, affecting at least 1 in 4300 individuals across all ages. Significant progress has been made in recent years to improve understanding of mitochondrial biology and disease pathophysiology.
Recent Findings
Markedly improved understanding of the highly diverse molecular etiologies of multisystemic phenotypes in primary mitochondrial disease has resulted from massively parallel genomic sequencing technologies and improved bioinformatic resources that enable identification in individual patients of their disease’s precise genetic etiology. Key informatics resources of particular utility to the mitochondrial disease genomics community have been developed, including: (1) Mitocarta 2.0 repository of 1200+ verified mitochondria-localized proteins, (2) MITOMAP Web resource of curated mtDNA genome variants, and (3) Mitochondrial Disease Sequence Data Resource (MSeqDR) that centralizes Web curation and annotation of mitochondrial disease genes and variants in both genomes, ontology-defined phenotypes, and access to many analytic tools to support dual genomic data mining and interpretation. Gene and mutation-based disease categorization has proven particularly useful to identify the full clinical spectrum of disease that may affect a given individual.
Summary
Extensive genomic advances, both in technologic platforms and bioinformatics resources, have facilitated dramatic improvement in the accurate recognition and understanding of primary mitochondrial disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Evaluation of ataxia in children is challenging in clinical practice. This is particularly true for highly heterogeneous conditions such as primary mitochondrial disorders (PMD). This study aims to ...explore cerebellar and brain abnormalities identified on MRI as potential predictors of ataxia in patients with PMD and, likewise, to determine the effect of the patient’s genetic profile on these predictors as well as determination of the temporal relationship of clinical ataxia with MRI findings. We evaluated clinical, radiological, and genetic characteristics of 111 PMD patients younger than 21 years of age at The Children’s Hospital of Philadelphia. Data was extracted from charts. Blinded radiological evaluations were carried out by experienced neuroradiologists. Multivariate logistic regression and generalized equation estimates were used for analysis. Ataxia was identified in 41% of patients. Cerebellar atrophy or putaminal involvement with mitochondrial DNA (mtDNA) mutations (OR 1.18, 95% CI 1.1–1.3,
p
< 0.001) and nuclear DNA mutation with no atrophy of the cerebellum (OR 1.14, 95% CI 1.0–1.3,
p
= 0.007) predicted an increased likelihood of having ataxia per year of age. Central tegmental tract predicted the presence of ataxia independent of age and pathogenic variant origin (OR 9.8, 95% CI 2–74,
p
= 0.009). Ataxia tended to precede the imaging finding of cerebellar atrophy. Cerebellar atrophy and putaminal involvement on MRI of pediatric-onset PMD may predict the presence of ataxia with age in patients with mtDNA mutations. This study provides predicted probabilities of having ataxia per year of age that may help in family counseling and future research of the population.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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