ABSTRACT
BACKGROUND AND PURPOSE: Late-onset mitochondrial disorders are diagnostically challenging with significant heterogeneity in disease presentation. A case is reported of a 67-year-old gentleman who presented with a 3-month history of seizures, recurrent encephalopathy, ataxia and weight loss, preceded by recent initiation of haemodialysis for end-stage chronic kidney disease. METHODS: Extensive work-up including serological, cerebrospinal fluid, magnetic resonance imaging and electroencephalography was performed. Whole exome sequencing and muscle biopsy confirmed the diagnosis. RESULTS: Magnetic resonance imaging brain demonstrated a single non-enhancing T2 fluid attenuated inversion recovery hyperintense cortical/subcortical signal change in the right temporal lobe and cerebellar atrophy. Given the subacute presentation of uncertain aetiology, he was empirically treated for autoimmune/paraneoplastic encephalitis. Despite radiological resolution of the cortical abnormality 2 weeks later, there was no clinical improvement. Further collateral history unveiled a mildly ataxic gait and longstanding hearing loss suggestive of a genetic cause. Whole exome sequencing revealed a likely pathogenic, heteroplasmic mitochondrial DNA variant in the MT-TV gene, m.1659T>C, present at higher levels of heteroplasmy in muscle (91%) compared to other mitotic tissues. A high fat/protein diet and multivitamins including co-enzyme Q10 were commenced. Treatment of the nutritional deficiency and avoidance of intermittent fasting due to unreliable oral intake secondary to encephalopathy probably contributed to the clinical improvement seen over the ensuing few months, with resolution of his encephalopathy and return to his baseline gait and weight. CONCLUSION: An adult case is reported with an acute neurological presentation mimicking encephalitis, caused by a heteroplasmic m.1659T>C MT-TV variant, previously reported once in a child who displayed a different clinical phenotype.
ABSTRACT
Given the current paucity of effective treatments in many neurological disorders, delineating pathophysiological mechanisms among the major psychiatric and neurodegenerative diseases may fuel the development of novel, potent treatments that target shared pathways. Recent evidence suggests that various pathological processes, including bioenergetic failure in mitochondria, can perturb the function of fast-spiking, parvalbumin-positive neurons (PV+). These inhibitory neurons critically influence local circuit regulation, the generation of neuronal network oscillations and complex brain functioning. Here, we survey PV+ cell vulnerability in the major neuropsychiatric, and neurodegenerative diseases and review associated cellular and molecular pathophysiological alterations purported to underlie disease aetiology.
Subject(s)
Mitochondria , Neurodegenerative Diseases , Neurons , Parvalbumins , Humans , Parvalbumins/metabolism , Neurodegenerative Diseases/metabolism , Mitochondria/metabolism , Animals , Neurons/metabolism , Nervous System Diseases/metabolism , Brain/metabolismABSTRACT
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.
Subject(s)
Anticonvulsants , Mitochondrial Diseases , Seizures , Humans , Mitochondrial Diseases/complications , Mitochondrial Diseases/therapy , Seizures/therapy , Seizures/drug therapy , Anticonvulsants/therapeutic use , Consensus , Epilepsy/therapy , Epilepsy/drug therapy , Delphi TechniqueABSTRACT
With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid, finely granulated, digital health measures are highly warranted to augment clinical and patient-reported outcome measures. Gait and balance disturbances most often present as the first signs of degenerative cerebellar ataxia and are the most reported disabling features in disease progression. Thus, digital gait and balance measures constitute promising and relevant performance outcomes for clinical trials.This narrative review with embedded consensus will describe evidence for the sensitivity of digital gait and balance measures for evaluating ataxia severity and progression, propose a consensus protocol for establishing gait and balance metrics in natural history studies and clinical trials, and discuss relevant issues for their use as performance outcomes.
ABSTRACT
Mitochondrial diseases comprise a common group of neurometabolic disorders resulting from OXPHOS defects, that may manifest with neurological impairments, for which there are currently no disease-modifying therapies. Previous studies suggest inhibitory interneuron susceptibility to mitochondrial impairment, especially of parvalbumin-expressing interneurons (PV+). We have developed a mouse model of mitochondrial dysfunction specifically in PV+ cells via conditional Tfam knockout, that exhibited a juvenile-onset progressive phenotype characterised by cognitive deficits, anxiety-like behaviour, head-nodding, stargazing, ataxia, and reduced lifespan. A brain region-dependent decrease of OXPHOS complexes I and IV in PV+ neurons was detected, with Purkinje neurons being most affected. We validated these findings in a neuropathological study of patients with pathogenic mtDNA and POLG variants showing PV+ interneuron loss and deficiencies in complexes I and IV. This mouse model offers a drug screening platform to propel the discovery of therapeutics to treat severe neurological impairment due to mitochondrial dysfunction.
Subject(s)
Mitochondrial Diseases , Parvalbumins , Mice , Animals , Humans , Parvalbumins/metabolism , Neurons/metabolism , Interneurons/metabolism , Mitochondrial Diseases/genetics , Mitochondrial Diseases/metabolism , MitochondriaABSTRACT
Mitochondrial dysfunction, especially perturbation of oxidative phosphorylation and adenosine triphosphate (ATP) generation, disrupts cellular homeostasis and is a surprisingly frequent cause of central and peripheral nervous system pathology. Mitochondrial disease is an umbrella term that encompasses a host of clinical syndromes and features caused by in excess of 300 different genetic defects affecting the mitochondrial and nuclear genomes. Patients with mitochondrial disease can present at any age, ranging from neonatal onset to late adult life, with variable organ involvement and neurological manifestations including neurodevelopmental delay, seizures, stroke-like episodes, movement disorders, optic neuropathy, myopathy, and neuropathy. Until relatively recently, analysis of skeletal muscle biopsy was the focus of diagnostic algorithms, but step-changes in the scope and availability of next-generation sequencing technology and multiomics analysis have revolutionized mitochondrial disease diagnosis. Currently, there is no specific therapy for most types of mitochondrial disease, although clinical trials research in the field is gathering momentum. In that context, active management of epilepsy, stroke-like episodes, dystonia, brainstem dysfunction, and Parkinsonism are all the more important in improving patient quality of life and reducing mortality.
Subject(s)
Mitochondrial Diseases , Mitochondrial Encephalomyopathies , Stroke , Adult , Infant, Newborn , Humans , Mitochondrial Encephalomyopathies/diagnosis , Mitochondrial Encephalomyopathies/genetics , DNA, Mitochondrial/genetics , Quality of Life , Mitochondrial Diseases/geneticsABSTRACT
Pathogenic mitochondrial DNA (mtDNA) single-nucleotide variants are a common cause of adult mitochondrial disease. Levels of some variants decrease with age in blood. Given differing division rates, longevity, and energetic requirements within haematopoietic lineages, we hypothesised that cell-type-specific metabolic requirements drive this decline. We coupled cell-sorting with mtDNA sequencing to investigate mtDNA variant levels within progenitor, myeloid, and lymphoid lineages from 26 individuals harbouring one of two pathogenic mtDNA variants (m.3243A>G and m.8344A>G). For both variants, cells of the T cell lineage show an enhanced decline. High-throughput single-cell analysis revealed that decline is driven by increasing proportions of cells that have cleared the variant, following a hierarchy that follows the current orthodoxy of T cell differentiation and maturation. Furthermore, patients with pathogenic mtDNA variants have a lower proportion of T cells than controls, indicating a key role for mitochondrial function in T cell homeostasis. This work identifies the ability of T cell subtypes to selectively purify their mitochondrial genomes, and identifies pathogenic mtDNA variants as a new means to track blood cell differentiation status.
Subject(s)
DNA, Mitochondrial , Mitochondria , Adult , Humans , DNA, Mitochondrial/genetics , Cell Differentiation/genetics , Mitochondria/genetics , Lymphocyte Activation , Cell LineageABSTRACT
Mitochondrial diseases represent the most common inherited neurometabolic disorders, for which no effective therapy currently exists for most patients. The unmet clinical need requires a more comprehensive understanding of the disease mechanisms and the development of reliable and robust in vivo models that accurately recapitulate human disease. This review aims to summarise and discuss various mouse models harbouring transgenic impairments in genes that regulate mitochondrial function, specifically their neurological phenotype and neuropathological features. Ataxia secondary to cerebellar impairment is one of the most prevalent neurological features of mouse models of mitochondrial dysfunction, consistent with the observation that progressive cerebellar ataxia is a common neurological manifestation in patients with mitochondrial disease. The loss of Purkinje neurons is a shared neuropathological finding in human post-mortem tissues and numerous mouse models. However, none of the existing mouse models recapitulate other devastating neurological phenotypes, such as refractory focal seizures and stroke-like episodes seen in patients. Additionally, we discuss the roles of reactive astrogliosis and microglial reactivity, which may be driving the neuropathology in some of the mouse models of mitochondrial dysfunction, as well as mechanisms through which cellular death may occur, beyond apoptosis, in neurons undergoing mitochondrial bioenergy crisis.
Subject(s)
Cerebellar Ataxia , Mitochondrial Diseases , Mice , Animals , Humans , Ataxia/genetics , Cerebellar Ataxia/pathology , Purkinje Cells/pathology , Mitochondrial Diseases/genetics , Mitochondrial Diseases/pathology , Seizures/pathology , Phenotype , Disease Models, AnimalABSTRACT
Stroke-like episode is a paroxysmal neurological manifestation which affects a specific group of patients with mitochondrial disease. Focal-onset seizures, encephalopathy, and visual disturbances are prominent findings associated with stroke-like episodes, with a predilection for the posterior cerebral cortex. The most common cause of stroke-like episodes is the m.3243A>G variant in MT-TL1 gene followed by recessive POLG variants. This chapter aims to review the definition of stroke-like episode and delineate the clinical phenomenology, neuroimaging and EEG findings typically seen in patients. In addition, several lines of evidence supporting neuronal hyper-excitability as the key mechanism of stroke-like episodes are discussed. The management of stroke-like episodes should focus on aggressive seizure management and treatment for concomitant complications such as intestinal pseudo-obstruction. There is no robust evidence to prove the efficacy of l-arginine for both acute and prophylactic settings. Progressive brain atrophy and dementia are the sequalae of recurrent stroke-like episode, and the underlying genotype in part predicts prognosis.
Subject(s)
MELAS Syndrome , Mitochondrial Diseases , Stroke , Humans , Adult , MELAS Syndrome/complications , MELAS Syndrome/genetics , Stroke/complications , Mitochondrial Diseases/genetics , Mitochondria , Brain , SeizuresABSTRACT
Mitochondrial genetic diseases are a very diverse group of conditions. A recent report by Mootha and colleagues in NEJM describes the underlying genetic defect and clinical findings in monozygotic twins with uncoupling of ATP production.
Subject(s)
Mitochondrial Diseases , Twins, Monozygotic , Mitochondrial Diseases/geneticsABSTRACT
Mitochondrial diseases are a group of common inherited diseases causing disruption of oxidative phosphorylation. Some patients with mitochondrial disease have endocrine manifestations, with diabetes mellitus being predominant but also include hypogonadism, hypoadrenalism, and hypoparathyroidism. There have been major developments in mitochondrial disease over the past decade that have major implications for all patients. The collection of large cohorts of patients has better defined the phenotype of mitochondrial diseases and the majority of patients with endocrine abnormalities have involvement of several other systems. This means that patients with mitochondrial disease and endocrine manifestations need specialist follow-up because some of the other manifestations, such as stroke-like episodes and cardiomyopathy, are potentially life threatening. Also, the development and follow-up of large cohorts of patients means that there are clinical guidelines for the management of patients with mitochondrial disease. There is also considerable research activity to identify novel therapies for the treatment of mitochondrial disease. The revolution in genetics, with the introduction of next-generation sequencing, has made genetic testing more available and establishing a precise genetic diagnosis is important because it will affect the risk for involvement for different organ systems. Establishing a genetic diagnosis is also crucial because important reproductive options have been developed that will prevent the transmission of mitochondrial disease because of mitochondrial DNA variants to the next generation.
Subject(s)
Diabetes Mellitus , Mitochondrial Diseases , Diabetes Mellitus/genetics , Genetic Testing , Humans , Mitochondria , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Mitochondrial Diseases/therapy , PhenotypeABSTRACT
AIMS: To define the prevalence of non-sustained tachyarrhythmias and bradyarrhythmias in patients with the m.3243A>G mitochondrial genotype and a previously defined, profile, associated with 'high sudden-death risk'. METHODS AND RESULTS: Patients at high risk of sudden death because of combinations of ventricular hypertrophy, mitochondrial encephalopathy, lactic acidosis and stroke-like episodes family phenotype, epilepsy or high mutation load, due to the m.3243A>G mutation, were identified from a mitochondrial cohort of 209 patients. All recruited had serial ECG and echo assessments previously according to schedule, had an ECG-loop recorder implanted and were followed for as long as the device allowed. Devices were programmed to detect non-sustained brady- or tachy-arrhythmias. This provided comprehensive rhythm surveillance and automatic downloads of all detections to a monitoring station for cardiology interpretation. Those with sinus tachycardia were treated with beta-blockers and those with ventricular hypertrophy received a beta-blocker and ACE-inhibitor combination.Nine consecutive patients, approached (37.2±3.9 years, seven males) and consented, were recruited. None died and no arrhythmias longer than 30s duration occurred during 3-year follow-up. Three patients reported palpitations but ECGs correlated with sinus rhythm. One manifest physiological, sinus pauses >3.5 s during sleep and another had one asymptomatic episode of non-sustained ventricular tachycardia. CONCLUSIONS: Despite 'high-risk' features for sudden death, those studied had negligible prevalence of arrhythmias over prolonged follow-up. By implication, the myocardium in this genotype is not primarily arrhythmogenic. Arrhythmias may not explain sudden death in patients without Wolff-Parkinson-White or abnormal atrioventricular conduction or, it must require a confluence of other, dynamic, proarrhythmic factors to trigger them.
Subject(s)
Arrhythmias, Cardiac , Mitochondrial Diseases , Adrenergic beta-Antagonists , Arrhythmias, Cardiac/diagnosis , Arrhythmias, Cardiac/epidemiology , Arrhythmias, Cardiac/genetics , Death, Sudden/etiology , Humans , Hypertrophy/complications , Male , Mitochondrial Diseases/complications , PrevalenceABSTRACT
BACKGROUND AND OBJECTIVES: Stroke management in the context of primary mitochondrial disease is clinically challenging, and the best treatment options for patients with stroke-like episodes remain uncertain. We sought to perform a systematic review of the safety and efficacy of l-arginine use in the acute and prophylactic management of stroke-like episodes in patients with mitochondrial disease. METHODS: The systematic review was registered in PROSPERO (CRD42020181230). We searched 6 databases from inception to January 15, 2021: MEDLINE, Embase, Scopus, Web of Science, CINAHL, and ClinicalTrials.gov. Original articles and registered trials available, in English, reporting l-arginine use in the acute or prophylactic management of stroke-like episodes in patients with genetically confirmed mitochondrial disease were eligible for inclusion. Data on safety and treatment response were extracted and summarized by multiple observers. Risk of bias was assessed by the methodologic quality of case reports, case series, and a risk-of-bias checklist for nonrandomized studies. Quality of evidence was synthesized with the Oxford Centre for Evidence-Based Medicine Levels of Evidence and Grade of Recommendations. The predetermined main outcome measures were clinical response to l-arginine treatment, adverse events, withdrawals, and deaths (on treatment and/or during follow-up), as defined by the author. RESULTS: Thirty-seven articles met inclusion criteria (0 randomized controlled trials; 3 open-label; 1 retrospective cohort; 33 case reports/case series) (N = 91 patients; 86% m.3243A>G). In the case reports, 54% of patients reported a positive clinical response to acute l-arginine, of which 40% were concomitantly treated with antiepileptic drugs. Improved headache at 24 hours was the greatest reported benefit in response to IV l-arginine in the open-label trials (31 of 39, 79%). In 15 of 48 patients (31%) who positively responded to prophylactic l-arginine, antiepileptic drugs were either used (7 of 15) or unreported (8 of 15). Moderate adverse events were reported in the follow-up of both IV and oral l-arginine treatment, and 11 patients (12%) died during follow-up or while on prophylactic treatment. DISCUSSION: The available evidence is of poor methodologic quality and classified as Level 5. IV and oral l-arginine confers no demonstrable clinical benefit in either the acute or prophylactic treatment of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes, with more robust controlled trials required to assess its efficacy and safety profile.
Subject(s)
Acidosis, Lactic , Mitochondrial Diseases , Stroke , Anticonvulsants/therapeutic use , Arginine/therapeutic use , Humans , Mitochondrial Encephalomyopathies , Retrospective Studies , Stroke/drug therapyABSTRACT
In this retrospective, multicentre, observational cohort study, we sought to determine the clinical, radiological, EEG, genetics and neuropathological characteristics of mitochondrial stroke-like episodes and to identify associated risk predictors. Between January 1998 and June 2018, we identified 111 patients with genetically determined mitochondrial disease who developed stroke-like episodes. Post-mortem cases of mitochondrial disease (n = 26) were identified from Newcastle Brain Tissue Resource. The primary outcome was to interrogate the clinico-radiopathological correlates and prognostic indicators of stroke-like episode in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). The secondary objective was to develop a multivariable prediction model to forecast stroke-like episode risk. The most common genetic cause of stroke-like episodes was the m.3243A>G variant in MT-TL1 (n = 66), followed by recessive pathogenic POLG variants (n = 22), and 11 other rarer pathogenic mitochondrial DNA variants (n = 23). The age of first stroke-like episode was available for 105 patients [mean (SD) age: 31.8 (16.1)]; a total of 35 patients (32%) presented with their first stroke-like episode ≥40 years of age. The median interval (interquartile range) between first and second stroke-like episodes was 1.33 (2.86) years; 43% of patients developed recurrent stroke-like episodes within 12 months. Clinico-radiological, electrophysiological and neuropathological findings of stroke-like episodes were consistent with the hallmarks of medically refractory epilepsy. Patients with POLG-related stroke-like episodes demonstrated more fulminant disease trajectories than cases of m.3243A>G and other mitochondrial DNA pathogenic variants, in terms of the frequency of refractory status epilepticus, rapidity of progression and overall mortality. In multivariate analysis, baseline factors of body mass index, age-adjusted blood m.3243A>G heteroplasmy, sensorineural hearing loss and serum lactate were significantly associated with risk of stroke-like episodes in patients with the m.3243A>G variant. These factors informed the development of a prediction model to assess the risk of developing stroke-like episodes that demonstrated good overall discrimination (area under the curve = 0.87, 95% CI 0.82-0.93; c-statistic = 0.89). Significant radiological and pathological features of neurodegeneration were more evident in patients harbouring pathogenic mtDNA variants compared with POLG: brain atrophy on cranial MRI (90% versus 44%, P < 0.001) and reduced mean brain weight (SD) [1044 g (148) versus 1304 g (142), P = 0.005]. Our findings highlight the often idiosyncratic clinical, radiological and EEG characteristics of mitochondrial stroke-like episodes. Early recognition of seizures and aggressive instigation of treatment may help circumvent or slow neuronal loss and abate increasing disease burden. The risk-prediction model for the m.3243A>G variant can help inform more tailored genetic counselling and prognostication in routine clinical practice.
Subject(s)
MELAS Syndrome , Mitochondrial Diseases , Stroke , Adult , DNA, Mitochondrial/genetics , Humans , MELAS Syndrome/genetics , Mitochondrial Diseases/complications , Mitochondrial Diseases/genetics , Mutation , Retrospective Studies , Stroke/diagnostic imaging , Stroke/geneticsABSTRACT
OBJECTIVE: This observational cohort study aims to quantify disease burden over time, establish disease progression rates, and identify factors that may determine the disease course of Leigh syndrome. METHODS: Seventy-two Leigh syndrome children who completed the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) at baseline at 3.7 years (interquartile range [IQR] = 2.0-7.6) and follow-up assessments at 7.5 years (IQR = 3.7-11.0) in clinics were enrolled. Eighty-two percent of this cohort had a confirmed genetic diagnosis, with pathogenic variants in the MT-ATP6 and SURF1 genes being the most common cause. The total NPMDS scores denoted mild (0-14), moderate (15-25), and severe (>25) disease burden. Detailed clinical, neuroradiological, and molecular genetic findings were also analyzed. RESULTS: The median total NPMDS scores rose significantly (Z = -6.9, p < 0.001), and the percentage of children with severe disease burden doubled (22% â 42%) over 2.6 years of follow-up. Poor function (especially mobility, self-care, communication, feeding, and education) and extrapyramidal features contributed significantly to the disease burden (τb ≈ 0.45-0.68, p < 0.001). These children also deteriorated to wheelchair dependence (31% â 57%), exclusive enteral feeding (22% â 46%), and one-to-one assistance for self-care (25% â 43%) during the study period. Twelve children (17%) died after their last NPMDS scores were recorded. These children had higher follow-up NPMDS scores (disease burden; p < 0.001) and steeper increase in NPMDS score per annum (disease progression; p < 0.001). Other predictors of poor outcomes include SURF1 gene variants (p < 0.001) and bilateral caudate changes on neuroimaging (p < 0.01). INTERPRETATION: This study has objectively defined the disease burden and progression of Leigh syndrome. Our analysis has also uncovered potential influences on the trajectory of this neurodegenerative condition. ANN NEUROL 2022;91:117-130.
Subject(s)
Leigh Disease , Child , Child, Preschool , Cohort Studies , Cost of Illness , Disease Progression , Female , Humans , Infant , Longitudinal Studies , MaleABSTRACT
Background and Aims: Gastrointestinal (GI) dysmotility is a common and debilitating clinical manifestation in patients with mitochondrial DNA (mtDNA)-related disease with no curative and few effective symptomatic therapies. A low-residue diet (LRD) has been shown to be effective at reducing bowel urgency, pain, and distension in functional GI-related conditions. We assessed tolerability and effects of an LRD on bowel habits in patients with mtDNA-related disease. Methods: This was a 12-week single-arm pilot study in patients with genetically determined primary mtDNA-related disease, meeting the ROME III constipation criteria. The co-primary outcomes were tolerability of an LRD (<10 g fiber per day) assessed by food diaries and changes in stool frequency and consistency. The secondary outcomes included GI symptoms, disease burden, laxatives, physical activity levels, colonic transit time using radiopaque markers, gut microbiome (patients and controls), and metabolomics. The gut microbiome of the mtDNA-related disease patients was compared against controls for observational purpose only. Results: Twenty-eight patients were enrolled, and 24 completed the LRD intervention. The LRD was well tolerated with a mean fold change of -34% in dietary fiber (5.3 ± 10.4 grams) per day (P = .03, confidence interval = 0.7-9.9) with no adverse events. The proportion of stool samples with normal stool consistency increased from 36% to 49% (P = .01); GI symptoms and laxative use were reduced. However, the LRD did not change stool frequency, stool output, and colonic transit time. The gut microbiome was significantly different between patients and controls but was not modulated by the dietary intervention. Conclusion: The LRD in patients with mtDNA-related mitochondrial disease and significant constipation is well tolerated and a promising treatment for alleviating GI symptoms. These positive findings should be confirmed in a randomized controlled trial.ClinicalTrials.gov Identifier: NCT03388528.
ABSTRACT
Pathogenic variants in mitochondrial DNA (mtDNA) are associated with significant clinical heterogeneity with neuromuscular involvement commonly reported. Non-syndromic presentations of mtDNA disease continue to pose a diagnostic challenge and with genomic testing still necessitating a muscle biopsy in many cases. Here we describe an adult patient who presented with progressive ataxia, neuropathy and exercise intolerance in whom the application of numerous Mendelian gene panels had failed to make a genetic diagnosis. Muscle biopsy revealed characteristic mitochondrial pathology (cytochrome c oxidase deficient, ragged-red fibers) prompting a thorough investigation of the mitochondrial genome. Two heteroplasmic MT-CO2 gene variants (NC_012920.1: m.7887G>A and m.8250G>A) were identified, necessitating single fiber segregation and familial studies - including the biopsy of the patient's clinically-unaffected mother - to demonstrate pathogenicity of the novel m.7887G>A p.(Gly101Asp) variant and establishing this as the cause of the mitochondrial biochemical defects and clinical presentation. In the era of high throughput whole exome and genome sequencing, muscle biopsy remains a key investigation in the diagnosis of patients with non-syndromic presentations of adult-onset mitochondrial disease and fully defining the pathogenicity of novel mtDNA variants.
Subject(s)
Cerebellar Ataxia/diagnosis , Mitochondrial Diseases/diagnosis , Muscle, Skeletal/pathology , Mutation/genetics , Base Sequence , Biopsy , DNA, Mitochondrial , Diagnosis, Differential , Humans , Male , Middle Aged , Exome SequencingABSTRACT
Mitochondrial diseases are some of the most common inherited neurometabolic disorders, and major progress has been made in our understanding, diagnosis, and treatment of these conditions in the past 5 years. Development of national mitochondrial disease cohorts and international collaborations has changed our knowledge of the spectrum of clinical phenotypes and natural history of mitochondrial diseases. Advances in high-throughput sequencing technologies have altered the diagnostic algorithm for mitochondrial diseases by increasingly using a genetics-first approach, with more than 350 disease-causing genes identified to date. While the current management strategy for mitochondrial disease focuses on surveillance for multisystem involvement and effective symptomatic treatment, new endeavours are underway to find better treatments, including repurposing current drugs, use of novel small molecules, and gene therapies. Developments made in reproductive technology offer women the opportunity to prevent transmission of DNA-related mitochondrial disease to their children.
Subject(s)
Mitochondrial Diseases/genetics , Mitochondrial Diseases/physiopathology , Mitochondrial Diseases/therapy , DNA, Mitochondrial/genetics , Genetic Therapy/methods , Genetic Therapy/trends , High-Throughput Nucleotide Sequencing/methods , Humans , Mutation/geneticsABSTRACT
Mitochondrial DNA (mtDNA) disorders are recognized as one of the most common causes of inherited metabolic disorders. The mitochondrial genome occurs in multiple copies resulting in both homoplasmic and heteroplasmic pathogenic mtDNA variants. A biochemical defect arises when the pathogenic variant level reaches a threshold, which differs between variants. Moreover, variants can segregate, clonally expand, or be lost from cellular populations resulting in a dynamic and tissue-specific mosaic pattern of oxidative deficiency. MtDNA is maternally inherited but transmission patterns of heteroplasmic pathogenic variants are complex. During oogenesis, a mitochondrial bottleneck results in offspring with widely differing variant levels to their mother, whilst highly deleterious variants, such as deletions, are not transmitted. Complemented by a complex interplay between mitochondrial and nuclear genomes, these peculiar genetics produce marked phenotypic variation, posing challenges to the diagnosis and clinical management of patients. Novel therapeutic compounds and several genetic therapies are currently under investigation, but proven disease-modifying therapies remain elusive. Women who carry pathogenic mtDNA variants require bespoke genetic counselling to determine their reproductive options. Recent advances in in vitro fertilization techniques, have greatly improved reproductive choices, but are not without their challenges. Since the first pathogenic mtDNA variants were identified over 30 years ago, there has been remarkable progress in our understanding of these diseases. However, many questions remain unanswered and future studies are required to investigate the mechanisms of disease progression and to identify new disease-specific therapeutic targets.
Subject(s)
DNA, Mitochondrial , Genetic Association Studies , Genetic Predisposition to Disease , Genetic Variation , Mitochondrial Diseases/genetics , Disease Management , Extrachromosomal Inheritance , Humans , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/therapyABSTRACT
OBJECTIVE: To determine the prevalence of neuromuscular junction (NMJ) abnormalities in patients with mitochondrial disease. METHODS: Eighty patients with genetically proven mitochondrial disease were recruited from a national center for mitochondrial disease in the United Kingdom. Participants underwent detailed clinical and neurophysiologic testing including single-fiber electromyography. RESULTS: The overall prevalence of neuromuscular transmission defects was 25.6%. The highest prevalence was in patients with pathogenic dominant RRM2B variants (50%), but abnormalities were found in a wide range of mitochondrial genotypes. The presence of NMJ abnormalities was strongly associated with coexistent myopathy, but not with neuropathy. Furthermore, 15% of patients with NMJ abnormality had no evidence of either myopathy or neuropathy. CONCLUSIONS: NMJ transmission defects are common in mitochondrial disease. In some patients, NMJ dysfunction occurs in the absence of obvious pre- or post-synaptic pathology, suggesting that the NMJ may be specifically affected.