Mitochondrial disease and epilepsy

Mitochondrial diseases are a group of diseases caused by dysfunctional mitochondria, organelles that generate energy for the cell. Mitochondrial diseases are often caused by mutations, acquired, or inherited in the mitochondrial DNA or nuclear genes that code for respiratory chain complexes in the mitochondrion. Mitochondrial diseases involve multiple organs and show heterogeneous and unpredictable progression. The most common clinical presentation of mitochondrial diseases is encephalomyopathy, and epileptic seizures can frequently occur as a presenting sign of mitochondrial encephalopathy. While whether mitochondrial dysfunction or epilepsy is the cause or consequence is still debatable, they may be interrelated to create a vicious cycle. Epileptic phenotypes vary in different mitochondrial diseases. At present, there are no curative treatments for mitochondrial diseases, and the efficacy of many anticonvulsants, vitamins, nutritional supplements, and the ketogenic diet remain to be proven. Understanding the pathophysiology of mitochondrial diseases may further facilitate effective diagnostic and therapeutic approaches to these diseases.     

Mitochondrial respiratory chain defects: underlying etiology in various epileptic conditions

PURPOSE: To determine if defects in mitochondrial respiratory chain enzyme complexes (MRCs) contribute to the etiology of childhood epilepsy. METHODS: We reviewed the clinical and laboratory features of 48 epileptic patients (23 male, 25 female) with MRC defects that were confirmed by biochemical assays using muscle biopsies. RESULTS: (1) Thirty-five cases (72.9%) were MRC I deficient, one case (2.1%) was MRC II deficient, 11 cases (22.9%) were MRC IV deficient, and one case (2.1%) had combined MRC I and IV deficiencies. (2) In our clinical diagnosis, there were 10 cases (20.8%) with Leigh disease and one case each with myopathy, encephalopathy, lactic acidosis, stroke-like episodes (MELAS) or Alpers' disease (2.1%). Most of the remaining cases (75.0%) had uncategorized mitochondrial cytopathy with nonspecific encephalopathy. (3) For epileptic classification, there were two cases (4.2%) of Ohtahara syndrome, 10 cases (20.8%) of West syndrome, 12 cases (25.0%) of Lennox-Gastaut syndrome, two cases (4.2%) of Landau-Kleffner syndrome, 14 cases (29.2%) of generalized epilepsy, and eight cases (16.7%) of partial epilepsy. (4) The mean age of seizure onset was 2.68 +/- 2.21 (range: 1 month - 5.5 years). (5) Magnetic resonance imaging (MRI) showed diffuse cortical atrophy in 34 cases (70.8%), basal ganglia signal changes in 18 cases (37.5%) and thalamus signal changes in 12 cases (25.0%). (6) A ketogenic diet produced clinical improvements, including seizure reduction and global functional improvement in 75% of 24 patients. CONCLUSIONS: MRC defects are one of the important causes of probably symptomatic childhood epilepsy. A ketogenic diet should be carefully considered for treatment of intractable epilepsy related to MRC defects.     

Multisystem manifestations of mitochondrial disorders

Mitochondria are cytoplasmic organelles in eukaryotic cells that accomplish several distinct vital functions, including oxidative phosphorylation, metabolic anaplerotic and degradative pathways, and integration of signaling for apoptosis. Impaired oxidative phosphorylation, the common final pathway of mitochondrial metabolism, results in a variety of clinical manifestations, and the term mitochondrial disorders is currently ascribed to (mostly) genetic diseases of the respiratory chain associated with mitochondrial DNA mutation or nuclear DNA mutations. Genetic disorders with impaired oxidative phosphorylation are extremely heterogeneous, as their clinical presentation ranges from lesions of single tissues or specialized structures, such as the optic nerve in the mitochondrial DNA-associated Leber’s hereditary optic neuropathy and in the nuclear DNA-associated dominant optic atrophy, to more widespread pathologies, including myopathies, peripheral neuropathies, encephalomyopathies, cardiopathies, or complex multisystem disorders. The age at onset ranges from neonatal to adult life. This review focuses on mitochondrial diseases that find significant expression outside the central nervous system and the peripheral neuromuscular system, and manifest with substantial clinical signs and symptoms in tissues and organs such as the heart, endocrine system, liver, kidney, blood, and gastrointestinal tract. The available information on putative genotype–phenotype correlations and the related pathogenic mechanisms are summarized when appropriate. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Mitochondrial disorders in degenerative ataxias

Current theory implicates mitochondrial defects in the mechanism of neuronal degeneration in several movement disorders. We performed analyses of mitochondrial function in 61 patients with different forms of degenerative ataxias. Mitochondrial enzyme defects were proven in five of 16 (31V.) patients with Friedreich's ataxia, in 14 of 30 (47%) patients with autosomal dominant late onset cerebellar ataxia, and in three of six (50%) patients with sporadic cerebellar atrophy. No abnormalities were found in secondary forms of cerebellar degenerations (due to paraneoplastic disorder, alcohol or sprue) or in spastic paraplegia. Mitochondrial defects affected most frequently the respiratory chain (19 patients) and especially its complex I (11 patients). Carnitine deficiency was found in three patients and severe loss of myoadenylate deaminase in one patient Genetic abnormalities could be proved neither in mitochondrial DNA nor in recently defined ataxia genes. Our results indicate that mitochondrial dysfunction occurs frequently in cerebellar atrophies. Therefore, disturbance of oxidative energy metabolism may be involved in the pathogenesis of degenerative ataxias, but it remains to be elucidated whether mitochondrial defects are primary or secondary effects.     

Myoclonus epilepsy in mitochondrial disorders

Mitochondrial disorders is a group of clinical entities associated with abnormalities of the mitochondrial respiratory chain (MRC), which carries out the oxidative phosphorylation (OXPHOS) of ADP into ATP. As the MRC is the result of genetic complementation between two separate genomes, nuclear and mitochondrial, OXPHOS failure can derive from mutations in either nuclear‐encoded, or mitochondrial‐encoded, genes. Epilepsy is a relatively common feature of mitochondrial disease, especially in early‐onset encephalopathies of infants and children. However, the two most common entities associated with epilepsy include MERRF, for Myoclonic Epilepsy with Ragged Red Fibers, and AHS, or Alpers‐Huttenlocher syndrome, also known as hepatopathic poliodystrophy. Whilst MERRF is a maternally inherited condition caused by mtDNA mutations, particularly the 8344A>G substitution in the gene encoding mt‐tRNA^Lys, AHS is typically caused by recessive mutations in POLG, encoding the catalytic subunit of polymerase gamma, the only mtDNA polymerase in humans. AHS is the most severe, early‐onset, invariably fatal syndrome within a disease spectrum, which also include other epileptogenic entities, all due to POLG mutations and including Spino‐cerebellar Ataxia and Epilepsy (SCAE). This review reports the main clinical, neuroimaging, biochemical, and molecular features of epilepsy‐related mitochondrial syndrome, particularly MERRF and AHS.     

Therapy for neurobehavioral disorders in epilepsy

Neurobehavioral disorders commonly affect patients with epilepsy. In addition to the behavioral changes during and immediately after seizures, the epileptogenic disorder of function often extends further into the postictal and interictal period. Cognitive impairments commonly affect attention, memory, mental speed, and language, as well as executive and social functions. Reducing seizure frequency and the antiepileptic drug burden can reduce these problems. Attentional deficits may respond to therapies for attention-deficit/hyperactivity disorder, but apart from patients with this comorbid disorder, their efficacy is unproven in other epilepsy patients. No effective therapies are established for other cognitive problems, but pragmatic, compensatory strategies can be helpful. Behavioral disorders include fatigue, depression, anxiety, and psychosis. Many of these disorders usually respond well to pharmacotherapy, which can be supplemented by psychotherapy. Cognitive and behavioral disorders can be the greatest cause of morbidity and impaired quality of life, often overshadowing seizures. Yet these problems often go unrecognized and, even when identified, are often undertreated or untreated.     

肌阵挛发作癫痫共济失调

患者男性,16岁。发作性意识丧失伴肢体抽搐4年、双上肢抖动2年、加重2个月,于2013年9月4日人院。患者于4年前玩游戏时出现双眼反复眨眼,随即意识丧失、呼之不应,伴四肢抽搐、双眼上翻、面部发紫,无大小便失禁和舌咬伤,每次发作持续约2min后自行缓解。当地医院诊断为“癫痫”,     

Genetic and biochemical findings in Chinese children with Leigh syndrome

This study investigated the genetic and enzymological features of Leigh syndrome due to respiratory chain complex deficiency in Chinese patients. The clinical features of 75 patients were recorded. Mitochondrial respiratory chain enzyme activities were determined via spectrophotometry. Mitochondrial gene sequence analysis was performed in 23 patients. Five core pedigrees were investigated via restriction fragment length polymorphism and gene sequencing. Psychomotor retardation (55%), motor regression (20%), weakness (29%), and epilepsy (25%) were the most frequent manifestations. Sixty-four patients (85.3%) had isolated respiratory complex deficiencies: complex I was seen in 28 patients (37.3%); complex II, seven (9.3%); complex III, six (8%); complex IV, ten (13.3%); and complex V, 13 patients (17.3%). Eleven patients (14.7%) had combined complex deficiencies. Mitochondrial DNA mutations were detected in 10 patients. Eight point mutations were found in mitochondrial structural genes: m.4833A > G in ND2, m.10191T > C in ND3, m.12338T > C and m.13513G > A in ND5, m.14502T > C and m.14487T > C in ND6, m.8108A > G in COXII, and m.8993T > G in ATPase6. Three mutations were found in tRNA genes: m.4395A > G in tRNA-Gln, m.10454T > C in tRNA-Arg, and m.5587T > C in tRNA-Ala. One patient and their mother both had the m.12338T > C and m.8993T > C mutations. In conclusion, mitochondrial respiratory chain complex I deficiency and structural gene mutations frequently occur in Chinese Leigh syndrome patients.     

喹硫平治疗癫痫所致精神障碍的临床研究

目的探讨喹硫平治疗癫痫所致精神障碍的临床效果及安全性。方法选取2012年1月-2013年12月在新乡医学院第二附属医院住院的,符合《中国精神障碍分类与诊断标准(第3版)》(CCMD-3)的癫痫所致精神障碍患者52例。给予喹硫平治疗4周,自小剂量25mg/d开始,逐渐增加剂量,最高为400mg/d,早晚两次口服。采用阳性和阴性症状量表(PANSS)和副反应量表(TESS)分别评定临床疗效和不良反应。结果喹硫平治疗4周后显效率为71.1%,有效率为88.4%。PANSS阳性症状、阴性症状、精神病理及总评分均低于治疗前,差异有统计学意义(P0.05或0.01)。治疗2周内13例(25.0%)发生不良反应。结论喹硫平可能是一种安全、有效的治疗癫痫所致精神障碍的药物。     

Safe and effective use of the ketogenic diet in children with epilepsy and mitochondrial respiratory chain complex defects

PURPOSE: To evaluate the clinical efficacy and safety of the ketogenic diet (KD) for patients with intractable childhood epilepsy and mitochondrial respiratory chain (RC) complex defects. METHODS: A retrospective analysis evaluated outcomes in 14 children with intractable epilepsy and RC complex defects who were treated with the classic KD involving a 4:1 lipid to nonlipid ratio (% by weight), but without an initial fast and fluid restriction. Outcome measures included seizure frequency, electroencephalography (EEG) findings, the number of antiepileptic drugs, and adverse reactions. RESULTS: Of the 14 patients, 9 had Complex I defects, 1 had a Complex II defect, 3 had Complex IV defects, and 1 had combined Complex I and IV defects. Two patients with Complex IV defects showed clinical progress compatible with the Leigh disease. The epileptic diagnoses were as follows: 5 patients were diagnosed with infantile spasms, 4 with the Lennox-Gastaut syndrome, 1 with the Landau-Kleffner syndrome, 1 with nonspecific generalized seizure disorder, and 3 with partial seizure disorder. The study found that 7 patients became seizure-free after commencing the KD, three of whom successfully completed the diet without relapse. One patient with a greater than 90% seizure reduction, and 2 patients with seizure reductions between 50% and 90%, remained on the diet. Four patients, including two diagnosed with the Leigh disease, did not show any favorable responses to the diet or ceased the diet due to complications. CONCLUSIONS: The KD was a safe and effective therapy for seizures in children with intractable epilepsy and RC complex defects.     

Familial clustering of epilepsy and behavioral disorders: evidence for a shared genetic basis

Purpose: To examine whether family history of unprovoked seizures is associated with behavioral disorders in epilepsy probands, thereby supporting the hypothesis of shared underlying genetic susceptibility to these disorders. Methods: We conducted an analysis of the 308 probands with childhood onset epilepsy from the Connecticut Study of Epilepsy with information on first‐degree family history of unprovoked seizures and of febrile seizures whose parents completed the Child Behavior Checklist (CBCL) at the 9‐year follow‐up. Clinical cutoffs for CBCL problem and Diagnostic and Statistical Manual of Mental Disorders (DSM)–Oriented scales were examined. The association between first‐degree family history of unprovoked seizure and behavioral disorders was assessed separately in uncomplicated and complicated epilepsy and separately for first‐degree family history of febrile seizures. A subanalysis, accounting for the tendency for behavioral disorders to run in families, was adjusted for siblings with the same disorder as the proband. Prevalence ratios were used to describe the associations. Key Findings: In probands with uncomplicated epilepsy, first‐degree family history of unprovoked seizure was significantly associated with clinical cutoffs for Total Problems and Internalizing Disorders. Among Internalizing Disorders, clinical cutoffs for Withdrawn/Depressed, and DSM‐Oriented scales for Affective Disorder and Anxiety Disorder were significantly associated with family history of unprovoked seizures. Clinical cutoffs for Aggressive Behavior and Delinquent Behavior, and DSM‐Oriented scales for Conduct Disorder and Oppositional Defiant Disorder were significantly associated with family history of unprovoked seizure. Adjustment for siblings with the same disorder revealed significant associations for the relationship between first‐degree family history of unprovoked seizure and Total Problems and Aggressive Behavior in probands with uncomplicated epilepsy; marginally significant results were seen for Internalizing Disorder, Withdrawn/Depressed, and Anxiety Disorder. There was no association between family history of unprovoked seizure and behavioral problems in probands with complicated epilepsy. First‐degree family history of febrile seizure was not associated with behavioral problems in probands with uncomplicated or in those with complicated epilepsy. Significance: Increased occurrence of behavioral disorders in probands with uncomplicated epilepsy and first degree family history of unprovoked seizure suggests familial clustering of these disorders. This supports the idea that behavioral disorders may be another manifestation of the underlying pathophysiology involved in epilepsy or closely related to it.     

Brain perfusion SPECT and EEG findings in children with autism spectrum disorders and medically intractable epilepsy

Objective: We performed brain perfusion single-photon emission computed tomography (SPECT) to detect the abnormal brain region in children with both autism spectrum disorders (ASD) and medically intractable epilepsy. Methods: Fifteen children aged 4–16 years underwent multimodal examinations (MRI, interictal and/or ictal ECD-SPECT, EEG and MEG) to investigate their indications for surgical treatment. All children were diagnosed with ASD according to DSM-IV criteria and intractable epilepsy. Despite medical treatment for more than a year, all experienced at least one seizure per month. All had no underlying basic disorders. Each SPECT result was statistically analyzed by comparing with standard SPECT images obtained from our institute (easy Z-score imaging system; eZIS). The relationship between the eZIS pattern and EEG abnormalities or clinical symptoms was investigated. Results: All children showed focal abnormal patterns on eZIS and focal spikes on EEG. In all children, eZIS revealed a mixed hypoperfusion pattern, especially in the prefrontal cortex, medial frontal cortex, anterior cingulate cortex, medial parietal cortex, and/or anterior temporal cortex. In seven of 12 children who underwent interictal SPECT studies, areas of hypoperfusion were related to the focus observed on EEG; in six children, the focal EEG spikes represented areas of hyperperfusion. The children were divided into two groups according to the main type of hypoperfusion patterns seen on eZIS; medial-cingulate type and temporal type. No significant relationship was observed between the areas of hypoperfusion and clinical symptoms. eZIS showed the epileptic focus clearly on ictal SPECT. Conclusions: SPECT was useful to detect the abnormal brain region not only in searching for the epileptic focus but also in assessing the low or high functioning region of the brain.     

The role of SLC2A1 mutations in myoclonic astatic epilepsy and absence epilepsy,and the estimated frequency of GLUT1 deficiency syndrome

The first mutations identified in SLC2A1, encoding the glucose transporter type 1 (GLUT1) protein of the blood–brain barrier, were associated with severe epileptic encephalopathy. Recently, dominant SLC2A1 mutations were found in rare autosomal dominant families with various forms of epilepsy including early onset absence epilepsy (EOAE), myoclonic astatic epilepsy (MAE), and genetic generalized epilepsy (GGE). Our study aimed to investigate the possible role of SLC2A1 in various forms of epilepsy including MAE and absence epilepsy with early onset. We also aimed to estimate the frequency of GLUT1 deficiency syndrome in the Danish population. One hundred twenty patients with MAE, 50 patients with absence epilepsy, and 37 patients with unselected epilepsies, intellectual disability (ID), and/or various movement disorders were screened for mutations in SLC2A1. Mutations in SLC2A1 were detected in 5 (10%) of 50 patients with absence epilepsy, and in one (2.7%) of 37 patient with unselected epilepsies, ID, and/or various movement disorders. None of the 120 MAE patients harbored SLC2A1 mutations. We estimated the frequency of SLC2A1 mutations in the Danish population to be approximately 1:83,000. Our study confirmed the role of SLC2A1 mutations in absence epilepsy with early onset. However, our study failed to support the notion that SLC2A1 aberrations are a cause of MAE without associated features such as movement disorders.     

Mitochondrial involvement in temporal lobe epilepsy

Mitochondrial dysfunction has been identified as a potential cause of epileptic seizures and therapy-resistant forms of severe epilepsy. Thus, a broad variety of mutation in mitochondrial DNA or nuclear genes leading to the impairment of mitochondrial respiratory chain or of mitochondrial ATP synthesis has been associated with epileptic phenotypes. Additionally, with a variety of different methods impaired mitochondrial function has been reported for the seizure focus of patients with temporal lobe epilepsy and Ammon's horn sclerosis and of animal models of temporal lobe epilepsy. Since mitochondrial oxidative phosphorylation provides the major source of ATP in neurons and mitochondria participate in cellular Ca²⁺ homeostasis, their dysfunction strongly affects neuronal excitability and synaptic transmission, which is proposed to be highly relevant for seizure generation. Additionally, mitochondrial dysfunction is known to trigger neuronal cell death, which is a prominent feature of therapy-resistant temporal lobe epilepsy. Therefore, mitochondria have to be considered as promising targets for neuroprotective strategies in epilepsy.     

A multicenter study on the prevalence of psychiatric disorders among new referrals for epilepsy in Japan

PURPOSE: To investigate the prevalence rate and risk factors of psychiatric disorders among new referrals for epilepsy, a multicenter study was conducted by using the International League Against Epilepsy (ILAE) criteria for epilepsy and the ICD-10 criteria for psychiatric disorders. METHODS: From April 2000 to March 2001, 398 patients with epilepsy, who were referred to nine neuropsychiatric outpatient clinics specialized for epilepsy in the Tokyo metropolitan area, were evaluated by using a newly developed five-axis classification scheme. RESULTS: Forty-two percent of the subjects showed a psychiatric disorder. Twenty-four percent of the total showed psychiatric disorders, including neurotic disorders in 8%, psychotic disorders in 7%, and affective disorders in 1%. In addition, 23% of the total showed mental retardation, and 18% showed personality disorders. A logistic regression analysis revealed that the three risk factors for a psychiatric disorder were mental retardation, temporal lobe epilepsy (as opposed to other subtypes), and a high seizure frequency. CONCLUSIONS: The presence of mental retardation was the primary risk factor for developing a psychiatric disorder, especially a schizophrenia-spectrum disorder. The type of epilepsy alone is not a strong predictor of psychiatric illness, and intractable temporal lobe epilepsy with a high seizure frequency is accountable for the link between the epilepsy and the psychiatric illness.     

Usefulness of diagnostic tools in a GLUT1 deficiency syndrome patient with 2 inherited mutations

In some patients with GLUT1 deficiency syndrome (GLUT1-DS), the diagnosis can be difficult to reach. We report a child with 2 inherited mutations suggesting an autosomal recessive transmission of SLC2A1 mutations.MethodsThe child and her parents were explored with erythrocyte 3-O-methyl-d-Glucose uptake, glucose uptake in oocytes expressing GLUT1 with the gene mutations and measure of the expression of GLUT1 at the surface of the circulating red blood cells by flow cytometry (METAglut1™ test).ResultsBoth erythrocyte glucose uptake and glucose uptake in oocyte with the patient’s mutations did not support the diagnosis of a mild GLUT1-DS phenotype with autosomal recessive transmission of SLC2A1 mutations. Instead, GLUT-1 expression at the surface of the erythrocytes appeared to better correlate with the clinical phenotypes in this family.ConclusionThe diagnostic value of these functional/expression tools need to be further studied with a focus on mild phenotype of GLUT1-DS.     

A prospective case control study of psychiatric disorders in adults with epilepsy and intellectual disability

Purpose: No study to date has prospectively investigated the impact of epilepsy on psychiatric disorders among adults with an intellectual disability (ID). This study aimed to determine prospectively the influence of epilepsy on the development of psychiatric disorders in adults with ID. Method: Psychiatric symptoms were measured prospectively over a 1‐year period among 45 adults with ID and active epilepsy and 45 adults with ID without epilepsy, matched on level of ID. The 1‐year incidence rate (IR) of commonly occurring Axis 1 psychiatric disorders was compared with and without controlling for possible confounding factors. Total psychiatric symptom scores over the period were compared between the two groups using repeated‐measures analysis of covariance. Key Findings: Adults with epilepsy and ID had a more than seven times increased risk for developing psychiatric disorders, particularly depression and unspecified disorders of presumed organic origin, including dementia, over a 1‐year period compared to those with ID only. Comparison of the psychiatric scores showed the epilepsy group to have significantly higher unspecified disorder and depression symptom scores. Significance: The findings point to an increased risk of depression and unspecified disorders, including dementia, among adults with ID and epilepsy. Further exploration of the nature and treatment of these unspecified disorders may help the care of people with epilepsy and ID.     

Paroxysmal EEG abnormalities and epilepsy in pervasive developmental disorders: Follow-up study until adolescence and beyond

This study examined paroxysmal abnormalities and epilepsy in EEG for individuals with pervasive developmental disorders (PDD) in two parts: first with a large number of subjects (n = 1624); and second with extracted subjects followed from ?5 years into adolescence and beyond (n = 92). Many paroxysms in PDD patients in their childhood tended to appear at various sites and the same held for paroxysms at the time of epilepsy onset. However, in adolescence and beyond, paroxysms in the frontal region prevailed as those appearing at sites other than the frontal region tended to disappear. The same held for paroxysms at the time of epilepsy onset. These paroxysms in the frontal area characteristic of PDD were named “Paroxysms at F.” It was suggested that functional abnormality in the frontal region exists in PDD through paroxysmal EEG abnormalities and epilepsy.