Effective and safe diet therapies for Lennox-Gastaut syndrome with mitochondrial dysfunction

Background: Lennox-Gastaut syndrome (LGS) is a typical intractable form of epilepsy that most often occurs between the second and sixth year of life. This study aimed to evaluate the clinical efficacy and safety of ketogenic diet therapies (DTs) for LGS with mitochondrial dysfunction. Methods: This was a retrospective study involving 20 LGS patients with mitochondrial dysfunction who received several DTs from 2004 to 2014 at a single tertiary care center. Seizure reduction rate, cognitive function, retention rate, electroencephalography (EEG) changes, and adverse effects were examined before and after DTs. Results: The retention rates at 1 and 2 years after initiation of DTs were 45% and 40%, respectively. After 1-year follow up, we observed seizure freedom in two patients, 75% seizure reduction in two patients, 50% reduction in three patients, and 25% reduction in one patient. After 2-year follow up, the outcomes were seizure freedom in two patients, 90% seizure reduction in one patient, 75% reduction in two patients, and 50% reduction in two patients. EEG findings improved in nine patients. Nine patients were treated with DTs for 1 year; all patients demonstrated improved cognitive status. Eight patients were treated with DTs for 2 years, of whom seven had improved cognitive status. Poor tolerability of DTs was due to poor oral intake and gastrointestinal problems. Conclusions: We demonstrate that, in LGS with mitochondrial dysfunction, improvement of seizures and cognitive function are not inferior to those in other patients treated with DTs. This study showed that DTs are efficacious and feasible for LGS patients with mitochondrial dysfunction and can significantly improve their prognosis.ope

Systematic Approach for Drug Repositioning of Anti-Epileptic Drugs

Epilepsy is a central neurological disorder affecting individuals of all ages and causing unpredictable seizures. In spite of the improved efficacy of new antiepileptic drugs and novel therapy, there are still approximately 20%~30% of patients, who have either intractable or uncontrolled seizures. The epilepsy drug-target network (EDT) is constructed and successfully demonstrates the characteristics and efficacy of popularly used AEDs through the identification of causative genes for 60 epilepsy patients. We discovered that the causative genes of most intractable patients were not the targets of existing AEDs, as well as being very far from the etiological mechanisms of existing AEDs in the functional networks. We show that the existence of new drugs that target the causative genes of intractable epilepsy patients, which will be potential candidates for refractory epilepsy patients. Our systematic approach demonstrates a new possibility for drug repositioning through the combination of the drug-target and functional networks.ope

Intravenous Immunoglobulin in the Treatment of Neurological Diseases

Intravenous immunoglobulin (IVIG) is used in treating many cases of autoimmune and inflammatory conditions thanks to its multiple anti-inflammatory and immunomodulatory properties. The clinical use of IVIG has been for the patients with primary immunodeficiencies, but lately it is expanding its usage to the realms of treating patients with neurological conditions. Both the efficacy and safety of IVIG treatment in chronic inflammatory demyelinating polyradiculoneuropathy and Guillain–Barré syndrome have been studied successfully. However, the use of IVIG treatment in other neurological conditions still remains investigational despite several successful reports. Considerable numbers of mechanisms have been suggested in order to explain the effects of IVIG, but the exact mechanisms are not understood yet. This review covers the new developments in clinical fields and the possible ways in which IVIG could help in the future.ope

The Usefulness of Muscle Biopsy in Initial Diagnostic Evaluation of Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes

PURPOSE: The disease entity mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is characterized by an early onset of stroke-like episodes. MELAS is the most dominant subtype of mitochondrial disease. Molecular genetic testing is important in the diagnosis of MELAS. The mitochondrial DNA (mtDNA) 3243A>G mutation is found in 80% of MELAS patients. Nevertheless, molecular analysis alone may be insufficient to diagnose MELAS because of mtDNA heteroplasmy. This study aimed to evaluate whether muscle biopsy is useful in MELAS patients as an initial diagnostic evaluation method. MATERIALS AND METHODS: The medical records of patients who were diagnosed with MELAS at the Department of Pediatrics of Gangnam Severance Hospital between January 2006 and January 2017 were reviewed. The study population included 12 patients. They were divided into two subgroups according to whether the results of muscle pathology were in accordance with mitochondrial diseases. Clinical variables, diagnostic evaluations, and clinical outcomes were compared between the two groups. RESULTS: Of the 12 patients, seven were muscle pathology-positive for mitochondrial disease. No statistically significant difference in clinical data was observed between the groups that were muscle pathology-positive and muscle pathology-negative for mtDNA 3243A>G mutation. Additionally, the patients with weakness as the initial symptom were all muscle pathology-positive. CONCLUSION: The usefulness of muscle biopsy appears to be limited to an initial confirmative diagnostic evaluation of MELAS. Muscle biopsy can provide some information in MELAS patients with weakness not confirmed by genetic testing.ope

Lennox-Gastaut Syndrome in Mitochondrial Disease

PURPOSE: Previous studies have shown that neurologic symptoms are dominant in patients with mitochondrial diseases, and most of these patients have seizure-related disorders. The epileptic classification of these patients as Lennox-Gastaut syndrome (LGS) is as high as 25%. This study aimed to investigate the clinical manifestations, diagnoses, treatments, and epilepsy in LGS, which is associated with mitochondrial disease. MATERIALS AND METHODS: A retrospective study was conducted on 372 patients who were diagnosed with mitochondrial disease between 2006 and 2016. Of these 372 patients, 40 patients diagnosed with LGS were selected, and they were classified into two groups based on the history of West syndrome. Patient characteristics were reviewed, and associations between clinical factors and outcomes after the treatment were analyzed. RESULTS: The proportion of individuals with mitochondrial disease with LGS with a history of West syndrome was 32.5%. Among the patients with mitochondrial disease with LGS, neonatal seizure (p=0.029), seizure as the first symptom (p=0.018), and generalized paroxysmal fast activity frequency on electroencephalogram (p=0.018) in the group with a history of West syndrome were statistically significantly high. The first symptom onset (0.6±0.4 yrs vs. 1.6±0.9 yrs, p=0.003) and first seizure onset (0.9±0.7 yrs vs. 3.9±3.1 yrs, p<0.001) were significantly faster in patients with a history of West syndrome. CONCLUSION: Close monitoring of the medical condition and early intervention might improve the prognosis of individuals with mitochondrial disease with LGS and a history of West syndrome.ope

Leigh Syndrome: Subgroup Aanalysis according to Mitochondrial DNA Mutation

Purpose: Leigh syndrome (LS) is a rare, progressive neurodegenerative disorder with characteristic abnormalities in the central nervous system. Such patients present with heterogeneous clinical symptoms and genetic abnormalities; thus, prognosis is difficult to anticipate. The present study investigates whether distinct patient characteristics are associated with mitochondrial DNA (mtDNA) mutation in LS patients. Methods: : We retrospectively analyzed data from patients diagnosed with LS at our hospital who were assessed using genomic sequencing of mtDNA. A subgroup analysis was performed to divide patients according to the mtDNA sequencing results. Results: Among the 85 patients enrolled, 18 had mtDNA mutations. Most patients had lactic acidosis and a lactate/pyruvate ratio above 20, indicating respiratory chain abnormalities. In the subgroup analysis, the mutation group had a significantly higher female-to-male ratio, alanine level, ocular involvement, and midbrain and medulla abnormalities on magnetic resonance imaging (MRI). Conclusion: The subgroup analysis indicates that mtDNA sequencing is recommended for female patients, or those who exhibit ocular involvement, high alanine levels, or MRI findings with lesions in the midbrain and medulla.ope

Ophthalmoplegia in Mitochondrial Disease

PURPOSE: To evaluate the classification, diagnosis, and natural course of ophthalmoplegia associated with mitochondrial disease. MATERIALS AND METHODS: Among 372 patients with mitochondrial disease who visited our hospital between January 2006 and January 2016, 21 patients with ophthalmoplegia were retrospectively identified. Inclusion criteria included onset before 20 years of age, pigmentary retinopathy, and cardiac involvement. The 16 patients who were finally included in the study were divided into three groups according to disease type: Kearns-Sayre syndrome (KSS), KSS-like, and chronic progressive external ophthalmoplegia (CPEO). RESULTS: The prevalences of clinical findings were as follows: ptosis and retinopathy, both over 80%; myopathy, including extraocular muscles, 75%; lactic acidosis, 71%; and elevated levels of serum creatine kinase, 47%. Half of the patients had normal magnetic resonance imaging findings. A biochemical enzyme assay revealed mitochondrial respiratory chain complex I defect as the most common (50%). The prevalence of abnormal muscle findings in light or electron microscopic examinations was 50% each, while that of large-scale mitochondrial DNA (mtDNA) deletions in a gene study was 25%. We compared the KSS and KSS-like groups with the CPEO patient group, which showed pigmentary retinopathy (p<0.001), cardiac conduction disease (p=0.013), and large-scale mtDNA deletions (p=0.038). KSS and KSS-like groups also had gastrointestinal tract disorders such as abnormal gastrointestinal motility (p=0.013) unlike the CPEO group. CONCLUSION: Patients with KSS had gastrointestinal symptoms, which may indicate another aspect of systemic involvement. The presence of large-scale mtDNA deletions was an objective diagnostic factor for KSS and a gene study may be helpful for evaluating patients with KSS.ope

Identification of Missense ADGRV1 Mutation as a Candidate Genetic Cause of Familial Febrile Seizure 4

Febrile seizure (FS) is related to a febrile illness (temperature > 38 °C) not caused by an infection of central nervous system, without neurologic deficits in children aged 6-60 months. The family study implied a polygenic model in the families of proband(s) with single FS, however in families with repeated FS, inheritance was matched to autosomal dominance with reduced disease penetrance. A 20 month-old girl showed recurrent FS and afebrile seizures without developmental delay or intellectual disability. The seizures disappeared after 60 months without anti-seizure medication. The 35 year-old proband's mother also experienced five episodes of simple FS and two episodes of unprovoked seizures before 5 years old. Targeted exome sequencing was conducted along with epilepsy/seizure-associated gene-filtering to identify the candidate causative mutation. As a result, a heterozygous c.2039A>G of the ADGRV1 gene leading to a codon change of aspartic acid to glycine at the position 680 (rs547076322) was identified. This protein's glycine residue is highly conserved, and its allele frequency is 0.00002827 in the gnomAD population database. ADGRV1 mutation may have an influential role in the occurrence of genetic epilepsies, especially those with febrile and afebrile seizures. Further investigation of ADGRV1 mutations is needed to prove that it is a significant susceptible gene for febrile and/or afebrile seizures in early childhood.ope

Causality Assessment Guidelines for Adverse Events Following Immunization With a Focus on Guillain-Barré Syndrome

South Korea operates a National Vaccine Injury Compensation Program (VICP) for people who experience adverse events following immunization (AEFI). To run this program rationally, it is a prerequisite to confirm whether adverse events were caused by immunization. Guillain-Barré syndrome (GBS), a severe neurological disease with limb pain and muscle weakness as cardinal symptoms, is attracting attention as an AEFI. However, algorithm or guidelines for assessing the causality between vaccination and the incidence of GBS are lacking. We aimed to develop guidelines for causality assessment of GBS as an AEFI and suggest using these guidelines in alignment with the VICP. We systematically searched for other previously published algorithms or guidelines and found a WHO-AEFI guideline used worldwide; however, it only provides general instructions and is not tailored to specific adverse events. We translated and locally adapted the structure of this guideline and then added contents related to GBS. The GBS-specific guideline consists of four steps: case ascertainment of GBS, checklist (including (1) order of incidence, (2) temporal proximity, (3) evidence for other causes and (4) published evidence), an algorithm, and final classification. We listed key information on confirming GBS and whether any other causes of GBS were present. For real world application of the guideline along with the VICP, we collaborated with a panel of neurologists, epidemiologic investigators, and committee members from the VICP. To ensure transparency and a scientific approach, regular updates and collaboration with neurologists are essential. We expect that this guideline will contribute to logical causality assessment and compensation decisions for GBS and will provide the basic structure for causality assessment of other AEFIs.ope

Complete Penetrance but Different Phenotypes in a Korean Family with Maternal Interstitial Duplication at 15q11.2-q13.1: A Case Report

The 15q duplication syndrome (dup15q) is due to the presence of at least one additional derived copy of the Prader-Willi syndrome/Angelman syndrome (PWS/AS) critical region that is approximately 5 Mb long within chromosome 15q11.2-q13.1. This report describes distinct roles of the origin of interstitial (int) dup15q underlining the critical importance of maternally active imprinted genes in the contribution to complete penetrance but different phenotypes of neuropsychotic disorders such as schizophrenia (SCZ) and autism spectrum disorder (ASD) in a Korean family. The proband's mother as a consultant visited our hospital for her offspring's genetic counseling and segregation analysis. She had two daughters diagnosed as SCZ or ASD and one son diagnosed as ASD. To resolve the potential genetic cause of SCZ and ASD in the proband and her sibling, whole genomic screening of chromosomal rearrangements by array-comparative genomic hybridization (CGH) was performed using SurePrint G3 Human CGH + SNP Microarray 4 × 180 K. Results of the array-CGH analysis revealed an interstitial duplication at 15q11.2-q13.1 (duplication size of 5.4 Mb) in the mother and her three offspring with SCZ or ASD. Our case, together with previous findings of high occurrence of psychotic disorder, suggest that maternally expressed gene product in the critical region of PWS/AS might mediate the risk of neurodevelopmental disorder (ASD) as well as psychotic disorder (SCZ). Multiple cytogenetic and molecular methods are recommended for investigating children with 15q11.2-q13.1 duplication and neuropsychotic disorders.ope