Nusinersen for Spinal Muscular Atrophy Type I with Chronic Respiratory Failure: A Retrospective Study in South Korea

Purpose@#To analyze the efficacy and safety of nusinersen in patients with spinal muscular atrophy (SMA) type I with chronic respiratory failure. @*Materials and Methods@#We retrospectively reviewed seven patients diagnosed with SMA type I and chronic respiratory failure who were on permanent ventilation and treated with nusinersen at Gangnam Severance Hospital between January 2018 and July 2023. Patient demographics and clinical characteristics were recorded, and treatment progress was evaluated according to Hammersmith Infant Neurological Examination (HINE-2) and Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) scores. @*Results@#Patients initially developed hypotonia at a mean age of 3.7 months. Mean age at start of nusinersen was 7.3 years; the mean duration of follow-up after starting nusinersen was 46.2 months. At 6-, 18-, 38-, 58-, and 74-month follow-up, the mean changes in CHOP-INTEND scores were 1.0, 2.9, 1.8, 1.5, and 1.5, respectively, and the proportions of patients who showed disease amelioration were 28.6%, 71.4%, 75.0%, 100%, and 100%, respectively. @*Conclusion@#Nusinersen is safe and effective in patients with SMA type I, even those with chronic respiratory failure and those on permanent ventilation. No significant adverse effects of nusinersen were observed.

A female patient with Xp21 gene deletion syndrome

Xp21 contiguous gene deletion syndrome is associated with complex glycerol kinase deficiency, congenital adrenal hypoplasia, Duchene muscular dystrophy, and intellectual disability. Xp21 gene deletion syndrome is X-linked recessive, so most symptomatic patients are male, and only a few female symptomatic patients have been reported. We report the first female Korean case of an Xp21 deletion. NGS data were analyzed for copy number variation, and the Xp21 deletion (chr X:29301056-31838200) was confirmed using real-time PCR.

Epidemiological Features and Economic Burden of Guillain-Barré Syndrome in South Korea:A Nationwide Population-Based Study

Background@#and Purpose Guillain-Barré syndrome (GBS) is rare, but its symptoms are severe and they occasionally lead to long-term disability. Country-specific epidemiological evidence is useful for detecting potential problems at the population level. This study investigated the epidemiological and economic characteristics of GBS in South Korea. @*Methods@#The Korean National Health Insurance Service claims data from 2010 to 2016 were used to identify incident cases as newly hospitalized patients with a primary diagnosis of GBS (the 10th revision of the International Classification Disease code of G61.0). New cases were defined as patients not having claim records for GBS within one year prior to the hospital admission for GBS. @*Results@#The incidence rate increased by 45.6% between 2010 and 2016, from 1.28 to 1.82 per 100,000 population. All age groups other than <20 years showed increasing trends. The incidence rate was highest in those aged 65 years to 74 years. Approximately 72% of the incident GBS cases had antecedent infection within 42 days before GBS was diagnosed. Children younger than 10 years constituted the highest proportion of antecedent infections (93.7%).The average length of stay per GBS hospitalization was 33.5 days. Patients had an average of 7.48 outpatient visits for GBS treatment per year. The economic burden from a societal perspective of treating GBS during the first year was USD 16,428. @*Conclusions@#The increasing incidence trend and substantial economic burden of GBS strongly advocate the development of effective strategies for preventing and managing GBS.

Epidemiological Features and Economic Burden of Guillain-Barré Syndrome in South Korea:A Nationwide Population-Based Study

Background@#and Purpose Guillain-Barré syndrome (GBS) is rare, but its symptoms are severe and they occasionally lead to long-term disability. Country-specific epidemiological evidence is useful for detecting potential problems at the population level. This study investigated the epidemiological and economic characteristics of GBS in South Korea. @*Methods@#The Korean National Health Insurance Service claims data from 2010 to 2016 were used to identify incident cases as newly hospitalized patients with a primary diagnosis of GBS (the 10th revision of the International Classification Disease code of G61.0). New cases were defined as patients not having claim records for GBS within one year prior to the hospital admission for GBS. @*Results@#The incidence rate increased by 45.6% between 2010 and 2016, from 1.28 to 1.82 per 100,000 population. All age groups other than <20 years showed increasing trends. The incidence rate was highest in those aged 65 years to 74 years. Approximately 72% of the incident GBS cases had antecedent infection within 42 days before GBS was diagnosed. Children younger than 10 years constituted the highest proportion of antecedent infections (93.7%).The average length of stay per GBS hospitalization was 33.5 days. Patients had an average of 7.48 outpatient visits for GBS treatment per year. The economic burden from a societal perspective of treating GBS during the first year was USD 16,428. @*Conclusions@#The increasing incidence trend and substantial economic burden of GBS strongly advocate the development of effective strategies for preventing and managing GBS.

A case of Galloway-Mowat syndrome with novel compound heterozygous variants in the WDR4 gene

The combination of central nervous system abnormalities and renal impairment is a notable characteristic of GallowayMowat syndrome (GAMOS), a disease which often accompanies microcephaly, developmental delay, and nephrotic syndrome. Many subtypes exist having various phenotypes and genotypes, and many genetic causes are still being identified.An 18-month-old boy first visited our clinic for seizure, delayed development, and microcephaly. During follow-up visits he developed proteinuria and nephrotic syndrome at the age of 6. Nephrotic syndrome became refractory to treatment. These phenotypes were suggestive of GAMOS. Next generation sequencing was performed for genetic analysis and revealed novel compound heterozygous variants in the WDR4 gene: c.494G>A (p.Arg165Gln) and c.540C>G (p.Ile180Met). This is the first case in Korea of GAMOS involving the WDR4 gene.

A case of Galloway-Mowat syndrome with novel compound heterozygous variants in the WDR4 gene

The combination of central nervous system abnormalities and renal impairment is a notable characteristic of GallowayMowat syndrome (GAMOS), a disease which often accompanies microcephaly, developmental delay, and nephrotic syndrome. Many subtypes exist having various phenotypes and genotypes, and many genetic causes are still being identified.An 18-month-old boy first visited our clinic for seizure, delayed development, and microcephaly. During follow-up visits he developed proteinuria and nephrotic syndrome at the age of 6. Nephrotic syndrome became refractory to treatment. These phenotypes were suggestive of GAMOS. Next generation sequencing was performed for genetic analysis and revealed novel compound heterozygous variants in the WDR4 gene: c.494G>A (p.Arg165Gln) and c.540C>G (p.Ile180Met). This is the first case in Korea of GAMOS involving the WDR4 gene.

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.

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.

The Author Reply: Genetic Data Are a Prerequisite for Interpreting Clinical and Muscle Biopsy Findings in MELAS

No abstract available.

The Author Reply: Mitochondrial Ophthalmoplegia Is Not Only due to mtDNA Deletions

No abstract available.

Genotype-phenotype correlations in pediatric patients with myotonic dystrophy type 1 / 소아과

PURPOSE: Myotonic dystrophy, also known as dystrophia myotonica (DM), is an autosomal dominant disorder with 2 genetically distinct forms. DM type 1 (DM1) is the more common form and is caused by abnormal expansion of cytosine/thymine/guanine (CTG) repeats in the DM protein kinase (DMPK) gene. Our study aimed to determine whether the age of onset is correlated with CTG repeat length in a population of pediatric patients with DM1. METHODS: We retrospectively identified 30 pediatric patients with DM1 that underwent DMPK testing, of which the clinical data of 17 was sufficient. The cohort was divided into 2 subgroups based on the clinical phenotype (congenital-onset vs. late-onset) and number of CTG repeats ( < 1,000 vs. ≥1,000). RESULTS: We found no significant difference between the age of onset and CTG repeat length in our pediatric patient population. Based on clinical subgrouping, we found that the congenital-onset subgroup was statistically different with respect to several variables, including prematurity, rate of admission to neonatal intensive care unit, need for respiratory support at birth, hypotonia, dysphagia, ventilator dependence, and functional status on last visit, compared to the late-onset subgroup. Based on genetic subgrouping, we found a single variable (poor feeding in neonate) that was significantly different in the large CTG subgroup than that in the small CTG subgroup. CONCLUSION: Clinical variables exhibiting statistically significant differences between the subgroups should be focused on prognosis and designing tailored management approaches for the patients; our findings will contribute to achieve this important goal for treating patients with DM1.

Adverse Events During Perampanel Adjunctive Therapy in Intractable Epilepsy

BACKGROUND AND PURPOSE: Perampanel is the first α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-receptor antagonist developed to treat epilepsy. The effects of either rapid or slow dose titration on adverse events remain to be elucidated. METHODS: Eighty-five patients received perampanel between March 2016 and August 2016. Patients were divided into two groups according to their dosing schedule: rapid dose titration (2-mg increments at intervals of 1 to 2 weeks) and slow dose titration (2-mg increments at intervals of at least 3 weeks). Seizure frequency and adverse events were analyzed over 3 months. RESULTS: Adverse events were reported by 47 (58%) of the 81 patients analyzed, with 12 (15%) patients discontinuing perampanel due to adverse events. Common adverse events included dizziness (n=30, 37%), aggressive mood and behavior (n=19, 24%), gait disturbance (n=16, 20%), and sleep problems (n=10, 12.4%). The overall adverse events were similar in the slow-titration group (38 of 61 patients) and the rapid-titration group (8 of 20 patients, p=0.081). However, none of the 20 patients in the slow-titration group experienced gait disturbance, compared with 16 of the 61 patients in the rapid-titration group (p=0.009), while appetite change was experienced by 4 patients in the slow-titration group but only 1 in the rapid-titration group (p=0.003). No relationship was noted between adverse events and the maximum dose of perampanel (p=0.116). Sex differences were observed, with the response to perampanel being better and the rate of adverse events being higher in females (p=0.015 and p=0.046, respectively). CONCLUSIONS: Slow titration of perampanel may reduce perampanel-related adverse events.

Intravenous Immunoglobulin in the Treatment of Neurological Diseases / 대한소아신경학회지

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.

Leigh Syndrome: Subgroup Aanalysis according to Mitochondrial DNA Mutation / 대한소아신경학회지

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.

Age-Based Characteristics of West Syndrome in Patients with Mitochondrial Disease / 대한소아신경학회지

PURPOSE: West syndrome is a severe form of age-specific epilepsy that typically affects infants younger than 2 years of age with mitochondrial disease. We aimed to examine age-specific characteristics of the syndrome in these patients. METHODS: We retrospectively analyzed 54 patients with West syndrome diagnosed with mitochondrial disease between March 2006 and March 2016. We compared treatment strategies and diagnostic and clinical variables between patients with early-onset ( < 6 months of age) and late-onset (≥6 months of age) seizures. RESULTS: Seizure was the first symptom in 30 (90.9%) and 13 (65%) patients of the early-onset and late-onset groups, respectively (P=0.046). Delayed development was observed in 3 (9.1%) and 7 (35%) patients of the early-onset and late-onset groups, respectively (P=0.023). Lactate levels were normal in 17 patients (55%) of the early-onset group and 5 (25%) of the late-onset group (P=0.036), while initial brain magnetic resonance imaging (MRI) findings were normal in 23 (67.6%) and 8 (40%) patients of the early-onset and late-onset groups, respectively. Final MRI findings were abnormal in 32 patients (94.1%) of the early-onset group and 18 (90%) of the late-onset group (P=0.036). Although ketogenic diets reduced seizure frequency in both groups, the difference was not significant. CONCLUSION: There is no significant difference in epilepsy-related variables when patients are divided based on a cut-off age of 6 months. However, differences in the first symptom at onset and MRI findings were observed. Although lactate levels were not of significant diagnostic value in the early-onset group, they may be in the late-onset group.

Myocardial Layer-Specific Strain Analysis in Children with Mitochondrial Disease

PURPOSE: Children with mitochondrial disease (MD) have clinical phenotypes that are more severe than those found in adults. In this study, we assessed cardiac function in children with MD using conventional and advanced echocardiographic measurements, explored any unique patterns present, and investigated the development of early cardiomyopathy (CMP). MATERIALS AND METHODS: We retrospectively reviewed the medical records of 33 children with MD. All patients underwent transthoracic echocardiography with conventional and advanced myocardial analysis. We compared all data between patients and an age-matched healthy control group. RESULTS: Conventional echocardiographic diastolic measurements of mitral E, E/A, and tissue Doppler E′ were significantly lower and E/E′ was significantly higher in children with MD, compared with the measurements from the control group. There was no significant difference in longitudinal and radial strain between the groups. Circumferential strain in the endocardium (p=0.161), middle myocardium (p=0.008), and epicardium (p=0.042) were lower in patients, compared to the values in controls. Circumferential strain was correlated with E′ (p 0.60). CONCLUSION: In children with MD, myocardial circumferential strain may develop early in all three layers, even with normally preserved longitudinal and radial strain. This may be an early diagnostic indicator with which to predict CMP in this patient population.

Integrated diagnostic approach of pediatric neuromuscular disorders

Clinical and genetic heterogeneity in association with overlapping spectrum is characteristic in pediatric neuromuscular disorders, which makes confirmative diagnosis difficult and time consuming. Considering evolution of molecular genetic diagnosis and resultant upcoming genetically modifiable therapeutic options, rapid and cost-effective genetic testing should be applied in conjunction with existing diagnostic methods of clinical examinations, laboratory tests, electrophysiologic studies and pathologic studies. Earlier correct diagnosis would enable better clinical management for these patients in addition to new genetic drug options and genetic counseling.

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.

Ultrastructural Changes in Skeletal Muscle of Infants with Mitochondrial Respiratory Chain Complex I Defects

BACKGROUND AND PURPOSE: The pathogenesis of mitochondrial disease (MD) involves the disruption of cellular energy metabolism, which results from defects in the mitochondrial respiratory chain complex (MRC). We investigated whether infants with MRC I defects showed ultrastructural changes in skeletal muscle. METHODS: Twelve infants were enrolled in this study. They were initially evaluated for unexplained neurodegenerative symptoms, myopathies, or other progressive multiorgan involvement, and underwent muscle biopsies when MD was suspected. Muscle tissue samples were subjected to biochemical enzyme assays and observation by transmission electron microscopy. We compared and analyzed the ultrastructure of skeletal muscle tissues obtained from patients with and without MRC I defects. RESULTS: Biochemical enzyme assays confirmed the presence of MRC I defects in 7 of the 12 patients. Larger mitochondria, lipid droplets, and fused structures between the outer mitochondrial membrane and lipid droplets were observed in the skeletal muscles of patients with MRC I defects. CONCLUSIONS: Mitochondrial functional defects in MRC I disrupt certain activities related to adenosine triphosphate synthesis that produce changes in the skeletal muscle. The ultrastructural changes observed in the infants in this study might serve as unique markers for the detection of MD.

SCN1A Variants in Patients with Dravet Syndrome / 대한소아신경학회지

PURPOSE: The aim of this study is to examine the SCN1A variants in Korean patients with Dravet syndrome. METHODS: We conducted a retrospective study of clinically confirmed thirty-nine patients with Dravet syndrome who visit our hospital from January 2007 to May 2015. We analyzed the SCN1A variants by direct sequencing. We analyzed and classified SCN1A variants according to ACMG/AMP (American College of Medical Genetics and Genomics and the Association for Molecular Pathology) guideline. RESULTS: A total thirty-nine patients (female 22, male 17) were included. Among them, twenty patients (51.2%) with Dravet syndrome had pathogenic or likely pathogenic SCN1A mutations including fifteen truncating mutations (12 nonsense and 3 splice region mutations), 5 missense mutations. The remained variants in nineteen patients with Dravet syndrome classified into ten variants of unknown significances, and 9 benign variants. In our study, truncation mutations are located whole span of SCN1A protein, while half of missense mutations are located at higher density on pore loop (S5-S6) regions. CONCLUSION: Unlike previous known study, lower positive rate of SCN1A mutation of Dravet syndrome was revealed in our study. The importance of parental test (trio test) and other additional tests have been emphasized.