Clinical feature, GALC variant spectrum, and genotype-phenotype correlation in Korean Krabbe disease patients: Multicenter experience over 13 years.

Krabbe disease (KD) is an autosomal recessive neurodegenerative disorder caused by deficiency of the galactocerebrosidase (GALC) due to variants in the GALC gene. Here, we provide the first and the largest comprehensive analysis of clinical and genetic characteristics, and genotype-phenotype correlations of KD in Korean in comparison with other ethnic groups. From June 2010 to June 2023, 10 patients were diagnosed with KD through sequencing of GALC. Clinical features, and results of GALC sequencing, biochemical test, neuroimaging, and neurophysiologic test were obtained from medical records. An additional nine previously reported Korean KD patients were included for review. In Korean KD patients, the median age of onset was 2 years (3 months-34 years) and the most common phenotype was adult-onset (33%, 6/18) KD, followed by infantile KD (28%, 5/18). The most frequent variants were c.683_694delinsCTC (23%) and c.1901T>C (23%), while the 30-kb deletion was absent. Having two heterozygous pathogenic missense variants was associated with later-onset phenotype. Clinical features were similar to those of other ethnic groups. In Korean KD patients, the most common phenotype was the adult-onset type and the GALC variant spectrum was different from that of the Caucasian population. This study would further our understanding of KD.

Assessing the landscape of STXBP1-related disorders in 534 individuals.

Disease-causing variants in STXBP1 are among the most common genetic causes of neurodevelopmental disorders. However, the phenotypic spectrum in STXBP1-related disorders is wide and clear correlations between variant type and clinical features have not been observed so far. Here, we harmonized clinical data across 534 individuals with STXBP1-related disorders and analysed 19 973 derived phenotypic terms, including phenotypes of 253 individuals previously unreported in the scientific literature. The overall phenotypic landscape in STXBP1-related disorders is characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of individuals, including focal-onset seizures as the most common seizure type (47%). More than 88% of individuals with STXBP1-related disorders have seizure onset in the first year of life, including neonatal seizure onset in 47%. Individuals with protein-truncating variants and deletions in STXBP1 (n = 261) were almost twice as likely to present with West syndrome and were more phenotypically similar than expected by chance. Five genetic hotspots with recurrent variants were identified in more than 10 individuals, including p.Arg406Cys/His (n = 40), p.Arg292Cys/His/Leu/Pro (n = 30), p.Arg551Cys/Gly/His/Leu (n = 24), p.Pro139Leu (n = 12), and p.Arg190Trp (n = 11). None of the recurrent variants were significantly associated with distinct electroclinical syndromes, single phenotypic features, or showed overall clinical similarity, indicating that the baseline variability in STXBP1-related disorders is too high for discrete phenotypic subgroups to emerge. We then reconstructed the seizure history in 62 individuals with STXBP1-related disorders in detail, retrospectively assigning seizure type and seizure frequency monthly across 4433 time intervals, and retrieved 251 anti-seizure medication prescriptions from the electronic medical records. We demonstrate a dynamic pattern of seizure control and complex interplay with response to specific medications particularly in the first year of life when seizures in STXBP1-related disorders are the most prominent. Adrenocorticotropic hormone and phenobarbital were more likely to initially reduce seizure frequency in infantile spasms and focal seizures compared to other treatment options, while the ketogenic diet was most effective in maintaining seizure freedom. In summary, we demonstrate how the multidimensional spectrum of phenotypic features in STXBP1-related disorders can be assessed using a computational phenotype framework to facilitate the development of future precision-medicine approaches.

Complications of the Central Nervous System in Pediatric Patients With Common Cold Coronavirus Infection During 2014-2019.

BACKGROUND: In pediatric patients, the common cold coronavirus (ccCoV) usually causes mild respiratory illness. There are reports of coronavirus causing central nervous system (CNS) infection in experimental animal models. Some immunocompromised patients have also been reported to have fatal CNS infections with ccCoV. The aim of this study was to investigate the clinical characteristics of CNS complications related to ccCoV infection. METHODS: From January 2014 to December 2019, a retrospective analysis was performed of medical records from hospitalized patients under 19 years of age whose ccCoV was detected through polymerase chain reaction in respiratory specimens. The CNS complications were defined as clinically diagnosed seizure, meningitis, encephalopathy, and encephalitis. RESULTS: A total of 436 samples from 420 patients were detected as ccCoV. Among the 420 patients, 269 patients were immunocompetent and 151 patients were immunocompromised. The most common type of ccCoV was OC43 (52% in immunocompetent, 37% in immunocompromised). CNS complications were observed in 9.4% (41/436). The most common type of CNS complication was the fever-provoked seizure under pre-existing neurologic disease (42% in immunocompetent and 60% in immunocompromised patients). Among patients with CNS complications, two immunocompetent patients required intensive care unit admission due to encephalitis. Three patients without underlying neurological disease started anti-seizure medications for the first time at this admission. There was no death related to ccCoV infection. CONCLUSION: ccCoV infection may cause severe clinical manifestations such as CNS complications or neurologic sequelae, even in previously healthy children.

The longitudinal effect of oxcarbazepine on thyroid function in children and adolescents with epilepsy.

OBJECTIVE: Thyroid hormone abnormalities have been linked to antiseizure medications (ASMs). Oxcarbazepine is considered safer than carbamazepine because it induces the hepatic cytochrome P450 metabolic enzymes less than the carbamazepine does. However, limited data exist for the influence of oxcarbazepine on thyroid function in children and adolescents. The objective of this study was to determine the effect of oxcarbazepine on thyroid function in these patients. METHODS: A total of 162 pediatric patients with epilepsy who started oxcarbazepine for the first time between April 2003 and May 2020 were enrolled. The longitudinal effects of oxcarbazepine for thyroid functions were confirmed using general estimating equations. RESULTS: Serum triiodothyronine (T3), thyroxine (T4), and free thyroxine (fT4) levels decreased significantly during 5 years of follow-up (all p's < .001). In particular, T3 and fT4 levels were reduced steeply in the first 2 years of oxcarbazepine treatment. There was no significant change in thyroid-stimulating hormone during oxcarbazepine treatment. SIGNIFICANCE: Serum T3, T4, and fT4 levels decreased significantly during oxcarbazepine use, and this change was maintained during the treatment period. In patients receiving oxcarbazepine, it is recommended that periodic thyroid function testing should be performed, especially within the first 2 years after starting this ASM. Our results indicate that oxcarbazepine-induced hypothyroidism does not appear to be accompanied by a significant increase in TSH, and consequently might be missed if TSH alone is monitored as a measure of thyroid dysfunction.

A New Method of Myostatin Inhibition in Mice via Oral Administration of Lactobacillus casei Expressing Modified Myostatin Protein, BLS-M22.

Myostatin is a member of the transforming growth factor-beta superfamily and is an endogenous negative regulator of muscle growth. This study aimed to determine whether an oral administration of Lactobacillus casei expressing modified human myostatin (BLS-M22) could elicit sufficient levels of myostatin-specific antibody and improve the dystrophic features of an animal model of Duchenne muscular dystrophy (DMD; mdx mouse). BLS-M22 is a recombinant L. casei engineered to harbor the pKV vector and poly-gamma-glutamic acid gene linked to a modified human myostatin gene. Serological analysis showed that anti-myostatin IgG titers were significantly increased, and serum creatine kinase was significantly reduced in the BLS-M22-treated mdx mice compared to the control mice. In addition, treatment of BLS-M22 resulted in a significant increase in body weight and motor function (Rotarod behavior test). Histological analysis showed an improvement in the dystrophic features (fibrosis and muscle hypertrophy) of the mdx mice with the administration of BLS-M22. The circulating antibodies generated after BLS-M22 oral administration successfully lowered serum myostatin concentration. Myostatin blockade resulted in serological, histological, and functional improvements in mdx mice. Overall, the findings suggest the potential of BLS-M22 to treat DMD; however, further clinical trials are essential to ascertain its efficacy and safety in humans.

Anti-Fibrotic Effect of Human Wharton's Jelly-Derived Mesenchymal Stem Cells on Skeletal Muscle Cells, Mediated by Secretion of MMP-1.

Extracellular matrix (ECM) components play an important role in maintaining skeletal muscle function, but excessive accumulation of ECM components interferes with skeletal muscle regeneration after injury, eventually inducing fibrosis. Increased oxidative stress level caused by dystrophin deficiency is a key factor in fibrosis in Duchenne muscular dystrophy (DMD) patients. Mesenchymal stem cells (MSCs) are considered a promising therapeutic agent for various diseases involving fibrosis. In particular, the paracrine factors secreted by MSCs play an important role in the therapeutic effects of MSCs. In this study, we investigated the effects of MSCs on skeletal muscle fibrosis. In 2-5-month-old mdx mice intravenously injected with 1 × 105 Wharton's jelly (WJ)-derived MSCs (WJ-MSCs), fibrosis intensity and accumulation of calcium/necrotic fibers were significantly decreased. To elucidate the mechanism of this effect, we verified the effect of WJ-MSCs in a hydrogen peroxide-induced fibrosis myotubes model. In addition, we demonstrated that matrix metalloproteinase-1 (MMP-1), a paracrine factor, is critical for this anti-fibrotic effect of WJ-MSCs. These findings demonstrate that WJ-MSCs exert anti-fibrotic effects against skeletal muscle fibrosis, primarily via MMP-1, indicating a novel target for the treatment of muscle diseases, such as DMD.

Clinical and polysomnographic characteristics of excessive daytime sleepiness in children.

PURPOSE: This study aimed to delineate the clinical and polysomnography (PSG) characteristics of sleep disorders in children with excessive daytime sleepiness (EDS). METHODS: Between February 2002 and June 2015, 622 pediatric patients with EDS were evaluated with overnight PSG and the Multiple Sleep Latency Test at the Samsung Medical Center. The medical records; questionnaire responses about depression, sleepiness, sleep habits; and sleep study data of 133 patients without obstructive sleep apnea (OSA) were reviewed retrospectively. RESULTS: The patients (63 girls, 70 boys) slept for an average of 7 h 30 min and 8 h 44 min on weekdays and weekends, respectively. The mean Epworth Sleepiness Scale score was 11.01 ± 4.09 and did not differ significantly among sleep disorders. Among the 102 patients who completed the depression questionnaire, 53 showed depressive feelings, which were moderate or severe in 39, with no significant differences among specific sleep disorders. Thirty-four patients exhibited normal PSG results. Seventeen of them were concluded as not having any sleep disorders, and the others as having delayed sleep phase disorder (DSPD). Narcolepsy (n = 78) was the most common disorder, followed by DSPD (n = 17) and idiopathic hypersomnia (n = 12). CONCLUSIONS: Pediatric patients with EDS had various sleep disorders and some did not have any sleep disorder despite EDS. More than half the patients with EDS showed depressive feelings affecting their daily lives. For pediatric patients with EDS, a systematic diagnostic approach including questionnaires for sleep habits and emotion and PSG is essential for accurate diagnosis and treatment.

Paroxysmal nonepileptic events in pediatric patients.

OBJECTIVES: Paroxysmal nonepileptic events (PNEs) are frequently encountered phenomena in children. Although frequencies and types of PNEs have been extensively studied in adult populations, the data available for children and adolescents are limited, especially in patients without underlying neurologic disorders. In this study, we evaluated and compared the characteristics of PNEs between age groups and according to the presence of neurologic deficits to improve early detection and diagnosis of PNEs. METHODS: We retrospectively reviewed 887 pediatric patients who were admitted to the epilepsy monitoring unit at the Samsung Medical Center between December 2001 and July 2014. One hundred and forty-one patients (15.9%) were diagnosed as having PNEs on the basis of their clinical history and long-term video-electroencephalography (EEG) monitoring (VEM). RESULTS: Children with PNEs were divided into three groups by age: 1) the infant, toddler, and preschool group (<6 years, N=50, 35.5%); 2) the school-age group (6-<12 years, N=30, 21.3%); and 3) the adolescent group (12-<18 years, N=61, 43.3%). Physiologic disorders, such as normal infant behavior, sleep movement, and staring, were more common in patients younger than 6 years of age, whereas psychogenic nonepileptic seizures were predominant in patients older than 6 years. Vasogenic syncope was also frequently observed in the adolescent group and was confirmed by the head-up tilt test. There was no significant difference in specific PNE types between the groups of patients with or without neurologic deficits. CONCLUSIONS: Physiologic symptoms were predominant in the younger age group, whereas psychogenic nonepileptic seizures were observed in older age groups more often. Clinical pattern recognition by age plays an important role in clinical practice, because pediatric patients present various types of PNEs with age-specific patterns. Considering various and inconsistent presentations and the importance of correct diagnosis, long-term VEM can be helpful in diagnosing normal infant behavior and psychogenic nonepileptic seizures.

Iodine status in Korean preschool children as determined by urinary iodine excretion.

PURPOSE: Iodine is a trace element of thyroid hormones. Excessive or insufficient iodine intake is associated with various thyroid diseases. Urinary iodine (UI) is a sensitive indicator and a recommended barometer of population iodine intake. In Korea, there has been no available data regarding iodine intake in preschool children. We investigated the iodine intake status of Korean preschool children through examination of their UI. METHODS: This cross-sectional study was performed in 611 healthy preschool children (302 from Seoul and 309 from Masan), aged from 2 to 7 in 2010. UI concentration was measured by inductively coupled plasma-mass spectrometry. RESULTS: The median UI concentration was 438.8 µg/L. Insufficient iodine intakes (<100 µg/L) were seen in 24 children (3.9%), and excessive iodine ingestion (>300 µg/L) was found in 406 children (66.4%). There were no significant differences in UI between different sexes and ages. Additionally, the median UI concentration was higher in children from Seoul (512.2 µg/L) than that in children from Masan (362.4 µg/L, P < 0.001). CONCLUSION: About two-thirds of Korean preschool children were in the state of excessive iodine intake, and 3.9% of children showed insufficient iodine intake. Preventive measures and follow-up for iodine intake in preschool children are needed.

Improvement of CNS defects via continuous intrathecal enzyme replacement by osmotic pump in mucopolysaccharidosis type II mice.

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome (OMIM 309900), is a rare, X-linked lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS; EC 3.1.6.13), which is involved in the lysosomal degradation of glycosaminoglycans (GAG). Although intermittent intrathecal (IT) injection of the enzyme has been introduced as a method to overcome the blood-brain barrier, continuous IT infusion of the enzyme would be more physiologic. This study was performed to investigate responses in the brain of MPS II mice to varying doses of continuous IT infusion of recombinant human IDS (rh-IDS) in MPS II mice by osmotic pump in three different doses (2.4, 4.8, and 12 µg/day) of rh-IDS for 3 weeks. The results showed that the group treated with 12 µg/day doses of rh-IDS demonstrated decreased GAG concentrations compared to the untreated KO mice group (P = 0.003). After 3 weeks of continuous IT ERT, the brain tissues of the high-dose IT-treated KO mice showed a reduction of vacuolation in the cerebral cortex, thalamus and cerebellar cortex, which was not observed in the low- and medium-dose KO mice groups. Moreover, the anti-NeuN signal representing intact neuron was restored in the cortexes of the high-dose group. In conclusion, continuous IT infusion of the deficient enzyme was effective in improving CNS defects in the MPS II mice, and could be a valuable therapeutic method for treating neurological deterioration in patients with MPS II.

Amniopatch treatment for spontaneous previable, preterm premature rupture of membranes associated or not with incompetent cervix.

OBJECTIVE: We reviewed women with previable spontaneous premature rupture of membranes (sPPROM) in whom an amniopatch was performed and compared their pregnancy outcomes with a conservative management group. METHODS: Amniopatch, an amnioinfusion of autologous platelet concentrate followed by cryoprecipitate, was performed in 7 women with sPPROM diagnosed at 17-23 weeks' gestation, including one twin pregnancy. Three patients had incompetent cervices and the other 4 patients had sPPROM without incompetent cervices. Pregnancy outcomes of the cases were compared with the controls who were managed conservatively (n = 22). RESULTS: Amniopatch treatment was successful in 1 of 7 cases (14.3%), in which the ruptured membranes were completely sealed and the patient delivered a healthy baby at 39 weeks' gestation. No procedure-related complications were observed. Overall, neonatal outcome was similar in the amniopatch and conservatively managed groups, although the incidences of early neonatal sepsis and respiratory distress syndrome were lower in the amniopatch group. CONCLUSION: The overall success rate of amniopatch among our small number of cases was low. However, if successful, amniopatch may prolong a pregnancy with previable sPPROM to term.

PRRT2-positive self-limited infantile epilepsy: Initial seizure characteristics and response to sodium channel blockers.

OBJECTIVE: Self-limited infantile epilepsy (SeLIE) has distinctive clinical features, and the PRRT2 gene is known to be a considerable genetic cause. There have been a few studies on PRRT2-positive SeLIE only, and anti-seizure medications are often required due to frequent seizures at initial seizure onset. This study aimed to provide clinical information for the early recognition of patients with PRRT2-positive SeLIE and to propose effective anti-seizure medications for seizure control. METHODS: We retrospectively reviewed 36 patients diagnosed with SeLIE with genetically confirmed pathogenic variants of PRRT2. In addition, six atypical cases with neonatal-onset seizures and unremitting after 3 years of age were included to understand the expanded clinical spectrum of PRRT2-related epilepsy. We analyzed the initial presentation, clinical course, and seizure control response to anti-seizure medications. RESULTS: Patients with PRRT2-related epilepsy had characteristic seizure semiology at the initial presentation, including all afebrile, clustered (n = 23, 63.9%), short-duration (n = 33, 91.7%), and bilateral tonic-clonic seizures (n = 26, 72.2%). Genetic analysis revealed that c. 649dupC was the most common variant, and six patients had a 16p11.2 microdeletion containing the PRRT2 gene. One-third of the patients were sporadic cases without a family history of epilepsy or paroxysmal movement disorders. In the 33 patients treated with anti-seizure medications, sodium channel blockers, such as carbamazepine, were the most effective in seizure control. SIGNIFICANCE: Our results delineated the clinical characteristics of PRRT2-positive SeLIE, differentiating it from other genetic infantile epilepsies and discovered the effective anti-seizure medications for initial clustered seizure control. If afebrile bilateral tonic-clonic seizures develop in a normally developed infant as a clustered pattern, PRRT2-positive SeLIE should be considered as a possible diagnosis, and sodium channel blockers should be administered as the first medication for seizure control.

Case report: Suspecting guanine nucleotide-binding protein beta 1 mutation in dyskinetic cerebral palsy is important.

Herein, we describe the case of a 43-month-old girl who presented with clinical manifestations of dyskinetic cerebral palsy (CP), classified as the Gross Motor Function Classification System (GMFCS) V. The patient had no family history of neurological or perinatal disorders. Despite early rehabilitation, serial assessments using the Gross Motor Function Measure (GMFM) showed no significant improvements in gross motor function. Brain magnetic resonance imaging showed nonspecific findings that could not account for developmental delay or dystonia. Whole-genome sequencing identified a heterozygous NM_002074.5(GNB1):c.239T>C (p.Ile80Thr) mutation in guanine nucleotide-binding protein beta 1 (GNB1) gene. Considering this case and previous studies, genetic testing for the etiology of dyskinetic CP is recommended for children without relevant or with nonspecific brain lesions.

Genetic Diagnosis of Children With Neurodevelopmental Disorders Using Whole Genome Sequencing.

BACKGROUND: Neurodevelopmental disorders (NDDs) have diverse phenotypes. Their genetic diagnoses are often challenged by difficulties of targeting causative genes due to heterogeneous genetic etiologies. The objective of this study was to perform genetic diagnosis of children with NDDs using whole genome sequencing. METHODS: This study included 78 pediatric patients with NDDs and their 152 family members for whole genome sequencing (WGS). All cases except one were families with at least two members. Seventy-five patients had previously undergone other genetic tests besides WGS. Detected variants were classified according to the guidelines of the American College of Medical Genetics and Genomics. RESULTS: Among 78 probands, 26 patients were genetically diagnosed with NDDs through WGS, showing a diagnostic rate of 33.3%. Of them, 22 cases had de novo variants (DNVs) identified through trio analysis. Of these DNVs, half were novel variants. Three structural variants, including a multiexon deletion, a contiguous gene deletion involving 13 Mb, and a retrotransposon insertion, were revealed by WGS. All cases except one had defects in different genes, consistent with the phenotypically diverse nature of NDDs. In addition, three patients were inconclusive, two of them had one likely pathogenic variant in a gene associated with autosomal recessive disease and the other one had no clinical phenotypes associated with the detected DNV. CONCLUSIONS: Our experience demonstrates the advantage of WGS in the diagnosis of NDDs, including detection of copy number variations and also the advantage of trio sequencing for interpretation of DNVs.

Nusinersen demonstrates effectiveness in treating spinal muscular atrophy: findings from a three-year nationwide study in Korea.

Introduction: Nusinersen is the first drug approved for spinal muscular atrophy (SMA) treatment. In this study, we aimed to evaluate the long-term safety and efficacy of nusinersen, assess the therapeutic effects based on the treatment initiation timing and baseline motor function, and explore the perception of functional improvement from either parents or patients, utilizing 3-year nationwide follow-up data in South Korea. Methods: We enrolled patients with SMA who were treated with nusinersen under the National Health Insurance coverage, with complete motor score records available and a minimum treatment duration of 6 months. To evaluate the motor function of patients, the Hammersmith Infant Neurological Examination-2 (HINE-2) was used for type 1 and the Expanded Hammersmith Functional Motor Scale (HFMSE) was used for types 2 and 3 patients. A significant improvement was defined as a HINE-2 score gain ≥5 for patients with type 1 and an HFMSE score ≥ 3 for patients with types 2 and 3 SMA. Effects of treatment timing were assessed. Patients with type 2 were further categorized based on baseline motor scores for outcome analysis. We also analyzed a second dataset from five tertiary hospitals with the information on parents/patients-reported impressions of improvement. Results: The study comprised 137 patients, with 21, 103, and 13 patients representing type 1, 2, and 3 SMA, respectively. At the 3-year follow-up, the analysis encompassed 7 patients with type 1, 12 patients with type 2, and none with type 3. Nearly half of all enrolled patients across SMA types (42.8, 59.2 and 46.2%, respectively) reached the 2-year follow-up for analysis. Patients with type 1 SMA exhibited gradual motor function improvement over 1-, 2-, and 3-year follow-ups (16, 9, and 7 patients, respectively). Patients with type 2 SMA demonstrated improvement over 1-, 2-, and 3-year follow-ups (96, 61 and 12 patients, respectively). Early treatment from symptom onset resulted in better outcomes for patients with type 1 and 2 SMA. In the second dataset, 90.7% of 108 patients reported subjective improvement at the 1-year follow-up. Conclusion: Nusinersen treatment for types 1-3 SMA is safe and effective in long-term follow-up. Early treatment initiation was a significant factor affecting long-term motor outcome.

Neurodevelopmental outcomes in preterm infants: comparison of infants with and without diffuse excessive high signal intensity on MR images at near-term-equivalent age.

PURPOSE: To compare the neurodevelopmental outcomes between preterm infants with diffuse excessive high signal intensity (DEHSI) and those without DEHSI on magnetic resonance (MR) images, in association with other white matter lesions. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and requirement to obtain informed consent was waived. High-risk preterm infants (n = 126) who underwent screening brain MR imaging at near-term-equivalent age were classified into two groups according to the presence of DEHSI. Bayley Scales of Infant Development-II, presence of cerebral palsy, and neurosensory impairment between 18 and 24 months of age were compared between the two groups. The associations of MR findings of other white matter lesions (cystic encephalomalacia, punctate lesions, loss of volume, ventricular dilatation, and delayed myelination) and subsequent outcomes were also analyzed. Outcome data were evaluated by using exact logistic regression analyses and Fisher exact test. RESULTS: DEHSI was present in 75% (95 of 126) of infants. Subsequent neurodevelopmental outcomes did not differ significantly between the two groups. Severe motor delay and cerebral palsy were more common in infants with both DEHSI and other white matter lesions as compared with infants with normal white matter (P = .001 and P < .001, respectively). Among other white matter lesions, cystic encephalomalacia (odds ratio, 19.6; 95% confidence interval: 1.3, 333.3) and punctate lesions (odds ratio, 90.9; 95% confidence interval: 6.4, 1000) were significant predictors of cerebral palsy. CONCLUSION: Although the incidence of DEHSI was high (75%) in preterm infants at near-term-equivalent age MR imaging, DEHSI was not predictive of following adverse outcomes. Cystic encephalomalacia and punctate lesions were more significant predictors of cerebral palsy.

Enzyme replacement therapy improves joint motion and outcome of the 12-min walk test in a mucopolysaccharidosis type VI patient previously treated with bone marrow transplantation.

Mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome, OMIM #253200) is a rare disorder involving multiple organs and manifested particularly by severe skeletal abnormalities. Bone marrow transplantation (BMT) improves cardiopulmonary function and facial features, but has limited success in ameliorating skeletal abnormalities and short stature. Here, we report the outcome of enzyme replacement therapy (ERT) with recombinant human arylsulfatase-B (ASB, Naglazyme, BioMarin, Novato, CA) in an MPS VI patient who received BMT 10 years prior to ERT induction. Administration of weekly Naglazyme for 18 months was effective in improving range of motion in several joints [shoulders (improvement of flexion (Right/Left): 40°/55°; improvement of extension 30°/40°; improvement of abduction 10°/10°), elbows (improvement of flexion 25°/25°; improvement of extension 10°/15°), hips (improvement of flexion 25°/10°), and knees (improvement of flexion 45°/40°; improvement of extension 50°/60°)]. Improvement in the outcome of the 12-min walk test (70% increase) and 3-min stair-climbing test (29% increase) was also noted after ERT. Because ERT improved clinical features in an MPS VI patient who had undergone prior BMT, the role of ERT post successful BMT in MPS VI needs further investigation.

The clinical significance of preoperative brain magnetic resonance imaging in pediatric cochlear implant recipients.

Although central nervous system abnormalities are incidentally detected in preoperative brain magnetic resonance imaging (MRI) studies in pediatric cochlear implant (CI) candidates, the clinical significance of the abnormalities remains unclear. We aimed to assess post-implantation auditory and speech performance in patients with brain lesions seen on MRI. Pediatric CI recipients (n = 177) who underwent preoperative MRI scans of the brain between January 2002 and June 2009 were included in this study. Patients with brain lesions on MRI were reviewed and categorized into the following groups: brain parenchymal lesions (focal vs. diffuse), ventriculomegaly, and extra-axial lesion. The main communication mode as well as progress in auditory perception and speech production were evaluated preoperatively and at 3, 6, 12, and 24 months postoperatively. Performance in patients with brain lesions was compared with the age- and sex-matched control group. Various brain lesions were found in 27 out of 177 patients. Children with brain lesions who received CIs showed gradual progress in auditory and speech outcomes for 2 years, though performance was reduced compared with the control group. In addition, there was a significant difference in the main communication mode between the two groups at 2 years following cochlear implantation. This difference was especially significant in patients with diffuse brain parenchymal lesions after further stratification of the brain lesion group. Preoperative brain MRI may have a role in improving the prediction of adverse outcomes in pediatric CI recipients. In particular, children with diffuse brain parenchymal lesions should be counseled regarding the poor prognosis preoperatively, and followed up with special attention.

A successful treatment of arterial ischemic stroke with stent insertion in a child with congenital heart disease.

INTRODUCTION: Diagnosis of arterial ischemic stroke in pediatric patients is often delayed due to the uncertainty and variability of clinical symptoms. Early diagnosis of arterial ischemic stroke can bring a favorable prognosis with prompt thrombolytic therapy or stent insertion, via transfemoral cerebral arteriogram. Acute thrombolytic therapy is rarely attempted in children because of the delayed diagnosis. PATIENT AND METHOD: We report a case of a 4-year-old girl with complex heart disease who was presented with arterial ischemic stroke at the right distal internal carotid artery and successfully treated by stent insertion in which repeated thrombolysis or ballooning had failed. RESULT: Left hemiparesis was nearly recovered 6 days after the stent insertion. The mean flow velocity of the right middle cerebral artery has slightly improved compared to that of the initial study. She has been followed-up for 6 months in the outpatient clinic without neurologic sequelae. CONCLUSION: This case suggests that intracranial stent insertion may be a safe and an effective modality in young children, when the thrombolytic therapy or ballooning is inapplicable. Additionally, transcranial Doppler ultrasonography is useful to monitor the cerebral blood flow after stent insertion in children.

Genetic analysis of dystrophin gene for affected male and female carriers with Duchenne/Becker muscular dystrophy in Korea.

Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked recessive disorders caused by mutation in dystrophin gene. We analyzed the results of a genetic test in 29 DMD/BMD patients, their six female relatives, and two myopathic female patients in Korea. As the methods developed, we applied different procedures for dystrophin gene analysis; initially, multiplex polymerase chain reaction was used, followed by multiplex ligation-dependent probe amplification (MLPA). Additionally, we used direct DNA sequencing for some patients who had negative results using the above methods. The overall mutation detection rate was 72.4% (21/29) in DMD/BMD patients, identifying deletions in 58.6% (17/29). Most of the deletions were confined to the central hot spot region between exons 44 and 55 (52.9%, 7/19). The percentage of deletions and duplications revealed by MLPA was 45.5% (5/11) and 27.2% (3/11), respectively. Using the MLPA method, we detected mutations confirming their carrier status in all female relatives and symptomatic female patients. In one patient in whom MLPA revealed a single exon deletion of the dystrophin gene, subsequent DNA sequencing analysis identified a novel nonsense mutation (c.4558G > T; Gln1520X). The MLPA assay is a useful quantitative method for detecting mutation in asymptomatic or symptomatic carriers as well as DMD/BMD patients.