L-serine restored lysosomal failure in cells derived from patients with BPAN reducing iron accumulation with eliminating lipofuscin.

Defective mitochondria and autophagy, as well as accumulation of lipid and iron in WDR45 mutant fibroblasts, is related to beta-propeller protein-associated neurodegeneration (BPAN). In this study, we found that enlarged lysosomes in cells derived from patients with BPAN had low enzyme activity, and most of the enlarged lysosomes had an accumulation of iron and oxidized lipid. Cryo-electron tomography revealed elongated lipid accumulation, and spectrometry-based elemental analysis showed that lysosomal iron and oxygen accumulation superimposed with lipid aggregates. Lysosomal lipid aggregates superimposed with autofluorescence as free radical generator, lipofuscin. To eliminate free radical stress by iron accumulation in cells derived from patients with BPAN, we investigated the effects of the iron chelator, 2,2'-bipyridine (bipyridyl, BIP). To study whether the defects in patient-derived cells can be rescued by an iron chelator BIP, we tested whether the level of iron and reactive oxygen species (ROS) in the cells and genes related to oxidative stress were rescued BIP treatment. Although BIP treatment decreased some iron accumulation in the cytoplasm and mitochondria, the accumulation of iron in the lysosomes and levels of cellular ROS were unaffected. In addition, the change of specific RNA levels related to free radical stress in patient fibroblasts was not rescued by BIP. To alleviate free radical stress, we investigated whether l-serine can regulate abnormal structures in cells derived from patients with BPAN through the regulation of free radical stress. l-serine treatment alleviated increase of enlarged lysosomes and iron accumulation and rescued impaired lysosomal activity by reducing oxidized lipid accumulation in the lysosomes of the cells. Lamellated lipids in the lysosomes of the cells were identified as lipofuscin through correlative light and electron microscopy, and l-serine treatment reduced the increase of lipofuscin. These data suggest that l-serine reduces oxidative stress-mediated lysosomal lipid oxidation and iron accumulation by rescuing lysosomal activity.

l-Serine Protects Murine Retinal Ganglion Cells from Oxidative Stress via Modulation of Mitochondrial Dysfunction.

PURPOSE: This study aimed to investigate the effects of l-serine on mitochondrial dysfunction in retinal ganglion cells after exposure to H2O2-induced oxidative stress. METHODS: Retinal ganglion cells obtained from C57BL6 mice (postnatal days 1-4) were purified and cultured. A cell viability assay was performed following exposure to H2O2-induced oxidative stress to assess the cytoprotective effects of l-serine on retinal ganglion cells. Flow cytometry with CellROX Deep Red and MitoSOX dyes was performed to analyze the cytoplasmic and mitochondrial reactive oxygen species levels, respectively. Staining with the fluorescent probe JC-1 was used to detect changes in the mitochondrial membrane potential. The oxygen consumption rate and Bioenergetic Health Index were used to evaluate mitochondrial respiration. RESULTS: H2O2 treatment was found to induce mitochondrial dysfunction in retinal ganglion cells. Pretreatment with l-serine prevented cytotoxicity and significantly increased the viability of retinal ganglion cells following exposure to H2O2-induced oxidative stress (p < .05). l-Serine alleviated reactive oxygen species production in retinal ganglion cells following exposure to H2O2-induced oxidative (p < .05). Further, it successfully mitigated H2O2-induced mitochondrial depolarization in retinal ganglion cells (p < .05) and significantly increased the oxygen consumption rate and Bioenergetic Health Index in retinal ganglion cells following exposure to H2O2-induced oxidative stress (p < .05). CONCLUSION: Pretreatment with l-serine protected retinal ganglion cells from H2O2-induced oxidative stress by improving mitochondrial function. The findings of the present study suggest that l-serine is a potential candidate for treatment of reactive oxygen species-related ocular diseases such as mitochondrial optic neuropathies.

AST-001 Improves Social Deficits and Restores Dopamine Neuron Activity in a Mouse Model of Autism.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social communication and social interaction, restricted and repetitive behavior, and interests. The core symptoms of ASD are associated with deficits in mesocorticolimbic dopamine pathways that project from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). AST-001 is an investigational product currently in a phase 3 clinical trial for treating the core symptoms of ASD, with L-serine as the API (active pharmaceutical ingredient). Because the causes of ASD are extremely heterogeneous, a single genetic ASD model cannot represent all autism models. In this paper, we used the VPA-exposed model, which is more general and widely used than a single genetic model, but this is also one of the animal models of autism. Herein, we conducted experiments to demonstrate the efficacy of AST-001 as L-Serine that alters the regulation of the firing rate in dopamine neurons by inhibiting small conductance Ca2+-activated K+ channels (SK channels). Through these actions, AST-001 improved sociability and social novelty by rescuing the intrinsic excitabilities of dopamine neurons in VPA-exposed ASD mouse models that showed ASD-related behavioral abnormalities. It is thought that this effect of improving social deficits in VPA-exposed ASD mouse models is due to AST-001 normalizing aberrant SK channel activities that slowed VTA dopamine neuron firing. Overall, these findings suggest that AST-001 may be a potential therapeutic agent for ASD patients, and that its mechanism of action may involve the regulation of dopamine neuron activity and the improvement of social interaction.

Sirtuin 3 mutation- induced mitochondrial dysfunction and optic neuropathy: a case report.

BACKGROUND: Mitochondrial optic neuropathy is characterized by painless, progressive, symmetrical central vision loss, and dyschromatopsia owing to mitochondrial dysfunction. This report documents a rare case of mitochondrial optic neuropathy due to the SIRT3 gene mutation. CASE PRESENTATION: This report describes a case of a 17-year-old boy who presented with symptoms of bilateral painless, progressive vision decline over several years. Fundus examination revealed temporal pallor of the optic nerve head in both the eyes and an OCT showed considerable thinning of the retinal nerve fiber and ganglion cell layers. Pathogenicity was confirmed by decreased mitochondrial function measured by bioenergetic health index and oxygen consumption rate in this patient. Subsequent NGS revealed a missense mutation of the SIRT3 gene (c.1137G > C, p.Trp379Cys) in the patient. CONCLUSIONS: This case describes the clinical manifestation of mitochondrial optic neuropathy due to the SIRT3 gene mutation.

Changes of lysosome by L-serine in rotenone-treated hippocampal neurons.

Oxidative stress destroys cellular organelles and damages DNA, eventually leading to degenerative brain disorders. Persistent mitochondrial damage by oxidative stress eventually causes cells to inhibit the function of lysosomes. Rotenone used in this study inhibits complex 1 of the mitochondrial electron transport chain. Due to this inhibition, the production of free radicals is promoted, and oxidative stress can occur. To test as a role of antioxidant, L-serine was treated before treatment of rotenone to HT22 hippocampal cells. Then, changes in the activity and structure of lysosomes were analyzed. As a result, the oxidative stress caused by rotenone in HT22 cells was protected by L-serine. L-serine reduced free radicals in cells, and the damaged lysosomal structure and lysosome activity were also protected.

Restoration of Cathepsin D Level via L-Serine Attenuates PPA-Induced Lysosomal Dysfunction in Neuronal Cells.

L-serine is a non-essential amino acid endogenously produced by astrocytes and is abundant in human diets. Beneficial roles of the metabolic products from L-serine in various conditions in the brain including neuronal development have been reported. Through several preclinical studies, L-serine treatment was also shown to offer beneficial therapeutic effects for brain damage such as ischemic stroke, amyotrophic lateral sclerosis, and Parkinson's disease. Despite evidence for the value of L-serine in the clinic, however, its beneficial effects on the propionic acid (PPA)-induced neuronal toxicity and underlying mechanisms of L-serine-mediated neuroprotection are unknown. In this study, we observed that PPA-induced acidic stress induces abnormal lipid accumulation and functional defects in lysosomes of hippocampal neurons. L-serine treatment was able to rescue the structure and function of lysosomes in PPA-treated hippocampal neuronal cells. We further identified that L-serine suppressed the formation of lipid droplets and abnormal lipid membrane accumulations inside the lysosomes in PPA-treated hippocampal neuronal cells. Taken together, these findings indicate that L-serine can be utilized as a neuroprotective agent for the functionality of lysosomes through restoration of cathepsin D in disease conditions.

Population Pharmacokinetic Model of AST-001, L-Isomer of Serine, Combining Endogenous Production and Exogenous Administration in Healthy Subjects.

AST-001 is an L-isomer of serine that has protective effects on neurological disorders. This study aimed to establish a population pharmacokinetic (PK) model of AST-001 in healthy Korean to further propose a fixed-dose regimen in pediatrics. The model was constructed using 648 plasma concentrations from 24 healthy subjects, including baseline endogenous levels during 24 h and concentrations after a single dose of 10, 20, and 30 g of AST-001. For the simulation, an empirical allometric power model was applied to the apparent clearance and volume of distribution with body weight. The PK characteristics of AST-001 after oral administration were well described by a two-compartment model with zero-order absorption and linear elimination. The endogenous production of AST-001 was well explained by continuous zero-order production at a rate of 0.287 g/h. The simulation results suggested that 2 g, 4 g, 7 g, 10 g, and 14 g twice-daily regimens for the respective groups of 10-14 kg, 15-24 kg, 25-37 kg, 38-51 kg, 52-60 kg were adequate to achieve sufficient exposure to AST-001. The current population PK model well described both observed endogenous production and exogenous administration of AST-001 in healthy subjects. Using the allometric scaling approach, we suggested an optimal fixed-dose regimen with five weight ranges in pediatrics for the upcoming phase 2 trial.

Early Diagnosis of Pseudohypoparathyroidism before the Development of Hypocalcemia in a Young Infant.

Pseudohypoparathyroidism (PHP) is a rare, heterogeneous disorder characterized by end-organ resistance to parathyroid hormone (PTH). PTH resistance causes elevated PTH levels, hypocalcemia, and hyperphosphatemia. Since hypocalcemia causes life-threatening events, early diagnosis is crucial. However, the diagnosis of PHP is elusive during infancy because PHP is usually diagnosed with hypocalcemia-induced symptoms, which develop later in childhood when calcium requirements increase. A 1-month-old girl was referred to our clinic for elevated thyroid-stimulating hormone (TSH) levels on newborn screening. When measured 1 month after levothyroxine treatment, her TSH level normalized. At 4-months-old, multiple hard nodules were noted on her trunk. A punch skin biopsy revealed osteoma cutis associated with Albright's hereditary osteodystrophy, a major characteristic of PHP. We performed targeted sanger sequencing of the GNAS gene and detected a heterozygous variant c.150dupA (p.Ser51Ilefs*3) in both the proband and her mother, causing frameshift and premature termination mutations. The patient was diagnosed with PHP Ia when she had normal calcium, phosphorous, and PTH levels. We report the early diagnosis of PHP Ia without hypocalcemia. It emphasizes the importance of meticulous physical examination in patients with congenital hypothyroidism.

Atypical Presentation of Enlarged Vestibular Aqueducts Caused by SLC26A4 Variants.

Enlarged vestibular aqueduct is the most common inner ear malformation in pediatric patients with sensorineural hearing loss. Here, we report a new presentation of enlarged vestibular aqueduct in a Korean family. The family consists of two parents and five daughters, and the first and second daughters were diagnosed with bilateral enlarged vestibular aqueducts. The third daughter, who showed no signs of hearing deterioration, came to medical attention with incomplete Horner syndrome. Evaluations for localization of Horner syndrome on the patient and Sanger sequencing of SLC26A4 on the family members were performed. Although auditory brainstem response and pure tone audiometry of the third daughter were normal, temporal bone computed tomography demonstrated bilateral enlarged vestibular aqueducts. Sanger sequencing of SLC26A4 revealed compound heterozygous variants c.2168A>G and c.919-2A>G in the first, second, and third daughters. Diagnosis of enlarged vestibular aqueduct is often delayed because the degree of hearing loss can vary, and a considerable phenotypic variability can be shown even in family members with the same SLC26A4 variations. Fluctuations of CSF pressure into the cochlear duct and recurrent microruptures of the endolymphatic membrane could result in damage of sympathetic nerve supplying to the inner ear, which could explain the mechanism of Horner syndrome associated with enlarged vestibular aqueduct.

Dysfunction of NMDA receptors in neuronal models of an autism spectrum disorder patient with a DSCAM mutation and in Dscam-knockout mice.

Heterogeneity in the etiopathology of autism spectrum disorders (ASD) limits the development of generic remedies, requires individualistic and patient-specific research. Recent progress in human-induced pluripotent stem cell (iPSC) technology provides a novel platform for modeling ASDs for studying complex neuronal phenotypes. In this study, we generated telencephalic induced neuronal (iN) cells from iPSCs derived from an ASD patient with a heterozygous point mutation in the DSCAM gene. The mRNA of DSCAM and the density of DSCAM in dendrites were significantly decreased in ASD compared to control iN cells. RNA sequencing analysis revealed that several synaptic function-related genes including NMDA receptor subunits were downregulated in ASD iN cells. Moreover, NMDA receptor (R)-mediated currents were significantly reduced in ASD compared to control iN cells. Normal NMDA-R-mediated current levels were rescued by expressing wild-type DSCAM in ASD iN cells, and reduced currents were observed by truncated DSCAM expression in control iN cells. shRNA-mediated DSCAM knockdown in control iN cells resulted in the downregulation of an NMDA-R subunit, which was rescued by the overexpression of shRNA-resistant DSCAM. Furthermore, DSCAM was co-localized with NMDA-R components in the dendritic spines of iN cells whereas their co-localizations were significantly reduced in ASD iN cells. Levels of phospho-ERK1/2 were significantly lower in ASD iN cells, suggesting a potential mechanism. A neural stem cell-specific Dscam heterozygous knockout mouse model, showing deficits in social interaction and social memory with reduced NMDA-R currents. These data suggest that DSCAM mutation causes pathological symptoms of ASD by dysregulating NMDA-R function.

Case report of juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome: first report in Korea with a novel mutation in the SMAD4 gene.

Juvenile polyposis/hereditary hemorrhagic telangiectasia (JPS/HHT) syndrome is a rare, autosomal dominant disorder caused by mutations in the SMAD4 gene, presenting with features of both juvenile polyposis syndrome (JPS) and HHT. Reports and studies of JPS/HHT syndrome are mostly from Western countries, while there are scarce reports from East Asian countries. We report a case of a Korean boy who had been previously diagnosed with JPS at 7 years and had first visited to our center at 15 years of age. Genetic studies of the patient and parents revealed a novel variant in the SMAD4 gene, SMAD4 c.1146_1163del; p.His382_Val387del (NM_005359.5), which had developed de novo. Numerous pedunculated and sessile polyps were observed throughout the gastrointestinal (GI) tract. Mucocutaneous telangiectases were observed on the lips, tongue, and jejunum, and arteriovenous malformations (AVMs) were observed in both lungs. This is the first case report of JPS/HHT syndrome in Korea, with a novel deletion variant in the SMAD4 gene. Patients with JPS should undergo genetic evaluation of associated genes including SMAD4, and those with genetically confirmed SMAD4 variants should undergo further evaluation for coexisting asymptomatic AVMs in order to prevent life-threatening complications of thrombotic emboli and pulmonary hemorrhage.

Case report of compound CFTR variants in Korean siblings with cystic fibrosis: importance of differentiating cystic fibrosis from inflammatory bowel disease.

The prevalence of cystic fibrosis (CF) is considerably lower in Asian populations compared with that of Caucasians. Cases of CF are typically due to mutations in the CF transmembrane conductance regulator gene with autosomal recessive inheritance. Here, we report two cases of newly diagnosed CF in Korea-a 13-year-old boy and his 5-year-old brother. The older brother was admitted to our hospital for evaluation and treatment of recurrent abdominal pain, frequent diarrhea, and failure to thrive. Fecal calprotectin (FC) was elevated, and when combining this with his clinical presentation, inflammatory bowel disease (IBD) or eosinophilic gastroenteritis (EoGE) was the first impression of his disease. Several ulcerative lesions were observed on ileocolonoscopy. However, incidental findings of suspicious bronchiectatic lesions were observed on plain radiography, which were confirmed by chest computed tomography. Moreover, diffuse bowel wall thickening with pancreatic atrophy was also incidentally detected by computed tomography of the abdomen. Comprehensively, these findings were highly suggestive of CF. Therefore, diagnostic exome sequencing was conducted, which revealed compound heterozygous variants of c.263T>G (p.Leu88*) and c.2977G>T (p.Asp993Tyr) in the CF transmembrane conductance regulator gene. Although symptoms in the younger brother were not as prominent as the older brother, genetic test was also conducted, which revealed the same mutation. We report the identification of a novel variant, p.Asp993Tyr, in siblings with Korean heritage. Although CF is rare in Koreans, it should be included in the differential diagnosis of IBD.

A new type of oculocutaneous albinism with a novel OCA2 mutation.

Oculocutaneous albinism (OCA) is a group of rare genetically heterogeneous disorders, characterized by hypopigmentation of the eyes, skin, and hair, which result in ocular abnormalities and a risk of developing skin cancer. Currently, there is no ophthalmologic procedure or drug that prevents the clinical features of OCA. Here, we report a new type of OCA in two, unrelated Korean families with the same OCA2 mutation. Affected individuals in this study are different from those of previous reports in two aspects: an inheritance pattern and clinical presentation. All reported patients with OCA have shown an autosomal recessive inheritance pattern, while our patients showed an autosomal dominant inheritance pattern. Small amounts of pigment can be acquired with age in OCA, but there is no substantial variation from adolescence to adulthood in this regard. A case where the patient attained normal pigmentation levels has never been reported. However, our patients displayed completely normal pigmentation in their late twenties. Whole exome sequencing and in-silico analysis revealed a novel mutation, OCA2 c.2338G>A p.(G780S) (NM_000275) with a high likelihood of pathogenicity. Sanger sequencing of p.G780S identified the same mutation in the affected individuals, which was not found in the family members with normal phenotype. We hypothesize that OCA2 G780S not only acts as a pathogenic variant of OCA but also induces pigmentation by enhancing the melanogenesis gene expression of other modifier genes, such as SLC45A2 and TPC2. These findings may provide further understanding of melanin biosynthesis and new treatment methods for OCA.

G1 Cell Cycle Arrest and Extrinsic Apoptotic Mechanisms Underlying the Anti-Leukemic Activity of CDK7 Inhibitor BS-181.

In vitro antitumor activity of the CDK7 inhibitor BS-181 against human T-ALL Jurkat cells was determined. Treatment of Jurkat clones (JT/Neo) with BS-181 caused cytotoxicity and several apoptotic events, including TRAIL/DR4/DR5 upregulation, c-FLIP down-regulation, BID cleavage, BAK activation, ΔΨm loss, caspase-8/9/3 activation, and PARP cleavage. However, the BCL-2-overexpressing Jurkat clone (JT/BCL-2) abrogated these apoptotic responses. CDK7 catalyzed the activating phosphorylation of CDK1 (Thr161) and CDK2 (Thr160), and CDK-directed retinoblastoma phosphorylation was attenuated in both BS-181-treated Jurkat clones, whereas only JT/BCL-2 cells exhibited G1 cell cycle arrest. The G1-blocker hydroxyurea augmented BS-181-induced apoptosis by enhancing TRAIL/DR4/DR5 upregulation and c-FLIP down-regulation. BS-181-induced FITC-annexin V-positive apoptotic cells were mostly in the sub-G1 and G1 phases. BS-181-induced cytotoxicity and mitochondrial apoptotic events (BAK activation/ΔΨm loss/caspase-9 activation) in Jurkat clones I2.1 (FADD-deficient) and I9.2 (caspase-8-deficient) were significantly lower than in A3 (wild-type). Exogenously added recombinant TRAIL (rTRAIL) markedly synergized BS-181-induced apoptosis in A3 cells but not in normal peripheral T cells. The cotreatment cytotoxicity was significantly reduced by the DR5-blocking antibody but not by the DR4-blocking antibody. These results demonstrated that the BS-181 anti-leukemic activity is attributed to extrinsic TRAIL/DR5-dependent apoptosis preferentially induced in G1-arrested cells, and that BS-181 and rTRAIL in combination may hold promise for T-ALL treatment.

Congenital abnormalities of the retinal vasculature in neurofibromatosis type I.

The aim of this cross-sectional study was to investigate congenital abnormalities of the retinal vasculature (CARVs) in patients with neurofibromatosis type I (NF-1). Forty-eight patients (96 eyes) with NF-1 diagnosed according to the National Institutes of Health (NIH) criteria and 48 healthy controls were included in this study. Standard fundus photographs were obtained for each subject to evaluate the presence and frequency of CARVs. The sensitivity, specificity, and diagnostic accuracy of different cut-off numbers of CARVs were compared with those of the NIH criteria. Forty-four (91.7%) patients in the NF-1 group demonstrated either supranumeraty optic disc vessels or triple branching of the retinal vasculature, and 22 patients (45.8%) demonstrated both findings. The frequencies of these two CARVs were significantly different between the two groups (p < 0.00001). A cut-off value of either one for supranumerary optic disc vessels or triple branching showed the highest accuracy along with sensitivity and specificity of 91.7% and 87.5%. CARVs such as supranumerary optic disc vessels or triple branching were frequently observed in NF-1 patients, and their occurrence was unrelated to the age of patients. Thus, these CARVs could be added as new ophthalmologic manifestions for NF-1 and may potentially enable early diagnosis of NF-1.

Cohen Syndrome Patient iPSC-Derived Neurospheres and Forebrain-Like Glutamatergic Neurons Reveal Reduced Proliferation of Neural Progenitor Cells and Altered Expression of Synapse Genes.

Cohen syndrome (CS), a rare autosomal recessive disorder, has been associated with genetic mutations in the VPS13B gene, which regulates vesicle-mediated protein sorting and transport. However, the cellular mechanism underlying CS pathogenesis in patient-derived human neurons remains unknown. We identified a novel compound heterozygous mutation, due to homozygous variation of biparental origin and heterozygous variation inherited from the father, in the VPS13B gene in a 20-month-old female patient. To understand the cellular pathogenic mechanisms, we generated induced pluripotent stem cells (iPSCs) from the fibroblasts of the CS patient. The iPSCs were differentiated into forebrain-like functional glutamatergic neurons or neurospheres. Functional annotation from transcriptomic analysis using CS iPSC-derived neurons revealed that synapse-related functions were enriched among the upregulated and downregulated genes in the CS neurons, whereas processes associated with neurodevelopment were enriched in the downregulated genes. The developing CS neurospheres were small in size compared to control neurospheres, likely due to the reduced proliferation of SOX2-positive neural stem cells. Moreover, the number of SV2B-positive puncta and spine-like structures was significantly reduced in the CS neurons, suggesting synaptic dysfunction. Taking these findings together, for the first time, we report a potential cellular pathogenic mechanism which reveals the alteration of neurodevelopment-related genes and the dysregulation of synaptic function in the human induced neurons differentiated from iPSCs and neurospheres of a CS patient.

The molecular pathophysiology of vascular anomalies: Genomic research.

Vascular anomalies are congenital localized abnormalities that result from improper development and maintenance of the vasculature. The lesions of vascular anomalies vary in location, type, and clinical severity of the phenotype, and the current treatment options are often unsatisfactory. Most vascular anomalies are sporadic, but patterns of inheritance have been noted in some cases, making genetic analysis relevant. Developments in the field of genomics, including next-generation sequencing, have provided novel insights into the genetic and molecular pathophysiological mechanisms underlying vascular anomalies. These insights may pave the way for new approaches to molecular diagnosis and potential disease-specific therapies. This article provides an introduction to genetic testing for vascular anomalies and presents a brief summary of the etiology and genetics of vascular anomalies.

Variation in clinical usefulness of biomarkers of acute kidney injury in young children undergoing cardiac surgery.

BACKGROUND: Acute kidney injury (AKI) is one of the most significant postoperative complications of pediatric cardiac surgery. Because serum creatinine has limitations as a diagnostic marker of AKI, new biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) are being evaluated to overcome these limitations and detect AKI at an early stage after cardiac surgery. PURPOSE: This study aimed to investigate the clinical usefulness of these biomarkers in young children. METHODS: Thirty patients with congenital heart diseases who underwent cardiac surgery using cardiopulmonary bypass (CPB) were selected, and their urine and blood samples were collected at baseline and 6, 24, and 48 hours after surgery. Serum creatinine and blood urea nitrogen levels as well as NGAL, KIM-1, and IL-18 levels in urine samples were measured, and clinical parameters were evaluated. RESULTS: Of the 30 patients, 12 developed AKI within 48 hours after cardiac surgery. In the AKI group, 8 of 12 (66.6%) met AKI criteria after 24 hours, and urine KIM-1/creatinine (Cr) level (with adjustment of urine creatinine) peaked at 24 hours with significant difference from baseline level. Additionally, urine KIM-1/Cr level in the AKI group was significantly higher than in the non-AKI group at 6 hours. However, urine NGAL/Cr and IL-18/Cr levels showed no specific trend with time for 48 hours after cardiac surgery. CONCLUSION: It is suggested that urine KIM-1/Cr concentration could be considered a good biomarker for early AKI prediction after open cardiac surgery using CPB in young children with congenital heart diseases.

Real-Life Effectiveness and Tolerability of Perampanel in Pediatric Patients Aged 4 Years or Older with Epilepsy: A Korean National Multicenter Study.

BACKGROUND AND PURPOSE: The US Food and Drug Administration approval for perampanel has only recently been expanded to patients as young as 4 years, and so there have been few real-life studies of the effects of perampanel in pediatric patients. The aim of this study was to determine the long-term efficacy, factors affecting treatment response, and tolerability of perampanel as an add-on therapy in pediatric patients aged 4 years or older with epilepsy. METHODS: This multicenter retrospective observational study collected data from pediatric epilepsy centers of four Korean national universities. Changes in the seizure frequency from baseline, adverse events, and retention rates were obtained at 3, 6, and 12 months. Adverse events and discontinuation profiles were obtained to assess tolerability. RESULTS: This study included 220 children and adolescents (117 males and 103 females) aged 4 to 20 years. The overall response rate was 43.6%, and the seizure-freedom rate was 17.7%. Factors affecting a good treatment response were the absence of intellectual disability, small number of concomitant antiepileptic drugs, and low baseline seizure frequency. Eighty-eight patients (40%) experienced adverse events, but they mostly were of mild severity and resolved after the dose reduction or discontinuation of perampanel. The retention rates at 3, 6, and 12 months were 85.0%, 71.8%, and 50.5%, respectively. CONCLUSIONS: Adjunctive treatment with perampanel was efficacious and tolerated in pediatric patients aged 4 years or older with epilepsy. Early perampanel treatment may help to reduce the burden of their seizures and improve their quality of life.

Clinical Experience of Nusinersen in a Broad Spectrum of Spinal Muscular Atrophy: A Retrospective Study.

BACKGROUND: Nusinersen has recently been approved and more widely used as first-line treatment of spinal muscular atrophy (SMA). This study aimed to evaluate the real-world experience of nusinersen use for patients with a broad spectrum of SMA. METHODS: We reviewed consecutive patients with SMA treated with nusinersen from April 2018 to April 2020. Data collected included clinical and diagnostic characteristics, molecular genetics, functional motor outcomes, and adverse events. RESULTS: Seven patients including four with SMA type 1 and three with SMA type 2 were treated with nusinersen. The median disease duration at the time of the first dose and the median follow-up duration were 37 months (range: 0.5-254 months) and 6.1 months (range: 2.1-22.1 months), respectively. Of the 41 lumbar punctures (LPs), seven fluoroscopy-guided LPs were successfully performed for two patients without sedation. All patients showed improvement in motor function even though the current tools for motor assessment seemed unable to detect subtle subjective improvement. All patients maintained a stable respiratory status. No patient has experienced a severe adverse event or discontinued treatment so far. CONCLUSION: Although the number of patients in this study was small, our results suggest that nusinersen is effective even in patients with a later stage of the disease. Additional long-term prospective studies with more number of patients having a broad spectrum of diseases are needed to identify meaningful improvement in the motor function and quality of life after nusinersen treatment.