Eculizumab in Adolescent Patients With Refractory Generalized Myasthenia Gravis: A Phase 3, Open-Label, Multicenter Study.

BACKGROUND: This study evaluated the efficacy and safety of eculizumab, a terminal complement C5 inhibitor, in juvenile generalized myasthenia gravis (gMG). METHODS: Adolescents aged 12 to 17 years with refractory anti-acetylcholine receptor (AChR) antibody-positive gMG received eculizumab (weekly induction [one to two doses of 600 mg or four doses of 900 mg] followed by maintenance doses [300 to 1200 mg] every two weeks for up to 26 weeks) in a phase 3, open-label multicenter study (NCT03759366). Change from baseline to week 26 in Quantitative Myasthenia Gravis (QMG) total score (primary end point) and secondary end points including Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score, Myasthenia Gravis Composite score, Myasthenia Gravis Foundation of America postintervention status, EuroQol 5-Dimensions (Youth) and Neurological Quality-of-Life Pediatric Fatigue questionnaire scores, as well as pharmacokinetics, pharmacodynamics, and safety, were recorded. RESULTS: Eleven adolescents (mean ± S.D. age 14.8 ± 1.8 years) were enrolled; 10 completed the primary evaluation period. Least-squares mean changes from baseline at week 26 were -5.8 (standard error [SE] 1.2; P = 0.0004) for QMG total score and -2.3 (SE 0.6; P = 0.0017) for MG-ADL total score. Overall, the primary and all secondary efficacy end point analyses met statistical significance from the first assessment and were sustained throughout. Complete terminal complement inhibition was sustained through 26 weeks in all patients. Treatment-emergent adverse events were all mild/moderate and predominantly unrelated to eculizumab. CONCLUSIONS: Eculizumab was effective in reducing disease burden and was well tolerated in adolescents with refractory AChR antibody-positive gMG.

A case of rapid avacopan-induced liver injury in pediatric granulomatosis with polyangiitis.

Children with anti-neutrophil cytoplasmic antibody-associated vasculitis benefit immensely from avacopan as it reduces the requirement for steroids. However, descriptions of adverse drug reactions in children are lacking, and the dosage and follow-up intervals are unclear. A 10-year-old boy with initial granulomatosis and polyangiitis presented with diffuse pulmonary hemorrhage. Rituximab and 30 mg avacopan were administered twice daily as induction therapy following methylprednisolone pulse therapy. However, sudden liver function test abnormalities were observed on day 31 of avacopan treatment, despite liver enzyme levels being within the normal range 5 days earlier. A drug-induced lymphocyte stimulation and various infectious disease tests yielded negative results. Discontinuation of rituximab and avacopan resulted in improved liver function; no change in the Birmingham Vasculitis Activity Score during liver function test abnormalities was observed. Avacopan-associated abnormalities in liver function tests suggest that drug-induced liver injury may occur rapidly in children, and appropriate dosing strategies should be reconsidered.

Case Report: Tuberous sclerosis complex-associated hemihypertrophy successfully treated with mTOR inhibitor sirolimus.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by a mutation in either of the two tumor suppressor genes, TSC1 and TSC2. Due to dysregulated activity of the mammalian target of rapamycin (mTOR) pathway, hamartomas or benign tumors frequently occur in many organs and are often treated with mTOR inhibitors. Hemihypertrophy is a rare complication of TSC. Although not being a tumor, progressive overgrowth of the affected limb may cause cosmetic and functional problems, for which the efficacy of mTOR inhibitors has not been reported previously. We herein report a case of TSC-associated hemihypertrophy. In this case, genetic studies revealed TSC1 loss of heterozygosity as the cause of hemihypertrophy. Clinically, pharmacological treatment with an mTOR inhibitor sirolimus successfully ameliorated cosmetic and functional problems with no intolerable adverse effects.

Pathological Factors Affecting the R2* Values of the Kidney in Blood Oxygenation Level-dependent MR Imaging: A Retrospective Study.

PURPOSE: Despite the usefulness of blood oxygenation level-dependent (BOLD) MRI in assessing glomerulonephritis activity, its relationship with histological findings remains unclear. Because glomerulonephritis presents multiple complex injury patterns, analysis of each pattern is essential. We aimed to elucidate the relationship between the histological findings of the kidney and BOLD MRI findings in mesangial proliferative glomerulonephritis. METHODS: Children under 16 years of age diagnosed with mesangial proliferative glomerulonephritis by kidney biopsy at our university hospital between January 2013 and September 2022 were included in this study. Cortical and medullary spin relaxation rate (R2*) values were measured using BOLD MRI at 3T within two weeks before and after the kidney biopsy. The R2* values, including the fluctuations with low-dose oxygen administration, were retrospectively examined in relation to the cortical (mesangial proliferation, endothelial cell proliferation, crescent, sclerosis, and fibrosis) and medullary findings (fibrosis). RESULTS: Sixteen times kidney biopsies were performed for glomerulonephritis during the study period, and one patient was excluded because of comorbidities; the remaining 14 patients included six boys with a mean age of 11.9 ± 3.5 years at the BOLD examination. None of the patients had medullary fibrosis. Among the kidney tissue parameters, only sclerosis showed a significant correlation with R2* values: medulla with R2* values under atmospheric pressure (r = 0.53, P < 0.05) and cortex with the rate of change in R2* values with low-dose oxygen administration (r = -0.57, P < 0.03). In the multiple regression analysis, only sclerosis was an independent contributor to the change in R2* values with oxygen administration in the cortex (regression coefficient -0.109, P < 0.05). CONCLUSION: Since the R2* values reflect histological changes in the kidney, BOLD MRI may facilitate the evaluation of mesangial proliferative glomerulonephritis, potentially reducing the patient burden.

A Case of Shear Wave Velocity Reflecting the Disease Activity in Glomerulonephritis.

Ultrasound elastography can measure tissue elasticity using the shear wave velocity (SWV). Evaluating disease activity with elastography instead of renal biopsy may be less invasive. However, to the best of our knowledge, although there are studies comparing different glomerular diseases using SWV, there are no reports that have measured glomerulonephritis longitudinally from the acute phase of the disease. This study aimed to assess whether SWV reflects disease activity in glomerulonephritis, and we continued to observe children with post-streptococcal acute glomerulonephritis (PSAGN) from the acute phase to over a year later. In this case, a 6-year-old boy diagnosed with PSAGN had impaired renal function, and was admitted and tested. He was placed in a prone resting position and measurements were taken from the back. SWV was measured ≥50 times at each examination, and the mean was calculated when the net amount of effective SWV was ≥50%. The tests were performed once in the acute phase and thrice during the recovery phase for 13 months. SWV was found to be significantly lower in the recovery period than during the disease onset, and continued to stay lower at each test during the recovery period (P < 0.02). In conclusion, this indicated that SWV fluctuated similarly to the disease activity of glomerulonephritis; therefore, we suggest using SWV measurement to estimate the disease activity in glomerulonephritis in children. Although more clinical cases are needed, SWV measurement is a noninvasive and reproducible imaging modality to estimate the disease activity in glomerulonephritis.

Glomeruli Count and Arterial Injury in Real-Time Ultrasound-Guided Needle Kidney Biopsy Specimens: Adequacy of Three Approaches for Pig Kidneys.

INTRODUCTION: Real-time ultrasound-guided percutaneous kidney biopsy is essential for diagnosis and treatment planning; nonetheless, the optimal puncture approach has yet to be established. In vivo, performing different approaches on the same patient at once is not possible. This study aimed to determine the impact of different approaches on the number of obtained glomeruli and their potential to cause arterial injury using pig kidneys, which are similar to humans. METHODS: A total of 120 pig kidneys (60 right-sided kidneys and 60 left-sided kidneys) for research were obtained from a slaughterhouse. The specimens were collected from the lower pole on the sagittal plane of the kidney using three different approaches on the same kidney: caudocranial approach, caudal to cranial; craniocaudal approach, cranial to caudal; and vertical approach, through the surface cortex. Five blinded pediatric nephrologists assessed the number of glomeruli and arterial injuries. RESULTS: Overall, 360 specimens were collected from the kidneys through biopsy using a 16-gauge needle (mean vertical kidney length, 11.2 ± 0.7 cm; mean depth, 3.47 ± 0.23 cm). No significant difference in the incidence of arterial injury was observed between the three approaches (caudocranial vs. craniocaudal vs. vertical approaches: 78% vs. 87% vs. 87%, p = 0.14). In contrast, the vertical approach retrieved significantly more glomeruli than the caudocranial and craniocaudal approaches (caudocranial approach: 7.5 ± 2.8, craniocaudal approach: 7.8 ± 2.7, and vertical approach: 8.9 ± 3.3, p < 0.001). CONCLUSIONS: Considering its efficacy and safety profile, the vertical approach may be preferred, as more glomeruli can be obtained without increasing the incidence of arterial injury. Although the results cannot be directly extrapolated to humans due to the differences between species, they still offer important insights into the characteristics of each approach.

Fluctuation of R2* values in blood oxygenation level-dependent MRI during acute and remission phases of IgA vasculitis with nephritis in children.

PURPOSE: Noninvasive assessment of the kidney using blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) has progressed remarkably; indications have expanded to include the evaluation of glomerulonephritis. However, no longitudinal measurements from acute to post-treatment remission phases have been reported. Hence, this study aimed to investigate spin relaxation rate (R2*) values during acute and remission phases in children with glomerulonephritis. MATERIALS AND METHODS: All pediatric patients with IgA vasculitis with nephritis (IgAVN) diagnosed between January 2014 and October 2021 and requiring renal biopsy were retrospectively reviewed; four patients who were observed from onset to remission were included in this study. In total, eight MRIs were performed in the acute and remission phases, and R2* values and fluctuations induced by low-dose oxygen administration were determined from 10 echoes using a 1.5 T MRI system with 4.76-47.6 ms echo times and a 153 ms repetition time. RESULTS: The median age of patients undergoing MRI was 8.5 years in the acute phase and 13.9 years in the remission phase. R2* values of the acute phase were higher than those of the remission phase; however, the difference was not significant (cortex; p = 0.32 and medulla; p = 0.052). Oxygen administration did not cause fluctuations in the R2* values in the cortex or medulla during the acute phase (cortex; p = 0.67 and medulla; p = 0.76); however, in the remission phase, the R2* values in the cortex and medulla significantly decreased due to low-dose oxygen administration (cortex; p < 0.01 and medulla; p < 0.01). CONCLUSION: The fluctuation in R2* values observed during different phases of IgAVN indicates that BOLD MRI may be used to assess disease activity. Therefore, we propose BOLD MRI with low-dose oxygen administration as a noninvasive method to evaluate the activity of glomerulonephritis.

Valine metabolites analysis in ECHS1 deficiency.

Short-chain enoyl-CoA hydratase (ECHS1) is involved in amino acid and fatty acid catabolism in mitochondria and its deficiency causes Leigh syndrome or exercise-induced dystonia. More than 60 patients with this condition have been reported till date. The accumulation of intermediate metabolites of valine is assumed to be responsible for the cytotoxicity. Since protein restriction, including valine reportedly improves neurological symptoms, it is essential to consider the possible incidence of and diagnose ECHS1 syndrome in the earlier stages. This study reported the liquid chromatography with tandem mass spectrometry (LC-MS/MS) urine and plasma metabolite analysis in six cases, including four new cases with ECHS1 deficiency. The values of urine cysteine/cysteamine conjugates from valine metabolites, S-(2-carboxypropyl) cysteine/cysteamine from methacrylyl-CoA, and S-(2-carboxyethyl) cysteine/cysteamine from acryloyl-CoA were separated between six patients and six normal controls. The LC-MS/MS analysis revealed that these metabolites can be used for the early diagnosis and evaluation of diet therapy.

Acute encephalopathy in children with tuberous sclerosis complex.

OBJECTIVE: We examined the clinical manifestations of acute encephalopathy (AE) and identify risk factors for AE in children with tuberous sclerosis complex (TSC). METHODS: The clinical data of 11 children with clinically diagnosed TSC associated with AE and 109 children with clinically diagnosed TSC alone aged 4 years or older were collected from 13 hospitals. RESULTS: Of the 11 children with AE, 5 had histories of febrile seizures (FS), and all had histories of febrile status epilepticus (FSE). AE developed within 24 h after fever onset in all children with seizures lasting 30 min or longer. All children developed coma after seizure cessation. Head magnetic resonance imaging (MRI) revealed widespread abnormalities in the cerebral cortex, subcortical white matter, corpus callosum, basal ganglia, and thalamus. One child died; seven had severe neurological sequelae; and the other three, mild sequelae. Logistic regression analysis revealed that a history of FSE was correlated with the development of AE. SIGNIFICANCE: AE in children with TSC was characterized by sudden onset after fever, followed by coma, widespread brain edema evident on MRI, and poor outcomes. A history of FSE was a risk factor for the development of AE.

Brain edema with clasmatodendrosis complicating ataxia telangiectasia.

Ataxia-telangiectasia is a chronic progressive disorder affecting the nervous and immune systems, caused by a genetic defect in the ATM protein. Clasmatodendrosis, a distinct form of astroglial death, has rarely been reported in ataxia-telangiectasia. Neuropathology of our patient disclosed diffuse edema of the cerebral and cerebellar white matter with prominent clasmatodendrosis, implicating ATM in the regulation of astroglial cell death.

Holoprosencephaly with cerebellar vermis hypoplasia in 13q deletion syndrome: Critical region for cerebellar dysgenesis within 13q32.2q34.

We describe two unrelated patients with terminal deletions in the long arm of chromosome 13 showing brain malformation consisting of holoprosencephaly and cerebellar vermis hypoplasia. Array comparative genomic hybridization analysis revealed a pure terminal deletion of 13q31.3q34 in one patient and a mosaic ring chromosome with 13q32.2q34 deletion in the other. Mutations in ZIC2, located within region 13q32, cause holoprosencephaly, whereas the 13q32.2q32.3 region is associated with cerebellar vermis hypoplasia (Dandy-Walker syndrome). The rare concurrence of these major brain malformations in our patients provides further evidence that 13q32.2q32.3 deletion, harboring ZIC2 and ZIC5, leads to cerebellar dysgenesis.

Interstitial deletion of 13q14.13-q32.3 presenting with Arima syndrome and bilateral retinoblastoma.

A patient with a large deletion of the distal part of the long arm of chromosome 13 showed severe psychomotor retardation, a characteristic face, nystagmus, retinopathy, cystic kidney disease, and brain malformation with molar tooth sign and cerebellar vermis hypoplasia, a phenotype typical of Arima syndrome. This patient also had bilateral retinoblastoma. Fluorescent in situ hybridization and single-nucleotide-polymorphism genotyping microarray demonstrated an interstitial deletion of 54 Mbp, ranging from 13q14.13 to 13q32.3 and involving the RB1 gene. This patient is the first case of Arima syndrome, or a Joubert syndrome-related disorder, that showed linkage to chromosome 13q.

Comprehensive genetic analysis of overlapping syndromes of RAS/RAF/MEK/ERK pathway.

BACKGROUND: Germline mutations in several members of RAS/RAF/MEK/ERK pathway cause clinically similar genetic disorders, including Noonan syndrome (NS), Costello syndrome (CS) and cardio-facio-cutaneous syndrome (CFC). Each of these syndromes has a wide spectrum of molecular etiology. The aim of the present study was to conduct a comprehensive genetic analysis of RAS/RAF/MEK/ERK pathway in these syndromes. METHODS: Three patients with NS and two patients with CS/CFC were examined. Peripheral blood samples were collected from all patients as well as from 100 healthy Japanese volunteers. The protein phosphatase, non-receptor type II (PTPN11), KRAS, HRAS, NRAS, BRAF, RAF1, Son of Sevenless (SOS1) and MEK1genes were analyzed. RESULTS: In a patient with a severe Noonan phenotype, a rare PTPN11 mutation was detected: A to G transition at position 172, causing an N58D substitution within the N-SH2 domain. In a CS/CFC patient no HRAS mutations were found, but a novel SOS1 missense mutation was found: A to G transition at position 473, causing a T158A substitution within domain of histone-like fold (HF). CONCLUSIONS: A case mimicking CS with SOS1 T158A substitution, which has not been reported previously in CS, revealed the complex relationship between the genotype and phenotype of overlapping syndromes of the RAS/RAF/MEK/ERK pathway.

Hepatoblastoma in a patient with sotos syndrome.

We report a case of hepatoblastoma that developed in a child with Sotos syndrome, an overgrowth syndrome with an increased risk of neoplasms. Genome-wide analysis of copy number alterations showed a gain of chromosome 2, uniparental disomy of 18q, and microdeletion of 5q35.