Detecting Alu Element Insertion Variant in RP1 Gene Using Whole Genome Sequencing in Patients with Retinitis Pigmentosa.

Background/Objectives:Alu element insertion in the exon 4 of the RP1 gene was newly identified through whole genome sequencing (WGS). This was not detected in previous next-generation sequencing (NGS) analysis. We report three cases of Korean retinitis pigmentosa (RP) patients with compound heterozygous variants including Alu element insertion in the RP1 gene, indicating that Alu element insertion could be a cause of RP; Methods: Among patients diagnosed with RP having variants in the RP1 gene in the Asan Medical Center, WGS was additionally performed for genetically unsolved cases in previous NGS analysis to detect any presence of Alu element insertion. For cases detected to have Alu element insertion in the exon 4 of the RP1 gene, genetic and clinical characteristics were analyzed; Results: Among 16 patients with RP, 3 patients were detected to have Alu element insertion in the RP1 gene. Alu element insertion in the RP1 gene was also detected using WGS. It was revealed to be a pathogenic variant. Therefore, RP1 gene mutation was the confirmed genetic cause of RP for these three cases and genetic counseling was enabled for them; Conclusions: Alu element insertion in the RP1 gene could be a genetic cause of autosomal recessive RP patients with compound heterozygous variants. Through WGS, the identification of this pathogenic variant was possible. Confirmation is needed to check the presence of Alu element insertion in patients with compound heterozygous variants in the RP1 gene.

Endocrine Complications in Hepatic Glycogen Storage Diseases: A Long-term Perspective.

OBJECTIVE: Patients with hepatic type of glycogen storage diseases (GSDs) can manifest endocrine features such as hypoglycemia, dyslipidemia, or osteoporosis. This study aimed to investigate the long-term endocrine consequences in patients with hepatic GSDs. METHODS: This study included 64 patients from 52 families with hepatic GSDs including GSD type Ia (41 patients from 37 families), Ib (3 unrelated), III (8 from 6 families), IV (one patient), and IX (11 from 5 families). All patients were genetically confirmed. Clinical and endocrine findings were retrospectively analyzed. RESULTS: The median age at diagnosis and current age were 2.4 years (range, 0.1-42.4 years) and 17.6 years (range, 1.0-47.8 years), respectively. The mean height SDS at diagnosis was -3.5 ± 1.4, and short stature was observed in 35.6% of patients. Patients diagnosed after the age of 3.4 years exhibited a high risk of short stature (OR = 36.1; P-value < 0.001). Among 33 patients who reached final height, 23 (69.7%) showed delayed puberty. Hypertriglyceridemia was observed in 46 patients (71.9%), whereas 25 patients (39%) had elevated low-density lipoprotein cholesterol levels during the follow-up period. Among 24 patients who underwent dual energy X-ray absorptiometry, 22 showed a low bone mineral density Z-score of -3.0 ± 1.3 at the L-spine. CONCLUSIONS: This study described the long-term endocrine consequences in patients with hepatic GSDs. Pediatric endocrinologists should be aware of the presenting features and long-term endocrine sequelae of GSDs to provide proper management and decrease its morbidities.

Exploring novel MYH7 gene variants using in silico analyses in Korean patients with cardiomyopathy.

BACKGROUND: Pathogenic variants of MYH7, which encodes the beta-myosin heavy chain protein, are major causes of dilated and hypertrophic cardiomyopathy. METHODS: In this study, we used whole-genome sequencing data to identify MYH7 variants in 397 patients with various cardiomyopathy subtypes who were participating in the National Project of Bio Big Data pilot study in Korea. We also performed in silico analyses to predict the pathogenicity of the novel variants, comparing them to known pathogenic missense variants. RESULTS: We identified 27 MYH7 variants in 41 unrelated patients with cardiomyopathy, consisting of 20 previously known pathogenic/likely pathogenic variants, 2 variants of uncertain significance, and 5 novel variants. Notably, the pathogenic variants predominantly clustered within the myosin motor domain of MYH7. We confirmed that the novel identified variants could be pathogenic, as indicated by high prediction scores in the in silico analyses, including SIFT, Mutation Assessor, PROVEAN, PolyPhen-2, CADD, REVEL, MetaLR, MetaRNN, and MetaSVM. Furthermore, we assessed their damaging effects on protein dynamics and stability using DynaMut2 and Missense3D tools. CONCLUSIONS: Overall, our study identified the distribution of MYH7 variants among patients with cardiomyopathy in Korea, offering new insights for improved diagnosis by enriching the data on the pathogenicity of novel variants using in silico tools and evaluating the function and structural stability of the MYH7 protein.

Cross-cultural validation of the genetic counseling outcome scale in Korea.

The Genetic Counseling Outcome Scale (GCOS-24) was developed to measure patient-reported outcomes to evaluate the effectiveness of genetic counseling and testing services. In the current study, the Korean version of GCOS (K-GCOS) was developed to reflect the sociocultural characteristics of Korea, and its clinical applicability was assessed. Overall, 231 Koreans, including patients with genetic diseases and their family members, participated and completed the K-GCOS, Hospital Anxiety and Depression Scale (HADS), Multidimensional Health Locus of Control (MHLC) scale, and Satisfaction with Life Scale (SWLS). Validity was examined by assessing the correlations between K-GCOS scores and other relevant scale scores. Reliability was confirmed using Cronbach's alpha and test-retest scores, measured over 2 weeks. We performed exploratory factor analysis of the five structures of GCOS-24. For K-GCOS, four-factor structures were identified: "cognitive-behavioral control," "uncertainty about control," "hope," and "emotional regulation." Four original GCOS-24 items were removed because of low factor loadings and small inter-item correlations. K-GCOS-20 scores were positively correlated with SWLS (r = 0.456) and MHLC-internal (r = 0.213) scores but negatively correlated with HADS (anxiety r = -0.428, depression r = -0.469) and MHLC-internal (r = -0.278) scores. These findings demonstrate that K-GCOS-20 is a reliable and valid tool for evaluating genetic counseling services in Korea.

Safety and efficacy of selumetinib in pediatric and adult patients with neurofibromatosis type 1 and plexiform neurofibroma.

BACKGROUND: The MEK inhibitor, selumetinib, reduces plexiform neurofibroma (PN) in pediatric patients with neurofibromatosis type 1 (NF1). Its safety and efficacy in adults with PN and effectiveness in other NF1manifestations (e.g., neurocognitive function, growth reduction, and café-au-lait spots) are unknown. METHODS: This open-label, phase 2 trial enrolled 90 pediatric or adult NF1 patients with inoperable, symptomatic, or potentially morbid, measurable PN (≥ 3 cm). Selumetinib was administered at doses of 20 or 25 mg/m2 or 50 mg q 12 hrs for 2 years. Pharmacokinetics, PN volume, growth parameters, neurocognitive function, café-au-lait spots, and quality of life (QoL) were evaluated. RESULTS: Fifty-nine children and 30 adults (median age, 16 years; range, 3-47) received an average of 22±5 (4-26) cycles of selumetinib. Eighty-eight (98.9%) out of 89 per-protocol patients showed volume reduction in the target PN (median, 40.8%; 4.2%-92.2%), and 81 (91%) patients showed partial response (≥ 20% volume reduction). The response lasted until cycle 26. Scores of neurocognitive functions (verbal comprehension, perceptual reasoning, processing speed, and full-scale IQ) significantly improved in both pediatric and adult patients (P <0.05). Prepubertal patients showed increases in height score and growth velocity (P <0.05). Café-au-lait spot intensity decreased significantly (P <0.05). Improvements in QoL and pain scores were observed in both children and adults. All adverse events were CTCAE grade 1 or 2 and were successfully managed without drug discontinuation. CONCLUSION: Selumetinib decrease PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in non-malignant diverse NF1 manifestations.

Development and verification of the Korean version of the genetic counseling self-efficacy scale.

A self-reported Genetic Counseling Self-Efficacy Scale (GCSES) was developed in English to measure genetic counselors' self-efficacy, a factor known to affect their job performance. This study verified the reliability and validity of the GCSES for use in Korea. The scale was translated and back-translated into Korean for cultural fit verification. Expert analysis was performed to ensure content validity. For construct validity, a confirmatory factor analysis of the six-factor structures of the GCSES and an exploratory factor analysis (EFA) of the K-GCSES were conducted. To confirm the convergent validity and discriminant validity of the items, a multitrait/multi-item matrix analysis of the relationship between items and subscales was conducted. The reliability was evaluated by examining internal consistency and test-retest reliability. A total of 62 participants were recruited from certified genetic counselors associated with the Korean Society of Medical Genetics and Genomics and from four graduate schools offering genetic counseling programs. Confirmatory factor analysis showed an inadequate fit to the original GCSES structure. Through EFA, three-factor structures were identified: "counseling competence and psychosocial skills," "genetic testing," and "information gathering." Of the original 38 GCSES items, five were removed due to low factor loadings and small inter-item correlations. The item convergent validity and discriminant validity of the Korean version of the GCSES were established, and the correlation between the subfactors showed statistical significance (0.711-0.983). Cronbach's alpha was 0.985, and the intraclass correlation coefficient ranged from 0.882 to 0.897, securing reliability. The K-GCSES has a three-factor structure with acceptable reliability and sufficient validity. Differences in the factor structure between the K-GCSES and GCSES may be due to cultural factors. K-GCSES can be used as a tool to evaluate the competence of genetic counselors and genetic counseling students in Korea and to improve the quality of professionalism and education.

Clinical and molecular characteristics of Korean patients with Kabuki syndrome.

INTRODUCTION: Kabuki syndrome (KS) is a rare disorder characterized by typical facial features, skeletal anomalies, fetal fingertip pad persistence, postnatal growth retardation, and intellectual disabilities. Heterozygous variants of the KMT2D and KDM6A genes are major genetic causes of KS. This study aimed to report the clinical and genetic characteristics of KS. METHODS: This study included 28 Korean patients (14 boys and 14 girls) with KS through molecular genetic testing, including direct Sanger sequencing, whole-exome sequencing, or whole-genome sequencing. RESULTS: The median age at clinical diagnosis was 18.5 months (IQR 7-58 months), and the median follow-up duration was 80.5 months (IQR 48-112 months). Molecular genetic testing identified different pathogenic variants of the KMT2D (n = 23) and KDM6A (n = 3) genes, including 15 novel variants. Patients showed typical facial features (100%), such as long palpebral fissure and eversion of the lower eyelid; intellectual disability/developmental delay (96%); short stature (79%); and congenital cardiac anomalies (75%). Although 71% experienced failure to thrive in infancy, 54% of patients showed a tendency toward overweight/obesity in early childhood. Patients with KDM6A variants demonstrated severe genotype-phenotype correlation. CONCLUSION: This study enhances the understanding of the clinical and genetic characteristics of KS.

Inherited CARD9 Deficiency Due to a Founder Effect in East Asia.

Autosomal recessive CARD9 deficiency can underly deep and superficial fungal diseases. We identified two Japanese patients, suffering from superficial and invasive Candida albicans diseases, carrying biallelic variants of CARD9. Both patients, in addition to another Japanese and two Korean patients who were previously reported, carried the c.820dup CARD9 variant, either in the homozygous (two patients) or heterozygous (three patients) state. The other CARD9 alleles were c.104G > A, c.1534C > T and c.1558del. The c.820dup CARD9 variant has thus been reported, in the homozygous or heterozygous state, in patients originating from China, Japan, or South Korea. The Japanese, Korean, and Chinese patients share a 10 Kb haplotype encompassing the c.820dup CARD9 variant. This variant thus originates from a common ancestor, estimated to have lived less than 4,000 years ago. While phaeohyphomycosis caused by Phialophora spp. was common in the Chinese patients, none of the five patients in our study displayed Phialophora spp.-induced disease. This difference between Chinese and our patients probably results from environmental factors. (161/250).

Survey of patient satisfaction with genetic counseling services in Korea.

Since the 1990s, genetic clinics have been established in South Korea, enabling the provision of clinical genetics services. However, genetic counseling services are not widely used in the medical system. In contrast, recently, the demand for genetic counseling has increased due to the rapid development of genomic medicine. Therefore, it is important for medical geneticists and genetic counselors to collaboratively provide genetic counseling services. This study aimed to evaluate the perception and satisfaction of patients with rare genetic diseases and their families regarding genetic counseling services provided by a genetics team at the medical genetics center of a tertiary general hospital for rare genetic diseases. From April to November 2021, a survey was conducted with 203 individuals, including 111 and 92 individuals in the patient and family groups, respectively. Overall, 164 individuals (80.8%) responded that they were aware of genetic counseling services, and 135 individuals (66.5%) responded that they were aware of the role of genetic counselors. Patients and their families wanted to receive information about the following from genetic counseling: clinical manifestation and prognosis of the diagnosed disease (78.8%), treatment and management of the disease (60.6%), risk of recurrence within the family (55.7%), treatment options and alternatives for family and prenatal testing, and various support services. The score of satisfaction with genetic counseling services provided by the genetics team was 8.19 ± 1.68 out of 10. Patients with rare genetic diseases and their families were satisfied with genetic counseling services regarding their diseases, test results, and treatment options. Moreover, the patients could receive psychosocial support and referrals to other medical service providers and support services. As a genetic team approach, collaboration between medical geneticists and certified genetic counselors would be useful in providing information and in diagnosing, treating, and managing patients.

A 10-year follow-up of high-dose ambroxol treatment combined with enzyme replacement therapy for neuropathic Gaucher disease.

High-dose ambroxol therapy combined with ERT in patients with neuropathic Gaucher disease.

Clinical and genetic characteristics of three patients with congenital insensitivity to pain with anhidrosis: Case reports and a review of the literature.

BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder caused by loss-of-function mutations of the NTRK1 gene, affecting the autonomic and sensory nervous system. Clinical manifestation is varied and includes recurrent fever, pain insensitivity, anhidrosis, self-mutilating behavior, and intellectual disability. METHODS: Clinical and genetic features were assessed in two males and one female with genetically confirmed CIPA using exome or genome sequencing. RESULTS: CIPA symptoms including recurrent fever, pain insensitivity, and anhidrosis manifested at the age of 1 year (age range: 0.3-8 years). Two patients exhibited self-mutilation tendencies, intellectual disability, and developmental delay. Four NTRK1 (NM_002529.3) mutations, c.851-33T>A (p.?), c.2020G>T (p.Asp674Tyr), c.2303C>T (p.Pro768Leu), and c.574-156_850+1113del (exons 5-7 del) were identified. Two patients exhibited early onset and severe phenotype, being homozygous for c.851-33T>A (p.?) mutations and compound heterozygous for c.851-33T>A (p.?) and c.2020G>T (p.Asp674Tyr) mutation of NTRK1. The third patient with compound heterozygous mutations of c.2303C>T (p.Pro768Leu) and c.574-156_850+1113del (exons 5-7 del) displayed a late onset and milder clinical manifestation. CONCLUSION: All three patients exhibited variable phenotypes and disease severity. This research enriches our understanding of clinical and genetic aspects of CIPA, highlighting variable phenotypes and disease severity.

Identification of a complex intrachromosomal inverted insertion in the long arm of chromosome 9 as a cause of tuberous sclerosis complex in a Korean family.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder, caused by a loss-of-function of either TSC1 or TSC2 gene. However, in 10%-15% TSC patients there is no pathogenic variant identified in either TSC1 or TSC2 genes based on standard clinical testing. METHODS: In this study, genome sequencing was performed for families with clinical diagnosis of TSC with negative results from TSC1 and TSC2 single-gene tests. RESULTS: Herein, we report a family presenting a classical TSC phenotype with an unusual, complex structural variant involving the TSC1 gene: an intrachromosomal inverted insertion in the long arm of chromosome 9. We speculate that the inverted 9q33.3q34.13 region was inserted into the q31.2 region with the 3'-end of the breakpoint of the inversion being located within the TSC1 gene, resulting in premature termination of TSC1. CONCLUSIONS: In this study, we demonstrate the utility of genome sequencing for the identification of complex chromosomal rearrangement. Because the breakpoints are located within the deep intronic/intergenic region, this copy-neutral variant was missed by the TSC1 and TSC2 single-gene tests and contributed to an unknown etiology. Together, this finding suggests that complex structural variants may be underestimated causes for the etiology of TSC.

Genetic heterogeneity of cardiomyopathy and its correlation with patient care.

BACKGROUND: Cardiomyopathy, which is a genetically and phenotypically heterogeneous pathological condition, is associated with increased morbidity and mortality. Genetic diagnosis of cardiomyopathy enables accurate phenotypic classification and optimum patient management and counseling. This study investigated the genetic spectrum of cardiomyopathy and its correlation with the clinical course of the disease. METHODS: The samples of 72 Korean patients with cardiomyopathy (43 males and 29 females) were subjected to whole-exome sequencing (WES). The familial information and clinical characteristics of the patients were reviewed and analyzed according to their genotypes. RESULTS: Dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), left ventricular non-compaction cardiomyopathy, and restrictive cardiomyopathy was detected in 41 (56.9%), 25 (34.7%), 4 (5.6%), and 2 (2.8%) patients, respectively. WES analysis revealed positive results in 37 (51.4%) patients. Subsequent familial testing identified ten additional familial cases. Among DCM cases, 19 (46.3%) patients exhibited positive results, with TTN variants being the most common alteration, followed by LMNA and MYH7 variants. Meanwhile, among HCM cases, 15 (60%) patients exhibited positive results with MYH7 variants being the most common alteration. In six patients with positive results, extracardiac surveillance was warranted based on disease information. The incidence of worse outcomes, such as mortality and life-threatening arrhythmic events, in patients with DCM harboring LMNA variants, was higher than that in patients with DCM harboring TTN or MYH7 variants. CONCLUSIONS: Diverse genotypes were identified in a substantial proportion of patients with cardiomyopathy. Genetic diagnosis enables personalized disease surveillance and management.

Case report: a premature infant with severe intrauterine growth restriction, adrenal insufficiency, and inflammatory diarrhea: a genetically confirmed case of MIRAGE syndrome.

Introduction: MIRAGE syndrome is a rare disease characterized by myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy. Herein, we report the case of a girl with MIRAGE syndrome who presented with adrenal insufficiency and chronic diarrhea. Case presentation: The patient was born at 29 + 6 weeks of gestational age with a birth weight of 656 g (<3p). Her height and head circumference were also <3p. At birth, she presented with respiratory distress, meconium staining, and pneumomediastinum, which were managed with high-frequency ventilation and empirical antibiotics. Physical examination showed generalized hyperpigmentation and normal female genitalia. A few days after birth, polyuria and hypotension developed, and laboratory findings revealed hypoglycemia, hyponatremia, and hyperkalemia. Plasma adrenocorticotropic hormone levels were elevated with low serum cortisol levels and high plasma renin activity, which were suggestive of adrenal insufficiency. Hydrocortisone and fludrocortisone were introduced and maintained, and hyperpigmentation attenuated with time. Both kidneys looked dysplastic, and adrenal glands could not be traced on abdominal ultrasound. From the early days of life, thrombocytopenia and anemia were detected, but not to life-threatening level and slowly recovered up to the normal range. Despite aggressive nutritional support, weight gain and growth spurt were severely retarded during the hospital stay. Additionally, after introducing enteral feeding, she experienced severe diarrhea and subsequent perineal skin rashes and ulcerations. Fecal calprotectin level was highly elevated; however, a small bowel biopsy resulted in non-specific submucosal congestion. The patient was diagnosed with MIRAGE syndrome with SAMD9 gene mutation. She was discharged with tube feeding and elemental formula feeding continued, but chronic diarrhea persisted. By the time of the last follow-up at 15 months of corrected age, she was fortunately not subjected to severe invasive infection and myelodysplastic syndrome. However, she was dependent on tube feeding and demonstrated a severe developmental delay equivalent to approximately 5-6 months of age. Conclusion: The early diagnosis of adrenal crisis and hormone replacement therapy can save the life of -patients with MIRAGE syndrome; however, chronic intractable diarrhea and growth and developmental delay continue to impede the patient's well-being.

Genetic diagnosis of kidney disease by whole exome sequencing and its clinical application.

The genetic spectrum of genetic kidney diseases (GKD) and the application of genetic diagnoses to patient care were assessed by whole exome sequencing (WES) of the DNA of 172 pediatric or adult patients with various kidney diseases. WES diagnosed genetic diseases in 63 (36.6%) patients. The diagnostic yields in patients with glomerulopathy were 33.8% (25/74 pts) due to variants in 10 genes, 58.8% (20/34) in patients with tubulointerstitial disease due to variants in 18 genes, 33.3% (15/45) in patients with cystic disease/ciliopathy due to variants in 10 genes, 18.2% (2/11) in patients with congenital anomalies of the kidneys and urinary tract (CAKUT) due to variants in two genes, and 12.5% (1/8) in patients with end stage kidney disease (ESKD). The diagnosis rate was high in patients aged <1-6 years (46-50.0%), and low in patients aged ≥40 years (9.1%). Renal phenotype was reclassified in 10 (15.9%) of 63 patients and clinical management altered in 10 (15.9%) of 63 patients after genetic diagnosis. In conclusion, these findings demonstrated the diagnostic utility of WES and its effective clinical application in patients, with various kinds of kidney diseases, across the different age groups.

Selection of iPSCs without mtDNA deletion for autologous cell therapy in a patient with Pearson syndrome.

Screening for genetic defects in the cells should be examined for clinical application. The Pearson syndrome (PS) patient harbored nuclear mutations in the POLG and SSBP1 genes, which could induce systemic large-scale mitochondrial genome (mtDNA) deletion. We investigated iPSCs with mtDNA deletions in PS patient and whether deletion levels could be maintained during differentiation. The iPSC clones derived from skin fibroblasts (9% deletion) and blood mononuclear cells (24% deletion) were measured for mtDNA deletion levels. Of the 13 skin-derived iPSC clones, only 3 were found to be free of mtDNA deletions, whereas all blood-derived iPSC clones were found to be free of deletions. The iPSC clones with (27%) and without mtDNA deletion (0%) were selected and performed in vitro and in vivo differentiation, such as embryonic body (EB) and teratoma formation. After differentiation, the level of deletion was retained or increased in EBs (24%) or teratoma (45%) from deletion iPSC clone, while, the absence of deletions showed in all EBs and teratomas from deletion-free iPSC clones. These results demonstrated that non-deletion in iPSCs was maintained during in vitro and in vivo differentiation, even in the presence of nuclear mutations, suggesting that deletion-free iPSC clones could be candidates for autologous cell therapy in patients. [BMB Reports 2023; 56(8): 463-468].

Therapeutic gene correction for Lesch-Nyhan syndrome using CRISPR-mediated base and prime editing.

Lesch-Nyhan syndrome (LNS) is inherited as an X-linked recessive genetic disorder caused by mutations in hypoxanthine-guanine phosphoribosyl transferase 1 (HPRT1). Patients with LNS show various clinical phenotypes, including hyperuricemia, gout, devastating behavioral abnormality, intellectual disability, and self-harm. Although uric acid overproduction can be modulated with the xanthine oxidase inhibitor allopurinol, there exists no treatment for behavioral and neurological manifestations of LNS. In the current study, CRISPR-mediated base editors (BEs) and prime editors (PEs) were utilized to generate LNS-associated disease models and correct the disease models for therapeutic approach. Cytosine BEs (CBEs) were used to induce c.430C>T and c.508C>T mutations in HAP1 cells, and then adenine BEs (ABEs) were used to correct these mutations without DNA cleavage. PEs induced a c.333_334ins(A) mutation, identified in a Korean patient with LNS, in HAP1 cells, which was corrected in turn by PEs. Furthermore, improved PEs corrected the same mutation in LNS patient-derived fibroblasts by up to 14% without any unwanted mutations. These results suggest that CRISPR-mediated BEs and PEs would be suggested as a potential therapeutic strategy of this extremely rare, devastating genetic disease.

Fasudil alleviates the vascular endothelial dysfunction and several phenotypes of Fabry disease.

Fabry disease (FD), a lysosomal storage disorder, is caused by defective α-galactosidase (GLA) activity, which results in the accumulation of globotriaosylceramide (Gb3) in endothelial cells and leads to life-threatening complications such as left ventricular hypertrophy (LVH), renal failure, and stroke. Enzyme replacement therapy (ERT) results in Gb3 clearance; however, because of a short half-life in the body and the high immunogenicity of FD patients, ERT has a limited therapeutic effect, particularly in patients with late-onset disease or progressive complications. Because vascular endothelial cells (VECs) derived from FD-induced pluripotent stem cells display increased thrombospondin-1 (TSP1) expression and enhanced SMAD2 signaling, we screened for chemical compounds that could downregulate TSP1 and SMAD2 signaling. Fasudil reduced the levels of p-SMAD2 and TSP1 in FD-VECs and increased the expression of angiogenic factors. Furthermore, fasudil downregulated the endothelial-to-mesenchymal transition (EndMT) and mitochondrial function of FD-VECs. Oral administration of fasudil to FD mice alleviated several FD phenotypes, including LVH, renal fibrosis, anhidrosis, and heat insensitivity. Our findings demonstrate that fasudil is a novel candidate for FD therapy.

Pediatric hepatocellular carcinoma associated with Niemann-Pick disease type C: Case report and literature review.

Niemann-Pick disease type C (NPC) is a rare, autosomal recessive, lysosomal storage disease, resulting from mutations in the cholesterol trafficking proteins NPC1 or NPC2, which is characterized by progressive neurodegeneration and hepatic dysfunction. The hepatic involvement in NPC is usually neonatal cholestasis and hepatosplenomegaly. Only a few cases of severe hepatic complications were reported including acute liver failure, cirrhosis, and hepatocellular carcinoma (HCC). We described the case of a 6-year-old male with NPC with HCC. He had a history of neonatal cholestasis and motor delay. At the age of 6 months, he was diagnosed with NPC, which was confirmed by the detection of a compound heterozygous NPC1 mutation (p.C113Y/p.A927V). He presented recurrent hypoglycemia and abdominal distension. An ultrasound, computed tomography scan, and biopsy revealed that he had a stage IV HCC with pulmonary metastasis. With the literature review and this case, HCC can be a rare fatal comorbid condition in patients with NPC, particularly infantile-onset, male patients with a relatively long disease history, necessitating appropriate HCC surveillance.