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1.
J Clin Lipidol ; 17(6): 808-817, 2023.
Article in English | MEDLINE | ID: mdl-37858495

ABSTRACT

BACKGROUND: Lipoprotein lipase (LPL) deficiency, the most common familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disease characterized by chylomicronemia and severe hypertriglyceridemia (HTG), with limited clinical and genetic characterization. OBJECTIVE: To describe the manifestations and management of 19 pediatric patients with LPL-FCS. METHODS: LPL-FCS patients from 2014 to 2022 were divided into low-fat (LF), very-low-fat (VLF) and medium-chain-triglyceride (MCT) groups. Their clinical data were evaluated to investigate the effect of different diets. The genotype-phenotype relationship was assessed. Linear regression comparing long-chain triglyceride (LCT) intake and TG levels was analyzed. RESULTS: Nine novel LPL variants were identified in 19 LPL-FCS pediatric patients. At baseline, eruptive xanthomas occurred in 3/19 patients, acute pancreatitis in 2/19, splenomegaly in 6/19 and hepatomegaly in 3/19. The median triglyceride (TG) level (30.3 mmol/L) was markedly increased. The MCT group and VLF group with LCT intakes <20 en% (energy percentage) had considerably lower TG levels than the LF group (both p<0.05). The LF group presented with severe HTG and significantly decreased TG levels after restricting LCT intakes to <20 en% (p<0.05). Six infants decreased TG levels to <10 mmol/L by keeping LCT intake <10 en%. TG levels and LCT intake were positively correlated in both patients under 2 years (r=0.84) and those aged 2-9 years (r=0.89). No genotype-phenotype relationship was observed. CONCLUSIONS: This study broadens the clinical and genetic spectra of LPL-FCS. The primary therapy for LPL-FCS pediatric patients is restricting dietary LCTs to <10 en% or <20 en% depending on different ages. MCTs potentially provide extra energy.


Subject(s)
Hyperlipoproteinemia Type I , Hypertriglyceridemia , Pancreatitis , Infant , Humans , Child , Hyperlipoproteinemia Type I/therapy , Hyperlipoproteinemia Type I/drug therapy , Acute Disease , Genetic Profile , Pancreatitis/genetics , Hypertriglyceridemia/genetics , Triglycerides , China , Lipoprotein Lipase/genetics
2.
J Med Genet ; 61(1): 27-35, 2023 Dec 21.
Article in English | MEDLINE | ID: mdl-37586839

ABSTRACT

BACKGROUND: Primary adrenal insufficiency (PAI) is a rare but life-threatening condition. Differential diagnosis of numerous causes of PAI requires a thorough understanding of the condition. METHODS: To describe the genetic composition and presentations of PAI. The following data were collected retrospectively from 111 patients with non-21OHD with defined genetic diagnoses: demographic information, onset age, clinical manifestations, laboratory findings and genetic results. Patients were divided into four groups based on the underlying pathogenesis: (1) impaired steroidogenesis, (2) adrenal hypoplasia, (3) resistance to adrenocorticotropic hormone (ACTH) and (4) adrenal destruction. The age of onset was compared within the groups. RESULTS: Mutations in the following genes were identified: NR0B1 (n=39), STAR (n=33), CYP11B1 (n=12), ABCD1 (n=8), CYP17A1 (n=5), HSD3B2 (n=4), POR (n=4), MRAP (n=2), MC2R (n=1), CYP11A1 (n=1), LIPA (n=1) and SAMD9 (n=1). Frequent clinical manifestations included hyperpigmentation (73.0%), dehydration (49.5%), vomiting (37.8%) and abnormal external genitalia (23.4%). Patients with adrenal hypoplasia typically presented manifestations earlier than those with adrenal destruction but later than those with impaired steroidogenesis (both p<0.01). The elevated ACTH (92.6%) and decreased cortisol (73.5%) were the most common laboratory findings. We generated a differential diagnosis flowchart for PAI using the following clinical features: 17-hydroxyprogesterone, very-long-chain fatty acid, external genitalia, hypertension and skeletal malformation. This flowchart identified 84.8% of patients with PAI before next-generation DNA sequencing. CONCLUSIONS: STAR and NR0B1 were the most frequently mutated genes in patients with non-21OHD PAI. Age of onset and clinical characteristics were dependent on aetiology. Combining clinical features and molecular tests facilitates accurate diagnosis.


Subject(s)
Addison Disease , Adrenal Insufficiency , Humans , Addison Disease/genetics , Retrospective Studies , Adrenocorticotropic Hormone , China , Adrenal Insufficiency/diagnosis , Adrenal Insufficiency/genetics , Intracellular Signaling Peptides and Proteins
3.
Orphanet J Rare Dis ; 18(1): 126, 2023 05 26.
Article in English | MEDLINE | ID: mdl-37237297

ABSTRACT

BACKGROUND: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder characterized by primary adrenal insufficiency (PAI) and hypogonadotropic hypogonadism (HH), with limited clinical and genetic characterization. METHODS: The clinical, biochemical, genetic, therapeutic, and follow-up data of 42 patients diagnosed with X-linked AHC were retrospectively analysed. RESULTS: Hyperpigmentation (38/42, 90%), vomiting/diarrhoea (20/42, 48%), failure to thrive (13/42, 31%), and convulsions (7/42, 17%) were the most common symptoms of X-linked AHC at onset. Increased adrenocorticotropic hormone (ACTH) (42/42, 100%) and decreased cortisol (37/42, 88%) were the most common laboratory findings, followed by hyponatremia (32/42, 76%) and hyperkalaemia (29/42, 69%). Thirty-one patients presented with PAI within the first year of life, and 11 presented after three years of age. Three of the thirteen patients over the age of 14 exhibited spontaneous pubertal development, and ten of them experienced delayed puberty due to HH. Six patients receiving human chorionic gonadotropin (hCG) therapy exhibited a slight increase in testicular size and had rising testosterone levels (both P < 0.05). The testicular volumes of the three patients with pulsatile gonadotropin-releasing hormone (GnRH) therapy were larger than those of the six patients undergoing hCG therapy (P < 0.05), and they also exhibited some growth in terms of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. Of the 42 patients, three had an Xp21 deletion, and 39 had an isolated DAX1 defect. Most patients (9/10) with entire DAX1 deletion accounting for 23.8% (10/42) of the total variants had early onset age of less than one year. CONCLUSIONS: This study details the clinical features and genetic spectra of X-linked AHC. Patients with X-linked AHC show a bimodal distribution of the age of onset, with approximately 70% presenting within the first year of life. Pulsatile GnRH may be recommended for HH when hCG therapy is not satisfactory, although it is difficult to achieve normal testicular volume. The combination of clinical features and molecular tests provides information for an accurate diagnosis.


Subject(s)
East Asian People , Hypogonadism , Child , Humans , Male , Gonadotropin-Releasing Hormone/therapeutic use , Hypoadrenocorticism, Familial/genetics , Hypoadrenocorticism, Familial/drug therapy , Hypogonadism/drug therapy , Hypogonadism/genetics , Mutation , Retrospective Studies , Testosterone
4.
Front Med (Lausanne) ; 9: 885178, 2022.
Article in English | MEDLINE | ID: mdl-35755072

ABSTRACT

Steroid-resistant nephrotic syndrome (SRNS) is one of the major causes of end-stage kidney disease (ESKD) in children and young adults. For approximately 30% of children with SRNS results from a genetic cause. In this study, genotype-phenotype correlations in a cohort of 283 pediatric patients with SRNS or early-onset NS (nephrotic syndrome presenting within the first year of life) from 23 major pediatric nephrology centers in China were analyzed. All patients were performed with next-generation sequencing and Sanger sequencing. The overall mutation detection rate was 37.5% (106 of 283 patients). WT1 was the most frequently detected mutation, followed by NPHS1, NPHS2, and ADCK4, and these four major causative genes (WT1, NPHS1, NPHS2, and ADCK4) account for 73.6% of patients with monogenic SRNS. Thirteen of 106 individuals (12.3%) carried mutations in ADCK4 that function within the coenzyme Q10 biosynthesis pathway. In the higher frequently ADCK4-related SRNS, two mutations, c.737G>A (p.S246N) and c.748G>C (p.D250H), were the most prevalent. Our study provides not only definitive diagnosis but also facilitate available targeted treatment for SRNS, and prediction of prognosis and renal outcome. Our indications for genetic testing are patients with FSGS, initial SRNS, cases of positive family history or those with extra-renal manifestations.

5.
J Clin Lipidol ; 16(1): 40-51, 2022.
Article in English | MEDLINE | ID: mdl-34969652

ABSTRACT

BACKGROUND: Sitosterolemia is a rare autosomal recessive disease characterized by phytosterol accumulation in the blood and tissues. However, the detailed clinical and genetic spectra are lacking. OBJECTIVE: To describe and compare the clinical, biochemical, genetic, therapeutic, and follow-up characteristics of 55 pediatric and five adult sitosterolemia patients. METHODS: Clinical, genetic and therapeutic data from 60 patients at Xinhua Hospital from January 2016 to June 2021 were retrospectively collected. RESULTS: Pediatric patients' manifestations included xanthomas(93%), hematological disorders(30%), arthralgia(24%), splenomegaly(11%), atherosclerosis(10%). Adult patients had symptoms such as atherosclerosis(5/5), xanthomas(4/5), hematological disorders(3/5), arthralgia(3/5), splenomegaly(3/5). Elevated total cholesterol(TC) and low-density lipoprotein cholesterol(LDL-C) were observed in 96% patients (pediatric 98%, adult 3/4), and phytosterol levels in 100% patients. The age of onset was also negatively correlated with blood TC (P < 0.0001, r = -0.5548) and LDL-C (P = 0.0001, r = -0.4859) levels. Targeted treatments resulted in symptomatic remission(pediatric 96%, adult 4/5), and significantly decreased lipid and phytosterol levels(all P<0.05). In the dietary-therapy cohort(n=34), blood lipid levels decreased(all P<0.05). In the 13 pediatric patients from the dietary-therapy cohort who switched from dietary to combination therapy with ezetimibe, dietary therapy decreased TC and LDL-C levels by 54% and 52%, and ezetimibe further decreased them by 18% and 20%, respectively. Further, we identified 15 novel ABCG5/ABCG8 variants. CONCLUSIONS: This study expands the clinical and genetic spectra of sitosterolemia. The low-phytosterol diet is the cornerstone of sitosterolemia treatment. Ezetimibe can further decrease blood lipid levels and increase daily dietary phytosterol tolerance.


Subject(s)
Atherosclerosis , Intestinal Diseases , Lipid Metabolism, Inborn Errors , Phytosterols , Xanthomatosis , ATP Binding Cassette Transporter, Subfamily G, Member 5/genetics , Adult , Arthralgia/chemically induced , Arthralgia/drug therapy , Atherosclerosis/drug therapy , Child , Cholesterol, LDL , Ezetimibe/therapeutic use , Genetic Profile , Humans , Hypercholesterolemia , Intestinal Diseases/diagnosis , Intestinal Diseases/drug therapy , Intestinal Diseases/genetics , Lipid Metabolism, Inborn Errors/drug therapy , Lipid Metabolism, Inborn Errors/genetics , Lipoproteins/genetics , Phytosterols/adverse effects , Phytosterols/genetics , Retrospective Studies , Splenomegaly/chemically induced , Splenomegaly/drug therapy , Xanthomatosis/drug therapy
6.
Front Genet ; 10: 918, 2019.
Article in English | MEDLINE | ID: mdl-31636654

ABSTRACT

Previous studies have revealed that genetic variation in genes that regulate cell migration might be associated with susceptibility to recurrent spontaneous abortion. HULC regulates the migration of a variety of cells, and genetic polymorphisms of HULC are associated with susceptibility to a variety of diseases, but their association with susceptibility to recurrent spontaneous abortion has not been reported. This study included 610 cases of recurrent spontaneous abortion and 817 normal controls, and the polymorphisms of the four SNPs were genotyped using the TaqMan method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the associations between selected SNPs and susceptibility to recurrent spontaneous abortion. Our results showed that three SNPs were significantly associated with a reduced risk of recurrent spontaneous abortion: rs1041279 (GG vs. GC/CC: adjusted OR = 0.745, 95% CI = 0.559-0.993, P = 0.0445), rs7770772 (GC/CC vs. GG: adjusted OR = 0.757, 95% CI = 0.606-0.946, P = 0.0143), and rs17144343 (AA/GA vs GG adjusted OR = 0.526, 95% CI = 0.366-0.755, P = 0.0005). Individuals with one to four genotypes showed a reduced risk of recurrent spontaneous abortion (adjusted OR = 0.749, 95% CI = 0.598-0.939, P = 0.0123). This cumulative effect on protection increased with increases in the observed number of genotypes (adjusted OR = 0.727, 95% CI = 0.625-0.846, ptrend < 0.0001). Our study suggests that HULC might be a biomarker for risk for recurrent spontaneous abortion, but larger sample studies are needed to verify this result.

7.
Article in English | MEDLINE | ID: mdl-26160605

ABSTRACT

Two new organic-inorganic molecular solids of tetra(isothiocyanate)cobalt(II) dianion and disubstituted benzyl triphenylphosphinium, [2Cl4FBzTPP]2[Co(NCS)4] (1) and [2Cl4ClBzTPP]2[Co(NCS)4] (2) ([2Cl4FBzTPP](+)=1-(2'-chloro-4'-fluorobenzyltriphenylphosphonium) and [2Cl4ClBzTPP](+)=1-(2',4'-dichlorobenzyltriphenylphosphonium), were synthesized and characterized by elemental analysis, FT-IR, UV-Vis spectra, ESI-MS and single crystal X-ray diffraction method. Compounds 1 and 2 crystallize in the monoclinic Pc and triclinic P-1, respectively. The Co(II) ion of the [Co(NCS)4](2-) anion shows a distorted tetrahedral coordination geometry. The [2Cl4FBzTPP](+) cations containing P(2) atoms in 1 form a column by the Cl⋯π interactions, while the [2Cl4ClBzTPP](+) cations in 2 form two columns by the C-H⋯π and π⋯π interactions. The anion and the cation are linked by C-H⋯S hydrogen bonds and Cl⋯S interactions. Magnetic susceptibility measurement in the temperature range 2-300K shows that both 1 and 2 exhibit a weak antiferromagnetic exchange interaction as the temperature falls, and ultraviolet fluorescence emission in the solid state at room temperature.

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