Early-onset Gout Research Articles

The role of hepatocyte nuclear factor 1β in disease and development.

Heterozygous mutations in the gene that encodes the transcription factor hepatocyte nuclear factor 1β (HNF1B) result in a multi-system disorder. HNF1B was initially discovered as a monogenic diabetes gene; however, renal cysts are the most frequently detected feature. Other clinical features include pancreatic hypoplasia and exocrine insufficiency, genital tract malformations, abnormal liver function, cholestasis and early-onset gout. Heterozygous mutations and complete gene deletions in HNF1B each account for approximately 50% of all cases of HNF1B-associated disease and may show autosomal dominant inheritance or arise spontaneously. There is no clear genotype-phenotype correlation indicating that haploinsufficiency is the main disease mechanism. Data from animal models suggest that HNF1B is essential for several stages of pancreas and liver development. However, mice with heterozygous mutations in HNF1B show no phenotype in contrast to the phenotype seen in humans. This suggests that mouse models do not fully replicate the features of human disease and complementary studies in human systems are necessary to determine the molecular mechanisms underlying HNF1B-associated disease. This review discusses the role of HNF1B in human and murine pancreas and liver development, summarizes the disease phenotypes and identifies areas for future investigations in HNF1B-associated diabetes and liver disease.

Onset age of Parkinson’s disease is delayed by a common dysfunctional variant of ABCG2, a major causative gene for early-onset gout

CO RR EC TE D P RO OF effective in children between 2-6 years, but there were also satisfactory results in adults. The botulinum toxin effects remained for 3 months, gradually returning to original state. Better results are achieved when botulinum toxin treatment is associated with other tone recovery programs. The re-treatment must be carried out after 3-4 months, avoiding production of neutralizing antibodies. Conclusion: Treatment is safe, and achieves the aims for improvement of function, comfort, care, prevention or correction if deformities, reducing pain, physical and functional limitations. Most reported adverse reactions were mild, even in patients severely affected by cerebral palsy. The reduction of spasticity, improvement in motor coordination and trunk stability negatively influence production of strength and muscle volume.

A Major Risk of Early-Onset Gout: ABCG2 Dysfunction in a Japanese Male Population.

A Major Risk of Early-Onset Gout: ABCG2 Dysfunction in a Japanese Male Population.

ABCG2 variant has opposing effects on onset ages of Parkinson's disease and gout.

Uric acid (urate) has been suggested to play a protective role in Parkinson's disease onset through its antioxidant activity. Dysfunction of ABCG2, a high-capacity urate exporter, is a major cause for early-onset gout based on hyperuricemia. In this study, the effects of a dysfunctional ABCG2 variant (Q141K, rs2231142) were analyzed on the ages at onset of gout patients (N = 507) and Parkinson's disease patients (N = 1015). The Q141K variant hastened the gout onset (P = 0.0027), but significantly associated with later Parkinson's disease onset (P = 0.025). Our findings will be helpful for development of more effective prevention of Parkinson's disease.

HNF1B-associated renal and extra-renal disease-an expanding clinical spectrum.

Heterozygous mutations in the gene that encodes the transcription factor hepatocyte nuclear factor 1β (HNF1B) represent the most common known monogenic cause of developmental kidney disease. Renal cysts are the most frequently detected feature of HNF1B-associated kidney disease; however, other structural abnormalities, including single kidneys and renal hypoplasia, and electrolyte abnormalities can also occur. Extra-renal phenotypes might also be observed; consequently, HNF1B-associated disease is considered a multi-system disorder. Other clinical features include early-onset diabetes mellitus, pancreatic hypoplasia, genital tract malformations, abnormal liver function and early-onset gout. Heterozygous mutations in the coding region or splice sites of HNF1B, and complete gene deletion, each account for ∼50% of all cases of HNF1B-associated disease, respectively, and often arise spontaneously. There is no clear genotype-phenotype correlation, consistent with haploinsufficiency as the disease mechanism. Data from animal models suggest that HNF1B has an important function during several stages of nephrogenesis; however, the precise signalling pathways remain to be elucidated. This Review discusses the genetics and molecular pathways that lead to disease development, summarizes the reported renal and extra-renal phenotypes, and identifies areas for future research in HNF1B-associated disease.

Clinical Characteristics of and Relationship Between Metabolic Components and Renal Function Among Patients with Early-onset Juvenile Tophaceous Gout

Age of onset of gout has recently decreased; however, patients with early-onset gout remain uncommon, and relevant information is scant. We hypothesized that these patients might exhibit differences in serum urates and other comorbidities compared with adult-onset patients. Early-onset gout patients (i.e., juveniles) with (n = 40) and without tophi (n = 47) were enrolled for study. Their clinical characteristics were compared with those of 353 patients with middle-age-onset tophaceous gout and 64 age-matched healthy participants. Early-onset gout patients with tophi exhibited significantly higher body mass indices and serum urate levels and lower estimated glomerular filtration rates (eGFR) than did those without tophi. Early-onset gout patients with or without tophi demonstrated significantly abnormal lipid profiles and impaired liver or renal function compared with healthy patients. Serum urate levels and gout duration were identified as the principal determinants of tophi development. The presence of tophi might be crucial in decreasing eGFR, which is inversely related to tophi duration or gout duration. Unexpectedly, the most common site of initial gout attacks in early-onset tophaceous gout patients was the ankle, not the toe, which was the most common site in middle-age-onset tophaceous gout patients. The most common site of first tophi occurrence in early-onset patients was a finger, not a toe, which was the most common site in middle-age-onset patients. Early-onset tophaceous gout patients are more likely to exhibit comorbidities and renal dysfunction than middle-age-onset patients and exhibit distinct first sites of gout attack and tophi occurrence patterns.

Common dysfunctional variants in ABCG2 are a major cause of early-onset gout

Gout is a common disease which mostly occurs after middle age, but more people nowadays develop it before the age of thirty. We investigated whether common dysfunction of ABCG2, a high-capacity urate transporter which regulates serum uric acid levels, causes early-onset gout. 705 Japanese male gout cases with onset age data and 1,887 male controls were genotyped, and the ABCG2 functions which are estimated by its genotype combination were determined. The onset age was 6.5 years earlier with severe ABCG2 dysfunction than with normal ABCG2 function (P = 6.14 × 10−3). Patients with mild to severe ABCG2 dysfunction accounted for 88.2% of early-onset cases (twenties or younger). Severe ABCG2 dysfunction particularly increased the risk of early-onset gout (odds ratio 22.2, P = 4.66 × 10−6). Our finding that common dysfunction of ABCG2 is a major cause of early-onset gout will serve to improve earlier prevention and therapy for high-risk individuals.

Adenine Phosphoribosyltransferase Deficiency in a Chinese Man with Early-onset Gout

To the Editor: Early-onset gout is known to be often related to genetic factors. However, the molecular genetic issues are not understood for these patients. In 2007, a 25-year-old Hong Kong Chinese man was referred for advice on his early-onset gout. The first of his many attacks was at age 18 years. A severe attack appeared at his right first metatarsophalangeal joint when he was 22 years old. His serum uric acid then was 600 μmol/l (10 mg/dl) and serum creatinine was 1.1 mg/l. His creatinine clearance was about 80 cc/min 3 years ago compared to 88 cc/min 10 years ago. He had 24-h uric acid excretion (using a low purine diet) at 5625 μmol/day (940 mg/day), indicating overproduction of uric acid. The treatment of choice for gout with overproduction of uric acid is allopurinol, but the patient was worried about the safety of allopurinol because of his allergic history to other drugs and his father’s allergy to allopurinol. We suggested that the test of HLA-B*5801 might be … Address reprint requests to Dr. Chen E-mail: chungjen{at}adm.cgmh.org.tw