8-hydroxy-2--deoxyguanosine and Nephrotic-Syndrome

Nucleotide excision repair (NER) is an essential biological pathway protecting against ultraviolet light-induced DNA damage. Deficient NER causes a group of rare genetic disorders including two autosomal recessive diseases, xeroderma pigmentosum (XP) and Cockayne syndrome (CS). In addition to the cutaneous photosensitivity shared in XP and CS, CS is featured by growth failure, neurological deterioration, microcephaly, and deep sunken eyes. XP/CS complex is an extremely rare type of NER disorder with a distinct phenotype that is characterized by the skin and eye pathology of XP and the somatic and neurological abnormalities of CS. Some of CS cases have been reported to be complicated with renal failure, but the genetic background or the etiology of the renal failure has not been reported. We herein report a 1-year-old Japanese boy with XP/CS complex, complicated by nephrotic syndrome. Diagnosis was confirmed by the presence of compound heterozygous mutations, G47R (c.139G>A) and R616G (c.1846C>G), in the excision repair cross-complementation group 2 (ERCC2) gene. The kidney biopsies, performed at the age of 1 year and 2 months, revealed diffuse expansion of the mesangial matrix and segmental glomerulosclerosis under light microscopy, and diffused thin capillary walls with partially lamellated regions under electron microscopy. Notably, high levels of urinary 8-hydroxy-2'-deoxyguanosin, known as an oxidative stress marker, were observed during the clinical course. The patient died at the age of 1 year and 11 months because of renal failure. We suggest the involvement of oxidative stress in the pathogenesis of nephrotic syndrome in NER disorders.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Age of Onset; Base Sequence; Child; Cockayne Syndrome; Deoxyguanosine; DNA Mutational Analysis; DNA Repair; Fatal Outcome; Humans; Infant; Japan; Kidney; Male; Nephrotic Syndrome; Xeroderma Pigmentosum; Xeroderma Pigmentosum Group D Protein

Several diseases of prematurity are thought to be related to oxidative injury and many of the available markers are unsatisfactory. An assay was developed using HPLC with electrochemical detection for the quantitation of urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a proposed indicator for oxygen-derived free radical injury to DNA in preterm infants. A median value of 3.79 micromol/mol creatinine was obtained for normal children (2-15 years old, n=14). Urinary 8-OHdG excretion in neonates ranged from 0-99 micromol/mol creatinine. There were no gestation or birthweight related differences in urinary 8-OHdG, and no correlation with urinary malondialdehyde. Mean 8-OHdG excretion increased with postnatal age (r=0.80, p < 0.0001, n=15), mirroring the growth velocity curve. These changes could also be due to changes in the activity of the enzyme responsible for 8-OHdG excision. Urinary 8-OHdG levels are unlikely to accurately reflect oxygen derived free radical activity given the strength of the relationship with growth.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Age Factors; Birth Weight; Child, Preschool; Deoxyguanosine; Female; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Lipid Peroxidation; Male; Malondialdehyde; Nephrotic Syndrome; Reference Values; Sex Factors