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Cystinosis is an inherited metabolic disorder caused by autosomal recessive mutations in the  CTNS  gene leading to lysosomal cystine accumulation. The disease primarily affects the kidneys followed by extra‐renal organ involvement later in life. Azoospermia is one of the unclarified complications which are not improved by cysteamine, which is the only available disease‐modifying treatment. We aimed at unraveling the origin of azoospermia in cysteamine‐treated cystinosis by confirming or excluding an obstructive factor, and investigating the effect of cysteamine on fertility in the  Ctns  −/−  mouse model compared with wild type. Azoospermia was present in the vast majority of infantile type cystinosis patients. While spermatogenesis was intact, an enlarged caput epididymis and reduced levels of seminal markers for obstruction neutral α‐glucosidase (NAG) and extracellular matrix protein 1 (ECM1) pointed towards an epididymal obstruction. Histopathological examination in human and mouse testis revealed a disturbed blood‐testis barrier characterized by an altered zonula occludens‐1 (ZO‐1) protein expression. Animal studies ruled out a negative effect of cysteamine on fertility, but showed that cystine accumulation in the testis is irresponsive to regular cysteamine treatment. We conclude that the azoospermia in infantile cystinosis is due to an obstruction related to epididymal dysfunction, irrespective of the severity of an evolving primary hypogonadism. Regular cysteamine treatment does not affect fertility but has subtherapeutic effects on cystine accumulation in testis.

journal of inherited metabolic disease

Human and animal fertility studies in cystinosis reveal signs of obstructive azoospermia, an altered blood‐testis barrier and a subtherapeutic effect of cysteamine in testis