Abstract
Nephropathic cystinosis is a lysosomal storage disease due to biallelic pathogenic variants in the CTNS gene encoding the cystine transport protein cystinosin. Dysfunction of cystinosin results in the intralysosomal accumulation of the disulfide cystine, which crystallizes in some tissues and damages many parenchymal organs. Fanconi syndrome is the first presenting sign with all the features of generalized proximal tubular dysfunction. The natural history of cystinosis includes multisystem complications, the most prominent being glomerular failure at 9-10 years. If a kidney transplant prolongs life, other complications occur, with variable frequencies. Some of the most common are hypothyroidism, a distal vacuolar myopathy, pancreatic exocrine and endocrine insufficiency, male hypogonadism, and idiopathic intracranial hypertension. Cystinosis is diagnosed biochemically by measuring the cystine content of leucocyte and molecularly by identifying pathogenic variants in CTNS. Prenatal diagnosis is available. Treatment consists of replacement of kidney tubular losses, symptomatic management of systemic complications, and specific therapy directed at the basic defect, i.e., lysosomal cystine accumulation. This involves the free thiol cysteamine, which can deplete approximately 95% of the lysosomal cystine content. Oral cysteamine therapy has extended the time to kidney failure by approximately 7 years (to a mean of 16 years) and mitigates or prevents late complications of the disease. In addition, cysteamine eyedrops can dissolve corneal cystine crystals within months. Nevertheless, the mean age at death for individuals born between 1985 and 1999 has been 29 years, and earlier diagnosis by newborn screening, treatment with more palatable cystine-depleting agents, and trials with gene therapy are critical current pursuits.