Cystinosis

Cystinosis is the most common hereditary cause of renal Fanconi syndrome in children. It is an autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene encoding for the carrier protein cystinosin, transporting cystine out of the lysosomal compartment. Defective cystinosin function leads to intra-lysosomal cystine accumulation in all body cells and organs. The kidneys are initially affected during the first year of life through proximal tubular damage followed by progressive glomerular damage and end stage renal failure during mid-childhood if not treated. Other affected organs include eyes, thyroid, pancreas, gonads, muscles and CNS. Leucocyte cystine assay is the cornerstone for both diagnosis and therapeutic monitoring of the disease. Several lines of treatment are available for cystinosis including the cystine depleting agent cysteamine, renal replacement therapy, hormonal therapy and others; however, no curative treatment is yet available. In the current review we will discuss the most important clinical features of the disease, advantages and disadvantages of the current diagnostic and therapeutic options and the main topics of future research in cystinosis.

The endolysosomal system sustains the reabsorptive activity of specialized epithelial cells. Lysosomal storage diseases such as nephropathic cystinosis cause a major dysfunction of epithelial cells lining the kidney tubule, resulting in massive losses of vital solutes in the urine. The mechanisms linking lysosomal defects and epithelial dysfunction remain unknown, preventing the development of disease-modifying therapies. Here we demonstrate, by combining genetic and pharmacologic approaches, that lysosomal dysfunction in cystinosis results in defective autophagy-mediated clearance of damaged mitochondria. This promotes the generation of oxidative stress that stimulates Gα12/Src-mediated phosphorylation of tight junction ZO-1 and triggers a signaling cascade involving ZO-1-associated Y-box factor ZONAB, which leads to cell proliferation and transport defects. Correction of the primary lysosomal defect, neutralization of mitochondrial oxidative stress, and blockage of tight junction-associated ZONAB signaling rescue the epithelial function. We suggest a link between defective lysosome-autophagy degradation pathways and epithelial dysfunction, providing new therapeutic perspectives for lysosomal storage disorders.

Metabolite accumulation in lysosomal storage disorders (LSDs) results in impaired cell function and multi-systemic disease. Although substrate reduction and lysosomal overload-decreasing therapies can ameliorate disease progression, the significance of lysosomal overload-independent mechanisms in the development of cellular dysfunction is unknown for most LSDs. Here, we identify a mechanism of impaired chaperone-mediated autophagy (CMA) in cystinosis, a LSD caused by defects in the cystine transporter cystinosin (CTNS) and characterized by cystine lysosomal accumulation. We show that, different from other LSDs, autophagosome number is increased, but macroautophagic flux is not impaired in cystinosis while mTOR activity is not affected. Conversely, the expression and localization of the CMA receptor LAMP2A are abnormal in CTNS-deficient cells and degradation of the CMA substrate GAPDH is defective in Ctns(-/-) mice. Importantly, cysteamine treatment, despite decreasing lysosomal overload, did not correct defective CMA in Ctns(-/-) mice or LAMP2A mislocalization in cystinotic cells, which was rescued by CTNS expression instead, suggesting that cystinosin is important for CMA activity. In conclusion, CMA impairment contributes to cell malfunction in cystinosis, highlighting the need for treatments complementary to current therapies that are based on decreasing lysosomal overload.

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.