Cystinosis

Cystinosis is a lysosomal storage disease characterized by the abnormal accumulation of free cystine, the oxidized dimer of the amino acid cysteine in lysosomes, eventually leading to intracellular crystal formation throughout the body, e.g. in kidneys.

It is genetically inheritable in the autosomal recessive fashion via CTNS (AR) gene. It characterized by systemic accumulation of the amino acid cystine within lysosomes, proximal tubulopathy and by progressive chronic kidney disease. If untreated, it leads to progressive cellular dysfunction and multiorgan involvement. The disease most commonly presents in infancy with renal Fanconi syndrome and, without treatment, progresses to end-stage kidney disease (ESKD) in childhood. Extra-renal manifestations affecting the eyes, thyroid, muscle, pancreas, and central nervous system may develop later in life. Early diagnosis and lifelong cystine-depleting therapy improve growth, delay progression to ESKD, and reduce many systemic complications. Nevertheless, despite treatment, the mean age at death for individuals born between 1985 and 1999 has been 29 years.

Cystinosis is the most common cause of Fanconi syndrome in the pediatric age group. Fanconi syndrome occurs when the function of cells in renal tubules is impaired, leading to abnormal amounts of carbohydrates and amino acids in the urine, excessive urination, and low blood levels of potassium and phosphates.

Cystinosis was the first documented genetic disease belonging to the group of lysosomal storage disease disorders. Cystinosis is caused by mutations in the CTNS gene that codes for cystinosin, the lysosomal membrane-specific transporter for cystine. Intracellular metabolism of cystine, as it happens with all amino acids, requires its transport across the cell membrane. After degradation of endocytosed protein to cystine within lysosomes, it is normally transported to the cytosol. But if there is a defect in the carrier protein, cystine is accumulated in lysosomes. As cystine is highly insoluble, when its concentration in tissue lysosomes increases, its solubility is immediately exceeded and crystalline precipitates are formed in almost all organs and tissues.

However, the progression of the disease is not related to the presence of crystals in target tissues. Although tissue damage might depend on cystine accumulation, the mechanisms of tissue damage are not fully understood. Increased intracellular cystine profoundly disturbs cellular oxidative metabolism and glutathione status, leading to altered mitochondrial energy metabolism, autophagy, and apoptosis.

Cystinosis is usually treated with cysteamine, which is prescribed to decrease intralysosomal cystine accumulation. However, the discovery of new pathogenic mechanisms and the development of an animal model of the disease may open possibilities for the development of new treatment modalities to improve long-term prognosis.