Disease background

Types of cystinosis

There are three clinically recognised forms of cystinosis, depending on the age of presentation and degree of renal disease severity:^1,2

Infantile nephropathic cystinosis

The most severe and frequent form, accounting for 95% of patients^1,2

The major identifiable cause of renal Fanconi syndrome in children^1,2

If untreated, leads to end-stage renal disease in the first decade of life^1,2

Juvenile, or late-onset, nephropathic cystinosis

Accounts for 5% of patients^1,2

Usually diagnosed later in childhood or during adolescence²

Symptoms are often more unspecific and incomplete compared with the infantile form, e.g. nephrotic syndrome or mild proximal tubulopathy²

Slower progression to end-stage renal disease¹

Adult, or ocular, cystinosis

Rarely diagnosed before adulthood^1,2

Characterised by photophobia due to corneal cystine accumulation^1,2

Kidneys may still be affected^1,2

Pathophysiology

Nephropathic cystinosis occurs as a result of mutations in the gene CTNS, which codes for the lysosomal cystine-proton cotransporter cystinosin. To date, more than 160 pathogenic variants have been identified in the CTNS gene.^1-3

Cystinosin is ubiquitously expressed on lysosomal membranes; when the protein is functional, cystine efflux from the lysosome is driven by a proton gradient. However, in the absence of a functional transporter, cystine accumulates and crystallises inside the lysosome.^1,4

Normal lysosome

Lysosome in nephropathic cystinosis

Cystine crystals have a number of pathological effects, such as:^1,2

Activation of monocytes and macrophages, which leads to the production of pro-inflammatory substances

Enhanced apoptosis

Increased oxidative stress

More recent research has also demonstrated that cystinosin plays a broader role in intracellular vesicle trafficking, cell signalling, lysosomal dynamics and exocytosis, all of which may be disrupted by cystinosin dysfunction.⁵

To date, the exact mechanisms behind the clinical symptoms of the disease are not fully understood and may differ between tissues.^2,5