Cystinosis is a rare genetic disorder characterized by the accumulation of the amino acid cystine within cells. This accumulation leads to the formation of crystals that can build up and damage various organs and tissues throughout the body. The primary affected organ is the kidneys, and the condition can lead to kidney dysfunction. The incidence in Europe and the United States is estimated at 1 in 100.000-200.000 individuals, although it may be higher in certain geographic areas such as Brittany (France) and Quebec (Canada).
Cystinosis genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximetaly 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Key features of cystinosis include:
Genetic Basis: Cystinosis is caused by mutations in the CTNS gene, which provides instructions for producing a protein that transports cystine out of cellular compartments called lysosomes. Mutations in this gene impair cystine transport, leading to its accumulation.
Types of Cystinosis
- Nephropathic Cystinosis: This is the most common and severe form, with symptoms typically appearing in infancy. Kidney dysfunction is a hallmark, leading to renal Fanconi syndrome (a disorder of kidney tubule function).
- Intermediate Cystinosis: This form has a later onset and slower progression than nephropathic cystinosis, with kidneys affected to a lesser extent.
- Non-nephropathic or Ocular Cystinosis: This rare form primarily affects the eyes without significant kidney involvement.
Symptoms
- Renal Fanconi Syndrome: Impaired reabsorption of essential substances by the kidney tubules, leading to the loss of vital nutrients in the urine.
- Growth Retardation: Children with cystinosis may experience growth failure.
- Photophobia: Light sensitivity is common, especially in ocular cystinosis.
- Muscle Weakness and Fatigue: These symptoms may occur due to cystine accumulation in muscle tissue.
Treatment: Cystinosis is a chronic condition, and the mainstay of treatment is cysteamine therapy. Cysteamine helps reduce cystine accumulation by breaking it into a more soluble form. Kidney transplantation may be necessary in severe cases.
Prognosis: While cystinosis is a chronic and progressive condition, early diagnosis and appropriate treatment can significantly improve outcomes. Without treatment, however, kidney failure is likely to occur in late childhood.
Cystinosis requires a multidisciplinary approach involving nephrologists, ophthalmologists, geneticists, and other specialists for comprehensive management and care. Regular monitoring and treatment are crucial to managing symptoms and improving the quality of life for individuals with cystinosis.
Diagnosis: Diagnosis involves measuring cystine levels or through genetic testing to identify mutations in the CTNS gene.
Approximately 140 pathogenic variants have been described in cystinosis patients, with variable clinical manifestations in individuals from different geographic origins. The most frequent mutation is a 57 kb deletion in 50-70% of patients from Northern Europe and North America (not tested).
Another relatively frequent pathogenic variant is c.414G>A, which produces a stop codon at position 138 of cystinosin and leads to premature termination of translation. Its presence is estimated in 52% of French-Canadian patients affected with cystinosis, and it is also detected in Irish patients. It was also found in American patients of German, French, British, Scandinavian, and Romanian origin.
The pathogenic variant c.416C>T can cause the juvenile phenotype.
Individuals with intermediate cystinosis (nephropathic, but with late-onset) or non-nephropathic cystinosis (with corneal and marrow crystals, but without renal involvement) may have the juvenile phenotype but without renal involvement, have a severe pathogenic variant in the CTNS gene (typical of nephropathic cystinosis) and a mild pathogenic variant. The c.589G>A mutation is analyzed among the mild variants.
The genetic test of cystinosis analyzes the 6 most frequent pathogenic mutations of the CTNS gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as, e.g., next-generation sequencing (NGS).
