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 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 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.

Classification

  • Infantile nephropathic cystinosis : the most common and severe form, presenting within the first year of life with Fanconi syndrome and rapid progression to renal failure.
  • Juvenile cystinosis : later onset and slower progression.
  • Ocular cystinosis : primarily limited to the eyes with minimal or no renal involvement.

    Symptoms and signs

There are three distinct types of cystinosis each with slightly different symptoms: nephropathic cystinosis, intermediate cystinosis, and non-nephropathic or ocular cystinosis. Infants affected by nephropathic cystinosis initially exhibit poor growth and particular kidney problems. The kidney problems lead to the loss of important minerals, salts, fluids, and other nutrients. The loss of nutrients not only impairs growth, but may result in soft, bowed bones, especially in the legs. The nutrient imbalances in the body lead to increased urination, thirst, dehydration, and abnormally acidic blood.
Presentation in the first 6–12 months with poor growth, polyuria, polydipsia, dehydration, and rickets secondary to proximal renal tubular dysfunction causing urinary wasting of glucose, amino acids, bicarbonate, phosphate, and electrolytes. Progressive glomerular damage leading to chronic kidney disease and eventually to End Stage Kidney Disease typically in the first decade, if untreated.
By about age two, cystine crystals may also be present in the cornea. The buildup of these crystals in the eye causes an increased sensitivity to light. Without treatment, children with cystinosis are likely to experience complete kidney failure by about age ten. With treatment this may be delayed into the patients' teens or 20s. Other signs and symptoms that may occur in patients include muscle deterioration, blindness, inability to swallow, impaired sweating, decreased hair and skin pigmentation, diabetes, and thyroid and nervous system problems.
The signs and symptoms of intermediate cystinosis are the same as nephropathic cystinosis, but they occur at a later age. Intermediate cystinosis typically begins to affect individuals around age twelve to fifteen. Malfunctioning kidneys and corneal crystals are the main initial features of this disorder. If intermediate cystinosis is left untreated, complete kidney failure will occur, but usually not until the late teens to mid twenties.
People with non-nephropathic or ocular cystinosis do not usually experience growth impairment or kidney malfunction. The only symptom is photophobia due to cystine crystals in the cornea.

Crystal morphology and identification

Cystine crystals are hexagonal in shape and are colorless. They are not found often in alkaline urine due to their high solubility. The colorless crystals can be difficult to distinguish from uric acid crystals which are also hexagonal. Under polarized examination, the crystals are birefringent with a polarization color interference.

Pathophysiology

Nephropathic cystinosis is caused by pathogenic variants in the CTNS gene, located on chromosome 17p13, which encodes a lysosomal membrane protein required for cystine transport out of lysosomes. Loss of cystinosin function leads to intralysosomal accumulation of cystine crystals, which cause cellular dysfunction and apoptosis through mechanisms that include oxidative stress and impaired autophagy. The degree of residual cystinosin function correlates with disease severity, accounting for the spectrum from classic infantile to milder forms.

Diagnosis

Clinical suspicion:
Infants with Fanconi syndrome and failure to thrive; ophthalmologic findings support the diagnosis.
Measurement of leukocyte cystine levels: the diagnostic biochemical test is elevated cystine concentration in isolated white blood cells.
Genetic testing: molecular analysis of CTNS confirms the diagnosis and allows for carrier testing and prenatal diagnosis.
Additional testing: renal function and tubular markers, slit-lamp eye exam, thyroid function tests, and assessments for other systemic complications.

Complications

These complications often develop despite renal replacement therapy:
Ocular: corneal cystine crystal deposition causes photophobia, eye irritation, and decreased corneal sensitivity; crystals are visible on slit-lamp examination.
Endocrine: hypothyroidism is common; growth hormone deficiency and diabetes mellitus may occur later.
Myopathy and swallowing difficulties from progressive proximal muscle weakness and distal involvement in adults.
Neurologic: speech delay, cognitive impairment, and ataxia may appear in older children and adults.
Other: hepatomegaly, pancreatitis, and gonadal dysfunction have been reported.

Genetics

Cystinosis occurs due to a mutation in the gene CTNS, located on chromosome 17, which codes for cystinosin, the lysosomal cystine transporter. Symptoms are first seen at about 3 to 18 months of age with profound polyuria, followed by poor growth, photophobia, and ultimately kidney failure by age 6 years in the nephropathic form.
All forms of cystinosis are autosomal recessive, which means that the trait is located on an autosomal chromosome, and only an individual who inherits two copies of the gene – one from both parents – will have the disorder. There is a 25% risk of having a child with the disorder, when both parents are carriers of an autosomal recessive trait.
Cystinosis affects approximately 1 in 100,000 to 200,000 newborns. and there are only around 2,000 known individuals with cystinosis in the world. The incidence is higher in the province of Brittany, France, where the disorder affects 1 in 26,000 individuals.

Diagnosis

Cystinosis is a rare genetic disorder that causes an accumulation of the amino acid cystine within cells, forming crystals that can build up and damage the cells. These crystals negatively affect many systems in the body, especially the kidneys and eyes.
The accumulation is caused by abnormal transport of cystine from lysosomes, resulting in a massive intra-lysosomal cystine accumulation in tissues. Via an as yet unknown mechanism, lysosomal cystine appears to amplify and alter apoptosis in such a way that cells die inappropriately, leading to loss of renal epithelial cells. This results in renal Fanconi syndrome, and similar loss in other tissues can account for the short stature, retinopathy, and other features of the disease.
Definitive diagnosis and treatment monitoring are most often performed through measurement of white blood cell cystine level using tandem mass spectrometry.

Management

Current management aims to deplete intracellular cystine, treat renal tubular losses, preserve kidney function, and address systemic complications.
Cysteamine therapy: Cysteamine is the only specific disease-modifying therapy. It enters lysosomes and reacts with cystine to form cysteine–cysteamine mixed disulfides that can exit the lysosome via alternative transporters, thereby lowering intralysosomal cystine. Oral cysteamine, started early and given lifelong, markedly reduces leukocyte cystine levels, delays progression to ESKD, and decreases some systemic complications. Both immediate-release and delayed-release formulations are used; adherence and dose optimization are critical. Oral cysteamine therapy has extended the time to kidney failure by approximately 7 years and mitigates or prevents late complications of the disease. In addition, cysteamine eyedrops can dissolve corneal cystine crystals within months.
Supportive renal care: replacement of bicarbonate, phosphate, potassium, vitamin D and other supplements to manage Fanconi syndrome; growth monitoring and, when indicated, growth hormone therapy.
Kidney transplantation: ESKD is managed with renal transplantation when necessary; however, transplantation does not correct systemic cystine accumulation, so cysteamine therapy should be continued after transplant.
Ocular treatment: topical cysteamine eye drops reduce corneal crystal burden and symptoms.
Multidisciplinary follow-up: regular monitoring by nephrology, ophthalmology, endocrinology, neurology, nutrition, and other specialties is recommended to manage complications and optimize quality of life.