Cystinosis in Focus

Overview

Cystinosis is an autosomal recessive genetic disorder,¹ which affects lysosomal storage function, resulting in cystine crystal accumulation.² An estimated 2,000 people worldwide have cystinosis, with just over 600 of those diagnosed living in the U.S.³

The symptoms of cystinosis can be very damaging if not managed appropriately.

Estimated incidence of 1 case per 100,000 to 200,000 births^1,2

Affects males and females in equal proportions²

Generally diagnosed by the age of 2 years, with severe kidney manifestations⁴

Areas of Impact

A closer look: lysosomal storage
dysfunction

Due to mutations in the CTNS gene, the lack of the transporter protein cystinosin causes cystine to accumulate in the lysosomes of cells throughout the body. The accumulation of cystine leads to the formation of cystine crystals in cells throughout the body and slowly damages organs, including the eyes.

Cystinosis is an autosomal recessive lysosomal storage disease caused by mutations in the CTNS gene.¹

The CTNS gene encodes a cystine-specific transporter, cystinosin, which normally transports cystine out of lysosomes.^5,6

CTNS mutations result in absent or defective cystinosin, which prevents the normal transport of cystine out of the lysosomes. This, in turn, results in cystine crystal accumulation within lysosomes.^2,5

Designed image of a healthy lysosome diagram

Designed image of a lysosome of a patient with cystinosis diagram

Select a state below

Pathophysiology: crystal accumulation in the lysosome

Without treatment, patients generally do not survive beyond the first or second decade of life, but with novel pharmacologic treatment, as well as advancements in renal dialysis and kidney transplantation, individuals now survive well into adulthood.

Ocular Manifestations

Cystinosis Classification

Three types of cystinosis

Cystinosis is differentiated into three groupings based on symptoms, severity, and age of onset:

1. Nephropathic Infantile Cystinosis
Ninety-five percent of patients⁶ have nephropathic infantile cystinosis, the most severe form of cystinosis.^2,6 Symptoms present by around 12 months of age, and patients are typically diagnosed by their second birthday.⁶ Patients generally present with polyuria, polydipsia, and failure to thrive caused by generalized proximal tubular damage, also known as renal Fanconi syndrome.⁶

2. Nephropathic Late-Onset Juvenile Cystinosis
Less than 5 percent of patients have nephropathic late-onset juvenile cystinosis, which presents with milder symptoms than nephropathic infantile cystinosis.^6,7

3. Non-Nephropathic Ocular Cystinosis 
Non-nephropathic ocular cystinosis is very rare with photophobia due to corneal crystal buildup being the only symptom.⁶

All patients with cystinosis will develop ocular manifestations, including corneal cystine crystals.⁶

Diagnosis & Treatment

Diagnosing cystinosis

It’s important to note that the diagnosis of cystinosis typically involves a combination of clinical findings, genetic testing, and specialized laboratory tests.

Primary diagnostic methods may include:

Medical history

Evaluation of symptoms

Eye examination: Eye exam using various methodologies to determine presence and levels of cystine crystals in the cornea.^5,8

Urinalysis: Urine test measuring excess loss of minerals, nutrients, electrolytes and amino acids, suggesting signs of renal dysfunction.⁵

Genetic testing to identify specific mutations in the CTNS gene, which are responsible for cystinosis:

These genetic tests can confirm the diagnosis and provide information about the inheritance pattern of the condition.^5,8
Prenatal diagnosis can be done via measurement of cystine in cultured amniocytes or in cultured or uncultured chorionic villi.⁵

Blood tests may include:^{5, 6, 8}

Cystine Measurement: Using high-performance liquid chromatography (HPLC), the level of cystine in leukocytes is measured. Elevated levels of cystine indicate impaired cystine transport.

Kidney Function Tests: Creatinine and blood urea nitrogen (BUN) tests are performed to assess kidney function. Elevated levels of these markers indicate kidney impairment.

Electrolyte Levels: Cystinosis can disrupt the balance of electrolytes, so levels of electrolytes such as sodium, calcium, and phosphorus are measured. Abnormalities in these levels provide additional diagnostic clues.

Liver Function Tests: Levels of liver enzymes, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are assessed. In some cases, cystinosis may affect liver function.

Ophthalmological Diagnostic Testing

Not an actual patient

Ocular involvement occurs in all classifications of cystinosis. Therefore, patients should be referred to an ophthalmologist for eye examination upon suspicion or diagnosis of cystinosis. It is important to assess the density of corneal cystine crystals over time, as the accumulation of crystals is strongly correlated with an increase in and severity of symptoms and complications.¹

The identification of cystine crystals in the cornea on slit-lamp examination is one way that cystinosis can be diagnosed.²

Ophthalmological examinations include:

Slit-lamp biomicroscopy
The major diagnostic procedure used for detecting corneal cystine crystals, a slit-lamp exam not only provides a magnified view of intraocular structure, but it also helps in qualitative and quantitative analysis of various parameters such as corneal endothelial cell count, corneal thickness, and more.⁹
Anterior segment optical coherence tomography (AS-OCT)
Another imaging modality, an AS-OCT scan performs high-resolution, cross-sectional tomographic imaging of the internal microstructure by measuring backscattered or backreflected light.¹⁰ Its capabilities allow for non-contact imaging, detailed visualization and analytics of anterior segment structures of the eye, including the cornea.¹¹
In-vivo confocal microscopy (IVCM)
IVCM’s high-resolution imaging allows for tissue characterization at the cellular level and provides a link between conventional ex-vivo histology and in vivo studies of ocular pathology.¹²

Treating cystinosis: a progressive but manageable condition

The management of cystinosis requires a multidisciplinary approach and may include various treatment modalities. The specific treatment plan for an individual with cystinosis will depend on factors such as the age of the patient, disease severity, organ involvement, and individual needs.

Cystine Depletion Therapy: The cornerstone of cystinosis treatment is cystine depletion therapy, which aims to reduce the accumulation of cystine crystals within cells. This therapy helps break down cystine crystals, allowing them to exit the lysosome and decreasing their buildup in various organs.⁸
Ophthalmic Treatment: Cystinosis can cause ocular manifestations, such as corneal crystal deposits and photophobia. Since the cornea is avascular, oral treatments cannot treat crystal accumulation within the cornea. Therefore, only ophthalmic solutions are effective in treating ocular manifestations of cystinosis.⁸
Renal Supportive Care: Cystinosis can lead to kidney dysfunction, thereby requiring supportive care for kidney function. This may involve maintaining proper hydration, managing electrolyte imbalances, and monitoring kidney function through regular blood tests. In some cases, kidney transplantation may be necessary if end-stage renal disease occurs.⁸
Nutritional Support: Nutritional support may be needed to address growth retardation, malnutrition, and other dietary challenges. A registered dietitian or nutritionist can help develop a suitable dietary plan to ensure adequate nutrition and growth.⁸
Management of Complications: Cystinosis can be associated with various complications affecting different organs, such as hypothyroidism, diabetes, muscle weakness, and bone abnormalities. These complications are managed through appropriate medical interventions, including hormone replacement therapy, glucose control, physical therapy, and orthopedic interventions.⁵
Regular Monitoring: Regular medical follow-up and monitoring are important to assess treatment response, monitor organ function, manage potential complications, and adjust treatment as needed.⁸

Eye Treatment Considerations

REFERENCES: 1. Gahl WA et al. N Engl J Med. 2002;347(2):111-121. 2. Cystinosis. National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/cystinosis/?filter=ovr-ds-resources. Updated August 1, 2022. Accessed February 8, 2023. 3. Cystinosis Research Network. About Cystinosis. https://cystinosis.org/about-cystinosis/. Accessed August 22, 2023. 4. Hohenfellner K et al. Mol Genet Metab. 2022;136(4):282-288. 5. Wilmer MJ et al. Pediatr Nephrol. 2011;26(2):205-215. 6. Besouw MTP, Levtchenko EN. Improving the prognosis of nephropathic cystinosis. Int J Nephrol Renovasc Dis. 2014;7:297-302. 7. Shams F et al. Clin Ophthalmol. 2014;8:2077-2084. 8. Nesterova G, Gahl WA. In: Adam MP et al, eds. GeneReviews^® [Internet]. Seattle, WA: University of Washington (Seattle). https://www.ncbi.nlm.nih.gov/books/NBK1400/. Updated December 7, 2017. Accessed February 10, 2023. 9. Kaur K, Gurnani B. Slit-Lamp Biomicroscope. [Updated 2023 Jun 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK587440/. 10. Fujimoto JG, Pitris C, Boppart SA, Brezinski ME. Optical coherence tomography: an emerging technology for biomedical imaging and optical biopsy. Neoplasia. 2000 Jan-Apr;2(1-2):9-25. doi: 10.1038/sj.neo.7900071. PMID: 10933065; PMCID: PMC1531864. 11. Asam JS, Polzer M, Tafreshi A, et al. Anterior Segment OCT. 2019 Aug 14. In: Bille JF, editor. High Resolution Imaging in Microscopy and Ophthalmology: New Frontiers in Biomedical Optics [Internet]. Cham (CH): Springer; 2019. Chapter 13. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554035/ doi: 10.1007/978-3-030-16638-0_13. 12. Stachs O, Guthoff RF, Aumann S. In Vivo Confocal Scanning Laser Microscopy. 2019 Aug 14. In: Bille JF, editor. High Resolution Imaging in Microscopy and Ophthalmology: New Frontiers in Biomedical Optics [Internet]. Cham (CH): Springer; 2019. Chapter 12. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554050/ doi: 10.1007/978-3-030-16638-0_12.

HCP Directory Form

The Cystinosis Eye Care Specialist Directory Participation Form

The Cystinosis Eye Care Specialist Directory aims to connect patients with healthcare professionals knowledgeable about ocular care in cystinosis.

Recordati Rare Diseases created this physician directory to help patients and caregivers find a healthcare professional that fits their needs. Patients can access the directory through cystinosisinfocus.com.

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Cystinosis Overview