Cystinosis is a lysosomal storage disorder. It is an autosomal recessive disease characterized by excessive accumulation of cystine (an amino acid) within lysosomes of cells throughout the body.
The causative gene is CTNS (located on chromosome 17p13), with over 100 mutations reported. It encodes the lysosomal membrane transport protein cystinosin; mutations cause cystinosin dysfunction, leading to cystine crystal accumulation in lysosomes. In Japan, the estimated number of patients is extremely low at 14 1). The 57-kb Nordic founder deletion common in Europe and North America is absent in Asia 1). The incidence is estimated at 1 in 100,000–200,000 births.
The disease is broadly classified into three types.
| Type | Alternative Name | Typical Onset | Main Symptoms |
|---|---|---|---|
| Nephropathic (most common, ~95%) | Infantile type | Infancy | Fanconi syndrome, renal failure |
| Intermediate type | Juvenile type | Adolescence | Slowly progressive renal impairment, ocular symptoms |
| Non-nephropathic | Ocular, adult type | Adulthood | Ocular symptoms only |
Advances in dialysis, kidney transplantation, and drug therapy now allow patients to survive into adulthood.
There are three types: nephropathic (infantile), intermediate (juvenile), and non-nephropathic (ocular, adult). Nephropathic type accounts for about 95% and is the most common, with progressive renal dysfunction from infancy. Non-nephropathic type presents only ocular symptoms and is often discovered incidentally during slit-lamp examination.
Note that the triad of photophobia, lacrimation, and blepharospasm is similar to symptoms of congenital glaucoma, so careful differentiation is needed.
Corneal findings
Cystine crystal deposition: Small, white, spangle-like or needle-shaped reflective crystals. They can involve the full thickness of the cornea but are mainly in the stroma. Detectable by slit-lamp microscopy after 16 months of age.
Progression pattern of deposition: Begins in the anterior periphery and extends centrally and posteriorly as the disease progresses.
Complications of severe cases: May include band keratopathy, corneal ulcer, and corneal neovascularization.
Retina and Other
Pigmentary retinopathy: The earliest ocular finding. In the infantile form, it can appear as early as 5 months of age. It presents as bilateral peripheral depigmentation and patchy changes of the retinal pigment epithelium.
Other intraocular findings: Crystal deposits may also involve the conjunctiva (ground-glass appearance), iris, anterior lens, choroid, and optic nerve. The optic nerve may show a cloudy disc appearance or increased pRNFL thickness.
The distribution of crystals within the cornea is characteristic. Because the corneal epithelium turns over every 1–2 weeks, crystals do not accumulate easily there; more than 80% of total deposits are concentrated in the middle five layers (from the basal epithelium to the deep stroma)1).
In 2025, the 3C classification system (Crystal-Complication-Compliance) was introduced, standardizing staging based on crystal load, complications, and compliance. Severity is assessed in five stages from Category 1 (low to moderate crystals, mild photophobia) to Category 4 end-stage (extensive crystals, significant vision loss, unresponsive to drug therapy).
Corneal cystine crystals begin to deposit by age 2 and become observable by slit-lamp microscopy after 16 months of age. Retinal pigmentary changes can appear as early as 5 months of age. In the non-nephropathic form, it is often discovered incidentally in adulthood.
Cystinosis is caused by mutations in the CTNS gene (17p13) with autosomal recessive inheritance; the only risk factor is genetic predisposition.
A definitive diagnosis of cystinosis is made by combining clinical findings, biochemical tests, and genetic testing.
The characteristics of the main testing methods are shown below.
| Test Method | Purpose | Features |
|---|---|---|
| Leukocyte cystine measurement | Definitive diagnosis | >1 nmol/mg protein |
| CTNS gene testing | Genetic diagnosis | Identifies pathogenic variants |
| IVCM | Corneal cystine quantification | Gold standard |
Treatment of cystinosis consists of two main pillars: systemic management and topical ocular therapy.
Systemic Therapy
Oral cysteamine (first-line): Should be started as soon as possible after diagnosis and continued lifelong2). It reduces leukocyte cystine levels, improves growth, preserves renal function, and improves life prognosis2). In Japan, Cystagon (cysteamine bitartrate) is approved for nephropathic cystinosis1).
Renal replacement therapy: Dialysis or kidney transplantation is indicated when renal failure progresses.
Topical Ocular Therapy
0.55% cysteamine hydrochloride ophthalmic solution (CYSTADROPS): A viscous formulation based on sodium hyaluronate. Administered 4 times daily at 4-hour intervals 1). Approved in Europe in 2017, the US in 2020, and Japan in 2024 (Viatris Pharmaceuticals) 1).
Why oral medications are ineffective for the cornea: Because the cornea is avascular, oral cysteamine does not reach the cornea. Topical treatment with eye drops is essential 1).
In a Japanese Phase III clinical trial (conducted 2021–2022, 6 patients enrolled, open-label, single-arm, 52 weeks), the efficacy and safety of 0.55% cysteamine hydrochloride ophthalmic solution were confirmed 1).
In the Japanese Phase III trial by Goi et al. (2024), the IVCM intermediate 5-layer score decreased from 8.48±0.82 before administration to 6.03±2.41 (difference −2.45±1.88) after 13–16 weeks 1). For photophobia, patient assessment showed improvement by one grade in 4 patients (7/10 eyes) at Week 16. Median treatment adherence was 95.85% (range 88.0%–99.4%).
In overseas comparative trials, 0.55% cysteamine hydrochloride (CH) was reported to significantly reduce IVCM scores by 29.9±26.29% compared to 0.1% CH (p=0.001) 1).
Conventional 0.44% cysteamine ophthalmic solution (FDA approved in 2012) requires refrigeration and use within one week after opening, which led to reduced adherence 1). The 0.55% formulation has improved storage stability due to the hyaluronic acid base. In Japan, conventional cysteamine hydrochloride eye drops were long unapproved, but with the 2024 approval, they became available as standard treatment 1).
In 2024, 0.55% cysteamine hydrochloride ophthalmic solution (CYSTADROPS, Viatris) was approved in Japan 1). It is administered 4 times daily at 4-hour intervals. This approval follows those in Europe (2017) and the United States (2020).
Because the cornea is an avascular tissue without blood vessels, orally ingested cysteamine cannot reach the cornea through the bloodstream 1). Therefore, topical treatment with eye drops is essential to dissolve corneal cystine crystals.
The CTNS gene (on chromosome 17 short arm 17p13) encodes the lysosomal membrane transport protein cystinosin 1). Cystinosin normally transports cystine (a byproduct of protein breakdown) from the lysosome into the cytoplasm.
When genetic mutations cause cystinosin dysfunction, cystine accumulates in lysosomes, forming crystals and ultimately leading to cell death 2). Crystals form most prominently in the kidneys (causing early renal failure), but also in the liver, thyroid, pancreas, muscles, brain, and eyes.
The detailed ophthalmic pathology is as follows.
Mechanism of action of oral cysteamine: It reacts with cystine in lysosomes to form mixed disulfides that can be exported from the cell without requiring cystinosin. This reduces intracellular cystine levels.
In the first Japanese Phase III trial (6 patients, 52 weeks) conducted from 2021 to 2022, the efficacy and safety of 0.55% cystamine eye drops were confirmed 1). A downward trend in IVCM scores was observed, but statistical significance was not reached due to the limited sample size. The median treatment adherence was 95.85%, indicating good results.
Due to the complexity of cystinosis treatment, the mental burden on patients’ families is also significant.
In the study by González et al. (2024), among caregivers of pediatric nephropathic cystinosis patients (mean age 12.6±4.2 years, n=9), 66.7% (6/9) had anxiety or depression, and 44.4% (4/9) showed severe caregiver burden 2). SF-36 QoL scores ranged from 40 to 85 (moderate to low), with particularly low scores in the “general health” and “health change” domains. Caregivers without anxiety or depression had significantly better QoL (p=0.02).
It is suggested that psychosocial support interventions may contribute to improved treatment adherence, and the establishment of multidisciplinary cystinosis clinics is considered effective.
Reports indicate that 66.7% of caregivers experience anxiety or depression 2), highlighting the importance of psychosocial support. Chronic sleep deprivation due to nighttime administration of immediate-release cysteamine also increases caregiver burden. Access to psychological counseling and multidisciplinary clinics is thought to contribute to improved treatment adherence.
Goi N, Iwata F, Sugihara Y, Higa S, Chikama T. An Open-Label, Phase III Study to Assess the Efficacy and Safety of Cysteamine Ophthalmic Solution 0.55% in Japanese Cystinosis Patients. Clin Ophthalmol. 2024;18:3457-3471.
González K, Eixarch T, Nuñez L, Ariceta G. Quality of life and mental health status in caregivers of pediatric patients with nephropathic cystinosis. Orphanet J Rare Dis. 2024;19:415.
